TMEM16A chloride channel does not drive mucus production.

Life Sci Alliance. 2019 Dec;2(6):

Authors: Simões FB, Quaresma MC, Clarke LA, Silva IA, Pankonien I, Railean V, Kmit A, Amaral MD

Abstract
Airway mucus obstruction is the main cause of morbidity in cystic fibrosis, a disease caused by mutations in the CFTR Cl- channel. Activation of non-CFTR Cl- channels such as TMEM16A can likely compensate for defective CFTR. However, TMEM16A was recently described as a key driver in mucus production/secretion. Here, we have examined whether indeed there is a causal relationship between TMEM16A and MUC5AC production, the main component of respiratory mucus. Our data show that TMEM16A and MUC5AC are inversely correlated during differentiation of human airway cells. Furthermore, we show for the first time that the IL-4-induced TMEM16A up-regulation is proliferation-dependent, which is supported by the correlation found between TMEM16A and Ki-67 proliferation marker during wound healing. Consistently, the notch signaling activator DLL4 increases MUC5AC levels without inducing changes neither in TMEM16A nor in Ki-67 expression. Moreover, TMEM16A inhibition decreased airway surface liquid height. Altogether, our findings demonstrate that up-regulation of TMEM16A and MUC5AC is only circumstantial under cell proliferation, but with no causal relationship between them. Thus, although essential for airway hydration, TMEM16A is not required for MUC5AC production.

PMID: 31732694 [PubMed - in process]

Burkholderia cenocepacia ET12 transmission in adults with cystic fibrosis.

Thorax. 2019 Nov 15;:

Authors: Blanchard AC, Tang L, Tadros M, Muller M, Spilker T, Waters VJ, LiPuma JJ, Tullis E

Abstract
This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.

PMID: 31732688 [PubMed - as supplied by publisher]

Acute kidney injury as the presenting complaint of ceftazidime-induced immune-mediated haemolysis.

BMJ Case Rep. 2019 Nov 14;12(11):

Authors: Ferro A, Griffiths M, Smith R, Fry A

Abstract
We present the case of ceftazidime-induced immune-mediated haemolysis with associated acute kidney injury in a 43-year-old woman. The patient initially presented to the regional cystic fibrosis centre for treatment of an infective exacerbation of cystic fibrosis. After initiation of ceftazidime (a third-generation cephalosporin), renal function rapidly deteriorated and a fall in haemoglobin was noted. On transfer to our care, a haemolysis screen identified immune-mediated haemolysis, and renal biopsy confirmed the finding of acute tubular necrosis secondary to haem pigment. The patient's renal function deteriorated such that she required haemodialysis, although she subsequently recovered and is now dialysis-independent. Although acute haemolytic reactions are recognised with third-generation cephalosporins, this is the first reported case of ceftazidime-induced immune-mediated haemolysis with acute kidney injury. Given the increased frequency of cephalosporin usage, it is important for both nephrologists and general physicians to be aware of this rare but very serious complication.

PMID: 31732539 [PubMed - in process]

The Sixty-five Roses of Cystic Fibrosis: A Report of Two Autopsy Cases with Kidney Involvement.

Cureus. 2019 Sep 13;11(9):e5641

Authors: Stoyanov GS, Popov H, Petkova L, Dzhenkov DL

Abstract
Cystic fibrosis (CF), also commonly referred to as mucoviscidosis, is a multigene related disorder, involving a defect in the CF transmembrane conductance regulator protein, with over 1,500 genes, being identified with the condition. The most commonly affected organs, often described in the literature, are the lungs, pancreas, intestines, and skin, which is one of the sites for early diagnostic testing. Herein we report two autopsy cases of CF, with multiorgan involvement and some rarely observed and reported changes. Two pediatric cases of clinically confirmed CF were referred for autopsy at the Department of General and Clinical Pathology, St. Marina University Hospital, Varna, Bulgaria. The first case was of a one-year-old female and the second of a six-month-old female. Both cases had classical CF-associated changes in the lungs, liver, pancreas, and small intestine. The kidneys although normal on gross inspection also had severe changes on histology with a compacted matter in the lumen of the distal tubules, some of which had undergone calcification. These histological renal changes are under-reported in literature, thus unlike the classical reported cystic changes we highlight lumen compaction and calcification as the primary histological hallmark in kidneys of patients with CF.

PMID: 31728230 [PubMed]

Multi-Target CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach.

J Med Chem. 2019 Nov 15;:

Authors: Tassini S, Langron E, Delang L, Mirabelli C, Lanko K, Crespan E, Kissova M, Tagliavini G, Fontò G, Bertoni S, Palese S, Giorgio C, Ravanetti F, Ragionieri L, Zamperini C, Mancini A, Dreassi E, Maga G, Vergani P, Neyts J, Radi M

Abstract
Cystic fibrosis (CF) is a multi-organ disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria triggers acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multi-target compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multi-dimensional SAR study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor and a promising in vitro ADME profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.

PMID: 31729878 [PubMed - as supplied by publisher]

Role play for genetic counseling learning: Value and students perceptions.

Tunis Med. 2019 Mar;97(3):426-431

Authors: Ben Abdelaziz R, Boudabous H, Hajji H, Ben Messaoud S, Azzouz H, Ben Chehida A, Tebib N

Abstract
BACKGROUND: Performing genetic counseling is one of the tasks of every paediatrician. This assumes prior training during the residency.
AIM: To assess the impact of role-play (RP) for training of paediatric residents in genetic counseling and participants' perception.
METHODS: Repetitive cross-sectional evaluation study. During two RP sessions, two residents played the role of the parents of a patient with cystic fibrosis, and another the role of the doctor. Residents had an evaluation by standardized patient exercises immediately before and after the session. Test scores were compared by the Wilcoxon rank test for associated samples. A satisfaction questionnaire was completed by the participants anonymously.
RESULTS: Post-test scores were better than pre-test scores overall (p = 0.002) and for items in the cognitive domain (p = 0.002). Of the 12 participants, only one had had previous training in genetic counseling. All participants were satisfied with the learning and felt that it would change the way they practice. All participants thought they could do genetic counseling autonomously, but nine of them wanted to have other RP sessions on the same theme. Only one participant found the session stressful and all wanted to multiply this type of sessions for other learning.
CONCLUSION: RP is an effective and well-accepted means for genetic counseling training. It should be integrated with paediatric resident training.

PMID: 31729716 [PubMed - in process]

Accuracy of Body Size Estimation in Youth with Cystic Fibrosis and Association with Health-Related Quality of Life.

J Clin Psychol Med Settings. 2019 Nov 14;:

Authors: Simon SL, Ferris KA, Durkin K, Riekert K, Duncan C

Abstract
Accuracy of body size estimation may impact motivation to adhere to treatment recommendations and health-related quality of life (HRQOL) in youth with cystic fibrosis (CF), but this has not yet been investigated. Thus, the goal of the current study was to examine accuracy of body size estimation in youth with CF, and associations with HRQOL, lung functioning, and dietary intake. Fifty-four youth diagnosed with CF (M = 13.61 years) completed the Figure Rating Scale, the Cystic Fibrosis Questionnaire-Revised, and a 24-h diet recall interview. Cohen's Weighted Kappa Coefficient evaluated agreement between body size estimation and BMI percentile. Binary logistic regression analyses examined associations between body size accuracy and HRQOL, lung functioning, and dietary intake. A less than adequate agreement was found between youth body size estimation and BMI percentile. Most participants overestimated body size (69.8%). Body Image HRQOL, but neither lung functioning nor dietary intake, was significantly associated with body size estimation accuracy. Working with patients to improve perceptions of body size may also improve HRQOL scores and allow for discussion about treatment goals related to body size.

PMID: 31728881 [PubMed - as supplied by publisher]

New severity assessment in cystic fibrosis: signal intensity and lung volume compared to LCI and FEV1: preliminary results.

Eur Radiol. 2019 Nov 14;:

Authors: Fleischer S, Kraus MS, Gatidis S, Baden W, Hector A, Hartl D, Tsiflikas I, Schaefer JF

Abstract
OBJECTIVES: Magnetic resonance imaging (MRI) aids diagnosis in cystic fibrosis (CF) but its use in quantitative severity assessment is under research. This study aims to assess changes in signal intensity (SI) and lung volumes (Vol) during functional MRI and their use as a severity assessment tool in CF patients.
METHODS: The CF intra-hospital standard chest 1.5 T MRI protocol comprises of very short echo-time sequences in submaximal in- and expiration for functional information. Quantitative measurements (Vol/SI at in- and expiration, relative differences (Vol_delta/SI_delta), and cumulative histograms for normalized SI values across the expiratory lung volume) were assessed for correlation to pulmonary function: lung clearance index (LCI) and forced expiratory volume in 1 s (FEV1).
RESULTS: In 49 patients (26 male, mean age 17 ± 7 years) significant correlation of Vol_delta and SI_delta (R = 0.86; p < 0.0001) during respiration was observed. Individual cumulated histograms enabled severity disease differentiation (mild, severe) to be visualized (defined by functional parameter: LCI > 10). The expiratory volume at a relative SI of 100% correlated significantly to LCI (R = 0.676 and 0.627; p < 0.0001) and FEV1 (R = - 0.847 and - 0.807; p < 0.0001). Clustering patients according to Vol_SI_100 showed that an amount of ≤ 4% was related to normal, while an amount of > 4% was associated with pathological pulmonary function values.
CONCLUSION: Functional pulmonary MRI provides a radiation-free severity assessment tool and can contribute to early detection of lung impairment in CF. Lung volume with SI below 100% of the inspiratory volume represents overinflated tissue; an amount of 4% of the expiratory lung volume was a relevant turning point.
KEY POINTS: • Signal intensity and lung volumes are used as potential metric parameters for lung impairment. • Quantification of trapped air impacts on therapy management. • Functional pulmonary MRI can contribute to early detection of lung impairment.

PMID: 31728685 [PubMed - as supplied by publisher]

Microbiological outliers in cystic fibrosis: resolving uncertainty.

Lancet Respir Med. 2019 Nov 11;:

Authors: Cunningham S

PMID: 31727594 [PubMed - as supplied by publisher]

Prevalence and clinical associations of Staphylococcus aureus small-colony variant respiratory infection in children with cystic fibrosis (SCVSA): a multicentre, observational study.

Lancet Respir Med. 2019 Nov 11;:

Authors: Wolter DJ, Onchiri FM, Emerson J, Precit MR, Lee M, McNamara S, Nay L, Blackledge M, Uluer A, Orenstein DM, Mann M, Hoover W, Gibson RL, Burns JL, Hoffman LR, SCVSA study group

Abstract
BACKGROUND: Staphylococcus aureus is the bacterium cultured most often from respiratory secretions of people with cystic fibrosis. Both meticillin-susceptible S aureus and meticillin-resistant S aureus (MRSA) can adapt to form slow-growing, antibiotic-resistant isolates known as small-colony variants that are not routinely identified by clinical laboratories. We aimed to determine the prevalence and clinical significance of S aureus small-colony variants and their subtypes among children with cystic fibrosis.
METHODS: The Small Colony Variant Staphylococcus aureus (SCVSA) study was a 2-year longitudinal study of children aged 6-16 years at five US cystic fibrosis centres, using culture methods sensitive for small-colony variants. Children were eligible if they had a documented diagnosis of cystic fibrosis and a minimum of two cystic fibrosis clinic visits and two respiratory cultures in the previous 12 months at enrolment. Participants attended clinic visits quarterly, at which respiratory tract samples were taken and measures of lung function (percentage of predicted forced expiratory volume in 1 s [FEV1] and frequency of respiratory exacerbations) were recorded. We determined the prevalence of small-colony variants and their subtypes, and assessed their independent associations with lung function and respiratory exacerbations using linear mixed-effects and generalised estimating equation logistic regression models. Analyses included both univariate models (unadjusted) and multivariate models that adjusted for potential confounders, including age, sex, race, baseline microbiology, treatment with CFTR modulator, and CTFR genotype.
FINDINGS: Between July 1, 2014, and May 26, 2015, we enrolled 230 children. Participants were followed-up for 2 years, with a mean of 6·4 visits (SD 1·14) per participant (range 2-9 visits) and a mean interval between visits of 3·94 months (SD 1·77). Across the 2-year period, S aureus small-colony variants were detected in 64 (28%) participants. Most (103 [56%] of 185) of the small-colony variants detected in these participants were thymidine dependent. Children with small-colony variants had significantly lower mean percentage of predicted FEV1 at baseline than did children without small-colony variants (85·5 [SD 19] vs 92·4 [SD 18·6]; p=0·0145). Small-colony variants were associated with significantly lower percentage of predicted FEV1 throughout the study in regression models, both in univariate analyses (regression coefficient -7·07, 95% CI -12·20 to -1·95; p=0·0068) and in multivariate analyses adjusting for potential confounders (-5·50, -10·51 to -0·48; p=0·0316). Small colony variants of the thymidine-dependent subtype had the strongest association with lung function in multivariate regression models (regression coefficient -10·49, -17·25 to -3·73; p=0·0024). Compared with children without small-colony variants, those with small-colony variants had significantly increased odds of respiratory exacerbations in univariate analyses (odds ratio 1·73, 95% CI 1·19 to 2·52; p=0·0045). Children with thymidine-dependent small-colony variants had significantly increased odds of respiratory exacerbations (2·81, 1·69-4·67; p=0·0001), even after adjusting for age, sex, race, genotype, CFTR modulator, P aeruginosa culture status, and baseline percentage of predicted FEV1 (2·17, 1·33-3·57; p=0·0021), whereas those with non-thymidine-dependent small-colony variants did not. In multivariate models including small-colony variants and MRSA status, P aeruginosa was not independently associated with lung function (regression coefficient -4·77, 95% CI -10·36 to 0·83; p=0·10) and was associated with reduced odds of exacerbations (0·54, 0·36 to 0·81; p=0·0028). Only the small-colony variant form of MRSA was associated with reduced lung function (-8·44, -16·15 to -0·72; p=0·0318) and increased odds of exacerbations (2·15, 1·24 to 3·71; p=0·0061).
INTERPRETATION: Infection with small-colony variants, and particularly thymidine-dependent small-colony variants, was common in a multicentre paediatric population with cystic fibrosis and associated with reduced lung function and increased risk of respiratory exacerbations. The adoption of small-colony variant identification and subtyping methods by clinical laboratories, and the inclusion of small-colony variant prevalence data in cystic fibrosis registries, should be considered for ongoing surveillance and study.
FUNDING: The Cystic Fibrosis Foundation and the National Institutes of Health.

PMID: 31727592 [PubMed - as supplied by publisher]

Prevalence and factors associated with overweight and obesity in adults with cystic fibrosis: A single-center analysis.

J Cyst Fibros. 2019 Nov 11;:

Authors: Harindhanavudhi T, Wang Q, Dunitz J, Moran A, Moheet A

Abstract
BACKGROUND: The relation between malnutrition and pulmonary death in patients with cystic fibrosis (CF) has resulted in intensive nutritional intervention over the last few decades, leading to a significant decline in underweight and the emergence of overweight/obesity as a potential new problem.
METHODS: We performed a cross-sectional database analysis of 484 adults with CF seen at the University of Minnesota CF Center between January 2015-January 2017, to determine the prevalence and pulmonary/cardiovascular risk factors associated with overweight and obesity in this population.
RESULTS: Mean age was 35.2 ± 11.6 years. 5.2% were underweight (BMI<18.5 kg/m2), 62.6% normal weight (BMI ≥ 18.5-24.9 kg/m2), 25.6% overweight (BMI ≥ 25-29.9 kg/m2) and 6.6% obese (BMI ≥ 30 kg/m2). In the subgroup with severe genotypes, 25% had BMI ≥ 25 kg/m2. In the entire cohort, overweight/obese were likely to be older (OR = 1.04, p < 0.0001) and to have a mild CFTR genotype (OR = 3.33, p = 0.0003) and modestly elevated triglyceride levels (OR = 1.008, p < 0.0001). The prevalence of hypertension was higher in overweight (25%) and obese (31%) than normal (17%) or underweight (16%), p = 0.01. Total cholesterol levels were higher in overweight/obese versus normal/underweight (144-147 vs 123-131 mg/dL, p = 0.04) as were LDL levels (70-71 vs 53-60 mg/dL, p = 0.02), but all were within the normal range. Percent predicted FEV1 was higher in overweight/obese (78-81%) versus underweight (59%) and normal (70%), p < 0.0001, and overweight/obese experienced significantly fewer acute pulmonary exacerbations.
CONCLUSIONS: Overweight/obesity is common in adults with CF including those with severe genotypes. Lung function is better in the overweight/obese and lipid levels are within the normal range, albeit higher than in normal/underweight.

PMID: 31727452 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance regulator ameliorates lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/AKT/mTOR pathway in mice.

Respir Physiol Neurobiol. 2019 Nov 11;:103338

Authors: Sui H, Luo M, Miao Y, Cheng W, Wen S, Zhao B, Li Y, Qiao Z, Liu Y, Xu C

Abstract
OBJECTIVE: The beneficial role of Cystic fibrosis transmembrane conductance regulator (CFTR) was reported in acute lung injury (ALI), however, there was no direct evidence supporting the relationship between CFTR and cell autophagy in ALI. Here, this study is to analyze the protective role of CFTR on autophagy in lipopolysaccharide (LPS)-induced ALI mice and its special mechanism.
METHODS: ALI mouse models were established by the stimulation of LPS. ALI mice were subjected to tail vein injection of Lv-CFTR, intraperitoneal injection of autophagy activator RAPA or tail vein injection of Lv-sh-HMGB1 before lung tissues and bronchoalveolar lavage fluid (BALF) were collected. The expression levels of CFTR, HMGB1, Beclin-1, p62, p-AKT, p-mTOR, and LC3-II/LC3-I ratio were estimated by qRT-PCR and Western blot. The lung edema in ALI mice was inspected by wet/dry weight (W/D) ratio. Hematoxylin and eosin (H&E) staining was utilized to observe pathological features of lung tissue. Immunofluorescence was applied to determine the expression intensity of LC-3. The superoxidase dismutase (SOD) and myeloperoxidase (MPO) activity and malondialdehyde (MDA) content were assayed, and inflammatory response in ALI mice was measured.
RESULTS: ALI mouse models were successfully induced by LPS, evidenced by an enhanced inflammatory response in lung tissues, heightened W/D ratio and cell autophagy markers. ALI mice had suppressed expression of CFTR, while injection of CFTR overexpression in ALI mice attenuates inflammation, autophagy, MPO activity and MDA content in addition to elevating SOD activity. Moreover, CFTR overexpression could increase the p-AKT, and p-mTOR. Overexpression of HMGB1 could reverse the expression pattern in mice injected with CFTR overexpression.
CONCLUSION: CFTR could inhibit cell autophagy by enhancing PI3K/AKT/mTOR signaling pathway, thereby playing a protective role in LPS-induced ALI in mice.

PMID: 31726235 [PubMed - as supplied by publisher]

Risk of piperacillin-induced hemolytic anemia in patients with cystic fibrosis and antipseudomonal treatment: a prospective observational study.

Transfusion. 2019 Nov 14;:

Authors: Roehmel J, Specht P, Staab D, Schwarz C, Salama A, Mayer B

Abstract
BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare but severe side effect caused by numerous drugs. Case reports and case series suggest that piperacillin-related DIIHA may be more common among patients with cystic fibrosis (CF). However, the prevalence is speculative. The aim of this prospective, observational study was determine the prevalence of DIIHA in such affected patients.
METHODS AND MATERIALS: Patients with CF hospitalized for parenteral antibiotic therapy at Charité Universitätsmedizin Berlin, who had previously been exposed to IV antibiotics, were enrolled. Blood samples were collected on Days 3 and 12 of antibiotic treatment courses. Serological studies were performed using standard techniques with gel cards. Screening for drug-dependent antibodies (ddab) was performed in the presence of the drugs and their urinary metabolites.
RESULTS: A total of 52 parenteral antibiotic cycles in 43 patients were investigated. Ddab against piperacillin were detected in two patients (4.7%). The direct AHG was positive with anti-IgG only in both patients. However only one of these patients developed mild immune hemolytic anemia. Both patients had been repeatedly treated with piperacillin without any evident hemolysis. There was no correlation between the exposure to piperacillin and the prevalence of ddab.
CONCLUSION: Our prospective study indicates that piperacillin-induced ddab occur more frequently in patients with CF than previously suggested. The question related to the significance of piperacillin-dependent antibodies may reflect new aspects in this field.

PMID: 31724753 [PubMed - as supplied by publisher]

Authors' response: Letter to the Editor 'Anaemia and iron deficiency in relation to fatigue in cystic fibrosis'.

J Cyst Fibros. 2019 01;18(1):e6-e7

Authors: Nap-van der Vlist MM, Burghard M, Hulzebos HJ, Doeleman WR, Heijerman HGM, van der Ent CK, Nijhof SL

PMID: 30318450 [PubMed - indexed for MEDLINE]

Measured fetal and neonatal exposure to Lumacaftor and Ivacaftor during pregnancy and while breastfeeding.

J Cyst Fibros. 2018 11;17(6):779-782

Authors: Trimble A, McKinzie C, Terrell M, Stringer E, Esther CR

Abstract
With the growing class of CFTR modulator therapy available to more patients and with increasing pregnancies in individuals with CF, there is a growing need to understand the effects of these agents during pregnancy. There are few reports of their continued use in the literature, although it is likely that this is not an uncommon occurrence. We report the uncomplicated and successful pregnancy of a woman treated with lumacaftor/ivacaftor, as well as the clinical course of the infant during the first 9 months of life. We also report drug levels in plasma from the mother, cord blood, breast milk, and infant to estimate fetal and infant drug exposure.

PMID: 29866531 [PubMed - indexed for MEDLINE]

Promoter hypermethylation of the CFTR gene as a novel diagnostic and prognostic marker of breast cancer.

Cell Biol Int. 2019 Nov 13;:

Authors: Liu K, Dong F, Gao H, Guo Y, Li H, Yang F, Zhao P, Dai Y, Wang J, Zhou W, Zou C

Abstract
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths among women. New biomarkers with definite diagnostic and prognostic efficacy are urgently needed. Here, we showed that promoter of cystic fibrosis transmembrane conductance regulator (CFTR) was hypermethylated in breast cancer. mRNA level of CFTR was downregulated in breast cancer. Notably, all the 19 breast cancer patients with hypermethylated CFTR were diagnosed with an invasive carcinoma. Moreover, CFTR was upregulated in decitabine (10 μM) treated breast cancer cells. Overexpression of CFTR inhibited cell growth whereas knockdown of CFTR promoted cell invasion. In the tissue array analysis, CFTR protein level decreased significantly in breast cancer and low CFTR protein level correlated with poor survival with a p-value of 0.034. Thus, promoter hypermethylation of the CFTR gene might be a novel diagnostic marker of breast cancer. This article is protected by copyright. All rights reserved.

PMID: 31721358 [PubMed - as supplied by publisher]

Safety, Tolerability, and Effects of Sodium Bicarbonate Inhalation in Cystic Fibrosis.

Clin Drug Investig. 2019 Nov 13;:

Authors: Gomez CCS, Parazzi PLF, Clinckspoor KJ, Mauch RM, Pessine FBT, Levy CE, Peixoto AO, Ribeiro MÂGO, Ribeiro AF, Conrad D, Quinton PM, Marson FAL, Ribeiro JD

Abstract
BACKGROUND: Among the many consequences of loss of CFTR protein function, a significant reduction of the secretion of bicarbonate (HCO3-) in cystic fibrosis (CF) is a major pathogenic feature. Loss of HCO3- leads to abnormally low pH and impaired mucus clearance in airways and other exocrine organs, which suggests that NaHCO3 inhalation may be a low-cost, easily accessible therapy for CF.
OBJECTIVE: To evaluate the safety, tolerability, and effects of inhaled aerosols of NaHCO3 solutions (4.2% and 8.4%).
METHODS: An experimental, prospective, open-label, pilot, clinical study was conducted with 12 CF volunteer participants over 18 years of age with bronchiectasis and pulmonary functions classified as mildly to severely depressed. Sputum rheology, pH, and microbiology were examined as well as spirometry, exercise performance, quality-of-life assessments, dyspnea, blood count, and venous blood gas levels.
RESULTS: Sputum pH increased immediately after inhalation of NaHCO3 at each clinical visit and was inversely correlated with rheology when all parameters were evaluated: [G' (elasticity of the mucus) = - 0.241; G″ (viscosity of the mucus) = - 0.287; G* (viscoelasticity of the mucus) = - 0.275]. G* and G' were slightly correlated with peak flow, forced expiratory volume in 1 s (FEV1), and quality of life; G″ was correlated with quality of life; sputum pH was correlated with oxygen consumption (VO2) and vitality score in quality of life. No changes were observed in blood count, venous blood gas, respiratory rate, heart rate, peripheral oxygen saturation of hemoglobin (SpO2), body temperature, or incidence of dyspnea. No adverse events associated with the study were observed.
CONCLUSION: Nebulized NaHCO3 inhalation appears to be a safe and well tolerated potential therapeutic agent in the management of CF. Nebulized NaHCO3 inhalation temporarily elevates airway liquid pH and reduces sputum viscosity and viscoelasticity.

PMID: 31721070 [PubMed - as supplied by publisher]

Simultaneous sulfur hexafluoride and nitrogen multiple-breath washout (MBW) to examine inherent differences in MBW outcomes.

ERJ Open Res. 2019 Oct;5(4):

Authors: Bayfield KJ, Horsley A, Alton E, Irving S, Bush A, Davies JC

Abstract
Multiple-breath washout (MBW) can be performed with different gases (sulfur hexafluoride (SF6-) and nitrogen (N2)) and different devices, all of which give discrepant results. This study aimed to confirm previously reported differences and explore factors influencing discrepant results; equipment factors or the physical properties of gases used.
Methods: Healthy controls (HCs) and participants with cystic fibrosis (CF) completed MBW trials on two commercially available devices (Exhalyzer D (N2) and Innocor (SF6)). Simultaneous washout of both gases at the same time on the commercial equipment and simultaneous washouts using a respiratory mass spectrometer (RMS) were completed in subsets. Primary outcomes were lung clearance index (LCI), breath number and time required to washout.
Results: Breath number was higher with N2 washout than SF6 in both HCs and patients with CF, whether washouts were completed individually or simultaneously. The difference was greater in more advanced disease, largely caused by differences in the final part of the washout. Results from commercial devices were similar to those obtained with the RMS.
Conclusions: N2 MBW results were higher than SF6 MBW, with some of the largest differences reported to date being observed. The biggest impact was at the end of the washout and this was even the case when gases were washed out simultaneously. N2 and SF6 MBW results are inherently different and should be considered as independent measurements.

PMID: 31720295 [PubMed]

Patient participation in research funding: an overview of when, why and how amongst Dutch health funds.

Res Involv Engagem. 2019;5:33

Authors: den Oudendammer WM, Noordhoek J, Abma-Schouten RY, van Houtum L, Broerse JEW, Dedding CWM

Abstract
Background: Patient participation in decision-making on health-related research has gained ground. Nineteen Dutch health-related research-funding organisations (HFs) have taken up the challenge to include patients in their funding process. A 'Patient participation (PP) advisory team' was set-up, with HF-representatives and patient advocates, who together initiated this study. We provide an overview of when, why, and how PP activities take place in HFs' funding processes, share main challenges and identify possible solutions.
Methods: A qualitative research design was used. Data was gathered by questionnaires (n = 14) and semi-structured interviews (n = 18) with HF employees responsible for patient participation, followed by a workshop (n = 27) with involved employees of HFs and key players in PP from national patient organisations and research organisations. A descriptive analysis was used for the questionnaire. A semi-directed content analysis was used for the interviews and the workshop.
Results: Three stages can be identified in the funding process in which HFs carry out PP activities: (1) strategic decision-making about focus of research (e.g. shared research agendas); (2) call for and receipt of research proposals (e.g. mandatory inclusion of letter of recommendation from patient organisation); (3) decision-making about the funding of research proposals (e.g. patients reside in a patient panel to co-review research proposals). Main challenges identified to carry out PP activities include: how to accommodate diversity of the patient body (mainly encountered in stage 1 and 3); to what extent should patients receive training to successfully participate (mainly encountered in stage 1 and 3); and who is responsible for patient-researcher dialogues (mainly encountered in stage 1 and 2). All nineteen HFs agree that patients should be included in at least one stage of the funding process for health-related research. CONCLUSION: Further broadening and optimising patient involvement is still needed. The proposed solutions to the identified challenges could serve as inspiration for national and international research funding foundations that aim to structurally include patients in their funding process.

PMID: 31720008 [PubMed]

Coexistence with Pseudomonas aeruginosa alters Staphylococcus aureus transcriptome, antibiotic resistance and internalization into epithelial cells.

Sci Rep. 2019 Nov 12;9(1):16564

Authors: Briaud P, Camus L, Bastien S, Doléans-Jordheim A, Vandenesch F, Moreau K

Abstract
Cystic fibrosis (CF) is the most common life-threatening genetic disease among Caucasians. CF patients suffer from chronic lung infections due to the presence of thick mucus, caused by cftr gene dysfunction. The two most commonly found bacteria in the mucus of CF patients are Staphylococcus aureus and Pseudomonas aeruginosa. It is well known that early-infecting P. aeruginosa strains produce anti-staphylococcal compounds and inhibit S. aureus growth. More recently, it has been shown that late-infecting P. aeruginosa strains develop commensal-like/coexistence interaction with S. aureus. The aim of this study was to decipher the impact of P. aeruginosa strains on S. aureus. RNA sequencing analysis showed 77 genes were specifically dysregulated in the context of competition and 140 genes in the context of coexistence in the presence of P. aeruginosa. In coexistence, genes encoding virulence factors and proteins involved in carbohydrates, lipids, nucleotides and amino acids metabolism were downregulated. On the contrary, several transporter family encoding genes were upregulated. In particular, several antibiotic pumps belonging to the Nor family were upregulated: tet38, norA and norC, leading to an increase in antibiotic resistance of S. aureus when exposed to tetracycline and ciprofloxacin and an enhanced internalization rate within epithelial pulmonary cells. This study shows that coexistence with P. aeruginosa affects the S. aureus transcriptome and virulence.

PMID: 31719577 [PubMed - in process]