Pediatr Pulmonol. 2024 Oct 11. doi: 10.1002/ppul.27296. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchopulmonary dysplasia, a sequela of preterm birth, is the most common chronic respiratory disorder in infancy, and the second most common in children. Despite this, clinical care remains highly variable with guidelines supported by limited evidence, and do not provide specific guidance for timing of clinical follow-up, echocardiography, modalities of pulmonary function testing, etc. OBJECTIVE/METHODS: To further our understanding of care delivery for BPD, we sought to describe outpatient care patterns at tertiary care centers through survey data from 27 well-established BPD programs.

RESULTS: We observed variability in referral patterns to outpatient BPD clinics, ancillary services provided, indications for follow-up echocardiograms, availability of lung function testing, and criteria for discharge from care.

CONCLUSION: More comprehensive and detailed clinical guidelines similar to other pulmonary diseases such as asthma and cystic fibrosis should be developed to help standardize care and may improve long term outcomes.

PMID:39392254 | DOI:10.1002/ppul.27296

Cell Insight. 2024 Sep 18;3(6):100201. doi: 10.1016/j.cellin.2024.100201. eCollection 2024 Dec.

ABSTRACT

Preclinical models serve as indispensable tools in translational medicine. Specifically, patient-derived models such as patient-derived xenografts (PDX), induced pluripotent stem cells (iPSC), organoids, and recently developed technique of conditional reprogramming (CR) have been employed to reflect the host characteristics of diseases. CR technology involves co-culturing epithelial cells with irradiated Swiss-3T3-J2 mouse fibroblasts (feeder cells) in the presence of a Rho kinase (ROCK) inhibitor, Y-27632. CR technique facilitates the rapid conversion of both normal and malignant cells into a "reprogrammed stem-like" state, marked by robust in vitro proliferation. This is achieved without reliance on exogenous gene expression or viral transfection, while maintaining the genetic profile of the parental cells. So far, CR technology has been used to study biology of diseases, targeted therapies (precision medicine), regenerative medicine, and noninvasive diagnosis and surveillance. Respiratory diseases, ranking as the third leading cause of global mortality, pose a significant burden to healthcare systems worldwide. Given the substantial mortality and morbidity rates of respiratory diseases, efficient and rapid preclinical models are imperative to accurately recapitulate the diverse spectrum of respiratory conditions. In this article, we discuss the applications and future potential of CR technology in modeling various respiratory tract diseases, including lung cancer, respiratory viral infections (such as influenza and Covid-19 and etc.), asthma, cystic fibrosis, respiratory papillomatosis, and upper aerodigestive track tumors. Furthermore, we discuss the potential utility of CR in personalized medicine, regenerative medicine, and clinical translation.

PMID:39391007 | PMC:PMC11462205 | DOI:10.1016/j.cellin.2024.100201

Pulm Ther. 2024 Oct 10. doi: 10.1007/s41030-024-00275-x. Online ahead of print.

ABSTRACT

INTRODUCTION: There are limited real-world data on outcomes in patients with non-cystic fibrosis bronchiectasis (NCFBE). This study assessed clinical characteristics and survival in patients with NCFBE by baseline exacerbation rate.

METHODS: Patients with bronchiectasis (≥ 1 inpatient or ≥ 2 outpatient claims with a bronchiectasis diagnosis code, or one outpatient claim with bronchiectasis code and a chest computed tomography scan) were from the 100% Medicare Fee-for-Service database (Jan 2014-Dec 2020). Patients had continuous enrollment ≥ 12 months pre-index (baseline) and post-index (follow-up), with index a random bronchiectasis claim preceded by ≥ 12 months bronchiectasis history. Patients with cystic fibrosis were excluded. Patients were stratified by exacerbations during baseline (0, 1, or ≥ 2). Follow-up exacerbation rate and all-cause mortality were assessed. Controls were identified using a multistep direct matching approach. Time to death from index was estimated by Kaplan-Meier analyses.

RESULTS: Exacerbation analysis included 92,529 patients with NCFBE and 92,529 matched controls. Exacerbations were common (43% had ≥ 1 exacerbation), with patients with more baseline exacerbations more likely to have ≥ 2 exacerbations during follow-up (11.4%, 24.2%, and 46.8% of patients with 0, 1, and ≥ 2 baseline exacerbations, respectively). Survival analysis included 110,298 patients with NCFBE and 110,298 controls. Time to death was shorter in patients with more baseline exacerbations (P < 0.0001). Five-year survival was 55.3%, 62.6%, and 65.4% for patients with ≥ 2, 1, and 0 baseline exacerbations, respectively, compared with 64.1% for controls.

CONCLUSIONS: In these patients with NCFBE, exacerbations were common. History of exacerbations was associated with future exacerbations and increased all-cause mortality.

PMID:39390311 | DOI:10.1007/s41030-024-00275-x

J Cyst Fibros. 2024 Oct 9:S1569-1993(24)01785-5. doi: 10.1016/j.jcf.2024.09.017. Online ahead of print.

ABSTRACT

RATIONALE: CF care guidelines recommend chronic inhaled antibiotics for chronic Pseudomonas aeruginosa (Pa) lung infection. These medications are costly, time consuming and prescription needs may change with improved outcomes.

OBJECTIVES: We determined the proportion of pwCF with chronic, intermittent or negative Pa infection categories, their clinical and demographic characteristics, factors associated with inhaled antibiotic prescription and changes between 2011 and 2019.

METHODS: This cohort study using the U.S. CF Foundation patient registry for pwCF >2 years, no prior lung transplant, and with ≥3 respiratory cultures/year determined chronic inhaled antibiotics (≥3 months per calendar year) and Pa infection status from encounter level data. Outcomes and odds of prescription for relevant clinical factors were evaluated using generalized estimating equation models with additional interaction between the predictor and the calendar year to examine changes of predictors over time.

RESULTS: Proportion of pwCF with chronic and intermittent Pa decreased and antibiotic prescription rates increased for these groups and decreased for Pa negative pwCF. Hispanic ethnicity, female sex, pancreatic insufficiency, CF diabetes, and ivacaftor/lumacaftor were associated with higher antibiotic prescriptions for each Pa status. Among Pa-negative pwCF prescriptions were higher with Burkholderia spp. (1.17, (CI95 1.03,1.34)) or MRSA (OR 1.45, (1.26,1.68)) but decreased between 2011 and 2019. For Aspergillus OR increased to 1.6,(1.3,1.8) in 2019. Prescriptions for pwCF on ivacaftor decreased, becoming lower in 2019 for chronic (OR 0.7, (0.5,0.8)) and Pa-negative pwCF (OR 0.7, (0.5,0.8)).

CONCLUSIONS: Factors predicting inhaled antibiotic prescription differed between 2011 and 2019 indicating changes in health and care for pwCF even prior to triple-modulators.

PMID:39389810 | DOI:10.1016/j.jcf.2024.09.017

Eur Respir J. 2024 Oct 10;64(4):2401573. doi: 10.1183/13993003.01573-2024. Print 2024 Oct.

NO ABSTRACT

PMID:39389615 | DOI:10.1183/13993003.01573-2024

Ann Am Thorac Soc. 2024 Oct 10. doi: 10.1513/AnnalsATS.202312-1070OC. Online ahead of print.

ABSTRACT

RATIONALE: The pathogenicity of Aspergillus in the cystic fibrosis (CF) airway is debated, leading to unclear clinical benefit of antifungal therapy for Aspergillus infection.

OBJECTIVE: To determine the real-world effectiveness of antifungal use in people with CF (PwCF) with Aspergillus species in the United States.

METHODS: We conducted a retrospective cohort study evaluating the association of antifungal use and respiratory outcomes in PwCF and Aspergillus positive cultures using the Cystic Fibrosis Foundation patient registry. Marginal structural models using inverse-probability treatment weighted estimators were used to test if antifungal exposure was associated with forced expiratory volume in one second percent predicted (FEV1pp) and pulmonary exacerbation rate, while controlling for fixed and time-varying confounders. We conducted sensitivity analyses on individuals with persistent Aspergillus and without concomitant allergic bronchopulmonary aspergillosis (ABPA).

RESULTS: A total of 14,754 individuals with Aspergillus positive cultures between 2006 and 2019 were identified. Antifungals were prescribed to 3,575 (24.2%) unique PwCF during the study period. Antifungal use was not associated with FEV1pp (adjusted estimate -0.96 percentage points, 95% CI -2.21,0.29). Antifungal use was associated with 29% increased rate of pulmonary exacerbations requiring intravenous (IV) antibiotics (adjusted IRR=1.29, 95% CI 1.22, 1.37). In sensitivity analyses limited to individuals without ABPA< antifungals were associated with 1.88 lower FEV1pp (95% CI -3.35, -0.41) and an increased rate of pulmonary exacerbations (adjusted IRR= 1.30, 95% CI 1.21,1.40). Whereas, in patients with persistent Aspergillus and persistent Aspergillus without concomitant ABPA, antifungals were not associated with FEV1pp.

CONCLUSIONS: Antifungal therapy in PwCF and Aspergillus positive cultures was not associated with improvements in FEV>1pp. While antifungal therapy was associated with increased risk for pulmonary exacerbations, this could reflect confounding by severity of disease. Randomized clinical trials examining the clinical efficacy of antifungals in Aspergillus infections are warranted.

PMID:39388639 | DOI:10.1513/AnnalsATS.202312-1070OC

Proc Natl Acad Sci U S A. 2024 Oct 15;121(42):e2414768121. doi: 10.1073/pnas.2414768121. Epub 2024 Oct 10.

ABSTRACT

The cotranslational misfolding of the cystic fibrosis transmembrane conductance regulator chloride channel (CFTR) plays a central role in the molecular basis of CF. The misfolding of the most common CF variant (ΔF508) remodels both the translational regulation and quality control of CFTR. Nevertheless, it is unclear how the misassembly of the nascent polypeptide may directly influence the activity of the translation machinery. In this work, we identify a structural motif within the CFTR transcript that stimulates efficient -1 ribosomal frameshifting and triggers the premature termination of translation. Though this motif does not appear to impact the interactome of wild-type CFTR, silent mutations that disrupt this RNA structure alter the association of nascent ΔF508 CFTR with numerous translation and quality control proteins. Moreover, disrupting this RNA structure enhances the functional gating of the ΔF508 CFTR channel at the plasma membrane and its pharmacological rescue by the CFTR modulators contained in the CF drug Trikafta. The effects of the RNA structure on ΔF508 CFTR appear to be attenuated in the absence of the ER membrane protein complex, which was previously found to modulate ribosome collisions during "preemptive quality control" of a misfolded CFTR homolog. Together, our results reveal that ribosomal frameshifting selectively modulates the assembly, function, and pharmacological rescue of a misfolded CFTR variant. These findings suggest that interactions between the nascent chain, quality control machinery, and ribosome may dynamically modulate ribosomal frameshifting in order to tune the processivity of translation in response to cotranslational misfolding.

PMID:39388263 | DOI:10.1073/pnas.2414768121

bioRxiv [Preprint]. 2024 Sep 25:2024.09.25.615034. doi: 10.1101/2024.09.25.615034.

ABSTRACT

The electrophile methylglyoxal (MG) is produced by microorganisms and host cells through central metabolic pathways. MG is a highly reactive electrophile, so it must be rapidly detoxified to prevent damaging modifications to macromolecules. Pseudomonas aeruginosa , a pathogen of concern due to its ability develop multidrug resistance, causes many types of infections that have been associated with elevated MG levels, including cystic fibrosis (CF). P. aeruginosa isolates commonly have mutations that lead to LasR loss-of-function (LasR-) and we found that lasR mutations confer sensitivity to MG in multiple strain backgrounds. LasR-strains have increased activity of the CbrAB two-component system which represses Crc regulation of metabolism. Here, we show that higher CbrAB activity and low Crc activity renders cells sensitive to MG. We found that P. aeruginosa LasR-strains are more sensitive to MG and have lower intracellular reduced glutathione (GSH) compared to their LasR+ comparators. Consistent with published reports, mutants lacking gloA3 , which encodes a MG-glyoxalase, and mutants lacking GSH biosynthesis enzymes ( gshA or gshB ) were sensitive to MG. Exogenous GSH rescued MG sensitivity in LasR-strains and gshA or gshB mutants, but not in a gloA3 mutant strain. We propose that low GSH levels in LasR-strains contribute to increased sensitivity to MG and H 2 O 2 .

SIGNIFICANCE: Methylglyoxal is a highly reactive metabolite that is detected in various disease states, including those where Pseudomonas aeruginosa is present and MG resistance requires the glutathione-dependent glyoxalase enzyme GloA3 enzyme. This study reveals that P . aeruginosa strains with LasR mutations, which are commonly found in clinical isolates, are more sensitive to methylglyoxal (MG) and hydrogen peroxide due to lower intracellular glutathione levels and high activity of the CbrAB-Crc regulatory pathway. This could be significant for understanding the selective pressures that drive P. aeruginosa evolution in infection sites, as well as a better understanding of LasR-strain metabolism in infections such as those associated with cystic fibrosis.

PMID:39386711 | PMC:PMC11463435 | DOI:10.1101/2024.09.25.615034

bioRxiv [Preprint]. 2024 Sep 25:2024.09.24.614743. doi: 10.1101/2024.09.24.614743.

ABSTRACT

Staphylococcus aureus is one of the most common pathogens isolated from the lungs of people with cystic fibrosis (CF), but little is known about its ability to colonize this niche. We performed a Tn-seq screen to identify genes necessary for S. aureus growth in media prepared from ex vivo CF sputum. We identified 19 genes that were required for growth in all sputum media tested and dozens more that were required for growth in at least one sputum medium. Depleted mutants of interest included insertions in many genes important for surviving metal starvation as well as the primary regulator of cysteine metabolism cymR . To investigate the mechanisms by which these genes contribute to S. aureus growth in sputum, we quantified low-molecular-weight thiols, nutrient transition metals, and the host metal-sequestration protein calprotectin in sputum from 11 individuals with CF. In all samples, the abundance of calprotectin exceeded nutrient metal concentration, explaining the S. aureus requirement for metal-starvation genes. Further, all samples contain potentially toxic quantities of cysteine and sufficient glutathione to satisfy the organic sulfur requirements of S. aureus . Deletion of the cysteine importer genes tcyA and tcyP in the Δ cymR background restored growth to wild-type levels in CF sputum, suggesting that the mechanism by which cymR is required for growth in sputum is to prevent uncontrolled import of cysteine or cystine from this environment. Overall, this work demonstrates that calprotectin and cysteine limit S. aureus growth in CF sputum.

IMPORTANCE: Staphylococcus aureus is a major cause of lung infections in people with cystic fibrosis (CF). This work identifies genes required for S. aureus growth in this niche, which represent potential targets for anti-Staphylococcal treatments. We show that genes involved in surviving metal starvation are required for growth in CF sputum. We also found that the primary regulator of cysteine metabolism, CymR, plays a critical role in preventing cysteine intoxication during growth in CF sputum. To support these models, we analyzed sputum from 11 individuals with CF to determine concentrations of calprotectin, nutrient metals, and low-molecular-weight thiols, which have not previously been quantified together in the same samples.

PMID:39386554 | PMC:PMC11463553 | DOI:10.1101/2024.09.24.614743

Front Pharmacol. 2024 Sep 25;15:1460692. doi: 10.3389/fphar.2024.1460692. eCollection 2024.

ABSTRACT

Exosomes, membrane-bound extracellular vesicles, ranging from approximately 30-200 nm in diameter, are released by almost all cell types and play critical roles in intercellular communication. In response to the prevailing stress, the exosome-bound protein signatures vary in abundance and composition. To identify the bronchoalveolar lavage fluid (BALF) exosome-bound proteins associated with mucoinflammatory lung disease and to gain insights into their functional implications, we compared BALF exosomes-derived proteins from adult Scnn1b transgenic (Scnn1b-Tg+) and wild type (WT) mice. A total of 3,144 and 3,119 proteins were identified in BALF exosomes from Scnn1b-Tg+ and WT mice, respectively. Using cutoff criteria (Log2 fold-change > 1 and adjusted p-value < 0.05), the comparison of identified proteins revealed 127 and 30 proteins that were significantly upregulated and downregulated, respectively, in Scnn1b-Tg+ versus WT mice. In addition, 52 and 27 proteins were exclusively enriched in Scnn1b-Tg+ and WT mice, respectively. The identified exosome-bound proteins from the homeostatic airspaces of WT mice were mostly relevant to the normal physiological processes. The protein signatures enriched in the BALF exosomes of Scnn1b-Tg+ mice were relevant to macrophage activation and mucoinflammatory processes. Ingenuity pathway analyses revealed that the enriched proteins in Scnn1b-Tg+ mice contributed to the inflammatory responses and antimicrobial defense pathways. Selective proteins including, RETNLA/FIZZ1, LGALS3/Galectin-3, S100A8/MRP8, and CHIL3/YM1 were immunolocalized to specific cell types. The comparative analysis between enriched BALF exosome proteins and previously identified differentially upregulated genes in Scnn1b-Tg+ versus WT mice suggested that the compartment-/cell-specific upregulation in gene expression dictates the enrichment of their respective proteins in the lung airspaces. Taken together, this study demonstrates that the BALF exosome-bound protein signatures reflect disease-relevant disturbances. Our findings suggest that the exosomes carry disease-relevant protein signatures that can be used as a diagnostic as well as predictive biomarkers for mucoinflammatory lung disease.

PMID:39386033 | PMC:PMC11461968 | DOI:10.3389/fphar.2024.1460692

Front Nutr. 2024 Sep 25;11:1441201. doi: 10.3389/fnut.2024.1441201. eCollection 2024.

ABSTRACT

INTRODUCTION: To achieve and maintain adequate weight, people with cystic fibrosis (CF) May often consume energy-dense, nutrient-poor foods high in added sugars and refined carbohydrates; however, little is known about the glycemic and metabolic effects of dietary composition in this patient population. The objective of this pilot study was to investigate the safety and tolerability of a low glycemic load (LGL) diet in adults with CF and abnormal glucose tolerance (AGT).

METHODS: Ten adults with CF and AGT completed this prospective, open-label pilot study. Mean age was 27.0 ± 2.1 years, 64% were female, and all had pancreatic insufficiency. Each participant followed his/her typical diet for 2 weeks, then transitioned to a LGL diet via meal delivery service for 8 weeks. The primary outcome was change in weight from baseline to study completion, with safety established if no significant decline was noted. Other key safety outcomes included change in hypoglycemia measured by patient report and continuous glucose monitoring (CGM). Exploratory outcomes included changes in other CGM measures, body composition by dual energy X-ray absorptiometry (DXA), and patient reported outcomes.

RESULTS: There were no significant changes in weight or in subjectively-reported or objectively-measured hypoglycemia. Favorable non-significant changes were noted in CGM measures of hyperglycemia and glycemic variability, DXA measures of fat mass, and gastrointestinal symptom surveys.

DISCUSSION: A LGL dietary intervention was safe and well tolerated in adults with CF and AGT. These results lay the groundwork for future trials investigating the impact of low-glycemic dietary interventions on metabolic outcomes in the CF population.

PMID:39385793 | PMC:PMC11462092 | DOI:10.3389/fnut.2024.1441201

Microbiome. 2024 Oct 9;12(1):196. doi: 10.1186/s40168-024-01893-y.

ABSTRACT

BACKGROUND: Progression of chronic lung disease may lead to the requirement for lung transplant (LTx). Despite improvements in short-term survival after LTx, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the molecular and microbial relationships between underlying lung disease and the development of CLAD in bronchoalveolar lavage fluid (BALF) from subjects post-LTx, which is crucial for tailoring treatment strategies specific to allograft dysfunctions.

METHODS: Paired 16S rRNA gene amplicon sequencing and untargeted LC-MS/MS metabolomics were performed on 856 BALF samples collected over 10 years from LTx recipients (n = 195) with alpha-1-antitrypsin disease (AATD, n = 23), cystic fibrosis (CF, n = 47), chronic obstructive pulmonary disease (COPD, n = 78), or pulmonary fibrosis (PF, n = 47). Data were analyzed using random forest (RF) machine learning and multivariate statistics for associations with underlying disease and CLAD development.

RESULTS: The BALF microbiome and metabolome after LTx differed significantly according to the underlying disease state (PERMANOVA, p = 0.001), with CF and AATD demonstrating distinct microbiome and metabolome profiles, respectively. Uniqueness in CF was mainly driven by Pseudomonas abundance and its metabolites, whereas AATD had elevated levels of phenylalanine and a lack of shared metabolites with the other underlying diseases. BALF microbiome and metabolome composition were also distinct between those who did or did not develop CLAD during the sample collection period (PERMANOVA, p = 0.001). An increase in the average abundance of Veillonella (AATD, COPD) and Streptococcus (CF, PF) was associated with CLAD development, and decreases in the abundance of phenylalanine-derivative alkaloids (CF, COPD) and glycerophosphorylcholines (CF, COPD, PF) were signatures of the CLAD metabolome. Although the relative abundance of Pseudomonas was not associated with CLAD, the abundance of its virulence metabolites, including siderophores, quorum-sensing quinolones, and phenazines, were elevated in those with CF who developed CLAD. There was a positive correlation between the abundance of these molecules and the abundance of Pseudomonas in the microbiome, but there was no correlation between their abundance and the time in which BALF samples were collected post-LTx.

CONCLUSIONS: The BALF microbiome and metabolome after LTx are particularly distinct in those with underlying CF and AATD. These data reflect those who developed CLAD, with increased virulence metabolite production from Pseudomonas, an aspect of CF CLAD cases. These findings shed light on disease-specific microbial and metabolic signatures in LTx recipients, offering valuable insights into the underlying causes of allograft rejection. Video Abstract.

PMID:39385282 | PMC:PMC11462767 | DOI:10.1186/s40168-024-01893-y

Int J Pharm. 2024 Oct 9;666:124813. doi: 10.1016/j.ijpharm.2024.124813. Online ahead of print.

ABSTRACT

This study focuses on developing of a novel inhalation therapy for managing lung hyper-inflammation, producing hybrid polymer-lipid nanoparticles loaded with Iloprost (Ilo). These nanoparticles showed a size of approximately 100 nm with a core-shell structure and provided prolonged drug release, reaching 28 wt% after 6 h of incubation. The phospholipid composition and quantity (64 wt% on the total sample weight) result in minimal interaction with mucin and a significant effect on the rheology of a cystic fibrosis mucus model, in terms of reducing complex viscosity. To obtain an inhalable microparticulate matrix suitable for incorporating Ilo@PEG-LPHNPs, the qualitative and quantitative composition of the feed fluid for the spray drying (SD) process was optimized. The selected composition (10 % wt/vol of mannitol and 10 % wt of ammonium bicarbonate relative to the weight of mannitol) was used to produce Nano-into Microparticles (NiM). The characterization of NiM revealed excellent aerodynamic properties, with a Mass Median Aerodynamic Diameter (MMAD) of 4.34 μm and a Fine Particle Fraction (FPF) of approximately 57 %. Biological characterization revealed that the particles are non-toxic to 16-HBE cells and can effectively evade macrophage uptake, likely due to the presence of PEG in their composition. Moreover, the delivered Iloprost significantly downregulates the production of the pro-inflammatory cytokine IL-6, showing the therapeutic potential of this drug delivery system.

PMID:39384025 | DOI:10.1016/j.ijpharm.2024.124813

Clin Nutr. 2024 Sep 25;43(11):156-163. doi: 10.1016/j.clnu.2024.09.036. Online ahead of print.

ABSTRACT

BACKGROUND: Gastrointestinal (GI) complications are a significant source of morbidity for people with cystic fibrosis (PwCF). Historically, dietary recommendations in CF have focused on calories, typically emphasizing a high fat diet. The changing landscape of CF highlights the need to update this nutritional strategy. There is little research into how the quality of calories consumed by PwCF influences nutritional outcomes, GI symptoms, or likely contributors: intestinal inflammation and GI microbiology. We assessed the feasibility of a whole foods-based diet (WFD) and avoidance of ultra-processed foods, measuring safety/tolerability, adherence, and GI symptoms, as well as fecal measures of inflammation and microbiota among children with CF (CwCF) with GI symptoms.

METHODS: Single center, 4-week dietary intervention involving CwCF aged 5-14 years who screened positive on GI symptom questionnaire. Assessments included weight, symptom questionnaires and adverse events (AEs). Stool was analyzed for microbiota (16S rRNA) and calprotectin.

RESULTS: 108 children were pre-screened, 9 enrolled and 8 initiated and completed the study. There were no significant changes in weight and no AEs. PEDS-QL GI identified overall improvement in symptoms. Certain symptom domains (constipation, diarrhea, gas/bloating, stomach pain and hurt) demonstrated significant improvement on the WFD. Of two participants with abnormal fecal calprotectin at enrollment, both exhibited decreased values on WFD. There was no significant change in microbiota diversity.

CONCLUSION: A WFD diet was feasible and safe in CwCF. There was improvement in GI symptom scores based on both parent and child assessments. Larger studies are needed to further investigate effects on intestinal inflammation and microbiota.

PMID:39383549 | DOI:10.1016/j.clnu.2024.09.036

Ann Am Thorac Soc. 2024 Oct 9. doi: 10.1513/AnnalsATS.202311-1008OC. Online ahead of print.

ABSTRACT

RATIONALE: Primary ciliary dyskinesia (PCD) and cystic fibrosis (CF) are both genetic diseases of mucociliary clearance resulting in progressive lung disease with onset in early life. PCD is often considered to be milder in childhood than CF, based on minimal evidence. Similar to CF, genotype-phenotype associations exist in PCD: pathogenic variants in CCDC39 and CCDC40, causing inner dynein arm/microtubular defects (IDA/MTD) are associated with more severe disease.

OBJECTIVES: To compare longitudinal outcomes in matched children with PCD and CF. We hypothesized that children with PCD with IDA/MTD defects would have lower lung function but better nutritional indices than matched children with CF with minimal function genotypes (i.e., those associated with pancreatic insufficiency).

METHODS: Children with PCD enrolled in a prospective, multicenter, observational study were matched with CF patients from the CF Foundation Patient Registry by birth cohort, age, sex, race/ethnicity and year of study visit. The association of disease group overall and by severity class (PCD-IDA/MTD versus all other defects and CF-minimal versus residual function) with longitudinal outcomes up to age 17 was evaluated with cubic spline mixed effects models.

MEASUREMENT AND MAIN RESULTS: Groups included 136 children with PCD (40 IDA/MTD, 96 other) and 476 with CF (446 minimal function, 30 residual function). Below age 14, the PCD group had similar or lower estimated mean FEV1 % predicted compared to CF (e.g., at age 10, -5.4 % predicted lower (95% CI: -7.7, -3.1)). Compared to the CF-minimal function (pancreatic insufficient) group, the PCD-IDA/MTD group had similar BMI; estimated mean FEV1 % predicted was significantly lower by age 10 (mean difference -10.6% (95% CI: -14.7, -6.4), increasing to -15.7% (95% CI: -20.3, -11.2) at age 14. The CF cohort had increased prevalence of Pseudomonas aeruginosa cultured on one or more occasions compared to children with PCD (67% vs 27%, p<0.001); there was no difference in prevalence of P. aeruginosa between children with PCD-IDA/MTD and PCD-other.

CONCLUSIONS: In childhood, average lung function abnormalities in PCD are not milder than CF, particularly for those with IDA/MTD ciliary defects. New guidelines and treatments to improve outcomes in PCD are urgently needed.

PMID:39383539 | DOI:10.1513/AnnalsATS.202311-1008OC

Compr Child Adolesc Nurs. 2024 Oct 9:1-17. doi: 10.1080/24694193.2024.2411986. Online ahead of print.

ABSTRACT

This paper focused on the effectiveness of a parent empowerment intervention based on nursing education (PEINE). This study examined whether the intervention improved the quality of life of children with cystic fibrosis (CF) and improved their caregivers learn about the disease and develop problem-solving and coping skills. This randomized-controlled trial used a pretest-posttest parallel-group research design. The sample consisted of 48 parents (caregivers) of children with CF. Participants were randomly assigned to an intervention (n = 24) and a control group (n = 24). The intervention group received PEINE and standard care and treatment for ten weeks. The control group received standard care and treatment. Data were collected using a Disease Information Survey (DIS), the Ways of Coping Inventory (WCI), the Problem-Solving Inventory (PSI), and the Cystic Fibrosis Questionnaire (CFQ-R). After the intervention, the intervention group DIS scores (d: 1,627 [CI: 0.934,2.305], had more correct answers than the control group. Nursing interventions were effective (p < .001). There was no significant difference in the mean pretest-posttest PSI scores (d: 0.378 [CI: -0.221-0.972], posttest WCI scores (d: 0.239 [CI:-0.356-0.831]) between the intervention and control groups (p>.05). There was a significant difference in the mean posttest CFQ-R scores between the intervention and control groups (d: 1.363 [CI: l.698, 2.015]);(p < .001). PEINE increased the intervention group participants develop disease-management skills. However, the increase in their PSI and WCI scores was statistically insignificant. PEINE also increased the quality of life of children with CF. Parents of children followed in pediatric pulmonary diseases participated in the study. Parents were informed during outpatient clinic visits. After the first meeting, the children and parents who voluntarily agreed to participate in the research were contacted by phone. The outpatient nurse assisted in communicating with children and parents.

PMID:39382937 | DOI:10.1080/24694193.2024.2411986

Crit Rev Microbiol. 2024 Oct 9:1-36. doi: 10.1080/1040841X.2024.2407378. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a versatile Gram-negative pathogen known for its ability to invade the respiratory tract, particularly in cystic fibrosis patients. This review provides a comprehensive analysis of the multifaceted strategies for colonization, virulence, and immune evasion used by P. aeruginosa to infect the host. We explore the extensive protein arsenal of P. aeruginosa, including adhesins, exotoxins, secreted proteases, and type III and VI secretion effectors, detailing their roles in the infective process. We also address the unique challenge of treating diverse lung conditions that provide a natural niche for P. aeruginosa on the airway surface, with a particular focus in cystic fibrosis. The review also discusses the current limitations in treatment options due to antibiotic resistance and highlights promising future approaches that target host-pathogen protein-protein interactions. These approaches include the development of new antimicrobials, anti-attachment therapies, and quorum-sensing inhibition molecules. In summary, this review aims to provide a holistic understanding of the pathogenesis of P. aeruginosa in the respiratory system, offering insights into the underlying molecular mechanisms and potential therapeutic interventions.

PMID:39381985 | DOI:10.1080/1040841X.2024.2407378

Oncoimmunology. 2024 Oct 7;13(1):2413719. doi: 10.1080/2162402X.2024.2413719. eCollection 2024.

ABSTRACT

Acyl CoA binding protein (ACBP, which is encoded by diazepam binding inhibitor, DBI) acts on the gamma-amino butyric acid (GABA) receptor type A via a specific binding site that is shared by diazepam and other benzodiazepines. Both ACBP/DBI and benzodiazepines act as positive allosteric modulators, hence increasing GABA effects on this receptor. Recently, we found that ACBP/DBI acts as an endogenous immunosuppressor, meaning that its antibody-mediated neutralization has immunostimulatory effects and enhances the efficacy of immunotherapy and chemoimmunotherapy in mouse models. Driven by these considerations, we investigated whether diazepam administration in mice would reverse the beneficial effects of ACBP/DBI neutralization on cancer chemoimmunotherapy. Indeed, diazepam abolished the therapeutic of anti-ACBP/DBI antibodies, supporting the idea that diazepam exerts immunosuppressive properties. Of note, treatment with benzodiazepines was associated with poor clinical responses to chemoimmunotherapy in patients with non-small cell lung cancer (NSCLC) as compared to individuals not receiving any psychotropic drugs. Medication with other psychotropic drugs than benzodiazepines did not compromise the outcome of chemoimmunotherapy, indicating that this immunosuppressive effect was benzodiazepine specific. We conclude that benzodiazepines may confer systemic immunosuppression. This hypothesis requires further epidemiological and clinical confirmation.

PMID:39381589 | PMC:PMC11459736 | DOI:10.1080/2162402X.2024.2413719

Oncoimmunology. 2024 Oct 7;13(1):2413200. doi: 10.1080/2162402X.2024.2413200. eCollection 2024.

ABSTRACT

Acyl CoA binding protein (ACBP) encoded by DBI is a tissue hormone that limits autophagy in multiple cell types, hence acting as an extracellular autophagy checkpoint. We recently reported in Molecular Cancer that monoclonal antibodies neutralizing ACBP improve immunosurveillance of breast and lung carcinomas. Moreover, ACBP neutralization improves the outcome of neoadjuvant chemoimmunotherapy with PD-1 blockade in preclinical models.

PMID:39381588 | PMC:PMC11459760 | DOI:10.1080/2162402X.2024.2413200

Heliyon. 2024 Sep 19;10(18):e37977. doi: 10.1016/j.heliyon.2024.e37977. eCollection 2024 Sep 30.

ABSTRACT

The study of many diseases is limited by the in vitro systems available. Cystic Fibrosis-Related Diabetes (CFRD), the main co-morbidity of Cystic Fibrosis (CF), is a perfect example. Cells in vivo experience glucose fluctuations after meals. In contrast, cells cultured in vitro are initially exposed to high glucose media. Glucose gets progressively depleted until the next media change days later, which is not physiologically relevant and could negatively impact the results of research studies. To better study the mechanisms driving CFRD pathophysiology, we developed a programmable and automated cell culture system (PACCS) capable of mimicking acute hyperglycemic episodes experienced by CFRD patients after meals. We adapted a commercially available perfusion system and performed 3D modeling to develop this system. Results show that PACCS can be successfully used to culture airway epithelial cells, both immortalized and primary cells. Further, CF cells responded differently to meal-like conditioning when compared to controls, suggesting impaired adaptative responses in CF cells. Overall, PACCS will allow us to better study CFRD pathophysiology, and it could be used for a wide range of other applications.

PMID:39381220 | PMC:PMC11459049 | DOI:10.1016/j.heliyon.2024.e37977