J Physiol Sci. 2022 Feb 23;72(1):4. doi: 10.1186/s12576-022-00828-2.

ABSTRACT

HCO3- secretion in distal airways is critical for airway mucosal defense. HCO3-/H+ transport across the apical membrane of airway surface epithelial cells was studied by measuring intracellular pH in luminally microperfused freshly dissected mice bronchioles. Functional studies demonstrated that CFTR, ENaC, Cl--HCO3- exchange, Na+-H+ exchange, and Na+-HCO3- cotransport are involved in apical HCO3-/H+ transport. RT-PCR of isolated bronchioles detected fragments from Cftr, α, β, γ subunits of ENaC, Ae2, Ae3, NBCe1, NBCe2, NBCn1, NDCBE, NBCn2, Nhe1, Nhe2, Nhe4, Nhe5, Slc26a4, Slc26a6, and Slc26a9. We assume that continuous decline of intracellular pH following alkaline load demonstrates time course of HCO3- secretion into the lumen which is perfused with a HCO3--free solution. Forskolin-stimulated HCO3- secretion was substantially inhibited by luminal application of CFTRinh-172 (5 μM), H2DIDS (200 μM), and amiloride (1 μM). In bronchioles from a cystic fibrosis mouse model, basal and acetylcholine-stimulated HCO3- secretion was substantially impaired, but forskolin transiently accelerated HCO3- secretion of which the magnitude was comparable to wild-type bronchioles. In conclusion, we have characterized apical HCO3-/H+ transport in native bronchioles. We have demonstrated that cAMP-mediated and Ca2+-mediated pathways are involved in HCO3- secretion and that apical HCO3- secretion is largely mediated by CFTR and H2DIDS-sensitive Cl--HCO3- exchanger, most likely Slc26a9. The impairment of HCO3- secretion in bronchioles from a cystic fibrosis mouse model may be related to the pathogenesis of early lung disease in cystic fibrosis.

PMID:35196991 | DOI:10.1186/s12576-022-00828-2

Am J Physiol Cell Physiol. 2022 Feb 23. doi: 10.1152/ajpcell.00363.2021. Online ahead of print.

ABSTRACT

Primary airway epithelial cells (pAEC) cultivated at air-liquid interface (ALI) conditions are widely used as surrogates for human in vivo epithelia. To extend the proliferative capacity and to enable serially passaging of pAECs, conditionally reprogramming (cr) has been employed in recent years. However, ALI epithelia derived from cr cells often display functional changes with increasing passages. This highlights the need for thorough validation of the ALI cultures for the respective application. In our study, we evaluated the use of serially passaged cr nasal epithelial cells (crNEC) as a model to study SARS-CoV-2 infection and effects on ion and water transport. NEC were obtained from healthy individuals and cultivated as ALI epithelia derived from passage 1, 2, 3 and 5. We compared epithelial differentiation, ion and water transport, and infection with SARS-CoV-2 between passages. Our results show that epithelia maintained major differentiation characteristics and physiological ion and water transport properties through all passages. However, the frequency of ciliated cells, short circuit currents reflecting epithelial Na+ channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR) activity and expression of aquaporin 3 and 5 decreased gradually over passages. crNEC also expressed SARS-CoV-2 receptors ACE2 and TMPRSS2 across all passages and allowed SARS-CoV-2 replication in all passages. In summary, we provide evidence that passaged CR NEC provide an appropriate model to study SARS-CoV-2 infection and also epithelial transport function when considering some limitations that we defined herein.

PMID:35196166 | DOI:10.1152/ajpcell.00363.2021

Minerva Endocrinol (Torino). 2022 Feb 23. doi: 10.23736/S2724-6507.21.03451-5. Online ahead of print.

NO ABSTRACT

PMID:35195379 | DOI:10.23736/S2724-6507.21.03451-5

Orphanet J Rare Dis. 2022 Feb 22;17(1):73. doi: 10.1186/s13023-022-02204-0.

ABSTRACT

INTRODUCTION: In France, the cystic fibrosis (CF) care pathway is coordinated by multidisciplinary teams from specialised CF centres or transplant centres. It includes the care provided at home or out of hospital, risk prevention in daily life and adjustments to social life, which together contribute to the person's quality of life. Patient experience is used to describe and evaluate the care and life of patients living with the disease.

OBJECTIVES: Our collaborative research aims to identify the most significant areas and criteria that characterise the CF pathway. It will lead to the development of a questionnaire to collect patients' experience, which can be administered to all patients or parents of children registered and followed in the centres. The article describes the protocol developed in partnership with patients and parents of children living with the disease.

METHOD: A multidisciplinary research group brings together researchers, patients, parents of children with CF and health care professionals. The patient partnership is involved in the 4 phases of the protocol: (1) setting up the study, recruiting patient and parent co-researchers, training them in qualitative research methods, defining the situations and profiles of patients in the study population, elaborating the protocol; (2) selecting the study sites, recruiting participants, carrying out semi-structured interviews, analysing verbatims using the grounded theory approach; (3) co-elaborating Patient-Reported Experience Measures (PREM) questionnaires adapted to the 4 types of participants: parents, adolescents, non-transplanted adults and transplanted adults; (4) validating the construct with participants and professionals from the study centres.

RESULTS: The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700). Training was provided to the 5 patients and 2 parent co-researchers to enable them to participate effectively in the research. Eleven centres participated in the recruitment of participants in mainland France and Reunion Island. Eighty hours of interviews were conducted.

DISCUSSION: The PREM questionnaires to be elaborated will have to undergo psychometric validation before being used by the actors of the CF network to assess the impact on the care pathways of quality approaches or new therapies available in cystic fibrosis. Trial Registration Registry: IRB00003888 - no. 20-700. Issue date: 06/09/2020.

PMID:35193621 | DOI:10.1186/s13023-022-02204-0

J Pediatr Gastroenterol Nutr. 2022 Feb 22. doi: 10.1097/MPG.0000000000003420. Online ahead of print.

ABSTRACT

OBJECTIVES: Abdominal pain, emergency department visits and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). However, data on health-related quality of life (HRQOL) in this population remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL.

METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment.

RESULTS: The sample included 368 children (54.3% females, mean age = 12.7 years, SD = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, p < .001), episodic and constant abdominal pain (B = -4.66, p = .03; B = -13.25, p < .001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine and endocrine disease (F (9, 271) = 8.34, p < .001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, p < .001; B = -15.98, p < .001), and constant pain (B = -4.46, p < .001) were associated with low psychosocial HRQOL (F (9, 271) = 17.18, p < .001).

CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.

An infographic is available for this article at:http://links.lww.com/MPG/C712.

PMID:35192575 | DOI:10.1097/MPG.0000000000003420

Am J Respir Crit Care Med. 2022 Feb 22. doi: 10.1164/rccm.202110-2389CI. Online ahead of print.

ABSTRACT

A dramatic global reduction in the incidence of common seasonal respiratory viral infections has resulted from measures to limit the transmission of SARS2-Cov-19 during the pandemic . This has been accompanied by falls reaching 50% internationally in the incidence of acute exacerbations of pre-existing chronic respiratory diseases that include asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). At the same time, the incidence of acute bacterial pneumonia and sepsis has fallen steeply world-wide. Such findings demonstrate the profound impact of common respiratory viruses on the course of these global illnesses. Reduced transmission of common respiratory bacterial pathogens and their interactions with viruses appear also as central factors. This review summarises pandemic changes in exacerbation rates of asthma, COPD, Cystic Fibrosis (CF) and pneumonia. We draw attention to the substantial body of knowledge about respiratory virus infections in these conditions, and that it has not yet translated into clinical practice. Now the large-scale of benefits that could be gained by managing these pathogens is unmistakable, we suggest the field merits substantial academic and industrial investment. We consider how pandemic-inspired measures for prevention and treatment of common infections should become a cornerstone for managing respiratory diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:35192447 | DOI:10.1164/rccm.202110-2389CI

Physiother Theory Pract. 2022 Feb 22:1-11. doi: 10.1080/09593985.2022.2041780. Online ahead of print.

ABSTRACT

Objective: There is no study in the literature evaluating impairments and functional limitations in adults with cystic fibrosis (CF) under the framework of the International Classification of Functioning, Disability, and Health (ICF). To evaluate the adults with CF using ICF model. Methods: Twenty-three adults with CF and 23 age-sex matched healthy individuals included in this cross-sectional study. The participants evaluated according to the selected items for domain b, domain s, and domain d from the Obstructive Pulmonary Diseases (OPD) Comprehensive Core Set. The body composition, pulmonary functions, respiratory and peripheral muscle strength/endurance tests and anxiety/depression level were evaluated for domain b and s. For domain d, the Incremental Shuttle Walk Test (ISWT) and Short Form-36 (SF-36) Health Survey were used. Results: The fat-free mass (p = .044), pulmonary functions (p < .05), respiratory muscle endurance (p = .010), absolute and %quadriceps muscle strength (p = .001, p = .025, respectively), number of sit-ups (p = .020), walking speed (p = .035), ISWT and ISWT% distance (p < .001) and peak oxygen consumption (p < .001) were significantly lower in adults with CF compared to healthy individuals (p < .05). There were only significant differences in SF-36 physical functioning and role physical subdimension scores between groups (p = .009, p = .045 respectively). Conclusions: The ICF framework is applicable to comprehensively evaluate limitations of adults with CF among rehabilitation professionals. Especially age, respiratory function, respiratory muscle strength and endurance, dyspnea perception, peripheral muscle endurance were related to activity and participation limitation.

PMID:35192420 | DOI:10.1080/09593985.2022.2041780

Diabetes Ther. 2022 Feb 21. doi: 10.1007/s13300-022-01223-1. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis-related diabetes mellitus (CFRDM) is becoming a more common issue in pregnancy care as the life expectancy of females living with cystic fibrosis has improved, with an increasing number of pregnancies in this population. Despite the Republic of Ireland having the highest incidence of cystic fibrosis globally, there is limited Irish data on pregnancy outcomes for those with CFRDM. This study aimed to retrospectively review maternal and foetal outcomes of pregnancies affected by maternal CFRDM.

METHODS: The patient records of all women with CFRDM who attended the National Maternity Hospital Dublin for obstetric care between 2015 and 2019 were retrospectively reviewed.

RESULTS: A search of patient records identified 15 pregnancies in 12 women with CFRDM during the study period. CFRDM was diagnosed pre-conception in ten of the 15 pregnancies. Median neonatal weight at birth was lower in women with CFRDM diagnosed pre-conception compared to women diagnosed during pregnancy (2.8 vs. 3.02 kg). The median weight gain in women with CFRDM diagnosed pre-conception was 10.9 kg compared to 11.9 kg for those diagnosed during pregnancy. The majority of women (62.5%) with CFRDM diagnosed pre-conception delivered via caesarean section. Admission for CF exacerbations during pregnancy in women with CFRDM diagnosed pre-conception was very common (87.5%) compared with 75% of those diagnosed during their pregnancy.

CONCLUSION: Women diagnosed with CFRDM were likely to require caesarean section, to be treated with insulin, and to be frequently admitted to hospital for CF exacerbations. Our review highlights the importance of good glucose control, stable cystic fibrosis before pregnancy and a multidisciplinary team approach.

PMID:35190969 | DOI:10.1007/s13300-022-01223-1

J Cyst Fibros. 2022 Feb 18:S1569-1993(22)00039-X. doi: 10.1016/j.jcf.2022.02.007. Online ahead of print.

ABSTRACT

BACKGROUND: Variation in respiratory response to cystic fibrosis (CF) small molecule therapies is due in part to the contribution of CF lung disease modifier genes. Cultured human bronchial epithelia (HBE) is the gold standard respiratory model for assessing CF therapeutic efficacy but it is hard to access. Cultured human nasal epithelia (HNE) is proposed as a more accessible surrogate model but it is unknown whether the expression profile of the modifier genes are comparable between HNE and HBE which we assess here.

METHODS: RNA-sequencing was conducted on paired cultured and fresh HNE and HBE (n = 71 samples) collected from 21 individuals with CF. Genome-wide gene expression was first compared between cultured and fresh cells and then between cultured HNE and HBE based on an equivalence testing procedure we implemented. The co-expression relationships of CFTR and CF lung disease modifier genes were compared between cultured HNE and HBE to determine equivalent interactions.

RESULTS: The culturing process had little impact on the expression level of CF lung disease modifier genes. Over 90% of expressed genes showed significant equivalent expression level across cultured HNE and HBE (expression fold-change<2, FDR<0.1), including CFTR and CF lung disease modifier genes. The difference in co-expression relationships among these genes was not significant (p-value=0.99), suggesting their functional interactions are likely to be consistent in the two models.

CONCLUSIONS: Cultured HNE recapitulates the expression profile of CF lung disease modifier genes in cultured HBE, suggesting the biological processes involving these genes are likely to be consistent across the two models.

PMID:35190293 | DOI:10.1016/j.jcf.2022.02.007

J Cyst Fibros. 2022 Feb 18:S1569-1993(22)00033-9. doi: 10.1016/j.jcf.2022.02.003. Online ahead of print.

ABSTRACT

BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.

METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI).

RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96.

CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

PMID:35190292 | DOI:10.1016/j.jcf.2022.02.003

Physiother Theory Pract. 2022 Feb 21:1-8. doi: 10.1080/09593985.2022.2043965. Online ahead of print.

ABSTRACT

BACKGROUND: The decline in ambulatory activities and negative alterations in gait characteristics may impair balance and increase fall risk in obstructive lung diseases. Few studies have evaluated balance and gait parameters in individuals with bronchiectasis.

PURPOSE: This study aimed to compare the gait parameters and functional balance in individuals with non-cystic fibrosis (CF) bronchiectasis and healthy subjects.

METHODS: This cross-sectional and retrospective study analyzed data from 22 individuals with non-CF bronchiectasis and 32 healthy controls recorded between July 2019 and July 2020. Functional balance was assessed using the Timed Up and Go (TUG) test. Gait parameters were evaluated using the Biodex Gait Trainer. Step cycle (s), gait speed (m/s), the number of steps per minute, and ambulation index were measured for 6 min.

Results The TUG time (s) was significantly longer (p = .019, effect size = 0.66), and gait speed (m/s) (p ˂ 0.001, effect size = 2.47), step cycle (s) (p ˂ 0.001, effect size = 2.23), and ambulation index (p ˂ 0.001, effect size = 2.56) were significantly reduced in individuals with non-CF bronchiectasis compared with healthy controls.

CONCLUSION: Non-CF bronchiectasis is related to unfavorable changes in gait characteristics, such as slower gait speed and the decreased average step cycle. In addition, impairment in functional balance and mobility exists in a small percentage of adults with non-CF bronchiectasis. In comprehensive pulmonary rehabilitation, balance and gait evaluations should be included to prevent falls in adults with non-CF bronchiectasis.

PMID:35189785 | DOI:10.1080/09593985.2022.2043965

Pharmacogenomics. 2022 Feb 22. doi: 10.2217/pgs-2021-0138. Online ahead of print.

ABSTRACT

Background: Intestinal pathology in cystic fibrosis (CF) remains mechanistically underexplored. Aim: We hypothesized that differential correlation network analysis of expression data would reveal hub genes of CF-related disturbance in the large bowel. Materials & methods: Transcriptomes of 29 rectal tissue samples were accessed at ArrayExpress (E-GEOD-15568 by Stanke et al.). Results: We identified 279 transcript pairs differentially correlating in CF and controls, including: ESRRA and RPL18 (rCF = 0.55; rcontrols = -0.68; padj = 1.60 × 10-100), SRP14 and FAU (rCF = -0.69; rcontrols = 0.48; padj = 2.99 × 10-90), SRP14 and GDI2 (rCF = -0.34; rcontrols = 0.60; padj = 1.05 × 10-78). The genes related to membrane protein targeting (q = 8.34 × 10-14) and one cluster was clearly linked to male infertility. Conclusion: FAU, SRP14 and GDI2 may be involved in a compensatory protein trafficking mechanism in CF rectum, highlighting their potential therapeutic value.

PMID:35189732 | DOI:10.2217/pgs-2021-0138

mBio. 2022 Feb 22:e0386921. doi: 10.1128/mbio.03869-21. Online ahead of print.

ABSTRACT

The type III secretion system (T3SS) is a needle-like structure found in Gram-negative pathogens that directly delivers virulence factors like toxins and effector molecules into eukaryotic cells. The T3SS is classified into different families according to the type of effector and host. Of these, the Ysc family T3SS, found in Yersinia species and Pseudomonas aeruginosa, confers high virulence to bacteria against eukaryotic hosts. Here, we present the first identification and transcriptional analyses of a Ysc T3SS in a non-aeruginosa Pseudomonas species, Pseudomonas lundensis, an environmental psychrotrophic bacterium and important agent of frozen food spoilage. We have identified and sequenced isolates of P. lundensis from three very distinct ecological niches (Antarctic temporary meltwater pond, U.S. supermarket 1% pasteurized milk, and cystic fibrosis lungs) and compared these to previously reported food spoilage isolates in Europe. In this paper, we show that strains of P. lundensis isolated from these diverse environments with ambient temperatures ranging from below freezing to 37°C all possess a Ysc family T3SS secretion system and a T3S effector, ExoU. Using in vitro and in vivo transcriptomics, we show that the T3SS in P. lundensis is transcriptionally active, is expressed more highly at mammalian body temperature (37°C) than 4°C, and has even higher expression levels when colonizing a host environment (mouse intestine). Thus, this Ysc T3SS-expressing psychrotrophic Pseudomonad has an even greater range of growth niches than previously appreciated, including diseased human airways. IMPORTANCE P. lundensis strains have been isolated from environments that are distinct and diverse in both nutrient availability and environmental pressures (cold food spoilage, Antarctic melt ponds, cystic fibrosis lungs). As a species, this bacterium can grow in diverse niches that markedly vary in available nutrients and temperature, and in our study, we show that these various strains share greater than 99% sequence similarity. In addition, all isolates studied here encoded complete homologs of the Ysc family T3SS seen in P. aeruginosa. Until recently, P. aeruginosa has remained as the only Pseudomonas species to have a characterized functional Ysc (Psc) family T3SS. With the identification of a complete Ysc T3SS in P. lundensis that is expressed at 37°C in vivo, it is intriguing to wonder whether this bacterium may indeed have some level of symbiotic activity, of yet unknown type, when consumed by a mammalian host.

PMID:35189702 | DOI:10.1128/mbio.03869-21

Front Cell Infect Microbiol. 2022 Feb 4;12:834015. doi: 10.3389/fcimb.2022.834015. eCollection 2022.

ABSTRACT

Over the past decade, Apiotrichum mycotoxinivorans has been recognized globally as a source of opportunistic infections. It is a yeast-like fungus, and its association as an uncommon pulmonary pathogen with cystic fibrosis patients has been previously reported. Immunocompromised patients are at the highest risk of A. mycotoxinivorans infections. Therefore, to investigate the genetic basis for the pathogenicity of A. mycotoxinivorans, we performed whole-genome sequencing and comparative genomic analysis of A. mycotoxinivorans GMU1709 that was isolated from sputum specimens of a pneumonia patient receiving cardiac repair surgery. The assembly of Oxford Nanopore reads from the GMU1709 strain and its subsequent correction using Illumina paired-end reads yielded a high-quality complete genome with a genome size of 30.5 Mb in length, which comprised six chromosomes and one mitochondrion. Subsequently, 8,066 protein-coding genes were predicted based on multiple pieces of evidence, including transcriptomes. Phylogenomic analysis indicated that A. mycotoxinivorans exhibited the closest evolutionary affinity to A. veenhuisii, and both the A. mycotoxinivorans strains and the formerly Trichosporon cutaneum ACCC 20271 strain occupied the same phylogenetic position. Further comparative analysis supported that the ACCC 20271 strain belonged to A. mycotoxinivorans. Comparisons of three A. mycotoxinivorans strains indicated that the differences between clinical and non-clinical strains in pathogenicity and drug resistance may be little or none. Based on the comparisons with strains of other species in the Trichosporonaceae family, we identified potential key genetic factors associated with A. mycotoxinivorans infection or pathogenicity. In addition, we also deduced that A. mycotoxinivorans had great potential to inactivate some antibiotics (e.g., tetracycline), which may affect the efficacy of these drugs in co-infection. In general, our analyses provide a better understanding of the classification and phylogeny of the Trichosporonaceae family, uncover the underlying genetic basis of A. mycotoxinivorans infections and associated drug resistance, and provide clues into potential targets for further research and the therapeutic intervention of infections.

PMID:35186802 | PMC:PMC8855340 | DOI:10.3389/fcimb.2022.834015

Front Microbiol. 2022 Feb 3;12:801152. doi: 10.3389/fmicb.2021.801152. eCollection 2021.

ABSTRACT

OBJECTIVES: To evaluate the in vitro antibacterial, antibiofilm, and antivirulence activities of apramycin, comparatively to tobramycin, against a set of P. aeruginosa from chronically infected cystic fibrosis (CF) patients.

METHODS: The activity of antibiotics against planktonic cells was assessed by performing MIC, MBC, and time-kill assays. The activity against mature biofilms was evaluated, in a microtiter plate, both in terms of dispersion (crystal violet assay) and residual viability (viable cell count). The effect of drug exposure on selected P. aeruginosa virulence genes expression was assessed by real-time Reverse Transcription quantitative PCR (RT-qPCR).

RESULTS: Apramycin MIC90 and MBC90 values were found at least fourfold lower than those for tobramycin. A comparable trend was observed for mucoid strains. Only 4 out of 24 strains (16.6%) showed an apramycin MIC higher than the epidemiological cut-off value of 64 mg/L, whereas a higher resistance rate was observed for tobramycin (62.5%; p < 0.01 vs. apramycin). In time-kill analyses, both aminoglycosides were found bactericidal, although apramycin showed a more rapid effect and did not allow for regrowth. Apramycin generally stimulated biofilm biomass formation, whereas tobramycin showed opposite trends depending on the strain tested. Both drugs caused a highly significant, dose-dependent reduction of biofilm viability, regardless of strain and concentration tested. The exposure to apramycin and tobramycin caused increased expression of mexA and mexC (multidrug efflux pumps), whereas tobramycin specifically increased the expression of aprA (alkaline protease) and toxA (exotoxin A). Neither apramycin nor tobramycin showed cytotoxic potential toward IB3-1 bronchial epithelial CF cells.

CONCLUSION: Our results warrant future pharmacokinetic and pharmacodynamic studies for supporting the rationale to repurpose apramycin, a veterinary aminoglycoside, for CF lung infections.

PMID:35185826 | PMC:PMC8851335 | DOI:10.3389/fmicb.2021.801152

J Cyst Fibros. 2022 Feb 17:S1569-1993(22)00035-2. doi: 10.1016/j.jcf.2022.02.001. Online ahead of print.

ABSTRACT

CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·γ) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the simple and widely used sweat chloride test can be calibrated to provide more accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects (hereafter 'CFTR activity'). Sweating stimulated by β-adrenergic agonists (β-sweat) is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity with carriers = 50% and CF = 0% of HC values set = 100%, but the β-sweat assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting mean sweat chloride values, taken from numerous studies and the CFTR2 database against mean β-sweat rates for CF, carriers and HC. The resulting inverse logarithmic relations indicate that sweat chloride values ≥60 mmol/L occur when CFTR activity is below 1.2% -10% of HC. These are lower than most previous estimates, which resulted from setting nasal potential difference (NPD) as linear rather than logarithmic measures of CFTR activity. Features of the sweat gland coil and duct are used to explain why readouts of CFTR activity are linear for β-sweat and logarithmic for sweat chloride. Sweat chloride values fall steeply for small increments of CFTR activity above zero-the most clinically relevant region. Thus, large health benefits can be achieved by restoring low levels of CFTR activity, especially if this is done before irreversible lung damage. Truncated Abstract: CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·γ) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the sweat chloride test can be calibrated to provide accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects. Sweating stimulated by β-adrenergic agonists is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity, but the assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting it against mean β-sweat rates for different groups. The resulting logarithmic relations indicate that CF sweat chloride values occur when CFTR activity is below 1.2% -10% of HC, and that large health benefits can be achieved by restoring low levels of CFTR activity if this is done early.

PMID:35184981 | DOI:10.1016/j.jcf.2022.02.001

Paediatr Respir Rev. 2022 Jan 25:S1526-0542(22)00004-5. doi: 10.1016/j.prrv.2022.01.004. Online ahead of print.

NO ABSTRACT

PMID:35184969 | DOI:10.1016/j.prrv.2022.01.004

Curr Opin Organ Transplant. 2022 Feb 18. doi: 10.1097/MOT.0000000000000975. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Over the past decade, the development of highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators has dramatically ameliorated the manifestations of CF for most patients. Perhaps most importantly, CFTR modulators impact the development and progression of advanced lung disease (ALD) and are changing the CF population accessing lung transplant.

RECENT FINDINGS: A recent phase 3 trial of elexacaftor/tezacaftor/ivacaftor (ETI) demonstrated efficacy for individuals with at least one copy of the most common CF mutation, F508del. Studies of CFTR modulator therapy in patients with ALD have demonstrated similar improvements in lung function, nutrition, and pulmonary exacerbation frequency as seen in individuals with higher lung function. Due to improvements with ETI, rates of lung transplant for CF have declined and individuals are achieving stability in lung function. Nevertheless, the Cystic Fibrosis Foundation guidelines for lung transplant referral should be used to guide referral decisions for all individuals with CF, including those on CFTR modulator therapy, to allow remediation of modifiable barriers to transplant. ETI may be used in the posttransplant setting but for selected individuals and with close monitoring.

SUMMARY: Increasing access to highly effective CFTR modulators has changed the trajectory of lung disease in CF for many, but not all, individuals and there remain individuals who cannot access therapy or whose mutations do not respond to modulators. Lung transplant remains an important treatment option for individuals with advanced CF lung disease. Increasing attention will be required to optimize decisions of when to list for transplant.

PMID:35184094 | DOI:10.1097/MOT.0000000000000975

Clin Imaging. 2022 Feb 12;84:118-129. doi: 10.1016/j.clinimag.2022.02.004. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations, affecting roughly 70,000 individuals worldwide. This autosomal recessive disorder causes a wide spectrum of multisystemic manifestations, most of which are either directly or indirectly related to defective epithelial chloride secretion. The current median life expectancy is 44 years; however, a significant proportion of the CF population now live into the 5th decade and beyond due to advances in treatment. As life expectancy of CF patients increases, there is a newly emerging adult CF population with unique radiological manifestations spanning multiple organ systems, which often require follow-up imaging. The goal of this article is to review the multiple systemic manifestations and complications of CF on different imaging modalities and explore the appropriate radiological follow up recommended.

PMID:35183916 | DOI:10.1016/j.clinimag.2022.02.004

Drug Deliv Transl Res. 2022 Feb 19. doi: 10.1007/s13346-021-01102-5. Online ahead of print.

ABSTRACT

It has recently emerged that drugs such as the mTOR inhibitor rapamycin (Rapa) may play a key role in the treatment of airway inflammation associated with lung diseases, such as chronic obstructive pulmonary disease, asthma, and cystic fibrosis. Nevertheless, Rapa clinical application is still prevented by its unfavorable chemical-physical properties, limited oral bioavailability, and adverse effects related to non-specific biodistribution. In this paper, the design and production of a novel formulation of Rapa based on nano into micro (NiM) particles are detailed. To achieve it, Rapa-loaded nanoparticles were produced by nanoprecipitation of an amphiphilic pegylated poly-ɛ-caprolactone/polyhydroxyethyl aspartamide graft copolymer. The obtained nanoparticles that showed a drug loading of 14.4 wt% (corresponding to an encapsulation efficiency of 82 wt%) did not interact with mucins and were able to release and protect Rapa from degradation in simulated lung and cell fluids. To allow their local administration to the lungs as a dry powder, particle engineering at micro-sized level was done by embedding nanoparticles into mannitol-based microparticles by spray drying. Obtained NiM particles had a mean diameter of about 2-µ, spherical shape and had good potential to be delivered to the lungs by a breath-activated dry powder inhalers. Rheological and turbidity experiments showed that these NiM particles can dissolve in lung simulated fluid and deliver the Rapa-loaded pegylated nanoparticles, which can diffuse through the mucus layer.

PMID:35182368 | DOI:10.1007/s13346-021-01102-5