Pediatr Pulmonol. 2021 Mar 3. doi: 10.1002/ppul.25351. Online ahead of print.

ABSTRACT

BACKGROUND: Median survival age in cystic fibrosis (CF) has increased in developed countries. Scarce literature exists about survival in Latin American, especially in Mexico. The aim of our study was to assess the median age of survival in CF patients and the impact of risk factors in Mexico over a 20-year period.

METHODS: We conducted a retrospective study with all patients registered and followed in the CF Center in Monterrey, Mexico from 2000 to 2020. Median survival age was the primary outcome, assessed with the Kaplan-Meier analysis. Influence of clinical, biological, and demographic factors on survival were analyzed with the Cox regression model.

RESULTS: Two-hundred five patients were included. Median survival for the cohort was 21.37 years (95% CI 17.20 - 25.55). In the multivariate Cox regression model, low socioeconomic status (hazard ratio [HR] 4.21, 95% CI 2.43 - 7.27), chronic Pseudomonas aeruginosa (P. aeruginosa) infection at 6 years (HR 10.45, 95% CI 5.66 - 19.28), and pancreatic insufficiency (HR 3.13, 1.38 - 7.13) were independent risk factors for mortality.

CONCLUSION: Median survival in Mexican patients with CF is lower than in high-income countries, and socioeconomic status plays a conspicuous role in the disparity. To increase patient survival for those residing in low-middle income countries, public health authorities must design policies that fully cover diagnosis and treatment strategies for the CF population. This article is protected by copyright. All rights reserved.

PMID:33656284 | DOI:10.1002/ppul.25351

Pediatr Pulmonol. 2021 Mar 3. doi: 10.1002/ppul.25353. Online ahead of print.

ABSTRACT

Acute pulmonary exacerbations (APE) are complications of cystic fibrosis (CF) and are associated with increased morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) and Aspergillus fumigatus are organisms that have been detected in the lungs of CF patients. The focus of this review is to provide an overview of the classes of antimicrobials used for MRSA and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction caused by Aspergillus fumigatus. The current anti-MRSA antibiotics and medications for ABPA dosing recommendations are discussed. This article also reviews the findings from the MRSA utilization surveys and the pharmacokinetic and pharmacodynamic differences between CF and non-CF patients. Anti-methicillin Staphylococcus aureus (S. aureus) antibiotics include ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim, and tetracycline derivatives (doxycycline, minocycline, tigecycline). Medications used for ABPA include corticosteroids, amphotericin B, azole anti-fungals (isavuconazole, itraconazole, posaconazole, and voriconazole), and a monoclonal antibody, omalizumab. This article is protected by copyright. All rights reserved.

PMID:33656280 | DOI:10.1002/ppul.25353

Pediatr Pulmonol. 2021 Mar 3. doi: 10.1002/ppul.25350. Online ahead of print.

ABSTRACT

BACKGROUND: The reflex zone stimulation technique (RST) activates complex motor responses and has a positive impact on the locomotor system. This technique may also indirectly affect breathing; however, the use of this technique as adjunct of the treatment of cystic fibrosis (CF) has not yet been characterised.

METHODS: We performed a randomised controlled single-centre interventional trial to evaluate the short-term effects of RST on lung function in 21 paediatric CF patients with normal baseline spirometry. The effect of 30 minutes of RST was compared to that of sham therapy in a crossover design. The interventions were performed in random order and planned 6 months apart. The primary outcome was a change in global ventilation inhomogeneity after intervention, assessed by lung clearance index (LCI2.5 ) derived from a nitrogen multiple breath washout test. Secondary outcomes included changes in regional ventilation inhomogeneity (indices of acinar [Sacin*Vt] and conductive airway [Scond*Vt] inhomogeneity) and spirometry parameters (inspiratory capacity, forced vital capacity, and forced expiratory volume in 1 second). Trunk deformity was assessed by physiotherapists at study entry.

RESULTS: After the RST intervention, the LCI2.5 (p = 0.004) and Scond*Vt (p = 0.009) decreased significantly, while inspiratory capacity increased (p = 0.012). In the sham-therapy group, none of the parameters changed significantly. Trunk deformity was seen in 76.5% of all patients, and 92.9% of those with trunk deformity showed a decrease in LCI2.5 after RST.

CONCLUSION: RST has multiple positive short-term effects on lung function, especially in CF patients with trunk deformities. This article is protected by copyright. All rights reserved.

PMID:33656249 | DOI:10.1002/ppul.25350

Intern Med J. 2021 Mar 3. doi: 10.1111/imj.15256. Online ahead of print.

ABSTRACT

BACKGROUND: Lung transplantation is a recognised treatment for end-stage lung disease due to bronchiectasis. Non-CF bronchiectasis and CF are often combined into one cohort, however outcomes for non-CF bronchiectasis patients varies between centres, and in comparison to those for CF.

AIMS: To compare lung transplantation mortality and morbidity of bronchiectasis (non-CF) patients to those with CF and other indications.

METHODS: Retrospective analysis of patients undergoing lung transplantation between 01 January 2008-31 December 2013. Time to and cause of lung allograft loss was censored on 01 April 2018. A case-note review was conducted on a sub-group of 78 patients, to analyse hospital admissions as a marker of morbidity.

RESULTS: 341 patients underwent lung transplantation, 22 (6%) had bronchiectasis compared to 69 (20%) with CF. The 5-year survival for the bronchiectasis group was 32%, compared to CF 69%, obstructive lung disease (OLD) 64%, pulmonary hypertension 62% and ILD 55% (p = 0.008). Lung allograft loss due to CLAD with predominant infection was significantly higher in the bronchiectasis group at 2 years. The rate of acute admissions was 2.24 higher in the bronchiectasis group when compared to OLD (p = 0.01). Patients with bronchiectasis spent 45.81 days in hospital per person year after transplantation compared with 18.21 days for CF.

CONCLUSIONS: Bronchiectasis patients in this study had a lower 5-year survival and poorer outcomes in comparison to other indications including CF. Bronchiectasis should be considered a separate entity to CF in survival analysis. This article is protected by copyright. All rights reserved.

PMID:33656222 | DOI:10.1111/imj.15256

J Bras Pneumol. 2021 Feb 24;47(2):e20200166. doi: 10.36416/1806-3756/e20200166. eCollection 2021.

ABSTRACT

OBJECTIVE: To describe causes of death and mortality data related to cystic fibrosis (CF) using a multiple-cause-of-death methodology.

METHODS: Annual mortality data for the 1999-2017 period were extracted from the Brazilian National Ministry of Health Mortality Database. All death certificates in which category E84 (CF) of the ICD-10, was listed as an underlying or associated cause of death were selected. Epidemiological and clinical data were described, and standardized mortality rates were calculated per year and for the 2000-2017 period. A joinpoint regression analysis was performed to detect changes in the mortality rates during the study period.

RESULTS: Overall, 2,854 CF-related deaths were identified during the study period, ranging from 68 in 1999 to 289 in 2017. CF was the underlying cause of death in 83.5% of the death certificates. A continuous upward trend in the death rates was observed, with a significant annual percent change of 6.84% (5.3-8.4%) among males and 7.50% (6.6-8.4%) among females. The median age at death increased from 7.5 years in 1999 to 56.5 years in 2017. Diseases of the respiratory system accounted for 77% of the associated causes in the death certificates that reported CF as the underlying cause of death.

CONCLUSIONS: A significant and continuous increase in CF-related death rates was found in Brazil in the last years, as well as a concurrent increase in the median age at death.

PMID:33656158 | DOI:10.36416/1806-3756/e20200166

J Bras Pneumol. 2021 Feb 24;47(2):e20200134. doi: 10.36416/1806-3756/e20200134. eCollection 2021.

ABSTRACT

OBJECTIVE: To investigate the validity of field walking tests to identify exercise-induced hypoxemia and to compare cardiorespiratory responses and perceived effort between laboratory-based and field-based exercise tests in subjects with bronchiectasis.

METHODS: This was a cross-sectional study involving 72 non-oxygen-dependent participants (28 men; mean age = 48.3 ± 14.5 years; and mean FEV1 = 54.1 ± 23.4% of the predicted value). The participants underwent cardiopulmonary exercise testing (CPET) on a treadmill and constant work-rate exercise testing (CWRET) on the same day (1 h apart). In another visit, they underwent incremental shuttle walk testing (ISWT) and endurance shuttle walk testing (ESWT; 1 h apart). Desaturation was defined as a reduction in SpO2 ≥ 4% from rest to peak exercise.

RESULTS: CPET results were compared with ISWT results, as were CWRET results with ESWT results. There was no difference in the magnitude of desaturation between CPET and ISWT (-7.7 ± 6.3% vs. -6.6 ± 5.6%; p = 0.10) and between CWRET and ESWT (-6.8 ± 5.8% vs. -7.2 ± 6.3%; p = 0.50). The incremental tests showed an agreement in the magnitude of desaturation in the desaturation and no desaturation groups (42 and 14 participants, respectively; p < 0.01), as did the endurance tests (39 and 16 participants; p < 0.01). The magnitude of desaturation was similar among the participants who did or did not reach at least 85% of the maximum predicted HR.

CONCLUSIONS: Field exercise tests showed good precision to detect desaturation. Field tests might be an alternative to laboratory tests when the clinical question is to investigate exercise-induced desaturation in subjects with bronchiectasis.

PMID:33656157 | DOI:10.36416/1806-3756/e20200134

Curr Pediatr Rev. 2021 Mar 3. doi: 10.2174/1573396317666210303151947. Online ahead of print.

ABSTRACT

In this paper we will review the dietary allowances of these fatty acids in the paediatric population, and also the indications in different pathologies within the field of pediatric gastroenterology. Finally, we will try to explain the reasons that may justify the difficulty in translating the good results in experimental studies to the usual clinical practice. This "good results" may be too little to be detected or there are other causes but misinterpreted as effects of dha.

PMID:33655869 | DOI:10.2174/1573396317666210303151947

Am J Physiol Gastrointest Liver Physiol. 2021 Mar 3. doi: 10.1152/ajpgi.00389.2020. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Cholangiocytes express cystic fibrosis transmembrane conductance regulator (CFTR) which is involved in bicarbonate secretion for the protection against bile toxicity. During liver transplantation prolonged hypoxia of the graft is associated with cholangiocyte loss and biliary complications. Hypoxia is known to diminish CFTR activity in the intestine, but whether it effects CFTR activity in cholangiocytes remains unknown. Thus, the aim of this study is to investigate the effect of hypoxia on CFTR activity in intrahepatic cholangiocyte organoids (ICOs) and test drug-interventions to restore bicarbonate secretion.

METHODS: Fifteen different human ICOs were cultured as monolayers and ion channel (CFTR and ANO1) activity was determined using an Ussing chamber assay with or without AMP kinase (AMPK)-inhibitor under hypoxic and oxygenated conditions. Bile-toxicity was tested by apical exposure of cells to fresh human bile.

RESULTS: Overall gene-expression analysis showed a high similarity between ICOs and primary cholangiocytes. Under oxygenated conditions, both CFTR and ANO1 channels were responsible for forskolin and UTP activated anion-secretion. Forskolin-stimulation in absence of intracellular chloride showed ion-transport, indicating that bicarbonate could be secreted by CFTR. During hypoxia, CFTR activity significantly decreased (p=0.01). Switching from oxygen to hypoxia during CFTR-measurements, reduced CFTR activity (p=0.03). Consequently, cell death increased when ICO-monolayers were exposed to bile during hypoxia compared to oxygen (p=0.04). Importantly, addition of AMPK-inhibitor restored CFTR-mediated anion-secretion during hypoxia.

CONCLUSION: ICOs provide an excellent model to study cholangiocyte anion channels and drug-related interventions. Here, we demonstrate that hypoxia affects cholangiocyte ion-secretion, leaving cholangiocytes vulnerable to bile toxicity. The mechanistic insights from this model maybe relevant for hypoxia-related biliary injury during liver transplantation.

PMID:33655768 | DOI:10.1152/ajpgi.00389.2020

Am J Physiol Lung Cell Mol Physiol. 2021 Mar 3. doi: 10.1152/ajplung.00411.2020. Online ahead of print.

ABSTRACT

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca2+ imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca2+. At stimulation levels >EC50 for Ca2+, serous cells simultaneously shrank ~20% over ~90 sec due to KCl efflux reflecting Ca2+-activated Cl- channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (<EC50 for Ca2+), shrinkage was not evident due to failure to activate CaCC. Low levels of cAMP-elevating VIP receptor (VIPR) stimulation, also insufficient to activate secretion alone, synergized with low level PAR-2 stimulation to elicit fluid secretion dependent on both cAMP and Ca2+ to activate CFTR and K+ channels, respectively. Polarized cultures of primary serous cells also exhibited synergistic fluid secretion. Pre-exposure to Pseudomonas aeruginosa conditioned media inhibited PAR-2 activation by proteases but not peptide agonists in primary nasal serous cells, Calu-3 bronchial cells, and primary nasal ciliated cells. Disruption of synergistic CFTR-dependent PAR-2/VIPR secretion may contribute to reduced airway surface liquid in CF. Further disruption of the CFTR-independent component of PAR-2-activated secretion by P. aeruginosa may also be important to CF pathophysiology.

PMID:33655758 | DOI:10.1152/ajplung.00411.2020

Pediatr Res. 2021 Mar 2. doi: 10.1038/s41390-021-01419-4. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) affects >70,000 people worldwide, yet the microbiologic trigger for pulmonary exacerbations (PExs) remains unknown. The objective of this study was to identify changes in bacterial metabolic pathways associated with clinical status.

METHODS: Respiratory samples were collected at hospital admission for PEx, end of intravenous (IV) antibiotic treatment, and follow-up from 27 hospitalized children with CF. Bacterial DNA was extracted and shotgun DNA sequencing was performed. MetaPhlAn2 and HUMAnN2 were used to evaluate bacterial taxonomic and pathway relative abundance, while DESeq2 was used to evaluate differential abundance based on clinical status.

RESULTS: The mean age of study participants was 10 years; 85% received combination IV antibiotic therapy (beta-lactam plus a second agent). Long-chain fatty acid (LCFA) biosynthesis pathways were upregulated in follow-up samples compared to end of treatment: gondoate (p = 0.012), oleate (p = 0.048), palmitoleate (p = 0.043), and pathways of fatty acid elongation (p = 0.012). Achromobacter xylosoxidans and Escherichia sp. were also more prevalent in follow-up compared to PEx (p < 0.001).

CONCLUSIONS: LCFAs may be associated with persistent infection of opportunistic pathogens. Future studies should more closely investigate the role of LCFA production by lung bacteria in the transition from baseline wellness to PEx in persons with CF.

IMPACT: Increased levels of LCFAs are found after IV antibiotic treatment in persons with CF. LCFAs have previously been associated with increased lung inflammation in asthma. This is the first report of LCFAs in the airway of persons with CF. This research provides support that bacterial production of LCFAs may be a contributor to inflammation in persons with CF. Future studies should evaluate LCFAs as predictors of future PExs.

PMID:33654282 | DOI:10.1038/s41390-021-01419-4

BMJ Open. 2021 Mar 2;11(3):e045803. doi: 10.1136/bmjopen-2020-045803.

ABSTRACT

INTRODUCTION: Engaging people with cystic fibrosis (CF) in clinical trials is critical to improving outcomes for this fatal disease. Following extensive exploration of engagement in CF trials we believe six key concepts require a quantitative understanding of their influence in the current CF trials landscape including how controversial issues like placebos, washouts, stipend provision and location of trial visits are viewed by the CF community and how these might be modified depending on the type of medicine being investigated and the mechanism of access to the drug on trial completion.

METHODS AND ANALYSIS: We have designed and will administer an online discrete choice experiment to elicit and quantify preferences of people with CF for these trials' attributes and estimate the relative importance of an attribute when choosing to participate in a trial. The cross-sectional data generated will be explored using conditional multinomial logit model. Mixed logit models such as the random-parameters logit and a latent class models will be used to explore preference heterogeneity. To determine the relative importance of an attribute, the difference between the attribute level with the highest preference weight and the level with the lowest preference weight will be calculated.

ETHICS AND DISSEMINATION: Imperial College London Joint Research Compliance Office has granted ethical approval for this study. Patient consent will be sought following full explanation. No identifying information will be collected. Dissemination will be via international conferences, peer-review publication and patient accessible forums. Major CF trials networks have agreed to incorporate our findings into their review process, meaning our results can realistically influence and optimise CF trial delivery.

PROSPERO REGISTRATION NUMBER: CRD42020184886.

PMID:33653764 | DOI:10.1136/bmjopen-2020-045803

Molecules. 2021 Feb 26;26(5):1275. doi: 10.3390/molecules26051275.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by mutations that impair the function of the CFTR chloride channel. The most frequent mutation, F508del, causes misfolding and premature degradation of CFTR protein. This defect can be overcome with pharmacological agents named "correctors". So far, at least three different classes of correctors have been identified based on the additive/synergistic effects that are obtained when compounds of different classes are combined together. The development of class 2 correctors has lagged behind that of compounds belonging to the other classes. It was shown that the efficacy of the prototypical class 2 corrector, the bithiazole corr-4a, could be improved by generating conformationally-locked bithiazoles. In the present study, we investigated the effect of tricyclic pyrrolothiazoles as analogues of constrained bithiazoles. Thirty-five compounds were tested using the functional assay based on the halide-sensitive yellow fluorescent protein (HS-YFP) that measured CFTR activity. One compound, having a six atom carbocyle central ring in the tricyclic pyrrolothiazole system and bearing a pivalamide group at the thiazole moiety and a 5-chloro-2-methoxyphenyl carboxamide at the pyrrole ring, significantly increased F508del-CFTR activity. This compound could lead to the synthesis of a novel class of CFTR correctors.

PMID:33652850 | DOI:10.3390/molecules26051275

Microorganisms. 2021 Feb 26;9(3):492. doi: 10.3390/microorganisms9030492.

ABSTRACT

The cystic fibrosis (CF) lung harbours a diverse microbiome and reduced diversity in the CF lung has been associated with advancing age, increased inflammation and poorer lung function. Data suggest that the window for intervention is early in CF, yet there is a paucity of studies on the lung microbiome in children with CF. The objective of this study was to thoroughly characterise the lower airway microbiome in pre-school children with CF. Bronchoalveolar lavage (BAL) samples were collected annually from children attending the three clinical centres. Clinical and demographic data were collated on all subjects alongside BAL inflammatory markers. 16S rRNA gene sequencing was performed on the Illumina MiSeq platform. Bioinformatics and data analysis were performed using Qiime and R project software. Data on 292 sequenced BALs from 101 children with CF and 51 without CF show the CF lung microbiome, while broadly similar to that in non-CF children, is distinct. Alpha diversity between the two cohorts was indistinguishable at this early age. The CF diagnosis explained only 1.1% of the variation between the cohort microbiomes. However, several key genera were significantly differentially abundant between the groups. While the non-CF lung microbiome diversity increased with age, diversity reduced in CF with age. Pseudomonas and Staphylococcus were more abundant with age, while genera such as Streptococcus, Porphyromonas and Veillonella were less abundant with age. There was a negative correlation between alpha diversity and interleukin-8 and neutrophil elastase in the CF population. Neither current flucloxacillin or azithromycin prophylaxis, nor previous oral or IV antibiotic exposure, was correlated with microbiome diversity. Consecutive annual BAL samples over 5 years from a subgroup of children demonstrated diverse patterns of development in the first years of life.

PMID:33652802 | DOI:10.3390/microorganisms9030492

Pediatr Pulmonol. 2021 Mar 2. doi: 10.1002/ppul.25348. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the reproducibility of the modified shuttle test (MST) and to determine whether the test needs to be performed more than once to assess the exercise capacity of children and adolescents with cystic fibrosis (CF).

METHODS: This was a longitudinal study including patients diagnosed with CF aged more than 6 years. The participants were followed for a period of 9 months and were evaluated at three different time points (visit 1, 2, and 3). Spirometric, anthropometric, clinical, and genetic data were collected, and two MSTs were performed at each visit.

RESULTS: Forty-eight clinically stable volunteers with a mean age of 10.1±2.7 years were initially included. The reproducibility of the test was evaluated using the distance achieved (DA) as the main variable. There were no significant differences in the DA (visit 1, p = 0.23; visit 2, p = 0.24; visit 3, p = 0.85), baseline heart rate (HR) (visit 1, p = 0.35; visit 2, p = 0.20; visit 3, p = 0.98), and peak HR (visit 1, p = 0.16; visit 2, p = 0.94; visit 3, p = 0.23) between the tests performed at each visit. The test-retest reliability demonstrated a high intraclass correlation coefficient (ICC) at all visits (visit 1, 2, and 3: 0.83, 0.90, and 0.80, respectively) and the variation in HR was the main factor associated with the DA in the MST over time.

CONCLUSION: The MST was found to be a reproducible and reliable test. The data presented here support the use of a single MST in order to evaluate and monitor exercise capacity of patients with CF during clinic visits. This article is protected by copyright. All rights reserved.

PMID:33650810 | DOI:10.1002/ppul.25348

J Asthma. 2021 Mar 2:1-14. doi: 10.1080/02770903.2020.1857396. Online ahead of print.

ABSTRACT

OBJECTIVE: The evidence pertaining to the effects of asthma on Coronavirus disease 2019 outcomes has been unclear. To improve our understanding of the clinically important association of asthma and Coronavirus disease 2019.

METHODS: A matched cohort study was performed using data from the Mass General Brigham Health Care System (Boston, MA). Adult (age ≥18 years) patients with confirmed Coronavirus disease 2019 and without chronic obstructive pulmonary disease, cystic fibrosis, or interstitial lung disease between March 4, 2020 and July 2, 2020 were analyzed. Up to five non-asthma comparators were matched to each asthma patient based on age (within 5 years), sex, and date of positive test (within 7 days). The primary outcomes were hospitalization, mechanical ventilation, and death, using multivariable Cox-proportional hazards models accounting for competing risk of death, when appropriate. Patients were followed for these outcomes from diagnosis of Coronavirus disease 2019 until July 2, 2020.

RESULTS: Among 562 asthma patients, 199 (21%) were hospitalized, 15 (3%) received mechanical ventilation, and 7 (1%) died. Among the 2686 matched comparators, 487 (18%) were hospitalized, 107 (4%) received mechanical ventilation, and 69 (3%) died. The adjusted Hazard Ratios among asthma patients were 0.99 (95% Confidence Internal 0.80, 1.22) for hospitalization, 0.69 (95% Confidence Internal 0.36, 1.29) for mechanical ventilation, and 0.30 (95% Confidence Internal 0.11, 0.80) for death.

CONCLUSIONS: In this matched cohort study from a large Boston-based healthcare system, asthma was associated with comparable risk of hospitalization and mechanical ventilation but a lower risk of mortality.

PMID:33650461 | DOI:10.1080/02770903.2020.1857396

Liver Int. 2021 Mar 1. doi: 10.1111/liv.14839. Online ahead of print.

ABSTRACT

BACKGROUND & AIM: ABCB4 is expressed at the canalicular membrane of hepatocytes. This ATP-binding cassette (ABC) transporter is responsible for the secretion of phosphatidylcholine into bile canaliculi. Missense genetic variations of ABCB4 are correlated with several rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). In a repurposing strategy to correct intracellularly retained ABCB4 variants, we tested 16 compounds previously validated as cystic fibrosis transmembrane conductance regulator (CFTR) correctors.

METHODS: The maturation, intracellular localization and activity of intracellularly retained ABCB4 variants were analyzed in cell models after treatment with CFTR correctors. In addition, in silico molecular docking calculations were performed to test the potential interaction of CFTR correctors with ABCB4.

RESULTS: We observed that the correctors C10, C13 and C17, as well as the combinations of C3+C18 and C4+C18, allowed the rescue of maturation and canalicular localization of four distinct traffic-defective ABCB4 variants. However, such treatments did not permit a rescue of the phosphatidylcholine secretion activity of these defective variants and were also inhibitory of the activity of wild type ABCB4. In silico molecular docking analyses suggest that these CFTR correctors might directly interact with transmembrane domains and/or ATP-binding sites of the transporter.

CONCLUSION: Our results illustrate the uncoupling between the traffic and the activity of ABCB4 since the same molecules can rescue the traffic of defective variants while they inhibit the secretion activity of the transporter. We expect that this study will help to design new pharmacological tools with potential clinical interest.

PMID:33650203 | DOI:10.1111/liv.14839

Sci Rep. 2021 Mar 1;11(1):4897. doi: 10.1038/s41598-021-84041-y.

ABSTRACT

The cystic fibrosis (CF) community seeks to explain heterogeneous outcomes of pulmonary exacerbation (PEX) treatment. Serum and sputum inflammatory mediators may identify people with CF (PwCF) at risk for suboptimal responses. However, lack of an established association between response phenotypes and these mediators limits clinical application. In this pilot study, we prospectively characterized treatment response phenotypes by assessing health-related quality-of-life (HRQoL) during PEX. We also measured lung function and iron-related biochemical parameters in serum and sputum. We classified subjects as sustained symptom-responders (SRs) or non-sustained symptom-responders (NSRs) based on the absence or presence, respectively, of worsened symptom scores after initial improvement. We used linear mixed models (LMMs) to determine whether trends in lung function, hematologic, serum, and sputum indices of inflammation differed between response cohorts. In 20 PwCF, we identified 10 SRs and 10 NSRs with no significant differences in lung function at PEX onset and treatment durations. SRs had better model-predicted trends in lung function than NSRs during PEX. Non-linear trends in serum and sputum iron levels significantly differed between SRs and NSRs. In adults with cystic fibrosis, PEX treatment response phenotypes may be correlated with distinctive trends in serum and sputum iron concentrations.

PMID:33649353 | DOI:10.1038/s41598-021-84041-y

J Cyst Fibros. 2021 Feb 26:S1569-1993(21)00044-8. doi: 10.1016/j.jcf.2021.02.009. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool.

METHODS: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R).

RESULTS: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers.

CONCLUSIONS: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

PMID:33648900 | DOI:10.1016/j.jcf.2021.02.009

J Cyst Fibros. 2021 Feb 26:S1569-1993(21)00045-X. doi: 10.1016/j.jcf.2021.02.010. Online ahead of print.

ABSTRACT

BACKGROUND: There is conflicting evidence regarding the presence of limb muscle impairments in adults with cystic fibrosis (CF), and the factors associated with these muscle impairments. The objectives of this study were to compare limb muscle size and function between adults with CF and healthy controls; and to examine their associations with demographic and clinical variables in adults with CF.

METHODS: The systematic review was performed using PRISMA guidelines. Studies were included if they measured any aspect of limb muscle size or function in adults with CF. Meta-analyses were performed to compare muscle variables between CF and healthy controls; and to examine their associations with demographic and clinical variables.

RESULTS: Twenty-eight studies were included, with 747 adults with CF. The meta-analyses showed that adults with CF have smaller thigh muscles [standardized mean difference (SMD) = 0.57, p<.0011, I2=0%], and lower handgrip strength (SMD = 0.89, p=.0034, I2=74.03%), which was weakly correlated with forced expiratory volume in one second (FEV1) (r=0.24, p=.035, I2=0%) and lower in females with CF (SMD = 2.05, p<.0001, I2=0%). There is no significant difference between adults with CF and controls in knee extensor strength (SMD = 0.25, p=.095, I2=42.79%).

CONCLUSIONS: Leg muscle atrophy and lower handgrip strength were noted. There may be a subgroup of adults with CF with knee extensor (quadriceps) weakness. Future studies are needed to better understand muscle impairments in people with CF; to explore the factors that can predict these muscle impairments; and to investigate their clinical significance in people with CF.

PMID:33648899 | DOI:10.1016/j.jcf.2021.02.010

J Pediatr Nurs. 2021 Feb 26:S0882-5963(21)00061-0. doi: 10.1016/j.pedn.2021.02.020. Online ahead of print.

ABSTRACT

PURPOSE: To identify the spiritual needs of children and adolescents with chronic illnesses and how these needs are met by health professionals during hospitalization.

DESIGN AND METHODS: A qualitative descriptive study was developed with 35 children and adolescents, between 7 and 18 years old, diagnosed with cancer, cystic fibrosis, and type 1 diabetes. Interviews with photo-elicitation were conducted during the hospitalization at a Brazilian public pediatric hospital. Findings were treated using thematic analysis, and the Consolidated Criteria for Reporting Qualitative Research (COREQ) was followed for quality reporting. This research was approved by a research committee.

RESULTS: Two themes emerged. The first, entitled 'Spiritual needs', encompasses five types of needs: (1) need to integrate meaning and purpose in life; (2) need to sustain hope; (3) need for expression of faith and to follow religious practices; (4) need for comfort at the end of life; and (5) need to connect with family and friends. The second theme was the 'Definition of spiritual care'.

CONCLUSIONS: Children and adolescents with chronic illnesses have spiritual needs while in hospital. Meeting these needs is essential for finding meaning, purpose and hope in the experience of living with chronic illnesses and at the end of life, based on their faith, beliefs and interpersonal relationships. But, these needs have not been fully addressed during hospitalization.

PRACTICE IMPLICATIONS: These results emphasize the need to implement spiritual care when caring for hospitalized pediatric patients, which includes addressing spiritual needs.

PMID:33648836 | DOI:10.1016/j.pedn.2021.02.020