Image-based β-adrenergic sweat rate assay captures minimal cystic fibrosis transmembrane conductance regulator function.

Pediatr Res. 2019 Jul 25;:

Authors: Salinas DB, Peng YH, Horwich B, Wee CP, Frisbee E, Maarek JM

Abstract
BACKGROUND: There is a need to prognosticate the severity of cystic fibrosis (CF) detected by newborn screening (NBS) by early assessment of CF transmembrane conductance regulator (CFTR) protein function. We introduce novel instrumentation and protocol for evaluating CFTR activity as reflected by β-adrenergically stimulated sweat secretion.
METHODS: A pixilated image sensor detects sweat rates. Compounds necessary for maximum sweat gland stimulation are applied by iontophoresis, replacing ID injections. Results are compared to a validated β-adrenergic assay that measures sweat secretion by evaporation (evaporimetry).
RESULTS: Ten healthy controls (HCs), 6 heterozygous (carriers), 5 with CF screen-positive, inconclusive diagnosis (CFSPID), and 12 CF individuals completed testing. All individuals with minimal and residual function CFTR mutations had low ratios of β-adrenergically stimulated sweat rate to cholinergically stimulated sweat rate (β/chol) as measured by either assay.
CONCLUSIONS: β-Adrenergic assays quantitate CFTR dysfunction in the secretory pathway of sweat glands in CF and CFTR-related metabolic syndrome (CRMS)/CFSPID populations. This novel image-sensor and iontophoresis protocol detect CFTR function with minimal and residual function and is a feasible test for young children because it is insensible to movement and it decreases the number of injections. It may also assist to distinguish between CF and CRMS/CFSPID diagnosis.

PMID: 31344706 [PubMed - as supplied by publisher]

Ursodeoxycholic acid inhibits ENaC and Na/K pump activity to restore airway surface liquid height in cystic fibrosis bronchial epithelial cells.

Steroids. 2019 Jul 22;:108461

Authors: Mroz MS, Harvey BJ

Abstract
Cystic fibrosis (CF) is a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that in the airways result in reduced Cl- secretion and increased Na+ absorption, airway surface liquid (ASL) dehydration, decreased mucociliary clearance, infection and inflammation leading to lung injury. Cystic fibrosis patients often present with bile acids in the lower airways, however the effects of bile acids on ASL and ion transport in CF airways are not known. Secondary bile acids, such as ursodeoxycholic acid (UDCA), have been shown to modulate immune responses and epithelial ion transport. Here we investigated the effects of UDCA in normal and CF airway epithelial cell models. NuLi-1 (normal genotype) and CuFi-1 (CF genotype, Δ508/Δ508) primary immortalized airway epithelial cells were grown under an air-liquid interface. Electrogenic transepithelial ion transport was measured by short-circuit current (Isc) across cell monolayers mounted in Ussing chambers. We observed that UDCA (500 μM, 60 min, bilateral) decreased the basal Isc and ENaC currents in both NuLi-1 and CuFi-1 cells. UDCA inhibited the amiloride-sensitive ENaC current by 44% in NulI-1 monolayers and by 30% in CuFi-1 cells. Interestingly, UDCA also inhibited currents through the basolateral Na/K pump in both Nuli-1 and CuFi-1 monolayers without alterting the expression of ENaC or Na+/K+-ATPase proteins. The airway surface liquid height is regulated by transpeithelial Na+ absorption (ENaC) and Cl- secretion (CFTR) in normal airway but mainly by ENaC activity in CF epithelia when Cl- secretion is compromised by CFTR mutations. UDCA increased ASL height by 50% in Nuli-1 and by 40% in CUFI-1 monolayers. In conclusion, we demonstrate a previously unknown effect of UDCA to inhibit ENaC activity and increase ASL height in normal and CF human airway epithelial cells suggesting a therapeutic potential for UDCA in CF lung disease.

PMID: 31344409 [PubMed - as supplied by publisher]

Exposure of P​seudomonas aeruginosa to bactericidal hypochlorous acid during neutrophil phagocytosis is compromised in cystic fibrosis.

J Biol Chem. 2019 Jul 24;:

Authors: Dickerhof N, Isles V, Pattemore P, Hampton MB, Kettle AJ

Abstract
Myeloperoxidase is a major neutrophil antimicrobial protein, but its role in immunity is often overlooked because individuals deficient in this enzyme are usually in good health. Within neutrophil phagosomes, myeloperoxidase uses superoxide generated by the NADPH oxidase to oxidize chloride to the potent bactericidal oxidant hypochlorous acid (HOCl). In this study, using phagocytosis assays and LC-MS analyses, we monitored glutathione oxidation in Pseudomonas aeruginosa to gauge their exposure to HOCl inside phagosomes. Doses of reagent HOCl that killed most of the bacteria oxidized half the cells' glutathione, producing mainly glutathione disulfide (GSSG) and other low-molecular-weight disulfides. Glutathione sulfonamide, a HOCl-specific product, was also formed. When neutrophils phagocytosed P. aeruginosa, half of the bacterial glutathione was lost. Bacterial glutathione sulfonamide production indicated that HOCl had reacted with the bacterial cells, oxidized their glutathione, and was sufficient to be solely responsible for bacterial killing. Inhibition of NADPH oxidase and myeloperoxidase lowered glutathione sulfonamide formation in the bacterial cells, but the bacteria were still killed, presumably by compensatory non-oxidative mechanisms. Of note, bacterial glutathione sulfonamide formation in neutrophils from patients with cystic fibrosis (CF) was normal during early phagocytosis, but was diminished at later time points, mirrored by a small decrease in bacterial killing. In conclusion, myeloperoxidase generates sufficient HOCl within neutrophil phagosomes to kill ingested bacteria. The unusual kinetics of phagosomal HOCl production in CF neutrophils confirm a role for the cystic fibrosis transmembrane conductance regulator (CFTR) in maintaining HOCl production in neutrophil phagosomes.

PMID: 31341024 [PubMed - as supplied by publisher]

SENSITIZATION TO ASPERGILLUS FUMIGATUS IN FIBROCYSTICS.

Rev Paul Pediatr. 2018 Jul-Sep;36(3):382

Authors: Rosario NA, Riedi CA

PMID: 30365816 [PubMed - indexed for MEDLINE]

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Comment on: In vitro activity of seven β-lactams including ceftolozane/tazobactam and ceftazidime/avibactam against Burkholderia cepacia complex, Burkholderia gladioli and other non-fermentative Gram-negative bacilli isolated from cystic fibrosis patients.

J Antimicrob Chemother. 2019 Jul 23;:

Authors: Baklouti S, Massip C, Mane C, Guet-Revillet H, Murris M, Concordet D, Gandia P

PMID: 31335940 [PubMed - as supplied by publisher]

Niflumic Acid Reverses Airway Mucus Excess and Improves Survival in the Rat Model of Steroid-Induced Pneumocystis Pneumonia.

Front Microbiol. 2019;10:1522

Authors: Pérez FJ, Iturra PA, Ponce CA, Magne F, Garcia-Angulo V, Vargas SL

Abstract
Although the role of adaptive immunity in fighting Pneumocystis infection is well known, the role of the innate, airway epithelium, responses remains largely unexplored. The concerted interaction of innate and adaptive responses is essential to successfully eradicate infection. Increased expression of goblet-cell-derived CLCA1 protein plus excess mucus in infant autopsy lungs and in murine models of primary Pneumocystis infection alert of innate immune system immunopathology associated to Pneumocystis infection. Nonetheless, whether blocking mucus-associated innate immune pathways decreases Pneumocystis-related immunopathology is unknown. Furthermore, current treatment of Pneumocystis pneumonia (PcP) relying on anti-Pneumocystis drugs plus steroids is not ideal because removes cellular immune responses against the fungal pathogen. In this study, we used the steroid-induced rat model of PcP to evaluate inflammation and mucus progression, and tested the effect of niflumic acid (NFA), a fenamate-type drug with potent CLCA1 blocker activity, in decreasing Pneumocystis-associated immunopathology. In this model, animals acquire Pneumocystis spontaneously and pneumonia develops owing to the steroids-induced immunodeficiency. Steroids led to decreased animal weight evidencing severe immunosuppression and to significant Pneumocystis-associated pulmonary edema as evidenced by wet-to-dry lung ratios that doubled those of uninfected animals. Inflammatory cuffing infiltrates were noticed first around lung blood vessels followed by bronchi, and both increased progressively. Similarly, airway epithelial and lumen mucus progressively increased. This occurred in parallel to increasing levels of MUC5AC and mCLCA3, the murine homolog of hCLCA1. Administration of NFA caused a significant decrease in total mucus, MUC5AC and mCLCA3 and also, in Pneumocystis-associated inflammation. Most relevant, NFA treatment improved survival at 8 weeks of steroids. Results suggest an important role of innate immune responses in immunopathology of steroid-induced PcP. They warrant evaluation of CLCA1 blockers as adjunctive therapy in this condition and describe a simple model to evaluate therapeutic interventions for steroid resistant mucus, a common condition in patients with chronic lung disease like asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis.

PMID: 31333624 [PubMed]

Draft genome and description of Chryseobacterium phocaeense sp. nov.: a new bacterial species isolated from the sputum of a cystic fibrosis patient.

Arch Microbiol. 2019 Jul 22;:

Authors: Abou Abdallah R, Okdah L, Bou Khalil J, Anani H, Fournier PE, Raoult D, Bittar F

Abstract
Strain 6021061333T was isolated from the sputum of 16-year-old girl with cystic fibrosis following a pulmonary exacerbation. This bacterial strain could not be identified by our systematic MALDI-TOF mass spectrometry screening on a MicroFlex. This led to the sequencing of the 16S rRNA gene, which shows 97.83% sequence identity with Chryseobacterium kwangjuense strain KJ1R5T, the phylogenetic closely related type strain of a species with standing in nomenclature, which putatively classifies it as a new species. Colonies are yellow, circular and 0.5-1 mm in diameter after cultivation at 28 °C for 24 h on 5% sheep blood-enriched Colombia agar. Growth occurs at temperatures in the range of 28-37 °C (optimally at 28 °C). Strain 6021061333T is Gram-negative, non-motile and strictly aerobic bacillus. It is catalase and oxidase positive. The 4,864,678 bp-long genome, composed of five contigs, has a G+C content of 38.86%. Out of the 4427 predicted genes, 4342 were protein-coding genes and 85 were RNAs. The major fatty acids are branched (13-methyl-tetradecanoic acid and 15-methyl-hexadecenoic acid). Digital DNA-DNA hybridization (dDDH) estimation and average nucleotide identity (ANI) of the strain 6021061333T against genomes of the type strains of related species ranged between 23.60 and 50.40% and between 79.31 and 93.06%, respectively. According to our taxonogenomics results, we propose the creation of Chryseobacterium phocaeense sp. nov. that contains the type strain 6021061333T (= CSUR P2660, = CECT 9670).

PMID: 31332473 [PubMed - as supplied by publisher]

Advances In Gene Therapy For Cystic Fibrosis Lung Disease.

Hum Mol Genet. 2019 Jul 23;:

Authors: Yan Z, McCray PB, Engelhardt JF

Abstract
Cystic fibrosis (CF) is a multi-organ recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Gene therapy efforts have focused on treating the lung, since it manifests the most significant life-threatening disease. Over two decades have past since the first CF lung gene therapy trials and significant advances in the therapeutic implementation of pharmacologic CFTR modulators have renewed the field's focus on developing gene therapies for the 10% of CF patients these modulators cannot help. This review summarizes recent progress made in developing vectors for airway transduction and CF animal models required for understanding the relevant cellular targets in the lung and testing the efficacy of gene therapy approaches. We also highlight future opportunities in emerging gene editing strategies that may offer advantages for treating diseases like CF where the gene target is highly regulated at the cellular level. The outcomes of CF lung gene therapy trials will likely inform productive paths towards gene therapy for other complex genetic disorders, while also advancing treatments for all CF patients.

PMID: 31332440 [PubMed - as supplied by publisher]

Magnetic microboats for floating, stiffness tunable, air-liquid interface epithelial cultures.

Lab Chip. 2019 Jul 23;:

Authors: Chandrasekaran A, Kouthouridis S, Lee W, Lin N, Ma Z, Turner MJ, Hanrahan JW, Moraes C

Abstract
To study respiratory diseases, in vitro airway epithelial models are commonly implemented by culturing airway cells on a porous surface at an air-liquid interface (ALI). However, these surfaces are often supraphysiologically stiff, which is known to affect the organization, maturation, and responses of cells to potential therapies in other biological culture models. While it is possible to culture cells on soft hydrogel substrates at an air-liquid interface, these techniques are challenging to implement particularly in high-throughput applications which require robust and repetitive material handling procedures. To address these two limitations and characterize epithelial cultures on substrates of varying stiffness at the ALI, we developed a novel "lung-on-a-boat", in which stiffness-tuneable hydrogels are integrated into the bottoms of polymeric microstructures, which normally float at the air-liquid interface. An embedded magnetic material can be used to sink the boat on demand when a magnetic field is applied, enabling reliable transition between submerged and ALI culture. In this work, we prototype a functional ALI microboat platform, with integrated stiffness-tunable polyacrylamide hydrogel surfaces, and validate the use of this technology with a model epithelial cell line. We verify sufficient transport through the hydrogel base to maintain cell viability and stimulate cultures, using a model nanoparticle with known toxicity. We then demonstrate significant morphological and functional effects on epithelial barrier formation, suggesting that substrate stiffness is an important parameter to consider in the design of in vitro epithelial ALI models for drug discovery and fundamental research.

PMID: 31332423 [PubMed - as supplied by publisher]

Nasal potential difference in suspected cystic fibrosis patients with 5T polymorphism.

J Cyst Fibros. 2019 Jul 19;:

Authors: Aalbers BL, Yaakov Y, Derichs N, Simmonds NJ, De Wachter E, Melotti P, De Boeck K, Leal T, Tümmler B, Wilschanski M, Bronsveld I

Abstract
BACKGROUND: 5T polymorphism is a CFTR mutation with unclear clinical consequences: the phenotype varies from healthy individuals to Cystic Fibrosis (CF). The aim of this study was to evaluate if nasal potential difference (NPD) and sweat testing correlate with symptoms and CF diagnosis in 5T patients.
METHODS: 86 patients with 5T who had undergone NPD measurement, were included (6 homozygous (5T/5T), 41 with a PI-CF causing mutation in trans (5T/PI-CF), 11 with a PS-CF causing mutation in trans (5T/PS-CF) and 28 without a known mutation in trans (5T/?). Data including age, phenotype, sweat chloride and follow up were collected.
RESULTS: 33% of the 5T/5T patients had abnormal NPD results, compared to 70% in 5T/PI-CF; 33% in 5T/PS-CF and 29% in 5T/?. The percentage of high or borderline sweat chloride was highest in 5T/PI-CF, and 5T/?, compared to 5T/5T and 5T/PS-CF (91, 96, 80, and 63%, respectively). TGm (number of TG repeats in intron 8) analysis was performed in 21 5T/PI-CF patients. TG11 was associated with lower sweat chloride, lower percentage of abnormal NPD and less progression of symptoms compared to TG12 and TG13.
CONCLUSION: There is much variation in clinical status among 5T patients. All patients in this study with 5T/PS CF, all patients with both normal NPD and sweat test, and most patients with TG11 were stable or improving over time. Therefore, NPD measurement and TGm status aid to assess if a patient is at high risk for developing CF or CFTR-related disease and if specific follow up in a CF center is required.

PMID: 31331863 [PubMed - as supplied by publisher]

Extract from Coriolus versicolor fungus partially prevents endotoxin tolerance development by maintaining febrile response and increasing IL-6 generation.

J Therm Biol. 2019 Jul;83:69-79

Authors: Jędrzejewski T, Piotrowski J, Pawlikowska M, Wrotek S, Kozak W

Abstract
Endotoxin tolerance is defined as a reduced endotoxin-induced fever following repeated injections of lipopolysaccharide (LPS). Clinical examples of endotoxin tolerance include sepsis or cystic fibrosis. This state is characterized by inhibition of pro-inflammatory cytokines production and decrease in nuclear factor-kappa B (NF-κB) activation. Extract from Coriolus versicolor (CV) fungus is classified as a biological response modifier, which exhibits various biological activities, including immunopotentiating properties. The aim of study was to examine the effect of CV extract injection on body core temperature of Wistar rats during LPS-induced endotoxin tolerance. Body temperature was measured using biotelemetry. CV extract was injected intraperitoneally (100 mg kg-1) 2 h prior to the first LPS peritoneal administration (50 μg/kg). Endotoxin tolerance was induced by three consecutive daily injections of LPS at the same dose. We also investigated the influence of CV extract pre-injection on the properties of peripheral blood mononuclear cells (PBMCs) isolated from LPS-treated rats in response to LPS stimulation ex vivo. PBMCs were isolated 2 h after the first LPS injection. After 24 h pre-incubation, the cells were stimulated with LPS (1 μg ml-1) for 4 h. Our results revealed that CV extract partially prevents endotoxin tolerance through maintaining febrile response in rats following consecutive exposure to LPS. This state was accompanied by the ability of PBMCs isolated from rats injected with CV extract and LPS to release larger amounts of interleukin 6 and greater NF-κB activation in response to LPS stimulation ex vivo compared with the cells derived from rats injected only with LPS. Data also showed that CV extract augmented mitogenic effect of LPS on PBMCs and caused increase in reactive oxygen species generation. We concluded that CV extract, by a modifying effect on body temperature during endotoxin tolerance, can be consider as the immunostimulating agent, which prevents the non-specific refractoriness described in patients with sepsis or ischemia.

PMID: 31331527 [PubMed - in process]

Inhaled Antibiotics for Mycobacterial Lung Disease.

Pharmaceutics. 2019 Jul 19;11(7):

Authors: Banaschewski B, Hofmann T

Abstract
Mycobacterial lung diseases are an increasing global health concern. Tuberculosis and nontuberculous mycobacteria differ in disease severity, epidemiology, and treatment strategies, but there are also a number of similarities. Pathophysiology and disease progression appear to be relatively similar between these two clinical diagnoses, and as a result these difficult to treat pulmonary infections often require similarly extensive treatment durations of multiple systemic drugs. In an effort to improve treatment outcomes for all mycobacterial lung diseases, a significant body of research has investigated the use of inhaled antibiotics. This review discusses previous research into inhaled development programs, as well as ongoing research of inhaled therapies for both nontuberculous mycobacterial lung disease, and tuberculosis. Due to the similarities between the causative agents, this review will also discuss the potential cross-fertilization of development programs between these similar-yet-different diseases. Finally, we will discuss some of the perceived difficulties in developing a clinically utilized inhaled antibiotic for mycobacterial diseases, and potential arguments in favor of the approach.

PMID: 31331119 [PubMed]

Enteral tube feeding for cystic fibrosis.

Cochrane Database Syst Rev. 2019 Jul 22;7:CD001198

Authors: Shimmin D, Lowdon J, Remmington T

Abstract
BACKGROUND: Enteral tube feeding is routinely used in many cystic fibrosis centres when oral dietary and supplement intake has failed to achieve an adequate nutritional status. The use of this method of feeding is assessed on an individual basis taking into consideration the patients age and clinical status. This is a final update of a previously published review.
OBJECTIVES: To examine the evidence that in people with cystic fibrosis, supplemental enteral tube feeding improves nutritional status, respiratory function, and quality of life without significant adverse effects.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also contacted the companies that market enteral feeds and reviewed their databases.Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 10 July 2019.Date of the most recent hand search of PubMed: 26 October 2018.
SELECTION CRITERIA: All randomised controlled trials comparing supplemental enteral tube feeding for one month or longer with no specific intervention in people with cystic fibrosis.
DATA COLLECTION AND ANALYSIS: The searches identified 44 trials; however, none were eligible for inclusion in this review.
MAIN RESULTS: There are no trials included in this review.
AUTHORS' CONCLUSIONS: Supplemental enteral tube feeding is widely used throughout the world to improve nutritional status in people with cystic fibrosis. The methods mostly used, nasogastric or gastrostomy feeding, are expensive and may have a negative effect on self-esteem and body image. Reported use of enteral tube feeding suggests that it results in nutritional and respiratory improvement; but, efficacy has not been fully assessed by randomised controlled trials. It is acknowledged, however, that performing a randomised controlled trial would be difficult due to the ethics of withholding an intervention in a group of people whose nutritional status necessitates it.

PMID: 31328789 [PubMed - as supplied by publisher]

Pancreatic insufficiency converted to pancreatic sufficiency with ivacaftor.

Pediatr Pulmonol. 2019 Jul 21;:

Authors: Hamilton JL, Zobell JT, Robson J

PMID: 31328424 [PubMed - as supplied by publisher]

Should isolated Pseudo-Bartter syndrome be considered a CFTR-related disorder of infancy?

Pediatr Pulmonol. 2019 Jul 21;:

Authors: Poli P, De Rose DU, Timpano S, Savoldi G, Padoan R

Abstract
BACKGROUND: Infants that are negative to cystic fibrosis (CF) newborn screening (NBS) programs, or in countries without NBS, may present with metabolic alkalosis and severe salt depletion, a well-known clinical manifestation of CF termed Pseudo-Bartter syndrome (PBS). Here, we report the cases of three CF-negative children, who carry rare mutations in the CF transmembrane conductance regulator (CFTR) gene, and, for whom, PBS was the only manifestation of CFTR protein dysfunction. There is no diagnostic label for these cases.
METHODS: Medical records of patients followed at our Cystic Fibrosis Centre were revised and data were collected for all patients who presented with an isolated PBS. The syndrome was defined as an episode of dehydration with low levels of serum sodium (<134mmol/L), potassium ( <3.4mmol/L), and chloride ( <100mmol/L), with metabolic alkalosis (bicarbonatemia >27mmol/L) in the absence of renal tubulopathy.
RESULTS: Three out of 73 (4%) CF infants presented with a severe metabolic alkalosis with salt depletion; two of these required admission to the intensive care unit. Two infants had a negative NBS, and one was identified as a CF carrier. Sweat test was repeatedly in the negative/borderline ranges for all patients. Less than two CF causing mutations were identified (F508del/R1070W, F508del; L467F/P5L, R1066H/P5L). During a mean follow-up of 9 years, the children had no other CF manifestations.
CONCLUSION: We suggest that PBS as the sole manifestation of CFTR dysfunction might be considered a CFTR-related disorder of infancy.

PMID: 31328366 [PubMed - as supplied by publisher]

Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis.

J Cyst Fibros. 2019 Jul 18;:

Authors: Singh S, Hornick D, Fedler J, Launspach JL, Teresi ME, Santacroce TR, Cavanaugh JE, Horan R, Nelson G, Starner TD, Zabner J, Durairaj L

Abstract
BACKGROUND: Cystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and recurrent pulmonary exacerbations. Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration and augment innate immunity. We examined the safety and efficacy of aerosolized xylitol use for 2 weeks in subjects hospitalized with a pulmonary exacerbation of CF.
METHODS: In a 2-week study, 60 subjects with cystic fibrosis and FEV1 > 30% predicted were enrolled to receive aerosolized 7% hypertonic saline (4 ml) or 15% xylitol (5 ml) twice a day for 14 days. Outcomes assessed included change from baseline in FEV1% predicted, change in sputum microbial density, revised CF quality of life questionnaire including the respiratory symptom score, time to next hospitalization for a pulmonary exacerbation, and frequency of adverse events.
RESULTS: 59 subjects completed the study (one subject in the saline group withdrew before any study product administration). No significant differences were noted between the 2 arms in mean changes in lung function, sputum microbial density for Pseudomonas aeruginosa and Staphylococcus aureus, body weight, quality of life, and frequency of adverse events.
CONCLUSIONS: Aerosolized hypertonic xylitol was well-tolerated among subjects hospitalized for CF pulmonary exacerbation. Future studies examining efficacy for long term use in patients with CF lung disease would be worthwhile. The clinical trial registration number for this study is NCT00928135.

PMID: 31327670 [PubMed - as supplied by publisher]

Healthcare transition for adolescents and young adults with long-term conditions: Qualitative study of patients, parents and healthcare professionals' experiences.

J Clin Nurs. 2019 Jul 20;:

Authors: Coyne I, Sheehan A, Heery E, While AE

Abstract
AIM AND OBJECTIVES: To examine the needs and perspectives regarding healthcare transition for adolescents and young adults with the following long-term conditions: diabetes, cystic fibrosis, and congenital heart disease.
BACKGROUND: Transition of adolescents and young adults within healthcare services has become increasingly important as more children are surviving into adulthood with long-term conditions. Yet limited empirical evidence exists regarding transition experiences.
DESIGN: Qualitative study fulfilling the completed consolidated criteria for reporting qualitative studies (COREQ) criteria (see supplementary File 1).
METHODS: Semi-structured interviews with adolescents and young adults aged 14-25 years (n=47), parents (n=37) and health professionals (n=32) which was part of a larger mixed-methods study. Sample was recruited from two children's hospitals and four general hospitals in Ireland.
RESULTS: Transfer occurred between the ages of 16 to early 20s years depending on the service. None of the hospitals had a transition policy and transition practices varied considerably. Adolescents worried about facing the unknown, communicating and trusting new staff and self-management. The transition process was smooth for some young adults, whilst others experienced a very abrupt transfer. Parents desired greater involvement in the transition process with some perceiving a lack of recognition of the importance of their role. In paediatric services, nurses reported following-up adolescents who struggled with treatment adherence and clinic attendance. Whereas after transfer, little effort was made to engage young adults if there were lapses in care, as this was generally considered the young adults' prerogative.
CONCLUSIONS: The amount of preparation and the degree to which the shift in responsibility had occurred prior to transition appeared to influence successful transition for adolescents and young adults and their parents.
RELEVANCE TO CLINICAL PRACTICE: Nurses in collaboration with the multidisciplinary team can help adolescents and young adults develop their self-management skills and guide parents on how to relinquish responsibility gradually prior to transition. This article is protected by copyright. All rights reserved.

PMID: 31327174 [PubMed - as supplied by publisher]

Discovering the chloride pathway in the CFTR channel.

Cell Mol Life Sci. 2019 Jul 20;:

Authors: Farkas B, Tordai H, Padányi R, Tordai A, Gera J, Paragi G, Hegedűs T

Abstract
Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

PMID: 31327045 [PubMed - as supplied by publisher]

Australian adults with bronchiectasis: The first report from the Australian Bronchiectasis Registry.

Respir Med. 2019 Jul 16;155:97-103

Authors: Visser SK, Bye PTP, Fox GJ, Burr LD, Chang AB, Holmes-Liew CL, King P, Middleton PG, Maguire GP, Smith D, Thomson RM, Stroil-Salama E, Britton WJ, Morgan LC

Abstract
BACKGROUND: /objective: There are no large, multi-centre studies of Australians with bronchiectasis. The Australian Bronchiectasis Registry (ABR) was established in 2015 to create a longitudinal research platform. We aimed to describe the baseline characteristics of adult ABR participants and assess the impact of disease severity and exacerbation phenotype on quality of life (QoL).
METHODS: The ABR is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis. We analysed the baseline data of adult patients (≥18 years).
RESULTS: From March 2016-August 2018, 799 adults were enrolled from 14 Australian sites. Baseline data were available for 589 adults predominantly from six tertiary centres (420 female, median age 71 years (interquartile range 64-77), 14% with chronic Pseudomonas aeruginosa infection). Most patients had moderate or severe disease based on the Bronchiectasis Severity Index (BSI) (84%) and FACED (59%) composite scores. Using Global Lung function Initiative-2012 reference equations, the majority of patients (48%) had normal spirometry; only 34% had airflow obstruction (FEV1/FVC < LLN). Disease severity scores (BSI and FACED) were negatively correlated with QoL-Bronchiectasis domain scores (rs between -0.09 and -0.58). The frequent exacerbator phenotype (≥3 in the preceding year) was identified in 23%; this group had lower scores in all QoL-B domains (p ≤ 0.001) and more hospitalisations (p < 0.001) than those with <3 exacerbations.
CONCLUSIONS: The largest cohort of Australian adults with bronchiectasis has been described. Using contemporary criteria, most patients with bronchiectasis did not have airflow obstruction. The frequent exacerbation trait connotes poorer QoL and greater health-care utilisation.

PMID: 31326739 [PubMed - as supplied by publisher]