Early disease surveillance in young children with cystic fibrosis: A qualitative analysis of parent experiences.

J Cyst Fibros. 2020 Oct 22;:

Authors: Douglas TA, Pooley JA, Shields L, Stick SM, Branch-Smith C, Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF)

Abstract
BACKGROUND: Sensitive measures of early lung disease are being integrated into therapeutic trials and clinical practice in cystic fibrosis (CF). The impact of early disease surveillance (EDS) using these novel and often intensive techniques on young children and their families is not well researched.
METHODS: The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has operated a combined clinical and research early disease surveillance program, based around annual chest CT scan, bronchoscopy and lung function from newborn screening diagnosis until age 6 years, for over two-decades. To explore parental experiences of EDS in their child, a qualitative study was conducted using audio-recorded, semi-structured interviews in n=46 mothers and n=21 fathers of children (aged 3-months to six years) attending CF centres in Perth and Melbourne, Australia. Themes were developed iteratively using thematic analysis and assessed for validity and confirmability.
RESULTS: Parents' experiences were positive overall; affording a sense of control over CF, disease knowledge, and belief that EDS was in the best interests of their child. Challenges included poor understanding about EDS measures leading to anxiety and distress, self-blame surrounding adverse findings, and emotional burden of surveillance visits. Tailored information regarding the practical and psychosocial aspects of EDS were endorsed.
CONCLUSION: While experiences were generally positive there is need for information and psychosocial support for parents to mitigate anxiety and develop positive coping strategies surrounding surveillance procedures and results. Managing expectations regarding risks and benefits of disease surveillance in clinical and research settings are important aspects of care.

PMID: 33268308 [PubMed - as supplied by publisher]

Immune defects in patients with pulmonary Mycobacterium abscessus disease without cystic fibrosis.

ERJ Open Res. 2020 Oct;6(4):

Authors: Schuurbiers MMF, Bruno M, Zweijpfenning SMH, Magis-Escurra C, Boeree M, Netea MG, van Ingen J, van de Veerdonk F, Hoefsloot W

Abstract
The prevalence of Mycobacterium abscessus infections in non-cystic fibrosis (CF) patients has increased in recent years. In this study, we investigate whether immune defects explain the apparent susceptibility to this opportunistic infection in non-CF patients. We performed stimulations of peripheral blood mononuclear cells and whole blood from 13 patients with M. abscessus pulmonary disease and 13 healthy controls to investigate their cytokine production after 24 h and 7 days. Patients were predominantly women (54%) with a mean age of 59 years; 62% had nodular bronchiectatic disease. Many patients had predisposing pulmonary diseases, such as COPD (46%), and asthma (23%). Patients with COPD showed an impaired interleukin (IL)-6 response to M. abscessus and a reduced IL-17 response to Candida, together with a M. abscessus-specific enhanced IL-22 production. Patients without COPD showed higher levels of interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory molecule. Within the non-COPD patients, those with bronchiectasis showed defective interferon (IFN)-γ production in response to Candida albicans. In conclusion, susceptibility to M. abscessus is likely determined by a combination of immunological defects and predisposing pulmonary disease. The main defect in the innate immune response was a shift of the ratio of IL-1β to IL-1Ra, which decreased the bioactivity of this pathway in the adaptive immune response. In the adaptive immune response there was defective IL-17 and IFN-γ production. Patients with COPD and bronchiectasis showed different cytokine defects. It is therefore crucial to interpret the immunological results within the clinical background of the patients tested.

PMID: 33263065 [PubMed]

COVID-19 in children with underlying chronic respiratory diseases: survey results from 174 centres.

ERJ Open Res. 2020 Oct;6(4):

Authors: Moeller A, Thanikkel L, Duijts L, Gaillard EA, Garcia-Marcos L, Kantar A, Tabin N, Turner S, Zacharasiewicz A, Pijnenburg MWH

Abstract
Background: Early reports suggest that most children infected with severe acute respiratory syndrome coronavirus 2 ("SARS-CoV-2") have mild symptoms. What is not known is whether children with chronic respiratory illnesses have exacerbations associated with SARS-CoV-2 virus.
Methods: An expert panel created a survey, which was circulated twice (in April and May 2020) to members of the Paediatric Assembly of the European Respiratory Society (ERS) and via the social media of the ERS. The survey stratified patients by the following conditions: asthma, cystic fibrosis (CF), bronchopulmonary dysplasia (BPD) and other respiratory conditions.
Results: In total 174 centres responded to at least one survey. 80 centres reported no cases, whereas 94 entered data from 945 children with coronavirus disease 2019 (COVID-19). SARS-CoV-2 was isolated from 49 children with asthma of whom 29 required no treatment, 19 needed supplemental oxygen and four children required mechanical ventilation. Of the 14 children with CF and COVID-19, 10 required no treatment and four had only minor symptoms. Among the nine children with BPD and COVID-19, two required no treatment, five required inpatient care and oxygen and two were admitted to a paediatric intensive care unit (PICU) requiring invasive ventilation. Data were available from 33 children with other conditions and SARS-CoV-2 of whom 20 required supplemental oxygen and 11 needed noninvasive or invasive ventilation.
Conclusions: Within the participating centres, in children with asthma and CF, infection with SARS-CoV-2 was well tolerated, but a substantial minority of children with BPD and other conditions required ventilatory support indicating that these latter groups are at risk from SARS-CoV-2 infection.

PMID: 33263054 [PubMed]

Multicentre feasibility of multiple-breath washout in preschool children with cystic fibrosis and other lung diseases.

ERJ Open Res. 2020 Oct;6(4):

Authors: Stahl M, Joachim C, Kirsch I, Uselmann T, Yu Y, Alfeis N, Berger C, Minso R, Rudolf I, Stolpe C, Bovermann X, Liboschik L, Steinmetz A, Tennhardt D, Dörfler F, Röhmel J, Unorji-Frank K, Rückes-Nilges C, von Stoutz B, Naehrlich L, Kopp MV, Dittrich AM, Sommerburg O, Mall MA

Abstract
Background: Multiple-breath washout (MBW)-derived lung clearance index (LCI) detects early cystic fibrosis (CF) lung disease. LCI was used as an end-point in single- and multicentre settings at highly experienced MBW centres in preschool children. However, multicentre feasibility of MBW in children aged 2-6 years, including centres naïve to this technique, has not been determined systematically.
Methods: Following central training, 91 standardised nitrogen MBW investigations were performed in 74 awake preschool children (15 controls, 46 with CF, and 13 with other lung diseases), mean age 4.6±0.9 years at investigation, using a commercially available device across five centres in Germany (three experienced, two naïve to the performance in awake preschool children) with central data analysis. Each MBW investigation consisted of several measurements.
Results: Overall success rate of MBW investigations was 82.4% ranging from 70.6% to 94.1% across study sites. The number of measurements per investigation was significantly different between sites ranging from 3.7 to 6.2 (p<0.01), while the mean number of successful measurements per investigation was comparable with 2.1 (range, 1.9 to 2.5; p=0.46). In children with CF, the LCI was increased (median 8.2, range, 6.7-15.5) compared to controls (median 7.3, range 6.5-8.3; p<0.01), and comparable to children with other lung diseases (median 7.9, range, 6.6-13.9; p=0.95).
Conclusion: This study demonstrates that multicentre MBW in awake preschool children is feasible, even in centres previously naïve, with central coordination to assure standardised training, quality control and supervision. Our results support the use of LCI as multicentre end-point in clinical trials in awake preschoolers with CF.

PMID: 33263048 [PubMed]

Non-invasive Ventilation for Children With Chronic Lung Disease.

Front Pediatr. 2020;8:561639

Authors: Atag E, Krivec U, Ersu R

Abstract
Advances in medical care and supportive care options have contributed to the survival of children with complex disorders, including children with chronic lung disease. By delivering a positive pressure or a volume during the patient's inspiration, NIV is able to reverse nocturnal alveolar hypoventilation in patients who experience hypoventilation during sleep, such as patients with chronic lung disease. Bronchopulmonary dysplasia (BPD) is a common complication of prematurity, and despite significant advances in neonatal care over recent decades its incidence has not diminished. Most affected infants have mild disease and require a short period of oxygen supplementation or respiratory support. However, severely affected infants can become dependent on positive pressure support for a prolonged period. In case of established severe BPD, respiratory support with non-invasive or invasive positive pressure ventilation is required. Patients with cystic fibrosis (CF) and advanced lung disease develop hypoxaemia and hypercapnia during sleep and hypoventilation during sleep usually predates daytime hypercapnia. Hypoxaemia and hypercapnia indicates poor prognosis and prompts referral for lung transplantation. The prevention of respiratory failure during sleep in CF may prolong survival. Long-term oxygen therapy has not been shown to improve survival in people with CF. A Cochrane review on the use NIV in CF concluded that NIV in combination with oxygen therapy improves gas exchange during sleep to a greater extent than oxygen therapy alone in people with moderate to severe CF lung disease. Uncontrolled, non-randomized studies suggest survival benefit with NIV in addition to being an effective bridge to transplantation. Complications of NIV relate mainly to prolonged use of a face or nasal mask which can lead to skin trauma, and neurodevelopmental delay by acting as a physical barrier to social interaction. Another associated risk is pulmonary aspiration caused by vomiting whilst wearing a face mask. Adherence to NIV is one of the major barriers to treatment in children. This article will review the current evidence for indications, adverse effects and long term follow up including adherence to NIV in children with chronic lung disease.

PMID: 33262959 [PubMed]

Ecological Succession of Polymicrobial Communities in the Cystic Fibrosis Airways.

mSystems. 2020 Dec 01;5(6):

Authors: Khanolkar RA, Clark ST, Wang PW, Hwang DM, Yau YCW, Waters VJ, Guttman DS

Abstract
Antimicrobial therapies against cystic fibrosis (CF) lung infections are largely aimed at the traditional, well-studied CF pathogens such as Pseudomonas aeruginosa and Burkholderia cepacia complex, despite the fact that the CF lung harbors a complex and dynamic polymicrobial community. A clinical focus on the dominant pathogens ignores potentially important community-level interactions in disease pathology, perhaps explaining why these treatments are often less effective than predicted based on in vitro testing. A better understanding of the ecological dynamics of this ecosystem may enable clinicians to harness these interactions and thereby improve treatment outcomes. Like all ecosystems, the CF lung microbial community develops through a series of stages, each of which may present with distinct microbial communities that generate unique host-microbe and microbe-microbe interactions, metabolic profiles, and clinical phenotypes. While insightful models have been developed to explain some of these stages and interactions, there is no unifying model to describe how these infections develop and persist. Here, we review current perspectives on the ecology of the CF airway and present the CF Ecological Succession (CFES) model that aims to capture the spatial and temporal complexity of CF lung infection, address current challenges in disease management, and inform the development of ecologically driven therapeutic strategies.

PMID: 33262240 [PubMed]

Extensive CFTR Gene Analysis Revealed a Higher Occurrence of Cystic Fibrosis Transmembrane Regulator-Related Disorders (CFTR-RD) among CF Carriers.

J Clin Med. 2020 Nov 27;9(12):

Authors: Esposito MV, Aveta A, Comegna M, Cernera G, Iacotucci P, Carnovale V, Taccetti G, Terlizzi V, Castaldo G

Abstract
Background: A wide range of cystic fibrosis (CF)-related conditions are reported in CF carriers, but no study has explored the possibility that such subjects may be affected by cystic fibrosis transmembrane regulator-related disorders (CFTR-RD). No data are available so far on the occurrence of CFTR-RD among CF carriers. Methods: We studied 706 CF carriers-first- and second-degree relatives of CF patients that carried the parental mutation; such subjects were divided in two groups: a first group (353 subjects, group A) performed at first only the analysis of the CFTR proband mutation; we retrospectively evaluated the number of cases that had been diagnosed as CFTR-RD based on subsequent symptoms; a second group (353 subjects, group B) performed extensive CFTR molecular analysis in absence of any reported symptoms, followed by a clinical evaluation in cases that carry a second CFTR mutation; we evaluated the number of cases that prospectively were diagnosed as CFTR-RD. Results: We found seven (2.0%) out of 353 subjects of group A and 24 (6.8%) out of 353 subjects of group B as affected by CFTR-RD (chi square, p = 0.002). Conclusions: A percentage of CF carriers are affected by undiagnosed CFTR-RD. Genetic tasting scanning analysis helps to identify CFTR-RD, some of which may benefit from follow-up and specific therapies improving their outcome.

PMID: 33260873 [PubMed]

Heterogeneous expression of CFTR in insulin-secreting β-cells of the normal human islet.

PLoS One. 2020;15(12):e0242749

Authors: Di Fulvio M, Bogdani M, Velasco M, McMillen TS, Ridaura C, Kelly L, Almutairi MM, Kursan S, Sajib AA, Hiriart M, Aguilar-Bryan L

Abstract
Cystic fibrosis (CF) is due to mutations in the CF-transmembrane conductance regulator (CFTR) and CF-related diabetes (CFRD) is its most common co-morbidity, affecting ~50% of all CF patients, significantly influencing pulmonary function and longevity. Yet, the complex pathogenesis of CFRD remains unclear. Two non-mutually exclusive underlying mechanisms have been proposed in CFRD: i) damage of the endocrine cells secondary to the severe exocrine pancreatic pathology and ii) intrinsic β-cell impairment of the secretory response in combination with other factors. The later has proven difficult to determine due to low expression of CFTR in β-cells, which results in the general perception that this Cl-channel does not participate in the modulation of insulin secretion or the development of CFRD. The objective of the present work is to demonstrate CFTR expression at the molecular and functional levels in insulin-secreting β-cells in normal human islets, where it seems to play a role. Towards this end, we have used immunofluorescence confocal and immunofluorescence microscopy, immunohistochemistry, RT-qPCR, Western blotting, pharmacology, electrophysiology and insulin secretory studies in normal human, rat and mouse islets. Our results demonstrate heterogeneous CFTR expression in human, mouse and rat β-cells and provide evidence that pharmacological inhibition of CFTR influences basal and stimulated insulin secretion in normal mouse islets but not in islets lacking this channel, despite being detected by electrophysiological means in ~30% of β-cells. Therefore, our results demonstrate a potential role for CFTR in the pancreatic β-cell secretory response suggesting that intrinsic β-cell dysfunction may also participate in the pathogenesis of CFRD.

PMID: 33264332 [PubMed - as supplied by publisher]

Nurse Sensemaking for Responding to Patient and Family Safety Concerns.

Nurs Res. 2020 Dec 01;:

Authors: Groves PS, Bunch JL, Cannava KE, Sabadosa KA, Williams JK

Abstract
BACKGROUND: Hospitals need to prevent, respond to, and learn from safety risks and events perceived by patients and families, who in turn rely on nurses to respond to and report their safety concerns.
OBJECTIVES: To describe the process by which bedside nurses evaluate and determine the appropriate response to safety concerns expressed by patients or their families.
METHODS: A qualitative design was employed. We recruited inpatient bedside nurses in an 811-bed Midwest academic medical center. Nurses provided demographic information and participated in semistructured interviews designed to elicit narratives related to evaluation and response to patient- or family-expressed safety concerns. Data analysis and interpretation were guided by grounded theory.
RESULTS: We enrolled 25 nurses representing 22 units. Based on these nurses' experiences, we developed a grounded theory explaining how nurses evaluate a patient or family safety concern. Nurses make sense of the patient's or family's safety concern in order to take action. Achieving this goal requires evaluation of the meaningfulness and reasonableness of the concern, as well as the potential effect of the concern on the patient. Based on this nursing evaluation, nurses respond in ways designed to (a) manage emotions, (b) immediately resolve concerns, (c) involve other team members, and (d) address fear or uncertain grounding in reality. Nurses reported routinely handling safety concerns at the bedside without use of incident reporting.
DISCUSSION: Safety requires an interpersonal and evaluative nursing process with actions responsive to patient and family concerns. Safety interventions designed to be used by nurses should be developed with the dynamic, cognitive, sensemaking nature of nurses' routine safety work in mind. Being sensitive to the vulnerability of patients, respecting patient and family input, and understanding the consequences of dismissing patient and family safety concerns is critical to making sense of the situation and taking appropriate action to maintain safety. Measuring patient safety or planning improvement based on patient or family expression of safety concerns would be a difficult undertaking using only standard approaches. A more complex approach incorporating direct patient engagement in data collection is necessary to gain a complete safety picture.

PMID: 33264259 [PubMed - as supplied by publisher]

Polysulfated Hyaluronan GM-1111 Inhibits Elastase and Improves Rheology in CF Sputum.

Am J Respir Cell Mol Biol. 2020 Dec 02;:

Authors: Kummarapurugu AB, Zheng S, Pulsipher A, Savage JR, Ma J, Rubin BK, Kennedy TP, Voynow JA

Abstract
Cystic fibrosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic, low molecular weight polysulfated hyaluronan (GM-1111) would be effective as an anti-NE drug using ex vivo CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of dornase alfa and/or hypertonic saline, using a spectrophotometric assay specific for human NE, and compared to unfractionated heparin. We tested whether GM-1111 disaggregated DNA from CF sputum by gel electrophoresis analysis, or modified CF sputum viscoelastic properties using a dynamic rheometer. GM-1111 and unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of dornase alfa. Both GM-1111 and unfractionated heparin retained anti-NE activity in hypertonic saline, but with decreased activity. GM-1111 increased release of soluble DNA in CF sputum, resulting in improved depolymerization efficacy of dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced DNA depolymerization by DNase, and decreased viscoelastic properties of CF sputum similar to that reported previously for unfractionated heparin. Unlike heparins, GM-1111 is synthetic with minimal anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over unfractionated heparin as a potential therapeutic for CF.

PMID: 33264072 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa in the CF Airway: Does it Deserve its Reputation as a Predatory 'Bully'?

Am J Respir Crit Care Med. 2020 Dec 02;:

Authors: Hughes DA, Price H, Rosenthal M, Davies JC

PMID: 33264066 [PubMed - as supplied by publisher]

Early COVID-19 infection after lung transplantation in a patient with cystic fibrosis.

Clinics (Sao Paulo). 2020 Nov 30;75:e2274

Authors: Athanazio RA, Costa AN, Carraro RM, Gonzalez D, Rached SZ, Samano MN, Teixeira RHOB, Campos SV

PMID: 33263634 [PubMed - as supplied by publisher]

Sleep-Disordered Breathing in Cystic Fibrosis.

Pediatr Pulmonol. 2020 Aug 17;:

Authors: Jagpal SK, Jobanputra AM, Ahmed OH, Santiago TV, Ramagopal M

Abstract
Sleep-disordered breathing(SBD) is an under recognized comorbidity in the cystic fibrosis (CF) population across the lifespan. Nocturnal hypoxemia, obstructive sleep apnea (OSA), and nocturnal hypoventilation are respiratory abnormalities that occur commonly during sleep in patients with lung disease, and have deleterious consequences to thequality of life in people with CF. Effective screening for these abnormalities is needed to allow for timely initiation of treatment, which has been reported to be efficacious. Lack of treatment leads to worsened pulmonary, cardiovascular, and metabolic outcomes in patients. In this review, we give an overview of sleep-disordered breathing for the CF clinician, includingprevalence, treatment, and suggestions for future research. We strongly encourage the CF community to incorporate evaluation for sleep-disordered breathing in CF clinical careso that outcomes for the subset of the CF patients with comorbid sleep-disordered breathing improve. This article is protected by copyright. All rights reserved.

PMID: 33263201 [PubMed - as supplied by publisher]

The Lung Microbiome of Three Young Brazilian Patients With Cystic Fibrosis Colonized by Fungi.

Front Cell Infect Microbiol. 2020;10:598938

Authors: de Almeida OGG, Capizzani CPDC, Tonani L, Grizante Barião PH, da Cunha AF, De Martinis ECP, Torres LAGMM, von Zeska Kress MR

Abstract
Microbial communities infiltrate the respiratory tract of cystic fibrosis patients, where chronic colonization and infection lead to clinical decline. This report aims to provide an overview of the diversity of bacterial and fungal species from the airway secretion of three young CF patients with severe pulmonary disease. The bacterial and fungal microbiomes were investigated by culture isolation, metataxonomics, and metagenomics shotgun. Virulence factors and antibiotic resistance genes were also explored. A. fumigatus was isolated from cultures and identified in high incidence from patient sputum samples. Candida albicans, Penicillium sp., Hanseniaspora sp., Torulaspora delbrueckii, and Talaromyces amestolkiae were isolated sporadically. Metataxonomics and metagenomics detected fungal reads (Saccharomyces cerevisiae, A. fumigatus, and Schizophyllum sp.) in one sputum sample. The main pathogenic bacteria identified were Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, and Achromobacter xylosoxidans. The canonical core CF microbiome is composed of species from the genera Streptococcus, Neisseria, Rothia, Prevotella, and Haemophilus. Thus, the airways of the three young CF patients presented dominant bacterial genera and interindividual variability in microbial community composition and diversity. Additionally, a wide diversity of virulence factors and antibiotic resistance genes were identified in the CF lung microbiomes, which may be linked to the clinical condition of the CF patients. Understanding the microbial community is crucial to improve therapy because it may have the opposite effect, restructuring the pathogenic microbiota. Future studies focusing on the influence of fungi on bacterial diversity and microbial interactions in CF microbiomes will be welcome to fulfill this huge gap of fungal influence on CF physiopathology.

PMID: 33262957 [PubMed - in process]

PEGylation of recombinant human deoxyribonuclease I deceases its transport across lung epithelial cells and uptake by macrophages.

Int J Pharm. 2020 Nov 28;:120107

Authors: Mahri S, Hardy E, Wilms T, De Keersmaecker H, Braeckmans K, De Smedt S, Bosquillon C, Vanbever R

Abstract
Conjugation to high molecular weight (MW) polyethylene glycol (PEG) was previously shown to largely prolong the lung residence time of recombinant human deoxyribonuclease I (rhDNase) and improve its therapeutic efficacy following pulmonary delivery in mice. In this paper, we investigated the mechanisms promoting the extended lung retention of PEG-rhDNase conjugates using cell culture models and lung biological media. Uptake by alveolar macrophages was also assessed in vivo. Transport experiments showed that PEGylation reduced the uptake and transport of rhDNase across monolayers of Calu-3 cells cultured at an air-liquid interface. PEGylation also decreased the uptake of rhDNase by macrophages in vitro whatever the PEG size as well as in vivo 4 h following intratracheal instillation in mice. However, the reverse was observed in vivo at 24 h. The uptake of rhDNase by macrophages was dependent on energy, time, and concentration and occurred at rates indicative of adsorptive endocytosis. The diffusion of PEGylated rhDNase in porcine tracheal mucus and cystic fibrosis sputa was slower compared with that of rhDNase. Nevertheless, no significant binding of PEGylated rhDNase to both media was observed. In conclusion, decreased transport across lung epithelial cells and uptake by macrophages appear to contribute to the longer retention of PEGylated rhDNase in the lungs.

PMID: 33259904 [PubMed - as supplied by publisher]

Extraction of the molecular level biomedical event trigger based on gene ontology using radial belief neural network techniques.

Biosystems. 2020 Nov 28;:104313

Authors: Devendra Kumar RN, Chakrapani A, Srihari K

Abstract
Detection of molecular level biomedical event extraction plays a vital role in creating and visualizing the applications related to natural language processing. Cystic Fibrosis is an inherited genetic and debilitating pathology involving the respiratory and digestive systems. The excessive production of thick sticky mucus on the outside of the cells is the main consequence of such disease. This includes disease prevention and medical search to signify the occurrence and detection of event triggers, which is regarded as a proper step in an event extraction of molecular level in biomedical applications. In this model, use a rich set of extracted features to feed the machine learning classifier that helps in better extraction of events. The study uses an automatic feature selection and a classification model using Radial Belief Neural Network (RBNN) for the optimal detection of molecular biomedical event detection. The Radial Belief Neural Network (RBNN) is the proposed system is implemented and it is the classifier to give accurate result of the disease detection. These three algorithms are used to enhance the generalization performance and scalability of detecting the molecular event triggers. The validation is conducted on the cystic fibrosis event trigger based on the gene ontology bio system using the RBNN model with a lung molecular event-level extraction dataset. The extensive computation shows that the Radial Belief Neural Network (RBNN) is proposed to given the better performance results like Accuracy, Sensitivity, Specificity, F-measure and Execution time.

PMID: 33259890 [PubMed - as supplied by publisher]

Repeated isolation of an antibiotic-dependent and temperature-sensitive mutant of Pseudomonas aeruginosa from a cystic fibrosis patient.

J Antimicrob Chemother. 2020 Dec 01;:

Authors: Wolter DJ, Scott A, Armbruster CR, Whittington D, Edgar JS, Qin X, Buccat AM, McNamara S, Blackledge M, Waalkes A, Salipante SJ, Ernst RK, Hoffman LR

Abstract
BACKGROUND: Bacteria adapt to survive and grow in different environments. Genetic mutations that promote bacterial survival under harsh conditions can also restrict growth. The causes and consequences of these adaptations have important implications for diagnosis, pathogenesis, and therapy.
OBJECTIVES: We describe the isolation and characterization of an antibiotic-dependent, temperature-sensitive Pseudomonas aeruginosa mutant chronically infecting the respiratory tract of a cystic fibrosis (CF) patient, underscoring the clinical challenges bacterial adaptations can present.
METHODS: Respiratory samples collected from a CF patient during routine care were cultured for standard pathogens. P. aeruginosa isolates recovered from samples were analysed for in vitro growth characteristics, antibiotic susceptibility, clonality, and membrane phospholipid and lipid A composition. Genetic mutations were identified by whole genome sequencing.
RESULTS: P. aeruginosa isolates collected over 5 years from respiratory samples of a CF patient frequently harboured a mutation in phosphatidylserine decarboxylase (psd), encoding an enzyme responsible for phospholipid synthesis. This mutant could only grow at 37°C when in the presence of supplemented magnesium, glycerol, or, surprisingly, the antibiotic sulfamethoxazole, which the source patient had repeatedly received. Of concern, this mutant was not detectable on standard selective medium at 37°C. This growth defect correlated with alterations in membrane phospholipid and lipid A content.
CONCLUSIONS: A P. aeruginosa mutant chronically infecting a CF patient exhibited dependence on sulphonamides and would likely evade detection using standard clinical laboratory methods. The diagnostic and therapeutic challenges presented by this mutant highlight the complex interplay between bacterial adaptation, antibiotics, and laboratory practices, during chronic bacterial infections.

PMID: 33259594 [PubMed - as supplied by publisher]

PROBIOTICS FOR PEOPLE WITH CYSTIC FIBROSIS (REVIEW).

Gastroenterol Nurs. 2020 Nov/Dec;43(6):474-476

Authors: Weeks SM

PMID: 33259435 [PubMed - as supplied by publisher]

The Effects of Ivacaftor on Bone Density and Microarchitecture in Children and Adults with Cystic Fibrosis.

J Clin Endocrinol Metab. 2020 Dec 01;:

Authors: Putman MS, Greenblatt LB, Bruce M, Joseph T, Lee H, Sawicki G, Uluer A, Sicilian L, Neuringer I, Gordon CM, Bouxsein ML, Finkelstein JS

Abstract
CONTEXT: Cystic fibrosis transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown.
OBJECTIVE: To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF.
DESIGN: Prospective observational multiple cohort study.
SETTING: Outpatient clinical research center within a tertiary academic medical center.
PATIENTS OR OTHER PARTICIPANTS: Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within three months (Ivacaftor cohort); 26 subjects with CF were not treated with ivacaftor (CF Control cohort); and 26 healthy volunteers.
INTERVENTIONS: All treatments, including ivacaftor, were managed by the subjects' pulmonologists.
MAIN OUTCOME MEASURES: Bone microarchitecture by high resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years.
RESULTS: Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children.
CONCLUSIONS: Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.

PMID: 33258950 [PubMed - as supplied by publisher]

Stenotrophomonas maltophilia phenotypic and genotypic features through 4-year cystic fibrosis lung colonization.

J Med Microbiol. 2020 Dec 01;:

Authors: Alcaraz E, Centrón D, Camicia G, Quiroga MP, Di Conza J, Passerini de Rossi B

Abstract
Introduction. Stenotrophomonas maltophilia has emerged as one of the most common multi-drug-resistant pathogens isolated from people with cystic fibrosis (CF). However, its adaptation over time to CF lungs has not been fully established.Hypothesis. Sequential isolates of S. maltophilia from a Brazilian adult patient are clonally related and show a pattern of adaptation by loss of virulence factors.Aim. To investigate antimicrobial susceptibility, clonal relatedness, mutation frequency, quorum sensing (QS) and selected virulence factors in sequential S. maltophilia isolates from a Brazilian adult patient attending a CF referral centre in Buenos Aires, Argentina, between May 2014 and May 2018.Methodology. The antibiotic resistance of 11 S. maltophilia isolates recovered from expectorations of an adult female with CF was determined. Clonal relatedness, mutation frequency, QS variants (RpfC-RpfF), QS autoinducer (DSF) and virulence factors were investigated in eight viable isolates.Results. Seven S. maltophilia isolates were resistant to trimethoprim-sulfamethoxazole and five to levofloxacin. All isolates were susceptible to minocycline. Strong, weak and normomutators were detected, with a tendency to decreased mutation rate over time. XbaI PFGE revealed that seven isolates belong to two related clones. All isolates were RpfC-RpfF1 variants and DSF producers. Only two isolates produced weak biofilms, but none displayed swimming or twitching motility. Four isolates showed proteolytic activity and amplified stmPr1 and stmPr2 genes. Only the first three isolates were siderophore producers. Four isolates showed high resistance to oxidative stress, while the last four showed moderate resistance.Conclusion. The present study shows the long-time persistence of two related S. maltophilia clones in an adult female with CF. During the adaptation of the prevalent clones to the CF lungs over time, we identified a gradual loss of virulence factors that could be associated with the high amounts of DSF produced by the evolved isolates. Further, a decreased mutation rate was observed in the late isolates. The role of all these adaptations over time remains to be elucidated from a clinical perspective, probably focusing on the damage they can cause to CF lungs.

PMID: 33258754 [PubMed - as supplied by publisher]