J Diabetes Complications. 2024 Feb 14;38(4):108703. doi: 10.1016/j.jdiacomp.2024.108703. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is commonly associated with declining lung function and nutritional status. We aimed to evaluate the pulmonary impact of early glucose abnormalities by using 2-h standard oral glucose tolerance testing (OGTT) and continuous glucose monitoring (CGM) in people with cystic fibrosis (PwCF).

METHODS: PwCF aged ≥10 years old without known CFRD were included in a five-year prospective multicentre study. Annual evaluation of nutritional status, lung function, OGTT and CGM was set up. Associations between annual rate changes (Δ) in lung function, ΔFEV1 (forced expiratory volume in 1 s) percentage predicted (pp) and ΔFVC (forced vital capacity) pp., and annual rate changes in OGTT or CGM variables were estimated with a mixed model with a random effect for subject.

RESULTS: From 2009 to 2016, 112 PwCF (age: 21 ± 11 years, BMI (body mass index) z-score: -0.55 ± 1.09, FEV1pp: 77 ± 24 %, 2-h OGTT glucose: 122 ± 44 mg/dL, AUC (area under curve) >140 mg/dL: 1 mg/dL/day (0.2, 3.0) were included. A total of 428 OGTTs and 480 CGMs were collected. The participants presented annual decline of FVCpp and FEV1pp at -1.0 % per year (-1.6, -0.4), p < 0.001 and - 1.9 % per year (-2.5, -1.3), p < 0.001 respectively without change in BMI z-score during the study. Variation of two-hour OGTT glucose was not associated with declining lung function, as measured by ΔFEV1pp (p = 0.94) and ΔFVCpp (p = 0.90). Among CGM variables, only increase in AUC >140 mg/dL between two annual visits was associated with a decrease in ΔFVCpp (p < 0.05) and ΔFEV1pp (p < 0.05).

CONCLUSIONS: This prospective study supports the fact that early glucose abnormalities revealed by CGM predict pulmonary function decline in PwCF, while 2-h standard OGTT glucose is not associated with pulmonary impairment.

PMID:38430625 | DOI:10.1016/j.jdiacomp.2024.108703

Eur J Pediatr. 2024 Mar 2. doi: 10.1007/s00431-024-05479-6. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a multisystemic disease in which airway obstruction, infection, and inflammation play a critical role in the pathogenesis and progression of CF lung disease. The carbohydrate-binding protein Galectin-3 is increased in several inflammatory and fibrotic diseases and has recently been forwarded as a biomarker in these diseases. We aimed to define the role of serum Galectin-3 in children with CF by comparison with healthy subjects. This is a cross-sectional, case-control study. 143 CF and 30 healthy subjects were enrolled in the study. Peripheral blood and sputum concentrations of Galectins-3, interleukin (IL)-17A, IL-8, and neutrophil elastase (NE) were determined with commercial ELISA kits. There was no significant difference between the groups in age and gender (p = 0.592, p = 0.613, respectively). Serum Galectin-3 and NE concentrations were higher in the patient group than in healthy controls (p = 0.002, p < 0.001, respectively). There were no significant differences between groups according to IL-17A and IL-8 concentrations. Serum Galectin-3 was correlated with age (r = 0.289, p < 0.001) and body mass index (BMI) (r = 0.493, p < 0.001) in children with CF. Sputum Galectin-3 levels are negatively correlated with percent predictive forced expiratory volume in 1 s (FEV1) (r = - 0.297, p = 0.029), FEV1 z-score, (r = - 0.316, p = 0.020), percent predictive forced vital capacity (FVC) (r = - 0.347, p = 0.010), and FVC z-score (r = - 0.373, p = 0.006). Conclusion: The study shows that serum Galectin-3 levels increased in clinically stable CF patients, and serum Galectin-3 response may depend on age, gender, and BMI. The sputum Galectin-3 was found to be negatively correlated with patients' lung functions. What is known: • Galectin-3 is a key regulator of chronic inflammation in the lung, liver, kidney, and tumor microenvironment. What is new: • Children with cystic fibrosis (CF) have higher serum Galectin-3 concentrations than healthy children. • Serum Galectin-3 expression influenced by age, BMI, and gender in children with CF.

PMID:38430280 | DOI:10.1007/s00431-024-05479-6

Nutr Clin Pract. 2024 Apr;39 Suppl 1:S57-S77. doi: 10.1002/ncp.11122.

ABSTRACT

Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF.

PMID:38429959 | DOI:10.1002/ncp.11122

J Cyst Fibros. 2024 Feb 29:S1569-1993(24)00023-7. doi: 10.1016/j.jcf.2024.02.011. Online ahead of print.

ABSTRACT

The COVID-19 pandemic necessitated a rapid shift in clinical research to perform virtual visits and remote endpoint assessments, providing a key opportunity to optimize the use of remote endpoints for clinical trials in cystic fibrosis. The use of remote endpoints could allow more diverse participation in clinical trials while minimizing participant burden but must be robustly evaluated to ensure adequate performance and feasibility. In response, the Cystic Fibrosis Foundation convened the Remote Endpoint Task Force (Supplemental Table 1), a multidisciplinary group of CF researchers with remote endpoint expertise and community members tasked to better understand the current and future use of remote endpoints for clinical research. Here, we describe the current use of remote endpoints in CF clinical research, address key unanswered questions regarding their use and feasibility, and discuss the next steps to determine clinical trial readiness.

PMID:38429150 | DOI:10.1016/j.jcf.2024.02.011

Biosens Bioelectron. 2024 Feb 23;253:116166. doi: 10.1016/j.bios.2024.116166. Online ahead of print.

ABSTRACT

Eccrine sweat can serve as a source of biomarkers for assessing physiological health and nutritional balance, for tracking loss of essential species from the body and for evaluating exposure to hazardous substances. The growing interest in this relatively underexplored class of biofluid arises in part from its non-invasive ability for capture and analysis. The simplest devices, and the only ones that are commercially available, exploit soft microfluidic constructs and colorimetric assays with purely passive modes of operation. The most sophisticated platforms exploit batteries, electronic components and radio hardware for inducing sweat, for electrochemical evaluation of its content and for wireless transmission of this information. The work reported here introduces a technology that combines the advantages of these two different approaches, in the form of a cost-effective, easy-to-use device that supports on-demand evaluation of multiple biomarkers in sweat. This flexible, skin-interfaced, miniaturized system incorporates a hydrogel that contains an approved drug to activate eccrine sweat glands, electrodes and a simple circuit and battery to delivery this drug by iontophoresis through the surface of the skin, microfluidic channels and microreservoirs to capture the induced sweat, and multiple colorimetric assays to evaluate the concentrations of chloride, zinc, and iron. As demonstrated in healthy human participants monitored before and after a meal, such devices yield results that match those of traditional laboratory analysis techniques. Clinical studies that involve cystic fibrosis pediatric patients illustrate the use of this technology as a simple, painless, and reliable alternative to traditional hospital systems for measurements of sweat chloride.

PMID:38428069 | DOI:10.1016/j.bios.2024.116166

Sci Adv. 2024 Mar;10(9):eadk1814. doi: 10.1126/sciadv.adk1814. Epub 2024 Mar 1.

ABSTRACT

Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding and trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were additive to the known corrector types, exerting a complementary "type IV" corrector mechanism. Macrocycles achieved wild-type-like folding efficiency of F508del-CFTR at the endoplasmic reticulum and normalized CFTR currents in reconstituted patient-derived bronchial epithelium. Using photo-activatable macrocycles, docking studies and site-directed mutagenesis a highly probable binding site and pose for type IV correctors was identified in a cavity between lasso helix-1 (Lh1) and transmembrane helix-1 of membrane spanning domain (MSD)-1, distinct from the known corrector binding sites. Since only F508del-CFTR fragments spanning from Lh1 until MSD2 responded to type IV correctors, these likely promote cotranslational assembly of Lh1, MSD1, and MSD2. Previously corrector-resistant CFTR folding mutants were also robustly rescued, suggesting substantial therapeutic potential for type IV correctors.

PMID:38427726 | DOI:10.1126/sciadv.adk1814

Microbiology (Reading). 2024 Mar;170(3). doi: 10.1099/mic.0.001445.

ABSTRACT

When cultured together under standard laboratory conditions Pseudomonas aeruginosa has been shown to be an effective inhibitor of Staphylococcus aureus. However, P. aeruginosa and S. aureus are commonly observed in coinfections of individuals with cystic fibrosis (CF) and in chronic wounds. Previous work from our group revealed that S. aureus isolates from CF infections are able to persist in the presence of P. aeruginosa strain PAO1 with a range of tolerances with some isolates being eliminated entirely and others maintaining large populations. In this study, we designed a serial transfer, evolution experiment to identify mutations that allow S. aureus to survive in the presence of P. aeruginosa. Using S. aureus USA300 JE2 as our ancestral strain, populations of S. aureus were repeatedly cocultured with fresh P. aeruginosa PAO1. After eight coculture periods, S. aureus populations that survived better in the presence of PAO1 were observed. We found two independent mutations in the highly conserved S. aureus aspartate transporter, gltT, that were unique to evolved P. aeruginosa-tolerant isolates. Subsequent phenotypic testing demonstrated that gltT mutants have reduced uptake of glutamate and outcompeted wild-type S. aureus when glutamate was absent from chemically defined media. These findings together demonstrate that the presence of P. aeruginosa exerts selective pressure on S. aureus to alter its uptake and metabolism of key amino acids when the two are cultured together.

PMID:38426877 | DOI:10.1099/mic.0.001445

Ann Am Thorac Soc. 2024 Mar;21(3):380-381. doi: 10.1513/AnnalsATS.202311-944ED.

NO ABSTRACT

PMID:38426830 | DOI:10.1513/AnnalsATS.202311-944ED

Pediatr Pulmonol. 2024 Mar 1. doi: 10.1002/ppul.26928. Online ahead of print.

NO ABSTRACT

PMID:38426813 | DOI:10.1002/ppul.26928

G Ital Nefrol. 2024 Feb 28;41(1):2024-vol1.

ABSTRACT

Cystic fibrosis is an autosomal recessive disorder caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most recent therapeutic approach to cystic fibrosis aims to correct structural and functional abnormalities of CFTR protein. CFTR modulators including ivacaftor-tezacaftor-elexacaftor are used in patients with F508del mutation, with clinical improvement. To date, there are no experiences of CFTR modulator therapy in cystic fibrosis patients with organ transplantation and severe renal impairment. We report the case of a patient diagnosed with cystic fibrosis with F508del mutation, who underwent liver transplantation at the age of 19 and started hemodialysis at the age of 24 due to end-stage renal disease secondary to membranous glomerulonephritis. She was treated with Kaftrio (ivacaftor-tezacaftor-elexacaftor) with clinical benefits on appetite, improvement of body mass index, and reduction of pulmonary exacerbations. A reduction of dosage to 75% of the standard dose was required due to alterations of the liver function. Conclusions. Use of CFTR modulators in patient with cystic fibrosis, liver transplant and end-stage renal disease could be considered safe but a clinical and laboratoristic monitoring of hepatic function is needed.

PMID:38426679

Biofilm. 2024 Feb 10;7:100181. doi: 10.1016/j.bioflm.2024.100181. eCollection 2024 Jun.

ABSTRACT

Pseudomonas aeruginosa is a biofilm forming pathogen commonly associated with infection of the cystic fibrosis (CF) lung, chronic wounds and indwelling medical devices. P. aeruginosa is a facultative aerobe that can use nitrate (NO3-) found in healthy and infected tissues and body fluids to generate energy through denitrification. Further, P. aeruginosa the expression of denitrification genes has been found in specimens from people with CF. The main aim of this study was to determine the relative energy contribution of oxygen (O2) respiration and denitrification in single Pseudomonas aeruginosa PAO1 biofilm colonies under different O2 concentrations to estimate the possible relative importance of these metabolic processes in the context of biofilm infections. We showed that the used strain PAO1 in biofilms denitrified with nitrous oxide (N2O), and not nitrogen (N2), as the end product in our incubations. From simultaneous O2 and N2O microprofiles measured with high spatial resolution by microsensors in agar colony biofilms under air, N2 and pure O2, the rates of aerobic respiration and denitrification were calculated and converted to ATP production rates. Denitrification occurred both in the oxic and anoxic zones, and became increasingly dominant with decreasing O2 concentrations. At O2 concentrations characteristic for tissues and wounds (20-60 μM), denitrification was responsible for 50% of the total energy conservation in the biofilm. In addition the formation of nitric oxide (NO), a precursor of N2O and an important regulator of many cellular processes, was strongly influenced by the local O2 concentrations. NO production was inhibited under pure O2, present under anoxia (∼1 μM) and remarkably high (up to 6 μM) under intermediate O2 levels, which can be found in infected tissues. Possible impacts of such NO levels on both the host and the biofilm bacteria are discussed.

PMID:38425549 | PMC:PMC10902143 | DOI:10.1016/j.bioflm.2024.100181

Eur Respir J. 2024 Feb 29;63(2):2301392. doi: 10.1183/13993003.01392-2023. Print 2024 Feb.

NO ABSTRACT

PMID:38423592 | DOI:10.1183/13993003.01392-2023

Eur Respir J. 2024 Feb 29;63(2):2400233. doi: 10.1183/13993003.00233-2024. Print 2024 Feb.

NO ABSTRACT

PMID:38423591 | DOI:10.1183/13993003.00233-2024

J Cyst Fibros. 2024 Feb 28:S1569-1993(24)00026-2. doi: 10.1016/j.jcf.2024.02.013. Online ahead of print.

ABSTRACT

BACKGROUND: Lung infections antibiotic treatment in Cystic Fibrosis patients (pwCF) is often complicated by bacterial persisters, including the so-called Viable but Non Culturable (VBNC) forms, live cells undetected by the routine cultural microbiological methods. This study investigated the occurrence of VBNC cells of five CF bacterial pathogens in 94 pwCF over one year and the possible associations with the patients' clinical features.

METHODS: Sputum samples, recovered at routine visits and during exacerbation episodes, were analyzed for the presence of the five pathogens by both routine culture-based assays and species-specific qPCR. VBNC cells were estimated as the difference between molecular and cultural counts and their presence was matched with the clinical data in particular the therapeutic regimens.

RESULTS: All but ten pwCF showed the presence of VBNC cells at least once during the study. Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus were the species most frequently found in the VBNC state. Only the former showed a significant association between chronic infection and VBNC cells presence; VBNC-MSSA positive patients significantly increased overtime. The presence of non culturable bacteria was generally concurrent with poor lung functionality and more frequent pulmonary exacerbations. No significant association with modulator treatment was evidenced.

CONCLUSIONS: The obtained data demonstrated the overwhelming occurrence of bacterial VBNC cells in CF lung infections, warranting a constant monitoring of pwCF and underlining the need of implementing the routine culture-based assays with culture-independent techniques. This is pivotal to understand the CF bacterial population dynamics and to efficiently contrast the lung infection progression and worsening.

PMID:38423895 | DOI:10.1016/j.jcf.2024.02.013

Am J Respir Crit Care Med. 2024 Feb 29. doi: 10.1164/rccm.202312-2326LE. Online ahead of print.

NO ABSTRACT

PMID:38422389 | DOI:10.1164/rccm.202312-2326LE

J Bras Pneumol. 2024 Feb 23;50(1):e20230230. doi: 10.36416/1806-3756/e20230230. eCollection 2024.

ABSTRACT

OBJECTIVES: This study primarily aimed to investigate the clinical determinants of the Modified Incremental Step Test (MIST) in adults with non-cystic fibrosis bronchiectasis (NCFB). A secondary objective was to compare the cardiopulmonary responses after the MIST and Incremental Shuttle Walk Test (ISWT), two commonly adopted symptom-limited maximum field tests in chronic respiratory diseases.

METHODS: Forty-six patients with clinically stable bronchiectasis participated in this cross-sectional study. MIST and ISWT were performed to determine exercise capacity, while disease severity, fatigue, and quality of life were assessed using the Bronchiectasis Severity Index (BSI), the Fatigue Severity Scale (FSS), and St. George's Respiratory Questionnaire (SGRQ), respectively. Quadriceps muscle strength was evaluated using a hand-held dynamometer, walking speed with a wireless inertial sensing device, and the level of physical activity (steps/day) with a pedometer.

RESULTS: The BSI score, quadriceps muscle strength, daily step count, and the SGRQ total score explained 61.9% of the variance in the MIST (p < 0.001, R2 = 0.67, AR2 = 0.619). The BSI score (r = -0.412, p = 0.004), quadriceps muscle strength (r = 0.574, p = 0.001), daily step count (r = 0.523, p < 0.001), walking speed (r = 0.402, p = 0.006), FSS score (r = -0.551, p < 0.001), and SGRQ total score (r = -0.570, p < 0.001) correlated with the MIST. The patients achieved higher heart rates (HR), HR%, desaturation, dyspnea, and leg fatigue in the MIST compared to the ISWT (p < 0.05).

CONCLUSIONS: Disease severity, quadriceps muscle strength, physical activity level, and quality of life were determinants of MIST. The advantages of the MIST, including higher cardiopulmonary response than ISWT and greater portability, which facilitates its use in various settings, make MIST the preferred choice for investigating symptom-limited exercise capacity in patients with NCFB.

PMID:38422338 | DOI:10.36416/1806-3756/e20230230

Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2316675121. doi: 10.1073/pnas.2316675121. Epub 2024 Feb 29.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease. Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTRinh-172 to an overall resolution of 2.7 Å by cryogenic electron microscopy. We observe that CFTRinh-172 binds inside the pore near transmembrane helix 8, a critical structural element that links adenosine triphosphate hydrolysis with channel gating. Binding of CFTRinh-172 stabilizes a conformation in which the chloride selectivity filter is collapsed, and the pore is blocked from the extracellular side of the membrane. Single-molecule fluorescence resonance energy transfer experiments indicate that CFTRinh-172 inhibits channel gating without compromising nucleotide-binding domain dimerization. Together, these data reconcile previous biophysical observations and provide a molecular basis for the activity of this widely used CFTR inhibitor.

PMID:38422021 | DOI:10.1073/pnas.2316675121

Microb Genom. 2024 Feb;10(2). doi: 10.1099/mgen.0.001205.

ABSTRACT

Pseudomonas aeruginosa, a harmful nosocomial pathogen associated with cystic fibrosis and burn wounds, encodes for a large number of LysR-type transcriptional regulator proteins. To understand how and why LTTR proteins evolved with such frequency and to establish whether any relationships exist within the distribution we set out to identify the patterns underpinning LTTR distribution in P. aeruginosa and to uncover cluster-based relationships within the pangenome. Comparative genomic studies revealed that in the JGI IMG database alone ~86 000 LTTRs are present across the sequenced genomes (n=699). They are widely distributed across the species, with core LTTRs present in >93 % of the genomes and accessory LTTRs present in <7 %. Analysis showed that subsets of core LTTRs can be classified as either variable (typically specific to P. aeruginosa) or conserved (and found to be distributed in other Pseudomonas species). Extending the analysis to the more extensive Pseudomonas database, PA14 rooted analysis confirmed the diversification patterns and revealed PqsR, the receptor for the Pseudomonas quinolone signal (PQS) and 2-heptyl-4-quinolone (HHQ) quorum-sensing signals, to be amongst the most variable in the dataset. Successful complementation of the PAO1 pqsR - mutant using representative variant pqsR sequences suggests a degree of structural promiscuity within the most variable of LTTRs, several of which play a prominent role in signalling and communication. These findings provide a new insight into the diversification of LTTR proteins within the P. aeruginosa species and suggests a functional significance to the cluster, conservation and distribution patterns identified.

PMID:38421269 | DOI:10.1099/mgen.0.001205

EClinicalMedicine. 2024 Feb 20;69:102487. doi: 10.1016/j.eclinm.2024.102487. eCollection 2024 Mar.

ABSTRACT

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

PMID:38420219 | PMC:PMC10900250 | DOI:10.1016/j.eclinm.2024.102487

Pneumologie. 2024 Mar;78(3):204-214. doi: 10.1055/a-1854-3006. Epub 2024 Feb 28.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a regular occurrence in everyday pneumology. ABPA should be considered in patients with severe asthma, in mould allergic patients with very high serum IgE levels and in patients with cystic fibrosis. The aim should be to make the diagnosis as early as possible in the course of the disease to avoid late complications such as bronchiectasis and fibrotic lung remodelling. Symptoms are highly variable and rather non-specific, overlapping with those of the underlying primary disease. However, clearly defined diagnostic criteria exist, so that the diagnosis can be made relatively easily if one thinks of it. In therapy, systemic steroids and antifungals (mainly azoles) play the leading role. However, biologics have been gaining in importance in recent years, especially in cases of insufficient therapy response or occurrence of side effects to standard therapies, as well as an alternative in permanently steroid-dependent patients.

PMID:38417459 | DOI:10.1055/a-1854-3006