Motility, Biofilm Formation and Antimicrobial Efflux of Sessile and Planktonic Cells of Achromobacter xylosoxidans.

Pathogens. 2019 Jan 27;8(1):

Authors: Nielsen SM, Penstoft LN, Nørskov-Lauritsen N

Abstract
Achromobacter xylosoxidans is an innately multidrug-resistant bacterium capable of forming biofilms in the respiratory tract of cystic fibrosis (CF) patients. During the transition from the planktonic stage to biofilm growth, bacteria undergo a transcriptionally regulated differentiation. An isolate of A. xylosoxidans cultured from the sputum of a CF patient was separated into sessile and planktonic stages in vitro, and the transcriptomes were compared. The selected genes of interest were subsequently inactivated, and flagellar motility was found to be decisive for biofilm formation in vitro. The spectrum of a new resistance-nodulation-cell division (RND)-type multidrug efflux pump (AxyEF-OprN) was characterized by inactivation of the membrane fusion protein. AxyEF-OprN is capable of extruding some fluoroquinolones (levofloxacin and ciprofloxacin), tetracyclines (doxycycline and tigecycline) and carpabenems (ertapenem and imipenem), which are classes of antimicrobials that are widely used for treatment of CF pulmonary infections.

PMID: 30691200 [PubMed]

Reply to Cooper.

J Appl Physiol (1985). 2019 Jan 01;126(1):265

Authors: Causer AJ, Shute JK, Cummings MH, Shepherd AI, Bright V, Connett G, Allenby MI, Carroll MP, Daniels T, Saynor ZL

PMID: 30694712 [PubMed - in process]

Supramax exercise testing in cystic fibrosis: not ready for prime time.

J Appl Physiol (1985). 2019 Jan 01;126(1):264

Authors: Cooper DM

PMID: 30694710 [PubMed - in process]

Cystic fibrosis in El Salvador.

Pediatr Pulmonol. 2019 Jan 29;:

Authors: Hinds DM, Sanders DB, Slaven JE, Romero M, Davis SD, Stevens JC

PMID: 30694614 [PubMed - as supplied by publisher]

Pharmacokinetic and Drug-Drug Interaction Profiles of the Combination of Tezacaftor/Ivacaftor.

Clin Transl Sci. 2019 Jan 29;:

Authors: Garg V, Shen J, Li C, Agarwal S, Gebre A, Robertson S, Huang J, Han L, Jiang L, Stephan K, Wang LT, Lekstrom-Himes J

Abstract
Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated. Effects of strong (itraconazole) and moderate (ciprofloxacin) CYP3A inhibitors on tezacaftor/ivacaftor PKs were also determined. Tezacaftor/ivacaftor increased digoxin area under the curve (AUC) by 30% but did not affect midazolam, ethinyl estradiol, or norethindrone exposures. Itraconazole increased the AUC of tezacaftor 4-fold and ivacaftor 15.6-fold. Ciprofloxacin had no significant effect on tezacaftor or ivacaftor exposure. Coadministration of tezacaftor/ivacaftor may increase exposure of sensitive P-gp substrates. Tezacaftor/ivacaftor is unlikely to impact exposure of drugs metabolized by CYP3A, including hormonal contraceptives. Strong CYP3A inhibitors significantly increase the exposures of tezacaftor and ivacaftor.

PMID: 30694595 [PubMed - as supplied by publisher]

Self-assembled peptide-poloxamine nanoparticles enable in vitro and in vivo genome restoration for cystic fibrosis.

Nat Nanotechnol. 2019 Jan 28;:

Authors: Guan S, Munder A, Hedtfeld S, Braubach P, Glage S, Zhang L, Lienenklaus S, Schultze A, Hasenpusch G, Garrels W, Stanke F, Miskey C, Johler SM, Kumar Y, Tümmler B, Rudolph C, Ivics Z, Rosenecker J

Abstract
Developing safe and efficient non-viral delivery systems remains a major challenge for in vivo applications of gene therapy, especially in cystic fibrosis. Unlike conventional cationic polymers or lipids, the emerging poloxamine-based copolymers display promising in vivo gene delivery capabilities. However, poloxamines are invalid for in vitro applications and their in vivo transfection efficiency is still low compared with viral vectors. Here, we show that peptides developed by modular design approaches can spontaneously form compact and monodisperse nanoparticles with poloxamines and nucleic acids via self-assembly. Both messenger RNA and plasmid DNA expression mediated by peptide-poloxamine nanoparticles are greatly boosted in vitro and in the lungs of cystic fibrosis mice with negligible toxicity. Peptide-poloxamine nanoparticles containing integrating vectors enable successful in vitro and in vivo long-term restoration of cystic fibrosis transmembrane conductance regulator deficiency with a safe integration profile. Our dataset provides a new framework for designing non-viral gene delivery systems qualified for in vivo genetic modifications.

PMID: 30692673 [PubMed - as supplied by publisher]

Burkholderia cepacia: An Outbreak in the Peritoneal Dialysis Unit.

Perit Dial Int. 2019 Jan-Feb;39(1):92-95

Authors: Gleeson S, Mulroy E, Bryce E, Fox S, Taylor SL, Talreja H

Abstract
Burkholderia cepacia is a ubiquitous, opportunistic, environmental gram-negative bacillus which most commonly affects cystic fibrosis and immunocompromised patients. Rarely, it can cause peritoneal dialysis (PD) exit-site infection (ESI). Information relating to predisposing factors, clinical course, and treatment options for B. cepacia ESIs is limited. Although reports of B. cepacia healthcare-associated infections exist, outbreaks in PD units have not previously been reported. A recent outbreak of B. cepacia ESI in our PD unit provided a unique opportunity to study B. cepacia ESIs and to outline an approach to investigating such an outbreak.After unexpectedly identifying B. cepacia as the cause of PD catheter ESIs in 3 patients over an 11-week period, we began systematically screening our PD population for B. cepacia exit-site colonization. A further 6 patients were found to be affected, 3 with asymptomatic colonization and 3 with symptomatic B. cepacia ESI. Four of the 6 developed tunnel infections requiring multiple courses of antibiotic treatment, and 3 patients required catheter removal; 2 patients with symptomatic ESIs without tunnel involvement responded to oral and topical antibiotics. Further investigation implicated 4% chlorhexidine aqueous bodywash used by all patients as the probable source of the outbreak.This is the first reported outbreak of B. cepacia ESIs. We noted an association between diabetes mellitus and refractory/more extensive infection. Our experience suggests that isolated ESIs can be treated successfully with oral antibiotics whereas tunnel infections generally require catheter removal.

PMID: 30692235 [PubMed - in process]

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COPD Exacerbator Phenotype is Inversely Associated with Current Smoking But Not with Haptoglobin Phenotype.

Isr Med Assoc J. 2019 Jan;21(1):19-23

Authors: Tal S, Adir Y, Stein N, Shalom H, Lache O, Levy A, Shteinberg M

Abstract
BACKGROUND: Frequent chronic obstructive pulmonary disease (COPD) exacerbators are at a higher risk of adverse health outcomes when compared to infrequent exacerbators. A COPD frequent exacerbator phenotype and its definition has been reported. Haptoglobin (Hp) polymorphism has been associated with differing clinical outcomes in cardiovascular and renal disease. The Hp 2-2 phenotype has been found to have bacteriostatic properties, while the Hp 1-1 phenotype was found to be associated with infections.
OBJECTIVES: To determine the correlation in haptoglobin phenotypes and the frequent exacerbator status compared to COPD non-exacerbators.
METHODS: Inclusion criteria included previous diagnosis of COPD and presence of at least two documented exacerbations of COPD in the previous 12 months (frequent exacerbator group) or absence of such exacerbations in the previous 24 months (non-exacerbator group). Descriptive data was analyzed using Fisher's exact test and the nonparametric Kruskal-Wallis test. Multivariate logistic regression analysis was performed.
RESULTS: The multivariate logistic regression yielded a model in which haptoglobin phenotype did not have a statistically significant association with frequent exacerbator status. Smoking status was found to be negatively related with the frequent exacerbator status (odds ratio [OR] 0.240, 95% confidence interval (95%CI) 0.068-0.843, P = 0.03). Number of pack-years was negatively related to being a frequent exacerbator (OR 0.979, 95%CI 0.962-0.996, P = 0.02).
CONCLUSIONS: We found no relationship between haptoglobin polymorphism and frequent exacerbator status. However, frequent exacerbator status had a statistically significant association with COPD Assessment Test scores and pack-years and a negative correlation with current smoking status.

PMID: 30685900 [PubMed - in process]

Metagenome - Inferred bacterial replication rates in cystic fibrosis airways.

J Cyst Fibros. 2019 Jan 23;:

Authors: Pienkowska K, Wiehlmann L, Tümmler B

Abstract
Bacterial replication rates were determined from metagenome sequencing of nasal lavage, throat swabs and induced sputa collected from healthy subjects and individuals with COPD or cystic fibrosis. More than 90% of peak-to-trough coverage ratios of major clones were above 1.4 indicating that the most abundant bacterial species in the microbial communities were replicating in the airways including common inhabitants such as Prevotella and Streptococcus species as well as the cystic fibrosis pathogens Staphylococcus aureus and Pseudomonas aeruginosa. The populations of P. aeruginosa and S. aureus were replicating their pool of chromosomes more slowly than the populations of the common inhabitants of a healthy airway microbial flora. The assessment of growth dynamics in microbial metagenomes could become a decision-making tool for the diagnosis and management of bacterial infections in cystic fibrosis.

PMID: 30685331 [PubMed - as supplied by publisher]

Corrigendum to: "Generation of two induced pluripotent stem cell (iPSC) lines from p.F508del Cystic Fibrosis patients" Stem Cell Res. 2018 May; 29:1-5.

Stem Cell Res. 2019 Jan 22;:101384

Authors: Fleischer A, Lorenzo IM, Palomino E, Aasen T, Gómez F, Servera M, Asensio VJ, Gálvez V, Izpisúa-Belmonte JC, Bachiller D

PMID: 30683491 [PubMed - as supplied by publisher]

[Multilocus sequence analysis, biofilm production, antibiotic susceptibility and synergy tests of Burkholderia species in patients with and without cystic fibrosis].

Mikrobiyol Bul. 2019 Jan;53(1):22-36

Authors: Akışoğlu Ö, Engin D, Sarıçam S, Müştak HK, Şener B, Hasçelik G

Abstract
Burkholderia spp. emerged as important pathogens in the airways of immunocompromised humans, especially those with cystic fibrosis (CF). Failure of identification with conventional techniques, high intrinsic resistance to most antibiotics and biofilm formation can cause difficulties in the treatment of these infections. The aim of this study was to identify Burkholderia spp. strains isolated from CF and non-CF patients with with routine microbiological methods, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and multilocus sequence analysis (MLSA), to determine of the antibiotic susceptibility and synergies, and to evaluate biofilm formation of these isolates. A total of 38 Burkholderia spp. (25 CF, 13 non-CF) from 26 patients were identified by biochemical, phenotypical and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and sequence types were revealed by multilocus sequence analysis (MLSA). Sequence types of isolates were identified using the PubMLST database. Characteristics of biofilm formation of clinical isolates were evaluated by microplate method. Antibiotic susceptibilities of ceftazidime, meropenem, trimethoprim-sulfamethoxazole (TMP-SXT) and levofloxacin were determined by broth microdilution method according to CLSI (2017) guidelines. Synergy tests were performed by checkerboard method. Clinical isolates were identified as Burkholderia cenocepacia (n= 16), Burkholderia contaminans (n= 11), Burkholderia gladioli (n= 4), Burkholderia dolosa (n= 4), Burkholderia multivorans (n= 2) and Burkholderia seminalis (n= 1). Sequence types of these isolates were determined as ST19, ST72, ST102, ST180, ST482, ST602, ST629, ST740, ST839 and ST1392. The correct identification at the species-level with MALDI-TOF MS was 94-100% for all isolates except B.contaminans. Biofilm formation among the identified species in the study was determined as 53% (n= 20). There was no statistical difference when the biofilm production was evaluated separately among Burkholderia species and biofilm production rates between CF (56%, 14/25) and non-CF (46%, 6/13) Burkholderia isolates (p> 0.05). Overall rates of resistance to ceftazidime, meropenem, TMP-SXT, and levofloxacin of the isolates were 35%, 66%, 50% and 40%, respectively. The antibiotic resistance against Burkholderia spp., isolates obtained from CF patients were more susceptible to ceftazidime, but no significant difference was found for other antibiotics. Synergy was determined between meropenem and TMP-SXT in two isolates. Antagonism was detected in 15 isolates, 12 of them were between meropenem and ceftazidime, three of them were between ceftazidime and TMP-SXT. Numerous resistance mechanisms may lead to higher resistance in this bacteria, whereas the antagonism between meropenem and ceftazidime in this study might be attributed to the expression of beta-lactamases. In this study, the distinctness of sequence types between Burkholderia spp. isolated from CF and non-CF patient, provided a better understanding about the importance of biofilm formation for the infections with these bacteria and emphasized that the management of therapy should be driven by the antibiotic test results.

PMID: 30683036 [PubMed - in process]

Tobramycin reduces key virulence determinants in the proteome of Pseudomonas aeruginosa outer membrane vesicles.

PLoS One. 2019;14(1):e0211290

Authors: Koeppen K, Barnaby R, Jackson AA, Gerber SA, Hogan DA, Stanton BA

Abstract
Tobramycin is commonly used to treat Pseudomonas aeruginosa lung infections in patients with Cystic Fibrosis (CF). Tobramycin treatment leads to increased lung function and fewer clinical exacerbations in CF patients, and modestly reduces the density of P. aeruginosa in the lungs. P. aeruginosa resides primarily in the mucus overlying lung epithelial cells and secretes outer membrane vesicles (OMVs) that diffuse through the mucus and fuse with airway epithelial cells, thus delivering virulence factors into the cytoplasm that modify the innate immune response. The goal of this study was to test the hypothesis that Tobramycin reduces the abundance of virulence factors in OMVs secreted by P. aeruginosa. Characterization of the proteome of OMVs isolated from control or Tobramycin-exposed P. aeruginosa strain PAO1 revealed that Tobramycin reduced several OMV-associated virulence determinants, including AprA, an alkaline protease that enhances P. aeruginosa survival in the lung, and is predicted to contribute to the inhibitory effect of P. aeruginosa on Phe508del-CFTR Cl- secretion by primary human bronchial epithelial cells. Deletion of the gene encoding AprA reduced the inhibitory effect of P. aeruginosa on Phe508del-CFTR Cl- secretion. Moreover, as predicted by our proteomic analysis, OMVs isolated from Tobramycin treated P. aeruginosa had a diminished inhibitory effect on Phe508del-CFTR Cl- secretion compared to OMVs isolated from control P. aeruginosa. Taken together, our proteomic analysis of OMVs and biological validation suggest that Tobramycin may improve lung function in CF patients infected with P. aeruginosa by reducing several key virulence factors in OMVs that reduce CFTR Cl- secretion, which is essential for bacterial clearance from the lungs.

PMID: 30682135 [PubMed - in process]

Airway Colonization by Candida and Aspergillus species in Iranian Cystic Fibrosis Patients.

Mycoses. 2019 Jan 25;:

Authors: Nasri E, Fakhim H, Vaezi A, Khalilzadeh S, Ahangarkani F, Laal Kargar M, Abtahian Z, Badali H

Abstract
Cystic fibrosis (CF) is associated with increased rates of morbidity and mortality due to fungal and bacterial colonization of the airways or respiratory infections. The prevalence of fungi in Iranian CF population has been underestimated. Therefore, the current study was conducted to define the frequency of fungi in respiratory specimens obtained from Iranian CF patients based on conventional and molecular assays. Furthermore, in vitro antifungal susceptibility testing was performed on the obtained isolates according to the guidelines from the Clinical and Laboratory Standards Institute. A cohort of 42 CF patients, including 29 males and 13 females, were categorized according to the referenced diagnostic criteria. Candida albicans (n=24, 80%), C. dubliniensis (n=2, 6.6%), C. parapsilosis (n=2, 6.6%), C. tropicalis (n=1, 3.3%), C. glabrata (n=1, 3.3%), and Meyerozyma caribbica (n=1, 3.3%) were isolated from 73.8% of the CF patients. Aspergillus terreus (n=3, 42.8%) was identified as the most common Aspergillus species, followed by A. fumigatus (n=2, 28.5%), A. oryzae (n=1, 14.2%), and A. flavus (n=1, 14.2%). Bacterial and fungal co-colonization was detected in 7 (16.6%) and 22 (52.3%) samples that were positive for Aspergillus and Candida species, respectively. However, Scedosporium species and Exophiala dermatitidis never were detected. In terms of geometric mean (GM) minimum inhibitory concentrations (MICs), posaconazole (0.018 μg/ml) and caspofungin (0.083 μg/ml) exhibited the highest antifungal activities against all Candida species. In addition, posaconazole exhibited the lowest MIC range (0.008-0.063 μg/ml) against all Aspergillus species, followed by caspofungin (0.016-0.125 μg/ml) and voriconazole (0.125-0.25 μg/ml). To conclude, it is essential to adopt a consistent method for the implementation of primary diagnosis and determination of treatment regimen for the CF patients. However, further studies are still needed to better define the epidemiology of fungal organisms in CF patients from the Middle East and the clinical significance of their isolation. This article is protected by copyright. All rights reserved.

PMID: 30681747 [PubMed - as supplied by publisher]

The Genetics of Pneumothorax.

Am J Respir Crit Care Med. 2019 Jan 25;:

Authors: Boone PM, Scott RM, Marciniak SJ, Henske EP, Raby BA

Abstract
A genetic influence on spontaneous pneumothoraces - those occurring without a traumatic or iatrogenic cause - is supported by several lines of evidence: 1) Pneumothorax can cluster in families (i.e. familial spontaneous pneumothorax); 2) Mutations in the FLCN gene have been found in both familial and sporadic cases; and 3) Pneumothorax is a known complication of several genetic syndromes. Herein we review known genetic contributions to both sporadic and familial pneumothorax. We summarize the pneumothorax-associated genetic syndromes, including Birt-Hogg-Dubé syndrome, Marfan syndrome, vascular (type IV) Ehlers-Danlos syndrome, alpha-1-antitrypsin deficiency, tuberous sclerosis complex/lymphangioleiomyomatosis (LAM), Loeys-Dietz syndrome, cystic fibrosis, homocystinuria, and cutis laxa, among others. At times, pneumothorax is their herald manifestation. These syndromes have serious potential extrapulmonary complications (e.g. malignant renal tumors in Birt-Hogg-Dubé syndrome), and surveillance and/or treatment is available for most disorders; thus, establishing a diagnosis is critical. To facilitate this, we provide an algorithm to guide the clinician in discerning which cases of spontaneous pneumothorax may have a genetic or familial contribution, which cases warrant genetic testing, and which cases should prompt an evaluation by a geneticist.

PMID: 30681372 [PubMed - as supplied by publisher]

Understanding FEV1 for the purpose of cystic fibrosis registry comparisons: Does bias in annual review FEV1 affect between-centre comparison within the UK? An analysis of registry data.

J Eval Clin Pract. 2019 Jan 25;:

Authors: Hoo ZH, Campbell MJ, Walters SJ, Wildman MJ

Abstract
RATIONALE, AIMS, AND OBJECTIVE: We previously demonstrated that annual review %FEV1 underestimates lung health of adults with CF compared with %FEV1 captured during periods of clinical stability. This has implications in the comparisons against registries with encounter-based FEV1 , such as the United States. It is uncertain whether this bias affects between-centre comparison within the United Kingdom. Previous funnel plot analyses have identified variation in annual review %FEV1 according to centre size; hence, we investigated whether paired differences between annual review and best %FEV1 also vary according to centre size.
METHODS: This registry analysis included 18 adult CF centres in the United Kingdom with ≥80% completeness for best FEV1 data in 2014. Mean discrepancy between annual review and best %FEV1 is a surrogate for the extent by which annual review %FEV1 underestimates lung health, and was plotted against centre size. A local polynomial regression (LOESS) curve was used to explore the relationship between the two variables. An appropriate model is fitted based on the LOESS curve to determine the strength of relationship between discrepancies in %FEV1 and centre size.
RESULTS: There is an inverted U-shaped relationship between mean discrepancies in %FEV1 and centre size. A regression of the paired mean difference in %FEV1 against centre size showed a significant improvement in the goodness of fit for a quadratic model (R2  = 23.8% for a quadratic model compared with 0.4% for a linear one; P = 0.048 for the quadratic term).
CONCLUSIONS: Annual review %FEV1 underestimated lung health of adults from small and large centres in the United Kingdom to a greater extent compared with medium-sized centres. A plot of %FEV1 against centre size (eg, funnel plot comparison) would be affected by systematic bias in annual review %FEV1 . Therefore, annual review %FEV1 is an unreliable metric to compare health outcomes of adult CF centres within the United Kingdom.

PMID: 30681238 [PubMed - as supplied by publisher]

Optimization of Normal Human Bronchial Epithelial (NHBE) Cell 3D Cultures for in vitro Lung Model Studies.

Sci Rep. 2019 Jan 24;9(1):500

Authors: Rayner RE, Makena P, Prasad GL, Cormet-Boyaka E

Abstract
Robust in vitro lung models are required for risk assessment to measure key events leading to respiratory diseases. Primary normal human bronchial epithelial cells (NHBE) represent a good lung model but obtaining well-differentiated 3D cultures can be challenging. Here, we evaluated the ability to expand primary NHBE cells in different culture conditions while maintaining their 3D culture characteristics such as ciliated and goblet cells, and ion channel function. Differentiated cultures were optimally obtained with PneumaCult-Ex Plus (expansion medium)/PneumaCult-ALI (differentiation medium). Primary cells passaged up to four times maintained airway epithelial characteristics as evidenced by ciliated pseudostratified columnar epithelium with goblet cells, trans-epithelial electrical resistance (TEER) (>400 Ohms.cm2), and cystic fibrosis transmembrane conductance regulator-mediated short-circuit currents (>3 µA/cm2). No change in ciliary beat frequency (CBF) or airway surface liquid (ASL) meniscus length was observed up to passage six. For the first time, this study demonstrates that CFTR ion channel function and normal epithelial phenotypic characteristics are maintained in passaged primary NHBE cells. Furthermore, this study highlights the criticality of evaluating expansion and differentiation conditions for achieving optimal phenotypic and functional endpoints (CBF, ASL, ion channel function, presence of differentiated cells, TEER) when developing in vitro lung models.

PMID: 30679531 [PubMed - in process]

Nebulized hypertonic saline triggers nervous system-mediated active liquid secretion in cystic fibrosis swine trachea.

Sci Rep. 2019 Jan 24;9(1):540

Authors: Luan X, Tam JS, Belev G, Jagadeeshan S, Murray B, Hassan N, Machen TE, Chapman LD, Ianowski JP

Abstract
Inhaled hypertonic saline (HTS) treatment is used to improve lung health in patients with cystic fibrosis (CF). The current consensus is that the treatment generates an osmotic gradient that draws water into the airways and increases airway surface liquid (ASL) volume. However, there is evidence that HTS may also stimulate active secretion of ASL by airway epithelia through the activation of sensory neurons. We tested the contribution of the nervous system and airway epithelia on HTS-stimulated ASL height increase in CF and wild-type swine airway. We used synchrotron-based imaging to investigate whether airway neurons and epithelia are involved in HTS treatment-triggered ASL secretion in CFTR-/- and wild-type swine. We showed that blocking parasympathetic and sensory neurons in airway resulted in ~50% reduction of the effect of HTS treatment on ASL volume in vivo. Incubating tracheal preparations with inhibitors of epithelial ion transport across airway decreased secretory responses to HTS treatment. CFTR-/- swine ex-vivo tracheal preparations showed substantially decreased secretory response to HTS treatment after blockage of neuronal activity. Our results indicated that HTS-triggered ASL secretion is partially mediated by the stimulation of airway neurons and the subsequent activation of active epithelia secretion; osmosis accounts for only ~50% of the effect.

PMID: 30679487 [PubMed - in process]

CyFiT telehealth: protocol for a randomised controlled trial of an online outpatient physiotherapy service for children with cystic fibrosis.

BMC Pulm Med. 2019 Jan 24;19(1):21

Authors: Lang RL, Wilson C, Stockton K, Russell T, Johnston LM

Abstract
BACKGROUND: Telehealth and telemonitoring is an emerging area of study in people with cystic fibrosis (CF), with the potential of increasing access to care, and minimising infection control risks to patients without compromising their health outcomes. To date, limited evidence is available to support the use of telehealth in paediatric population with CF in a clinical setting. This study aims to investigate the utility of a multimodal telehealth-based outpatient physiotherapy service and assess its effect on quality of life, functional exercise capacity, hospital admission and intravenous antibiotic requirements, lung function, processes of care, participation in activities of daily living, and health economics associated with operating an innovative service.
METHOD: This single centre, prospective, parallel, randomised, controlled, non-inferiority trial aims to recruit 110 children with CF between the ages 8 to 18 years of age. Participants will be randomised to the Usual Outpatient Physiotherapy Service group (Usual OPS) or the telehealth intervention group (CyFiT OPS). Quality of life, participation in activity of daily living, functional exercise capacity and patient perception of care will be examined every six months using the Cystic Fibrosis Questionnaire-Revised (CFQ-R), Children's Assessment of Participation and Enjoyment (CAPE), Preferences for Activities of Children (PAC) questionnaire, Modified Shuttle Test-25 (MST25), and Measure of Process of Care (MPOC-20) questionnaire. Physiological measurements collected during routine clinical visits such as spirometry, body weight and height, information will be retrospectively retrieved via a chart review at the end of the study.
DISCUSSION: We anticipate that this multi-modal telehealth service will deliver a comparable service to traditional face-to-face models. An alternative to existing outpatient physiotherapy services may potentially increase patient options for access to care and patient-orientated outcomes such as quality of life. If deemed appropriate, the new model of care can be integrated into clinical practice immediately.
TRIAL REGISTRATION: This trial is registered with the Australian and New Zealand Clinical Trial Registry ( ACTRN12617001035314 ) last updated 17th July 2018.

PMID: 30678670 [PubMed - in process]

Repairing folding-defective α-sarcoglycan mutants by CFTR correctors, a potential therapy for limb-girdle muscular dystrophy 2D.

Hum Mol Genet. 2018 03 15;27(6):969-984

Authors: Carotti M, Marsolier J, Soardi M, Bianchini E, Gomiero C, Fecchio C, Henriques SF, Betto R, Sacchetto R, Richard I, Sandonà D

Abstract
Limb-girdle muscular dystrophy type 2D (LGMD2D) is a rare autosomal-recessive disease, affecting striated muscle, due to mutation of SGCA, the gene coding for α-sarcoglycan. Nowadays, more than 50 different SGCA missense mutations have been reported. They are supposed to impact folding and trafficking of α-sarcoglycan because the defective polypeptide, although potentially functional, is recognized and disposed of by the quality control of the cell. The secondary reduction of α-sarcoglycan partners, β-, γ- and δ-sarcoglycan, disrupts a key membrane complex that, associated to dystrophin, contributes to assure sarcolemma stability during muscle contraction. The complex deficiency is responsible for muscle wasting and the development of a severe form of dystrophy. Here, we show that the application of small molecules developed to rescue ΔF508-CFTR trafficking, and known as CFTR correctors, also improved the maturation of several α-sarcoglycan mutants that were consequently rescued at the plasma membrane. Remarkably, in myotubes from a patient with LGMD2D, treatment with CFTR correctors induced the proper re-localization of the whole sarcoglycan complex, with a consequent reduction of sarcolemma fragility. Although the mechanism of action of CFTR correctors on defective α-sarcoglycan needs further investigation, this is the first report showing a quantitative and functional recovery of the sarcoglycan-complex in human pathologic samples, upon small molecule treatment. It represents the proof of principle of a pharmacological strategy that acts on the sarcoglycan maturation process and we believe it has a great potential to develop as a cure for most of the patients with LGMD2D.

PMID: 29351619 [PubMed - indexed for MEDLINE]