What She Leaves Behind.

Am J Nurs. 2019 Dec;119(12):65

Authors: Brown T

Abstract
Cystic fibrosis and an unfinished life.

PMID: 31764059 [PubMed - in process]

The lived experience of adults with cystic fibrosis: what they would tell their younger selves about the gut.

J Hum Nutr Diet. 2019 Nov 25;:

Authors: Cave L, Milnes LJ

Abstract
BACKGROUND: Little is known about adults' experience of living with cystic fibrosis (CF) specifically in relation to the gut. However, their unique perspectives may be meaningful to children with CF and inform the understanding and practice of dietitians. The present study aimed to explore adults' lived experience of the CF gut and how they learnt to manage the gut as they were growing up.
METHODS: Semi-structured interviews were conducted with adult inpatients (n = 10). Interviews were audio-recorded, transcribed verbatim and accounts analysed using interpretative phenomenological analysis.
RESULTS: Three super-ordinate themes were identified: taking Creon, the learning process and this much I (now) know. Participants accounts of how CF affects the gut predominantly focused on taking Creon (pancreatin, Mylan). Various strategies were employed for coping with peer responses to taking Creon at school. Several participants reached adulthood before they understood and/or accepted that taking Creon consistently needed to be normal for them. Knowledge and understanding developed over time, with 'CF experience' and was shaped by family, CF care teams and other children with CF. All had unmet information needs when growing up. Having key explanations earlier, to make connections between eating, taking Creon, gaining weight and growth, did or would have helped most participants. Participants urged children to be assertive, ask questions and not only be involved in managing their diet and gut, but also begin to take control of this aspect of their CF.
CONCLUSIONS: Supporting development of knowledge, skills and confidence to manage diet and the gut needs to be integral to care throughout childhood.

PMID: 31763740 [PubMed - as supplied by publisher]

Whole genome analysis of Pandoraea species strains from cystic fibrosis patients.

Future Microbiol. 2019 Nov 25;:

Authors: Bayjanov JR, Ekkelenkamp MB, Rogers MR, Cantón R, Benaissa-Trouw BJ, Díez-Aguilar M, Tunney M, Fluit AC

Abstract
Aim: Genetic characterization of Pandoraea strains recovered from cystic fibrosis patients. Materials & methods: The whole genome sequence of 12 Pandoraea strains was determined using Illumina technology. The position of the strains within the genus Pandoraea was analyzed using selected partial gene sequences, core genome multi-locus sequence typing and average nucleotide identity analysis. Furthermore, the sequences were annotated. Results: The results show that some strains previously identified as Pandoraea pnomenusa, Pandoraea sputorum, Pandoraea oxalativorans and Pandoraea pulmonicola belong to novel species. The strains did not harbor acquired antibiotic resistance genes but encoded an OXA-type ß-lactamase. Conclusion: The taxonomy of the genus Pandoraea needs to be revised.

PMID: 31762328 [PubMed - as supplied by publisher]

A Rare Case of Myonecrosis with Soft-Tissue Emphysema in a Diabetic Foot Caused by Streptococcus anginosus Isolated in Pure Culture: A Case Study.

J Am Podiatr Med Assoc. 2019 Jul;109(4):305-307

Authors: Route J, Anain J

Abstract
Streptococcus anginosus (SAG) is a known human pathogen and member of the Streptococcus milleri group. SAG is a known bacterial cause of soft-tissue abscesses and bacteremia and is an increasingly prevalent pathogen in infections in patients with cystic fibrosis. We describe a rare case of SAG as an infectious agent in a case of nonclostridial myonecrosis with soft-tissue emphysema. This is the only case found in the literature of SAG cultured as a pure isolate in this type of infection and was associated with a prolonged course of treatment in an otherwise healthy patient.

PMID: 31762305 [PubMed - in process]

Answering the call to address cystic fibrosis treatment burden in the era of highly effective CFTR modulator therapy.

J Cyst Fibros. 2019 Nov 21;:

Authors: Gifford AH, Mayer-Hamblett N, Pearson K, Nichols DP

Abstract
BACKGROUND: We recognize an unprecedented opportunity to study the effects of withdrawing one or more chronic treatments in people with CF (PwCF) who benefit greatly from CFTR modulator therapy, but feasibility and acceptance of such a study within the community is unknown.
METHODS: We surveyed PwCF, their families, and their acquaintances between November 16, 2018, and December 2, 2018, and CF clinicians between December 19, 2018, and January 2, 2019, about treatment withdrawal research. We sought feedback from these groups about their level of interest in this research, the consistency with which they were taking modulator and non-modulator treatments, the ways in which they conceptualized health changes, and what chronic non-modulator treatments they were most interested in stopping. We also asked for stakeholder perspectives on the design of a treatment withdrawal trial, but we intend to report these perspectives elsewhere.
RESULTS: Eighty percent (541/675) of CF community respondents and 95% (206/218) of CF clinicians said that a trial of treatment simplification should be performed in the context of highly effective modulator therapy. Most current CFTR modulator users (292/359, 81%) have not stopped another chronic treatment. Worsening lung function by spirometry or increased daily symptoms were important health indicators. PwCF, their families, and/or their acquaintances ranked airway clearance techniques and inhaled antibiotics as the most burdensome treatments.
CONCLUSIONS: There is considerable support among the CF community and CF clinicians in the U.S. for controlled trials to assess the safety and impact of treatment simplification in patients taking highly effective modulator therapy.

PMID: 31761739 [PubMed - as supplied by publisher]

Caregiver Burden Due to Pulmonary Exacerbations in Patients with Cystic Fibrosis.

J Pediatr. 2019 Dec;215:164-171.e2

Authors: Suthoff E, Mainz JG, Cox DW, Thorat T, Grossoehme DH, Fridman M, Sawicki GS, Rosenfeld M

Abstract
OBJECTIVE: To describe the poorly understood burden of pulmonary exacerbations experienced by primary caregivers of children (aged 2-17 years) with cystic fibrosis (CF), who frequently require prolonged hospitalizations for treatment of pulmonary exacerbations with intravenous (IV) antibiotics.
STUDY DESIGN: In this prospective observational study, 88 caregivers in Germany, Ireland, the United Kingdom, and the US completed a survey during pulmonary exacerbation-related hospitalizations (T1) and after return to a "well state" of health (T2). The impact of pulmonary exacerbations on caregiver-reported productivity, mental/physical health, and social/family/emotional functioning was quantified.
RESULTS: Primary caregivers of children with CF reported significantly increased burden during pulmonary exacerbations, as measured by the 12-item Short-Form Health Survey mental health component and the Work Productivity and Activity Impairment: Specific Health Problem absenteeism, presenteeism, work productivity loss, and activity impairment component scores. Compared to the "well state," during pulmonary exacerbations-related hospitalization caregivers reported lower physical health scores on the Child Health Questionnaire-Parent Form 28. Quality-of-life scores on the Caregiver Quality of Life Cystic Fibrosis scale and total support score on the Multidimensional Scale of Perceived Social Support did not differ significantly between T1 and T2. More caregivers reported a negative impact on family/social/emotional functioning during pulmonary exacerbations than during the "well state."
CONCLUSIONS: Pulmonary exacerbations necessitating hospitalization impose a significant burden on primary caregivers of children with CF. Preventing pulmonary exacerbations may substantially reduce this burden.

PMID: 31761140 [PubMed - in process]

The clinical and genetic relationships of cystic fibrosis to immotile cilia syndrome.

J Pediatr. 2019 Dec;215:1-3

Authors: Wilmott RW

PMID: 31761129 [PubMed - in process]

Streptococcus pseudopneumoniae, an opportunistic pathogen in patients with cystic fibrosis.

J Cyst Fibros. 2019 Nov 20;:

Authors: Dupont C, Michon AL, Normandin M, Salom G, Latypov M, Chiron R, Marchandin H

Abstract
The pathogenic power of Streptococcus pseudopneumoniae has been specified over years, particularly in case of chronic respiratory diseases; S. pseudopneumoniae isolation has however not been characterized before in CF patients. Identification of S. pseudopneumoniae remains challenging due to the high simila-rity level between species of the Streptococcus mitis group. Twenty CF patients with S. pseudopneumoniae were included. Isolates initially identified by phenotypic routine methods were subjected to both recA sequencing and amplification of S. pseudopneumoniae specific markers. Microbiological and clinical data were reviewed for patients with confirmed S. pseudopneumoniae. Thirteen isolates actually belong to S. pseudopneumoniae. S. pseudopneumoniae was associated with pulmonary exacerbation in 46% of the patients, either as the sole pathogen or as part of a polymicrobial infectious process. S. pseudopneumoniae has to be considered as an additional opportunistic pathogen in CF and additional studies are needed to increase knowledge of its epidemiology and clinical significance in CF.

PMID: 31759908 [PubMed - as supplied by publisher]

CFTR: New insights into structure and function and implications for modulation by small molecules.

J Cyst Fibros. 2019 Nov 20;:

Authors: Kleizen B, Hunt JF, Callebaut I, Hwang TC, Sermet-Gaudelus I, Hafkemeyer S, Sheppard DN

Abstract
Structural biology and functional studies are a powerful combination to elucidate fundamental knowledge about the cystic fibrosis transmembrane conductance regulator (CFTR). Here, we discuss the latest findings, including how clinically-approved drugs restore function to mutant CFTR, leading to better clinical outcomes for people with cystic fibrosis (CF). Despite the prospect of regulatory approval of a CFTR-targeting therapy for most CF mutations, strenuous efforts are still needed to fully comprehend CFTR structure-and-function for the development of better drugs to enable people with CF to live full and active lives.

PMID: 31759907 [PubMed - as supplied by publisher]

The MUC5B mucin polymer is dominated by repeating structural motifs and its topology is regulated by calcium and pH.

Sci Rep. 2019 Nov 22;9(1):17350

Authors: Hughes GW, Ridley C, Collins R, Roseman A, Ford R, Thornton DJ

Abstract
The polymeric mucin MUC5B provides the structural and functional framework of respiratory mucus, conferring both viscoelastic and antimicrobial properties onto this vital protective barrier. Whilst it is established that MUC5B forms disulfide-linked linear polymers, how this relates to their packaging in secretory granules, and their molecular form in mucus remain to be fully elucidated. Moreover, the role of the central heavily O-glycosylated mucin domains in MUC5B conformation is incompletely described. Here we have completed a detailed structural analysis on native MUC5B polymers purified from saliva and subsequently investigated how MUC5B conformation is affected by changes in calcium concentration and pH, factors important for mucin intragranular packaging and post-secretory expansion. The results identify that MUC5B has a beaded structure repeating along the polymer axis and suggest that these repeating motifs arise from distinct glycosylation patterns. Moreover, we demonstrate that the conformation of these highly entangled linear polymers is sensitive to calcium concentration and changes in pH. In the presence of calcium (Ca2+, 10 mM) at pH 5.0, MUC5B adopted a compact conformation which was lost either upon removal of calcium with EGTA, or by increasing the pH to 7.4. These results suggest a pathway of mucin collapse to enable intracellular packaging and mechanisms driving mucin expansion following secretion. They also point to the importance of the tight control of calcium and pH during different stages of mucin biosynthesis and secretion, and in the generation of correct mucus barrier properties.

PMID: 31758042 [PubMed - in process]

Closing the Brief Case: A Traveler's Tale-Burkholderia pseudomallei Infection in a Cystic Fibrosis Patient.

J Clin Microbiol. 2019 Dec;57(12):

Authors: Hettiarachchi IT, Duckers J, Lau D, Dhillon R

PMID: 31757886 [PubMed - in process]

The Brief Case: A Traveler's Tale-Burkholderia pseudomallei Infection in a Cystic Fibrosis Patient.

J Clin Microbiol. 2019 Dec;57(12):

Authors: Hettiarachchi IT, Duckers J, Lau D, Dhillon R

PMID: 31757885 [PubMed - in process]

Complementary feeding: new styles versus old myths.

Minerva Med. 2019 Nov 12;:

Authors: Dipasquale V, Romano C

Abstract
Early life feeding habits may potentially alter future metabolic programming and body composition. Complementary feeding is the period of time when infants introduce food different from milk in their diet, together with a gradual reduction of the intake of milk (either breast milk or formula), to finally acquire the diet model of their family. This period is important in the transition of the infant from milk feeding to family foods, and is necessary for both nutritional and developmental reasons. Over time, the timing for introducing complementary foods and the method of feeding have changed over time. Available literature data show increasing interest and concerns about the impact of complementary feeding timing and modality on the onset of later non-communicable disorders, such as overweight and obesity, allergic diseases, celiac disease, or diabetes. While international scientific guidelines on complementary feeding have been published, many baby food companies' websites, blogs, and books, in most European countries exist. The aim of this manuscript is to look over current recommendations, and to revise "old myths". The adoption of an adequate weaning method is a cornerstone in the development of life-long health status. A correct strategy could reduce the risk of feeding disorders and other health problems later in life.

PMID: 31755668 [PubMed - as supplied by publisher]

Author Correction: Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis.

Sci Rep. 2019 Nov 21;9(1):17535

Authors: Simonin J, Bille E, Crambert G, Noel S, Dreano E, Edwards A, Hatton A, Pranke I, Villeret B, Cottart CH, Vrel JP, Urbach V, Baatallah N, Hinzpeter A, Golec A, Touqui L, Nassif X, Galietta LJV, Planelles G, Sallenave JM, Edelman A, Sermet-Gaudelus I

Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PMID: 31754179 [PubMed - in process]

Substrate recognition by the Pseudomonas aeruginosa EF-Tu-modifying methyltransferase EftM.

J Biol Chem. 2019 Nov 21;:

Authors: Kuiper EG, Dey D, LaMore PA, Owings JP, Prezioso SM, Goldberg JB, Conn GL

Abstract
The opportunistic bacterial pathogen Pseudomonas aeruginosa is a leading cause of serious infections in individuals with cystic fibrosis, compromised immune systems, or severe burns. P. aeruginosa adhesion to host epithelial cells is enhanced by surface-exposed translation elongation factor EF-Tu carrying a Lys-5 trimethylation, incorporated by the methyltransferase EftM. Thus, the EF-Tu modification by EftM may represent a target to prevent P. aeruginosa infections in vulnerable individuals. Here, we extend our understanding of EftM activity by defining the molecular mechanism by which it recognizes EF-Tu. First, acting on the observation that EftM can bind to EF-Tu lacking its N-terminal peptide (encompassing the Lys-5 target site), we generated an EftM homology model and used it in protein-protein docking studies to predict EftM:EF-Tu interactions. Using site-directed mutagenesis of residues in both proteins, coupled with binding and methyltransferase activity assays, we experimentally validated the predicted protein-protein interface. We also show that EftM cannot methylate the isolated N-terminal EF-Tu peptide and that binding-induced conformational changes in EftM are likely needed to enable placement of the first 5-6 amino acids of EF-Tu into a conserved peptide-binding channel in EftM. In this channel, a group of residues that are highly conserved in EftM proteins position the N-terminal sequence to facilitate Lys-5 modification. Our findings reveal that EftM employs molecular strategies for substrate recognition common among both class I (Rossmann fold) and class II (SET domain) methyltransferases and pave the way for studies seeking a deeper understanding of EftM's mechanism of action on EF-Tu.

PMID: 31753919 [PubMed - as supplied by publisher]

Strategies for measuring airway mucus and mucins.

Respir Res. 2019 Nov 21;20(1):261

Authors: Atanasova KR, Reznikov LR

Abstract
Mucus secretion and mucociliary transport are essential defense mechanisms of the airways. Deviations in mucus composition and secretion can impede mucociliary transport and elicit airway obstruction. As such, mucus abnormalities are hallmark features of many respiratory diseases, including asthma, cystic fibrosis and chronic obstructive pulmonary disease (COPD). Studying mucus composition and its physical properties has therefore been of significant interest both clinically and scientifically. Yet, measuring mucus production, output, composition and transport presents several challenges. Here we summarize and discuss the advantages and limitations of several techniques from five broadly characterized strategies used to measure mucus secretion, composition and mucociliary transport, with an emphasis on the gel-forming mucins. Further, we summarize advances in the field, as well as suggest potential areas of improvement moving forward.

PMID: 31752894 [PubMed - in process]

Distinct Effects of Immunosuppressive Drugs on the Anti-Aspergillus Activity of Human Natural Killer Cells.

Pathogens. 2019 Nov 19;8(4):

Authors: Schmidt S, Schubert R, Demir A, Lehrnbecher T

Abstract
As the prognosis of invasive aspergillosis remains unacceptably poor in patients undergoing hematopoietic stem cell transplantation (HSCT), there is a growing interest in the adoptive transfer of antifungal effector cells, such as Natural Killer (NK) cells. Because immunosuppressive agents are required in most HSCT recipients, knowledge of the impact of these compounds on the antifungal activity of NK cells is a prerequisite for clinical trials. We, therefore, assessed the effect of methylprednisolone (mPRED), cyclosporin A (CsA) and mycophenolic acid (MPA) at different concentrations on proliferation, apoptosis/necrosis, and the direct and indirect anti-Aspergillus activity of human NK cells. Methylprednisolone decreased proliferation and increased apoptosis of NK cells in a significant manner. After seven days, a reduction of viable NK cells was seen for all three immunosuppressants, which was significant for MPA only. Cyclosporin A significantly inhibited the direct hyphal damage by NK cells in a dose-dependent manner. None of the immunosuppressive compounds had a major impact on the measured levels of interferon-γ, granulocyte-macrophage colony-stimulating factor and RANTES (regulated on activation, normal T cell expressed and secreted; CCL5). Our data demonstrate that commonly used immunosuppressive compounds have distinct effects on proliferation, viability and antifungal activity of human NK cells, which should be considered in designing studies on the use of NK cells for adoptive antifungal immunotherapy.

PMID: 31752374 [PubMed]

Abolition of Pseudomonas aeruginosa AUST-01 from an Australian CF center: Do other strains remain?

Pediatr Pulmonol. 2019 05;54(5):515-516

Authors: Kidd TJ, Grimwood K, Bell SC

PMID: 30741479 [PubMed - indexed for MEDLINE]

Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis.

ACS Med Chem Lett. 2019 Nov 14;10(11):1543-1548

Authors: Scanio MJC, Searle XB, Liu B, Koenig JR, Altenbach R, Gfesser GA, Bogdan A, Greszler S, Zhao G, Singh A, Fan Y, Swensen AM, Vortherms T, Manelli A, Balut C, Jia Y, Gao W, Yong H, Schrimpf M, Tse C, Kym P, Wang X

Abstract
Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure-activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.

PMID: 31749908 [PubMed]

Assessment of a Mobile App by Adolescents and Young Adults With Cystic Fibrosis: Pilot Evaluation.

JMIR Mhealth Uhealth. 2019 Nov 21;7(11):e12442

Authors: Rudolf I, Pieper K, Nolte H, Junge S, Dopfer C, Sauer-Heilborn A, Ringshausen FC, Tümmler B, von Jan U, Albrecht UV, Fuge J, Hansen G, Dittrich AM

Abstract
BACKGROUND: Cystic fibrosis (CF) continues to be the most common life-limiting chronic pulmonary disease in adolescents and young adults. Treatment of CF demands a high treatment time investment to slow the progression of lung function decline, the most important contributor to morbidity and mortality. Adherence is challenging in CF due to the high treatment burden and the lack of immediate health consequences in case of nonadherence. Lung function decline is particularly pronounced in the transition phase between 12 and 24 years of age. The improvement of self-management and self-responsibility and independence from parents and desire for normalcy are conflicting aspects for many adolescents with CF, which influence adherence to the time-consuming pulmonary therapy. Mobile health (mHealth) care apps could help to support self-management and independence and thereby reconcile seemingly conflicting goals to improve adherence, quality of life, and ultimately CF life expectancy.
OBJECTIVE: This study aimed to (1) assess user behavior and satisfaction among adolescents and young adults with CF over an observation period of three months using an mHealth app; (2) identify areas of improvement for this mHealth app; and (3) compare overall and disease-specific satisfaction, lung function, and anthropometry before and after using the mHealth app.
METHODS: A total of 27 adolescents and young adults with CF (age range 12-24 years, mean age 16 years, SD 3 years; 14 females, 11 males) used a free mHealth app for three months of whom 25 provided questionnaire data for analysis at the end of the study. Data collection was carried out using questionnaires on usage characteristics and life satisfaction, and standardized assessment of lung function and anthropometry.
RESULTS: The use of the reminder function for medication declined from 70% (15/21) of the participants at week 4 to 65% (13/20) at week 8 of the observation period. At the end of the study, only 17% (4/23) of the participants wanted to continue using the app. Nevertheless, 56% (14/25) of participants saw the mobile app as a support for everyday life. Potential improvements targeting hedonistic qualities were identified to improve mHealth app adherence. Comparisons of satisfaction with different life aspects hinted at improvements or stabilization for the subitem respiration and the subitem lack of handicap by CF, suggesting that app use might stabilize certain CF-specific aspects of the weighted satisfaction with life. Lung function and anthropometry were not affected consistently.
CONCLUSIONS: Most of the patients did not want to continue using the app after the study period. Only a few CF-specific aspects of weighted life satisfaction were possibly stabilized by the mHealth app; clinical parameters were not affected. Adaptation of the functions to adolescent-specific needs could improve the long-term use and thus positively affect the disease course.

PMID: 31750841 [PubMed - in process]