Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR.

JCI Insight. 2018 Dec 20;3(24):

Authors: Donaldson SH, Laube BL, Corcoran TE, Bhambhvani P, Zeman K, Ceppe A, Zeitlin PL, Mogayzel PJ, Boyle M, Locke LW, Myerburg MM, Pilewski JM, Flanagan B, Rowe SM, Bennett WD

Abstract
BACKGROUND: The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes.
METHODS: We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures.
RESULTS: Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores.
CONCLUSIONS: Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function.
TRIAL REGISTRATION: ClinicialTrials.gov, NCT01521338.
FUNDING: CFF Therapeutics (GOAL11K1).

PMID: 30568035 [PubMed - as supplied by publisher]

Autophagy delays progression of the two most frequent human monogenetic lethal diseases: cystic fibrosis and Wilson disease.

Aging (Albany NY). 2018 Dec 19;:

Authors: Maiuri L, Kroemer G

Abstract
Cystic fibrosis (CF) and Wilson disease (WD) are two monogenetic, recessively inherited lethal pathologies that are caused by ionic disequilibria. CF results from loss-of-function mutations in CF transmembrane conductance regulator (CFTR), a channel that conducts chloride across epithelial cell membranes, while WD is due to a deficiency of ATPase copper transporting beta (ATP7B), a plasma membrane protein that pumps out copper from cells. Recent evidence suggests that both diseases are linked to perturbations in autophagy. CFTR deficiency causes an inhibition of autophagic flux, thus locking respiratory epithelial cells in a pro-inflammatory state and subverting the bactericidal function of macrophages. WD is linked to an increase in autophagy, which, however, is insufficient to mitigate the cytotoxicity of copper. Pharmacological induction of autophagy may delay disease progression, as indicated by preclinical evidence (for CF and WD) and results from clinical trials, in particular in CF patients with the most frequent CTRT mutation (CFTRdel506). Thus, CF and WD exemplify pathologies in which insufficient autophagy plays a major role in determining the chronology of disease progression, much like the pace of 'normal' aging that is dictated by disabled autophagy as well.

PMID: 30568028 [PubMed - as supplied by publisher]

Percutaneous Endoscopic Gastrostomy Tubes May Be Associated With Preservation of Lung Function in Patients With Cystic Fibrosis.

Nutr Clin Pract. 2018 Nov 22;:

Authors: Khalaf RT, Green D, Amankwah EK, Peck J, Carr V, Goldenberg NA, Wilsey M

Abstract
BACKGROUND: Improving nutrition status of patients with cystic fibrosis (CF) has a positive effect on pulmonary function.
METHODS: We conducted a retrospective case-control study evaluating the effect of percutaneous endoscopic gastrostomy (PEG) placement on body mass index (BMI) and forced expiratory volume in 1 second percent predicted (FEV1 ) between matched subjects with CF who received PEG (n = 20) and controls who did not (n = 40).
RESULTS: We observed that after adjusting for mutation class and baseline BMI, BMI percentile increased per month for those with PEG (0.51, 95% confidence interval (CI) = -0.05-1.08, P = .08), but decreased for those without PEG (-0.03, 95% CI = -0.33-0.28, P = .86); however, the difference (0.54; 95% CI = -0.10-1.18, P = .10) was not statistically significant. FEV1 change with time showed a decrease for patients with PEG (-0.04; 95% CI = -0.30-0.22, P = .74) and those without PEG (-.22; 95% CI = -0.45-0.01, P = .06). Although the decrease for those without PEG was higher than those with PEG, the difference between the groups was not statistically significant (0.18; 95% CI = -0.17-0.52, P = .32) CONCLUSION: Lung function trajectory showed a trend towards preservation among patients with CF who receive PEG despite lack of significant difference in BMI. There may be a favorable effect of PEG on lung function independent of changes in BMI.

PMID: 30565731 [PubMed - as supplied by publisher]

Lung transplantation in two cystic fibrosis patients infected with previously pandrug-resistant Burkholderia cepacia complex treated with ceftazidime-avibactam.

Infection. 2018 Dec 19;:

Authors: Los-Arcos I, Len O, Martín-Gómez MT, González-López JJ, Saéz-Giménez B, Deu M, Nuvials X, Ferrer R, Román A, Gavaldà J

Abstract
We describe two cystic fibrosis patients infected with pandrug-resistant Burkholderia cepacia complex, with the exception of ceftazidime-avibactam, who received prophylaxis with this antibiotic during lung transplantation. Although both patients had a post-operative relapse of respiratory infection, one with positive blood cultures, ceftazidime-avibactam treatment yielded a favourable outcome. 12 months after transplantation, one patient presented an excellent clinical outcome. However, the other patient died 10 months later due to severe B. cepacia sinusitis with intracranial invasion.

PMID: 30565008 [PubMed - as supplied by publisher]

Isogenic cell models of cystic fibrosis-causing variants in natively expressing pulmonary epithelial cells.

J Cyst Fibros. 2018 Dec 15;:

Authors: Valley HC, Bukis KM, Bell A, Cheng Y, Wong E, Jordan NJ, Allaire NE, Sivachenko A, Liang F, Bihler H, Thomas PJ, Mahiou J, Mense M

Abstract
BACKGROUND: Assessment of approved drugs and developmental drug candidates for rare cystic fibrosis (CF)-causing variants of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) requires abundant material from relevant models.
METHODS: Isogenic cell lines harboring CFTR variants in the native genomic context were created through the development and utilization of a footprint-less, CRISPR/Cas9 gene editing pipeline in 16HBE14o- immortalized bronchial epithelial cells.
RESULTS: Isogenic, homozygous cell lines for three CFTR variants (F508del and the two most common CF-causing nonsense variants, G542X and W1282X) were established and characterized. The F508del model recapitulates the known molecular pathology and pharmacology. The two models of nonsense variants (G542X and W1282X) are sensitive to Nonsense Mediated mRNA Decay (NMD) and responsive to reference compounds that inhibit NMD and promote ribosomal readthrough.
CONCLUSIONS: We present a versatile, efficient gene editing pipeline that can be used to create CFTR variants in the native genomic context and the utilization of this pipeline to create homozygous cell models for the CF-causing variants F508del, G542X, and W1282X. The resulting cell lines provide a virtually unlimited source of material with specific pathogenic mutations that can be used in a variety of assays, including functional assays.

PMID: 30563749 [PubMed - as supplied by publisher]

Atypical pathogens in hospitalized patients with community-acquired pneumonia: a worldwide perspective.

BMC Infect Dis. 2018 Dec 18;18(1):677

Authors: Gramegna A, Sotgiu G, Di Pasquale M, Radovanovic D, Terraneo S, Reyes LF, Vendrell E, Neves J, Menzella F, Blasi F, Aliberti S, Restrepo MI, GLIMP Study Group

Abstract
BACKGROUND: Empirical antibiotic coverage for atypical pathogens in community-acquired pneumonia (CAP) has long been debated, mainly because of a lack of epidemiological data. We aimed to assess both testing for atypical pathogens and their prevalence in hospitalized patients with CAP worldwide, especially in relation with disease severity.
METHODS: A secondary analysis of the GLIMP database, an international, multicentre, point-prevalence study of adult patients admitted for CAP in 222 hospitals across 6 continents in 2015, was performed. The study evaluated frequency of testing for atypical pathogens, including L. pneumophila, M. pneumoniae, C. pneumoniae, and their prevalence. Risk factors for testing and prevalence for atypical pathogens were assessed through univariate analysis.
RESULTS: Among 3702 CAP patients 1250 (33.8%) underwent at least one test for atypical pathogens. Testing varies greatly among countries and its frequency was higher in Europe than elsewhere (46.0% vs. 12.7%, respectively, p < 0.0001). Detection of L. pneumophila urinary antigen was the most common test performed worldwide (32.0%). Patients with severe CAP were less likely to be tested for both atypical pathogens considered together (30.5% vs. 35.0%, p = 0.009) and specifically for legionellosis (28.3% vs. 33.5%, p = 0.003) than the rest of the population. Similarly, L. pneumophila testing was lower in ICU patients. At least one atypical pathogen was isolated in 62 patients (4.7%), including M. pneumoniae (26/251 patients, 10.3%), L. pneumophila (30/1186 patients, 2.5%), and C. pneumoniae (8/228 patients, 3.5%). Patients with CAP due to atypical pathogens were significantly younger, showed less cardiovascular, renal, and metabolic comorbidities in comparison to adult patients hospitalized due to non-atypical pathogen CAP.
CONCLUSIONS: Testing for atypical pathogens in patients admitted for CAP in poorly standardized in real life and does not mirror atypical prevalence in different settings. Further evidence on the impact of atypical pathogens, expecially in the low-income countries, is needed to guidelines implementation.

PMID: 30563504 [PubMed - in process]

Drug pipeline: 1Q18.

Nat Biotechnol. 2018 05 09;36(5):386

Authors: DeFrancesco L

PMID: 29734307 [PubMed - indexed for MEDLINE]

Acceptability of Electronic Visits for Return of Research Results in the Mayo Clinic Biobank.

Mayo Clin Proc Innov Qual Outcomes. 2018 Dec;2(4):352-358

Authors: Olson JE, Ryu E, Lyke KJ, Bielinski SJ, Winkler EM, Hathcock MA, Bublitz JT, Takahashi PY, Cerhan JR

Abstract
Objective: To understand patient characteristics related to acceptability of returning individual research results via various modalities, focusing on electronic visits (e-visits).
Patients and Methods: Twelve hundred participants from the Mayo Clinic Biobank were selected using a stratified random sampling approach based on sex, age, and education level. Mailed surveys ascertained return of results preferences for 2 disease vignettes (cystic fibrosis and hereditary breast cancer) and a pharmacogenomics vignette. The study was conducted from October 1, 2013, through March 31, 2014.
Results: In all, 685 patients (57%) responded, and 60% reported liking e-visits, although the option of receiving results in an office visit was liked most frequently. Multivariable logistic models showed that the odds of liking the use of e-visits for returning results for cystic fibrosis and hereditary breast cancer were higher among those with higher education and better genetic knowledge and among those not living in proximity to the Mayo Clinic (Rochester, Minnesota). Level of genetic knowledge was not considerably associated with accepting e-visits, whereas education level remained important. For all vignettes, those who are divorced were less likely to accept e-visits.
Conclusion: Researchers are faced with a difficult challenge of returning results with a method that is both acceptable to recipients and logistically feasible. This study implies that the use of e-visits may be a viable option for return of results to stratify the chasm between in-person genetic counseling and online portal receipt of results.

PMID: 30560237 [PubMed]

Host Variability in NTM Disease: Implications for Research Needs.

Front Microbiol. 2018;9:2901

Authors: Swenson C, Zerbe CS, Fennelly K

Abstract
Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that may cause opportunistic infections in susceptible hosts. Lung infections in immunocompetent persons with structural lung disease are most common, while disseminated disease occurs primarily in immunocompromised individuals. Human disease caused by certain species, such as Mycobacterium avium complex, Mycobacterium abscessus, and Mycobacterium kansasii, is increasing in incidence and varies by geographic distribution. The spectrum of NTM disease varies widely in presentation and clinical outcome, but certain patterns can be organized into clinical phenotypes. Treatment options are limited, lengthy, and often toxic. The purpose of this case-based review is to provide non-clinician scientists with a better understanding of human NTM disease with an aim to stimulate more research and development.

PMID: 30559727 [PubMed]

Knockdown of Gene Expression in Macrophages by microRNA Mimic-Containing Poly (Lactic-co-glycolic Acid) Microparticles.

Medicines (Basel). 2018 Dec 15;5(4):

Authors: McKiernan PJ, Lynch P, Ramsey JM, Cryan SA, Greene CM

Abstract
Background: microRNA (miRNA) regulate target gene expression through translational repression and/or mRNA degradation and are involved in the regulation of inflammation. Macrophages are key inflammatory cells that are important in chronic inflammatory lung diseases such as cystic fibrosis (CF). Macrophage-expressed miRNA represent therapeutic drug targets, yet delivery of nucleic acids to macrophages has proved challenging. Methods: miRNAs were encapsulated in poly (lactic-co-glycolic acid) (PLGA)-based microparticles using double emulsion solvent evaporation and characterised for physicochemical features. Phorbol myristic acetate (PMA)-differentiated U937 macrophages were transfected with empty PLGA microparticles or those encapsulating a premiR-19b-3p or scrambled control miRNA mimic. miRNA internalisation and knockdown of a miR-19b-3p target gene, secretory leucoprotease inhibitor (SLPI), were determined by qRT-PCR. Results: Microparticle formulations were consistently found to be 2⁻3μm and all had a negative ζ potential (-5 mV to -14 mV). Encapsulation efficiency of premiR-19b-3p was 37.6 ± 13.4%. Levels of mature miR-19b-3p were higher in macrophages after delivery of premiR-19b-3p microparticles compared to empty or scrambled control miRNA-containing microparticles. Significant SLPI knockdown was achieved 72 hours post-delivery of premiR-19b-3p microparticles compared to controls. Conclusions: miRNA-encapsulating PLGA microparticles offer a new treatment paradigm for delivery to macrophages that could potentially be administered to CF lungs via inhalation.

PMID: 30558310 [PubMed]

Experience of Using A Semi-Elemental Formula For Home Enteral Nutrition In Children: A Multicenter Cross-Sectional Study.

J Pediatr Gastroenterol Nutr. 2018 Dec 14;:

Authors: Leonard M, Caldari D, Mas E, Lambe C, Comte A, Ley D, Peretti N, Borderon C, Marinier E, Coste ME, Lamireau T, Rubio A, Turquet A, Dubern B, Dabadie A, Gautry J, Kyheng M, Guimber D, Gottrand F

Abstract
OBJECTIVES: The use of semi-elemental diets concerns a small proportion of children on enteral nutrition whose characteristics have never been reported. Our aim was to describe a cohort of patients on home enteral nutrition with Peptamen Junior, including the tolerance and nutritional efficacy of this product.
METHODS: We performed a retrospective multicenter survey on a cohort of patients receiving this semi-elemental diet at home between 2010 and 2015 in 14 tertiary pediatric French centers. We recorded at baseline, 3, 6 and 12 months, and then every year the anthropometric characteristics of the patients, indications and modalities of administration of the diet, and the tolerance and adverse events.
RESULTS: We recruited 136 patients aged 9.8 ± 4.4 years at baseline. Mean BMI z-score was -1.0 ± 1.8; mean height z-score was -1.1 ± 1.9. The main underlying diseases were digestive (35.3%), neurological (33.1%), and haematological (19.9%). The indications for a semi-elemental diet were failure of another diet in 70 patients (51.9%), severe malnutrition in 19 (14.1%), cystic fibrosis in 11 (8.1%) and switch from parenteral nutrition in 11 (8.1%). Side effects were observed in 39.2% of the patients, and required medical attention in 8.2%. Body mass index improved or remained normal in 88.3% of children.
CONCLUSIONS: This semi-elemental diet seems to be well tolerated and efficient in the setting of home enteral nutrition in children with complex diseases featuring malabsorption and/or after failure of polymeric diet.

PMID: 30562309 [PubMed - as supplied by publisher]

Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry.

Pediatr Pulmonol. 2018 Dec 18;:

Authors: Salvatore D, Padoan R, Buzzetti R, Amato A, Giordani B, Ferrari G, Majo F

Abstract
BACKGROUND: CFTR mutations permitting residual function (RF) of the CFTR protein are disease-causing. These mutations are associated with a pneumopathy that is delayed in onset and is slower in progression than are more common forms of cystic fibrosis (CF), although the disease may become severe in some patients. RF mutations are among the most frequent in Italy, thus encouraging investigation of their prevalence and associated phenotypes.
METHODS: Data from the Italian Registry were used to compare patients with at least one RF mutation with those homozygous for F508del.
RESULTS: A total of 806 patients bearing at least one RF mutation were identified among 5204 registered patients (15.5%). The RF patients were older than the F508del homozygotes (median age 26.0 years vs 19.8 years, respectively), with a higher median age at diagnosis (6.3 years vs 0.2 years, respectively) and a lower median sweat chloride value (76.0 mmol/L vs 100.0 mmol/L, respectively). In the RF group, lung infections and comorbidities were less prevalent than those in the F508del homozygotes, while better FEV1 and nutritional status were observed at all ages. Within the RF group, RF/F508del subjects showed more severe pneumopathy than did patients with RF/other mutations. In particular, the 3849 + 10kbC → T/F508del subjects had worse FEV1 and a higher prevalence of lung infections than did patients with other genotypes.
CONCLUSIONS: Patients with RF mutations are numerous in Italy and have a milder disease phenotype than do F508del homozygotes. Inside the RF group, F508del heterozygotes and, in particular, 3849 + 10kbC → T/F508del patients showed more severe pneumopathy.

PMID: 30561903 [PubMed - as supplied by publisher]

Early detection of non-tuberculous mycobacteria in children with cystic fibrosis using induced sputum at annual review.

Pediatr Pulmonol. 2018 Dec 18;:

Authors: Ahmed MI, Kulkarni H, Shajpal S, Patel D, Patel P, Claydon A, Modha DE, Gaillard EA

Abstract
AIM: Non-tuberculous mycobacteria (NTM) have emerged as an important pathogen in cystic fibrosis (CF). Early detection and treatment of NTM can preserve lung function and maintain good lung health. Many children with CF are not regular sputum producers and cough swabs cannot routinely be used to diagnose NTM. We aimed to test the hypothesis that performing sputum induction at routine annual review results in earlier identification of NTM in non-sputum producing children with CF.
METHOD: We conducted a 5-year prospective observational cohort study involving children with CF aged 5-17 years who had sputum induction with hypertonic saline for microbiological surveillance including NTM at their annual review.
RESULTS: Forty-two children (19 males, mean age 11.4 years ± 3.6, mean FEV1 % predicted 94.7 ± 20.6) participated in the study. Forty-one induced sputum samples from 29 children yielded bacterial pathogens. Six samples from six children (14% of the cohort) yielded NTM never previously isolated from the patient. We also detected three isolates of Pseudomonas aeruginosa and one isolate each of Burkholderia cepacia complex and Meticillin resistant Staphylococcus aureus (MRSA), all of which were first time isolates.
CONCLUSION: We conclude that annual induced sputum for microbiological surveillance is useful for early detection of NTM and other important respiratory pathogens, particularly in non-expectorating children. This may lead to earlier identification and help inform initiation of eradication treatment in children with NTM. Children can also be cohorted earlier, before they potentially infect other children in the clinic.

PMID: 30561865 [PubMed - as supplied by publisher]

A randomized trial of vitamin D in acute-stage allergic bronchopulmonary aspergillosis complicating asthma.

Mycoses. 2018 Dec 18;:

Authors: Dodamani MH, Muthu V, Thakur R, Pal A, Sehgal IS, Dhooria S, Aggarwal AN, Garg M, Chakrabarti A, Agarwal R

Abstract
Vitamin D has been demonstrated to have an immunomodulatory role in cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA). Herein, we evaluate supplemental vitamin D in acute-stage ABPA complicating asthma. Thirty subjects were randomized to receive either prednisolone (n=15, control) or prednisolone and oral vitamin D (n=15, intervention arm). Serum vitamin D levels were significantly higher in the intervention versus the control arm, following therapy. The mean decline in total IgE at two months (primary outcome) was 10% higher in the intervention arm than the control arm; however, this was not statistically significant (48.6% vs 38.1%, p=0.27). The percentage decline in total IgE after four and six months of randomization was also similar in the two arms. There was no difference in asthma exacerbations (0 vs. 2, intervention vs. control; p=0.16). No ABPA exacerbation occurred in either arm. The other outcomes including the Th2 (IL-4, IL-6 and IL-10) and Th17 (IL-17) cytokine levels were similar in the two groups. None of the participants experienced hypervitaminosis D. There was no significant improvement in the clinical or immunological outcomes following vitamin D supplementation. A larger trial is required to ascertain the role of vitamin D in ABPA complicating asthma.[Clinicaltrials. gov: NCT03133299] This article is protected by copyright. All rights reserved.

PMID: 30561849 [PubMed - as supplied by publisher]

Bile-derived organoids from patients with primary sclerosing cholangitis recapitulate their inflammatory immune profile.

Hepatology. 2018 Dec 18;:

Authors: Soroka CJ, Assis DN, Alrabadi LS, Roberts S, Cusack L, Jaffe AB, Boyer JL

Abstract
Primary sclerosing cholangitis (PSC) is a heterogeneous and progressive fibroinflammatory cholangiopathy with no known etiology or effective treatment. Studies of PSC are limited due to difficulty in accessing the cholangiocyte, the small percentage of these cells in the liver, instability of in vitro culture systems, and reliance on samples from end-stage disease. Here we demonstrate that stem cells can be isolated from the bile of PSC patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) earlier in their clinical course, and maintained long-term in vitro as 3D organoids that express a biliary genetic phenotype. Additionally, bile-derived organoids (BDOs) can be biobanked and samples obtained longitudinally over the course of the disease. These BDOs express known cholangiocyte markers including gamma glutamyl transferase, cytokeratin 19, epithelial cellular adhesion molecule, cystic fibrosis transmembrane conductance regulator, and anion exchanger 2. RNA sequence analysis identified 39 genes whose expression differed in organoids from PSC patients as compared to non-PSC controls, including HLA-DMA and CCL20, immune-related genes previously described in GWAS studies of PSC. Incubation of these BDOs with IL17A or TNFα lead to an immune reactive phenotype with a significant increase in secretion of proinflammatory mediators, including CCL20, a T-cell chemoattractant. Conclusions: This study demonstrates that bile can be used as a source of biliary-like cells that can be maintained long-term in vitro as 3D organoids. These BDOs retain features of cholangiopathies, including the ability to react to inflammatory stimuli by secreting chemokines, and propagating an immune reactive phenotype reflective of the pathogenesis of these diseases. Thus, BDOs represent a novel platform for the study of the pathogenesis and therapy of cholangiopathies, particularly PSC. This article is protected by copyright. All rights reserved.

PMID: 30561836 [PubMed - as supplied by publisher]

Protocol for psychosocial screening of adolescents and young adults with chronic illness.

Intern Med J. 2018 Dec 18;:

Authors: d'Emden H, McDermott B, Poulson K, McGahan G

Abstract
BACKGROUND: One in five adolescents and young adults (AYAs) have a chronic health condition necessitating on-going engagement with health care systems. Despite increasing prevalence there remains limited understanding of the burden of illness they experience. Living with a chronic illness can challenge healthy adolescent development, with the unique health and developmental issues affecting AYAs requiring different responses from the health care system.
METHODS: In a dedicated health service for AYA's aged 15-25 years with chronic health conditions, (13-25 years for those with substance use issues) we detail a protocol where demographics, general health, disease-specific indicators and comprehensive psychosocial variables will be collected. The health conditions include chronic gastrointestinal disease, cystic fibrosis, chronic rheumatic disease, phenylketonuria, craniomaxillofacial deformities, renal transplant recipients, and problematic substance use. Results will be compared to AYAs without chronic illness and AYAs with diabetes.
RESULTS: This protocol outlines a comprehensive screening study for AYAs with a large range of chronic health conditions, inclusive of medical, mental health, impairment and quality of life variables. It will inform service planning and provide a foundation upon which allied health service requirements (e.g. psychology) can be based. Whilst currently cross-sectional we anticipate further utility in broadening outcomes to include non-physical illness-related constructs.
CONCLUSIONS: The commonalities and differences between conditions will be examined to facilitate efficiencies of scale for systems and supports. Further iterations including quantifying access to allied health services will facilitate studying the impact of such interventions on treatment adherence and improving psychosocial functioning, quality of life and disease outcomes. This article is protected by copyright. All rights reserved.

PMID: 30561089 [PubMed - as supplied by publisher]

Exercise is commonly used as a substitute for traditional airway clearance techniques by adults with cystic fibrosis in Australia: a survey.

J Physiother. 2018 Dec 14;:

Authors: Ward N, Stiller K, Holland AE, Australian Cystic Fibrosis Exercise Survey group

Abstract
QUESTIONS: What airway clearance techniques and exercise regimens are used by adults with cystic fibrosis (CF) in Australia when well or unwell? What proportion of these adults believe that exercise can be used as a substitute for traditional airway clearance techniques, and how have they come to this belief? What type of exercise is used as a substitute for traditional airway clearance techniques?
DESIGN: Cross-sectional survey at 13 CF centres in Australia, using a purpose-designed questionnaire.
PARTICIPANTS: Six hundred and ninety-two adults with CF completed the questionnaire.
OUTCOME MEASURES: The questionnaire included questions about: the participants' current use of traditional airway clearance techniques and exercise, when well and unwell; and beliefs regarding the use of exercise as a substitute for traditional airway clearance techniques.
RESULTS: Coughing, huffing and positive expiratory pressure were the most commonly used airway clearance techniques. Walking, jogging and lifting weights were the most commonly used forms of exercise. Overall, 43% of participants believed that exercise could be used as a substitute for traditional airway clearance techniques, with 44% having substituted exercise for traditional airway clearance techniques in the previous 3 months. Personal experience was the most commonly reported factor influencing participants' beliefs about the use of exercise as a substitute for traditional airway clearance techniques.
CONCLUSION: Exercise is commonly used as a substitute for traditional airway clearance techniques. Physiotherapists should advise patients that whilst there is some research suggesting a possible mechanism for exercise as a form of airway clearance, there are currently no medium-term to long-term data supporting exercise as a stand-alone form of airway clearance. These results suggest that future research to investigate the clinical effectiveness of exercise as a substitute for traditional airway clearance techniques should be a priority.
REGISTRATION: ACTRN12616000994482.

PMID: 30559063 [PubMed - as supplied by publisher]

Cirrhosis associated with decreased survival and a 10-year lower median age at death of cystic fibrosis patients in the Netherlands.

J Cyst Fibros. 2018 Dec 14;:

Authors: Pals FH, Verkade HJ, Gulmans VAM, De Koning BAE, Koot BGP, De Meij TGJ, Hendriks DM, Gierenz N, Vreugdenhil ACE, Houwen RHJ, Bodewes FAJA

Abstract
BACKGROUND: Up to 10% of patients with Cystic Fibrosis develop cirrhotic CF-related liver disease with portal hypertension: CF cirrhosis (CFC). In a nationwide study, we aimed to determine the role of CFC on survival in the Netherlands between 1 and 1-2009 and1-1-2015.
METHODS: We identified all CFC patients in the Netherlands, based on ultrasonographic liver nodularity and portal hypertension. A non-cirrhotic control group was obtained from the national Dutch CF patient registry. We compared groups with regards to baseline lung function and nutritional status and survival and age at death over a 6-year period. In case of death of CFC patients, the clinical reported cause was recorded.
RESULTS: At baseline, we found no significant difference in lung function and nutritional status between the CFC patients (N = 95) and controls (N = 980). Both the 6-year survival rate (77 vs. 93%; P < .01) and the median age at death (27 vs. 37 years; P = .02) was significantly lower in CFC compared to controls. In the deceased CFC patients, the reported primary cause of death was pulmonary in 68% of cases, and liver failure related in 18% of cases.
CONCLUSIONS: In the Netherlands, the presence of CFC is associated with a higher risk for early mortality and an approximately 10-year lower median age at death. This substantial poorer outcome of CFC patients was not reflected in a lower baseline lung function or a diminished nutritional status. However, in the case of mortality, the reported primary cause of death in CFC patients is predominantly pulmonary failure and not end-stage liver disease.

PMID: 30558881 [PubMed - as supplied by publisher]

Privatisation rescues function following loss of cooperation.

Elife. 2018 Dec 18;7:

Authors: Andersen SB, Ghoul M, Marvig RL, Lee ZB, Molin S, Johansen HK, Griffin AS

Abstract
A single cheating mutant can lead to the invasion and eventual eradication of cooperation from a population. Consequently, cheat invasion is often considered equal to extinction in empirical and theoretical studies of cooperator-cheat dynamics. But does cheat invasion necessarily equate extinction in nature? By following the social dynamics of iron metabolism in Pseudomonas aeruginosa during cystic fibrosis lung infection, we observed that individuals evolved to replace cooperation with a 'private' behaviour. Phenotypic assays showed that cooperative iron acquisition frequently was upregulated early in infection, which, however, increased the risk of cheat invasion. With whole-genome sequencing we showed that if, and only if, cooperative iron acquisition is lost from the population, a private system was upregulated. The benefit of upregulation depended on iron availability. These findings highlight the importance of social dynamics of natural populations and emphasizes the potential impact of past social interaction on the evolution of private traits.

PMID: 30558711 [PubMed - in process]

Clinical and genetic characteristics of cystic fibrosis in CHINESE patients: a systemic review of reported cases.

Orphanet J Rare Dis. 2018 Dec 17;13(1):224

Authors: Guo X, Liu K, Liu Y, Situ Y, Tian X, Xu KF, Zhang X

Abstract
Cystic fibrosis (CF) is a rare disease most commonly seen in Caucasians. Only a few Chinese CF patients have been described in literature, taking into account the large population of China. In this systematic review, we collected the clinical and genetic information of 71 Chinese CF patients based on all available data. Compared with Caucasians, Chinese CF patients often present atypical symptoms, mainly displaying symptoms of pulmonary infection with fewer digestive symptoms. An ethnicity-specific CFTR variant spectrum was also observed in CF patients of Chinese origin, with p.Gly970Asp as the most common mutation while p.Phe508del, the most common pathogenic mutation in CF patients of Caucasian origin, is rare, suggesting the necessity of a Chinese-specific CFTR variant screening panel. Besides, multiplex ligation-dependent probe amplification analysis should be routinely considered, especially for those with unidentified mutations. Potential under-diagnosis of CF in Chinese patients might be caused by a combination of atypical clinical features and genetic heterogeneity in Chinese CF patients, the inaccessibility of sweat and genetic testing facilities, and the one-child policy in China. With the approval of promising small molecule correctors and potentiators, molecular characterization of Chinese-specific CFTR mutations will help to realize more precise treatment for Chinese CF patients.

PMID: 30558651 [PubMed - in process]