Pediatrics. 2024 Jul 17:e2023064546. doi: 10.1542/peds.2023-064546. Online ahead of print.

ABSTRACT

OBJECTIVES: This study described disease characteristics and long-term outcomes in patients diagnosed with very early onset inflammatory bowel disease (VEOIBD) (diagnosed before 6 years of age) and infantile-IBD (before 2 years).

METHODS: Cases from 21 centers worldwide diagnosed with VEOIBD (2008-2018), with minimum 2 years of follow-up, were retrospectively reviewed.

RESULTS: The cohort included 243 patients (52% males, median follow-up of 5.8 [range 2-18] years, including 69 [28%]) with infantile-IBD. IBD subtypes included Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU) in 30%, 59%, and 11%, respectively. Among patients with CD, 94% had colonic involvement, and among patients with UC/IBDU, 75% had pancolitis. Patients with infantile-IBD presented with higher rates of IBDU, lower hemoglobin and albumin levels, and higher C-reactive protein, and had lower response rates to first-induction therapy and corticosteroids therapy (P < .05 for all). Colectomy and diversion surgeries were performed in 11% and 4%, respectively, with no significant differences between age groups. Corticosteroid-free remission rates were 74% and 78% after 3 and 5 years, respectively, and 86% at end of follow-up. Genetic testing was performed in 96 (40%) patients. Among tested population, 15 (16%) were identified with monogenic disease. This group demonstrated lower response rates to induction therapies, higher rates of surgical intervention, and higher rates of major infections (P < .05 for all).

CONCLUSIONS: Patients with VEOIBD, including infantile-IBD, exhibit low rate of complications and surgical interventions at the long term. Patients with monogenic IBD are at risk for more severe disease course.

PMID:39015095 | DOI:10.1542/peds.2023-064546

Respir Care. 2024 Jul 16:respcare.11760. doi: 10.4187/respcare.11760. Online ahead of print.

ABSTRACT

BACKGROUND: Despite advancements in cystic fibrosis (CF) therapeutics, the persistence of chronic infections necessitates continued use of nebulized therapies. Though the Cystic Fibrosis Foundation recommends well-defined cleaning and disinfection of nebulizers to mitigate pathogen exposure risks, discrepancies between Cystic Fibrosis Foundation guidelines, manufacturers' instructions, and variability in center recommendations contribute to confusion and non-standardized practices.

METHODS: A digital survey was distributed to directors, associate directors, and care coordinators of CF centers across the United States to investigate the methods, frequency, and educational practices surrounding nebulizer care they provide patients. Responses were analyzed using descriptive techniques and chi-square analyses.

RESULTS: Of 855 distributed surveys, 129 respondents provided insights into nebulizer care recommendations. Discrepancies in disinfection frequency were notable, with 18% of respondents recommending disinfecting nebulizers less than daily. Approximately 20% of respondents were unsure if their recommendations aligned with Cystic Fibrosis Foundation guidelines while 73% reported that their recommendations strictly adhered to the published guidelines. Of this 73%, all recommended at least daily cleaning, with 69% specifying cleaning before reuse; and 88% recommended disinfection at least daily, with 36% specifying disinfection before reuse. Only 10% recommended both cleaning and disinfection after every use. Disinfection less than daily was recommended by 11% of the respondents who felt they were strictly following the guidelines. We also highlight respondents who cited barriers to strict adhesion to the published guidelines.

CONCLUSIONS: The highlighted variations in CF centers' recommendations for nebulizer care with deviations from Cystic Fibrosis Foundation guidelines underscore the necessity for developing clear and practical guidelines that consider both efficacy and the realities of patient adherence. Collaboration among CF care centers, patients, guideline committees, and other stakeholders is essential to develop recommendations that effectively address the challenges faced by the CF community, ensuring the safe and effective nebulizer use.

PMID:39013569 | DOI:10.4187/respcare.11760

Am J Respir Cell Mol Biol. 2024 Jul 16. doi: 10.1165/rcmb.2023-0398OC. Online ahead of print.

ABSTRACT

We broaden the clinical versatility of human nasal epithelial (HNE) cells. HNEs were isolated from 10 participants harboring CFTR variants: nine with rare variants (Q359R [n=2], G480S, R334W [n=5], and R560T) and one person harboring R117H;7T;TG10/5T;TG12. Cultures were differentiated at air-liquid interface. CFTR function was measured in Ussing chambers at three conditions - baseline, ivacaftor, and elexacaftor+tezacaftor+ivacaftor (ETI). Four participants initiated modulators. Q359R HNEs had 5.4% (%WT) baseline CFTR function and 25.5% with ivacaftor. With therapy, sweat [Cl-] decreased and symptoms resolved. G480S HNEs had 4.1% baseline and 32.1% CFTR function with ETI. Clinically, FEV1 increased and sweat [Cl-] decreased (119 to 46mmol/L) with ETI. In vitro cultures derived from five individuals harboring R334W showed a moderate increase in CFTR function with exposure to modulators. For one of these participants, ETI was begun in vivo; symptoms and FEV1 improved. c.1679G>C (R560T) HNEs had <4% baseline CFTR function and no modulator response. RNA analysis confirmed that c.1679G>C completely mis-splices. A symptomatic patient harboring R117H;7T;TG10/5T;TG12 exhibited reduced CFTR function (17.5%) in HNEs, facilitating mild CF diagnosis. HNEs responded to modulators (ivacaftor: 32.8%, ETI: 55.5%) and, since beginning therapy, lung function improved. While reaffirming HNE use for guiding therapeutic approaches, we inform predictions on modulator response (e.g. R334W) and closely assess variants affecting splicing (e.g. c.1679G>C). Notably, functional studies in HNEs harboring R117H;7T;TG10/5T;TG12 facilitated mild CF diagnosis, suggesting use for HNE functional studies as a clinical diagnostic test.

PMID:39012815 | DOI:10.1165/rcmb.2023-0398OC

JMIR Rehabil Assist Technol. 2024 Jul 15;11:e55718. doi: 10.2196/55718.

ABSTRACT

This viewpoint paper explores the dynamic intersection of physiotherapy and digital health technologies (DHTs) in enhancing the care of people with cystic fibrosis (CF), in the context of advancements such as highly effective modulator therapies that are enhancing life expectancy and altering physiotherapy needs. The role of DHTs, including telehealth, surveillance, home monitoring, and activity promotion, has expanded, becoming crucial in overcoming geographical barriers and accelerated by the recent pandemic. Physiotherapy, integral to CF care since 1946, has shifted toward patient-centered approaches, emphasizing exercise training and a physically active lifestyle. The reduction in inpatient admissions due to highly effective modulator therapies has led to increased home care and online or electronic consultations, and DHTs have revolutionized service delivery, offering flexibility, self-management, and personalized care options; however, there is a need to comprehensively understand user experiences from both people with CF and physiotherapists. This paper highlights the essential exploration of user experiences to facilitate clinician adaptation to the digital requirements of modern clinical management, ensuring equitable care in the "future hospitals" arena. Identifying research gaps, this paper emphasizes the need for a thorough evaluation of DHT use in CF physiotherapy education, training, and self-monitoring, as well as the experiences of people with CF with online or electronic consultations, self-monitoring, and remote interventions. Online group exercise platforms address historical challenges relating to infection control but necessitate comprehensive evaluations of user experiences and preferences. Future-proofing DHTs within the physiotherapy management of CF demands a shift toward full integration, considering stakeholder opinions and addressing barriers. While DHTs have the potential to extend physiotherapy beyond the hospital, this paper stresses the importance of understanding user experiences, addressing digital poverty, and working toward more equitable health care access. A flexible approach in the "future hospital" is advocated, emphasizing the need for a nuanced understanding of user preferences and experiences to optimize the integration of DHTs in CF care.

PMID:39012075 | DOI:10.2196/55718

Nucleic Acids Res. 2024 Jul 16:gkae624. doi: 10.1093/nar/gkae624. Online ahead of print.

ABSTRACT

Nonsense mutations account for >10% of human genetic disorders, including cystic fibrosis, Alagille syndrome, and Duchenne muscular dystrophy. A nonsense mutation results in the expression of a truncated protein, and therapeutic strategies aim to restore full-length protein expression. Most strategies under development, including small-molecule aminoglycosides, suppressor tRNAs, or the targeted degradation of termination factors, lack mRNA target selectivity and may poorly differentiate between nonsense and normal stop codons, resulting in off-target translation errors. Here, we demonstrate that antisense oligonucleotides can stimulate readthrough of disease-causing nonsense codons, resulting in high yields of full-length protein in mammalian cellular lysate. Readthrough efficiency depends on the sequence context near the stop codon and on the precise targeting position of an oligonucleotide, whose interaction with mRNA inhibits peptide release to promote readthrough. Readthrough-inducing antisense oligonucleotides (R-ASOs) enhance the potency of non-specific readthrough agents, including aminoglycoside G418 and suppressor tRNA, enabling a path toward target-specific readthrough of nonsense mutations in CFTR, JAG1, DMD, BRCA1 and other mutant genes. Finally, through systematic chemical engineering, we identify heavily modified fully functional R-ASO variants, enabling future therapeutic development.

PMID:39011883 | DOI:10.1093/nar/gkae624

Front Cell Infect Microbiol. 2024 Jul 1;14:1374318. doi: 10.3389/fcimb.2024.1374318. eCollection 2024.

ABSTRACT

BACKGROUND: In current literature there are only scarce data on the host inflammatory response during Burkholderia cepacia complex (Bcc) persistence. The primary objective of the present research was to carry out cross-sectional analyses of biomarkers and evaluate disease progression in cystic fibrosis (CF) patients with chronic Bcc infection and pathogen-free ones. The secondary aim was to assess prospectively overall survival of the study participants during up to 8 years of follow-up.

METHODS: The study included 116 paediatric patients with CF; 47 CF patients were chronically infected with Bcc, and 69 individuals were Bcc free. Plasma and sputum biomarkers (neutrophil elastase, MMP-8, MMP-9, MMP-12, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, IL-22, IL-23, IL-17, IFN-γ, TGFβ1, TNF-α) were analysed using commercially available kits. Besides, inhibitory effect of dexamethasone on proliferative response of PHA-stimulated peripheral blood lymphocytes had been assessed.

RESULTS: Bcc infected patients did not differ from Bcc free ones in demographic and clinical parameters, but demonstrated an increased rate of glucose metabolism disturbances and survival disadvantage during prolong follow-up period. Biomarkers analyses revealed elevated TNF-α and reduced IL-17F levels in sputum samples of Bcc infected patients. These patients also demonstrated improvement of peripheral blood lymphocyte sensitivity to steroid treatment and reduction in plasma pro-inflammatory (IL-17F and IL-18) and anti-inflammatory (TGFβ1 and IL-10) cytokine concentrations.

CONCLUSIONS: Reduction in IL-17F levels may have several important consequences including increase in steroid sensitivity and glycemic control disturbances. Further investigations are needed to clarify the role of IL-17 cytokines in CF complication development. Low plasma TGFβ1 and IL-10 levels in Bcc infected group may be a sign of subverted activity of regulatory T cells. Such immune alterations may be one of the factors contributing to the development of the cepacia syndrome.

PMID:39011515 | PMC:PMC11246859 | DOI:10.3389/fcimb.2024.1374318

Am J Physiol Lung Cell Mol Physiol. 2024 Jul 16. doi: 10.1152/ajplung.00279.2023. Online ahead of print.

ABSTRACT

Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. Scnn1b-Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model utilizing Scnn1b-Tg mice made diabetic by injection of streptozotocin. In Ussing chamber recordings of trachea, Scnn1b-Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in ATP-activated currents compared to wildtype (WT) littermates. Both diabetic WT (WT-D) and diabetic Scnn1b-Tg (Scnn1b-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 weeks; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF) Bulk lung RNA-seq data showed significant differences between WT-D and Scnn1b-Tg-D mice. Neutrophil counts in BALF were substantially increased in Scnn1b-Tg-D lungs compared to controls (Scnn1b-Tg-con) and compared to WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in Scnn1b-Tg-D mice compared to WT-D mice, consistent with development of a spontaneous lung infection. We intranasally administered Pseudomonas aeruginosa to induce lung infection in these mice for 24 hours, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the Scnn1b-Tg mice. The model can be utilized for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.

PMID:39010826 | DOI:10.1152/ajplung.00279.2023

Orphanet J Rare Dis. 2024 Jul 15;19(1):265. doi: 10.1186/s13023-024-03254-2.

ABSTRACT

BACKGROUND: Globally, researchers are working on projects aiming to enhance the availability of data for rare disease research. While data sharing remains critical, developing suitable methods is challenging due to the specific sensitivity and uniqueness of rare disease data. This creates a dilemma, as there is a lack of both methods and necessary data to create appropriate approaches initially. This work contributes to bridging this gap by providing synthetic datasets that can form the foundation for such developments.

METHODS: Using a hierarchical data generation approach parameterised with publicly available statistics, we generated datasets reflecting a random sample of rare disease patients from the United States (US) population. General demographics were obtained from the US Census Bureau, while information on disease prevalence, initial diagnosis, survival rates as well as race and sex ratios were obtained from the information provided by the US Centers for Disease Control and Prevention as well as the scientific literature. The software, which we have named SynthMD, was implemented in Python as open source using libraries such as Faker for generating individual data points.

RESULTS: We generated three datasets focusing on three specific rare diseases with broad impact on US citizens, as well as differences in affected genders and racial groups: Sickle Cell Disease, Cystic Fibrosis, and Duchenne Muscular Dystrophy. We present the statistics used to generate the datasets and study the statistical properties of output data. The datasets, as well as the code used to generate them, are available as Open Data and Open Source Software.

CONCLUSION: The results of our work can serve as a starting point for researchers and developers working on methods and platforms that aim to improve the availability of rare disease data. Potential applications include using the datasets for testing purposes during the implementation of information systems or tailored privacy-enhancing technologies.

PMID:39010138 | DOI:10.1186/s13023-024-03254-2

Int J Antimicrob Agents. 2024 Jul 13:107276. doi: 10.1016/j.ijantimicag.2024.107276. Online ahead of print.

ABSTRACT

Staphylococcus aureus and Pseudomonas aeruginosa co-infections in patients with cystic fibrosis (CF) are associated with disease severity. Their treatment is complicated by biofilm formation in the sticky mucus obstructing the airways. Using a dual species biofilm (P. aeruginosa/S. aureus) formed in artificial sputum medium, we investigated the activity of broad-spectrum antibiotics (meropenem, ceftazidime, ciprofloxacin, tobramycin) combined with a cocktail of two (bacterio)phages (PSP3 and ISP) proven active via spot tests and double agar on P. aeruginosa PAO1 and S. aureus ATCC 25923. At the highest tested concentrations (100 x MIC), antibiotics alone caused a 20-50% reduction in biomass and reduced S. aureus and P. aeruginosa CFU of 2.3 to 2.8 and 2.1 to 3.6 log10, respectively. Phages alone reduced biofilm biomass by 23% and reduced P. aeruginosa CFU of 2.1 log10, but did not affect S. aureus viability. Phages enhanced antibiotic effects on biomass and exhibited additive effects with antibiotics against P. aeruginosa, but not against S. aureus. Following inhibition of bacterial respiration by phages in planktonic cultures rationalized these observations by demonstrating that PSP3 was effective at multiplicities of infection (MOI) as low as 10-4 plaque forming units (PFU)/CFU on P. aeruginosa, but ISP, at higher MOI (> 0.1) against S. aureus. Thus, pre-screening inhibition of bacterial respiration by phages may assist in selecting those showing activity at sufficiently low titers to showcase anti-biofilm activity in this complex but clinically-relevant in vitro model of biofilm.

PMID:39009289 | DOI:10.1016/j.ijantimicag.2024.107276

Am J Respir Crit Care Med. 2024 Jul 15;210(2):249. doi: 10.1164/rccm.v209erratum10.

NO ABSTRACT

PMID:39007621 | DOI:10.1164/rccm.v209erratum10

Comput Struct Biotechnol J. 2024 Jun 15;23:2615-2622. doi: 10.1016/j.csbj.2024.06.011. eCollection 2024 Dec.

ABSTRACT

Despite the inevitable shift in medical practice towards a deeper understanding of disease etiology and progression through multigenic analysis, the profound historical impact of Mendelian diseases cannot be overlooked. These diseases, such as cystic fibrosis and thalassemia, are characterized by a single variant in a single gene leading to clinical conditions, and have significantly shaped our medical knowledge and treatments. In this respect, the monogenic approach inevitably results in the underutilization of Next-Generation Sequencing (NGS) data. Herein, a retrospective study was performed to assess the diagnostic value of the clinical exome in 32 probands with specific phenotypic characteristics (patients with autoinflammation and immunological dysregulation, N = 20; patients diagnosed with Hemolytic uremic syndrome N = 9; and patients with Waldenström macroglobulinemia, N = 3). A gene enrichment analysis was performed using the *. VCF file generated by SOPHiA-DDM-v4. This analysis selected a subset of genes containing pathogenic or likely pathogenic variants with autosomal dominant (AD) inheritance. In addition, all variants of uncertain significance (VUS) were included, filtered by AD inheritance mode, the presence of compound heterozygotes, and a minor allele frequency (MAF) cutoff of 0.05 %. The aim of the pipeline described here is based on a perspective shift that focuses on analyzing patients' gene assets, offering new light on the complex interplay between genetics and disease presentation. Integrating this approach into clinical practices could significantly enhance the management of patients with rare genetic disorders.

PMID:39006921 | PMC:PMC11245952 | DOI:10.1016/j.csbj.2024.06.011

ACS Omega. 2024 Jun 27;9(27):29870-29883. doi: 10.1021/acsomega.4c03796. eCollection 2024 Jul 9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) affects an estimated global population of around 3 million individuals. IPF is a medical condition with an unknown cause characterized by the formation of scar tissue in the lungs, leading to progressive respiratory disease. Currently, there are only two FDA-approved small molecule drugs specifically for the treatment of IPF and this has created a demand for the rapid development of drugs for IPF treatment. Moreover, denovo drug development is time and cost-intensive with less than a 10% success rate. Drug repurposing currently is the most feasible option for rapidly making the drugs to market for a rare and sporadic disease. Normally, the repurposing of drugs begins with a screening of FDA-approved drugs using computational tools, which results in a low hit rate. Here, an integrated machine learning-based drug repurposing strategy is developed to significantly reduce the false positive outcomes by introducing the predock machine-learning-based predictions followed by literature and GSEA-assisted validation and drug pathway prediction. The developed strategy is deployed to 1480 FDA-approved drugs and to drugs currently in a clinical trial for IPF to screen them against "TGFB1", "TGFB2", "PDGFR-a", "SMAD-2/3", "FGF-2", and more proteins resulting in 247 total and 27 potentially repurposable drugs. The literature and GSEA validation suggested that 72 of 247 (29.14%) drugs have been tried for IPF, 13 of 247 (5.2%) drugs have already been used for lung fibrosis, and 20 of 247 (8%) drugs have been tested for other fibrotic conditions such as cystic fibrosis and renal fibrosis. Pathway prediction of the remaining 142 drugs was carried out resulting in 118 distinct pathways. Furthermore, the analysis revealed that 29 of 118 pathways were directly or indirectly involved in IPF and 11 of 29 pathways were directly involved. Moreover, 15 potential drug combinations are suggested for showing a strong synergistic effect in IPF. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating IPF and other related conditions.

PMID:39005763 | PMC:PMC11238209 | DOI:10.1021/acsomega.4c03796

J Surg Case Rep. 2024 Jul 12;2024(7):rjae459. doi: 10.1093/jscr/rjae459. eCollection 2024 Jul.

ABSTRACT

Giant condyloma accuminata or Buschke-Lowenstein tumor is a rare entity characterized by a large verrucous or cauliflower-shaped lesion primarily affecting the anogenital region. It forms part of a disease spectrum between classic condyloma accuminata and squamous cell carcinoma. Classically, it is thought to arise from previous human papilloma virus infection. Surgical management is usually the treatment of choice despite their high rate of soft tissue infiltration and recurrence. We herein describe a case of a 40-year-old male patient with cystic fibrosis diagnosed with giant condyloma accuminata without human papilloma virus or other paradigmatic risk factors that was treated with near-total surgical resection.

PMID:39005635 | PMC:PMC11240157 | DOI:10.1093/jscr/rjae459

Thorax. 2024 Jul 14:thorax-2023-220964. doi: 10.1136/thorax-2023-220964. Online ahead of print.

ABSTRACT

BACKGROUND: Diagnosing cystic fibrosis (CF) is not always straightforward, in particular when sweat chloride concentration (SCC) is intermediate and <2 CF-causing CFTR variants are identified. The physiological CFTR assays proposed in the guidelines, nasal potential difference and intestinal current measurement, are not readily available nor feasible at all ages. Rectal organoid morphology analysis (ROMA) was previously shown to discriminate between organoids from subjects with and without CF based on a distinct phenotypical difference: compared with non-CF organoids, CF organoids have an irregular shape and lack a visible lumen. The current study serves to further explore the role of ROMA when a CF diagnosis is inconclusive.

METHODS: Organoid morphology was analysed using the previously established ROMA protocol. Two indices were calculated: the circularity index to quantify the roundness of organoids and the intensity ratio as a measure of the presence of a central lumen.

RESULTS: Rectal organoids from 116 subjects were cultured and analysed together with the 189 subjects from the previous study. ROMA almost completely discriminated between CF and non-CF. ROMA indices correlated with SCC, pancreatic status and genetics, demonstrating convergent validity. For cases with an inconclusive diagnosis according to current guidelines, ROMA provided additional diagnostic information, with a diagnostic ROMA classification for 18 of 24 (75%).

DISCUSSION: ROMA provides additional information to support a CF diagnosis when SCC and genetics are insufficient for diagnostic classification. ROMA is standardised and can be centralised, allowing future inclusion in the diagnostic work-up as first-choice physiological assay in case of an unclear diagnosis.

PMID:39004507 | DOI:10.1136/thorax-2023-220964

Nat Commun. 2024 Jul 13;15(1):5898. doi: 10.1038/s41467-024-50281-5.

ABSTRACT

Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10-19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.

PMID:39003323 | DOI:10.1038/s41467-024-50281-5

J Lipid Res. 2024 Jul 12;65(7):100551. doi: 10.1016/j.jlr.2024.100551. Online ahead of print.

ABSTRACT

Intestinal disease is one of the earliest manifestations of cystic fibrosis (CF) in children and is closely tied to deficits in growth and nutrition, both of which are directly linked to future mortality. Patients are treated aggressively with pancreatic enzyme replacement therapy and a high-fat diet to circumvent fat malabsorption, but this does not reverse growth and nutritional defects. We hypothesized that defects in chylomicron production could explain why CF body weights and nutrition are so resistant to clinical treatments. We used gold standard intestinal lipid absorption and metabolism approaches, including mouse mesenteric lymph cannulation, in vivo chylomicron secretion kinetics, transmission electron microscopy, small intestinal organoids, and chylomicron metabolism assays to test this hypothesis. In mice expressing the G542X mutation in cystic fibrosis transmembrane conductance regulator (CFTR-/- mice), we find that defective FFA trafficking across the epithelium into enterocytes drives a chylomicron formation defect. Furthermore, G542X mice secrete small, triglyceride-poor chylomicrons into the lymph and blood. These defective chylomicrons are cleared into extraintestinal tissues at ∼10-fold faster than WT chylomicrons. This defect in FFA absorption resulting in dysfunctional chylomicrons cannot be explained by steatorrhea or pancreatic insufficiency and is maintained in primary small intestinal organoids treated with micellar lipids. These studies suggest that the ultrahigh-fat diet that most people with CF are counselled to follow may instead make steatorrhea and malabsorption defects worse by overloading the absorptive capacity of the CF small intestine.

PMID:39002195 | DOI:10.1016/j.jlr.2024.100551

Int J Mol Sci. 2024 Jun 28;25(13):7113. doi: 10.3390/ijms25137113.

ABSTRACT

Persisters are antibiotic-tolerant bacteria, playing a role in the recalcitrance and relapse of many bacterial infections, including P. aeruginosa pulmonary infections in Cystic Fibrosis (CF) patients. Among novel antimicrobial strategies, the use of probiotics and their products is emerging as a particularly promising approach. The aim of this study was to evaluate the anti-persisters activity of culture filtrate supernatants of Lacticaseibacillus rhamnosus (LRM-CFS) against P. aeruginosa in artificial sputum medium (ASM), which resembles the CF lung environment. Planktonic persisters of two clinical strains of P. aeruginosa (PaCF1 and PaCF4) were obtained following two different procedures: (i) exposing stationary-phase cultures to cyanide m-chlorophenylhydrazone (CCCP) in LB medium; (ii) incubating stationary-phase cultures with high doses of tobramycin (128-fold MIC) in ASM. In addition, persisters from biofilm were obtained by exposing 48 h old biofilm of P. aeruginosa to 128 x MIC of ciprofloxacin. LRM-CFS at dilutions of 1:6 and 1:4 resulted in being bactericidal in ASM against both PaCF1 and PaCF4 persisters obtained after CCCP or tobramycin treatment. Moreover, LRM-CFS at dilution 1:4 caused a reduction of antibiotic-tolerant bacteria in the biofilm of both P. aeruginosa strains. Overall, LRM-CFS represents a promising adjuvant therapeutic strategy against P. aeruginosa recalcitrant infections in CF patients.

PMID:39000222 | DOI:10.3390/ijms25137113

Nutrients. 2024 Jul 3;16(13):2123. doi: 10.3390/nu16132123.

ABSTRACT

IL-17A drives inflammation and oxidative stress, affecting the progression of chronic lung diseases (asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis). Oleuropein (OLP) is a polyphenolic compound present in olive oil and widely included in the Mediterranean diet. It exerts antioxidant and anti-inflammatory activities, oxidative stress resistance, and anticarcinogenic effects with a conceivable positive impact on human health. We hypothesized that OLP positively affects the mechanisms of oxidative stress, apoptosis, DNA damage, cell viability during proliferation, and cell growth in alveolar epithelial cells and tested its effect in a human alveolar epithelial cell line (A549) in the presence of IL-17A. Our results show that OLP decreases the levels of oxidative stress (Reactive Oxygen Species, Mitochondrial membrane potential) and DNA damage (H2AX phosphorylation-ser139, Olive Tail Moment data) and increases cell apoptosis in A549 cells exposed to IL-17A. Furthermore, OLP decreases the number of viable cells during proliferation, the migratory potential (Scratch test), and the single cell capacity to grow within colonies as a cancer phenotype in A549 cells exposed to IL-17A. In conclusion, we suggest that OLP might be useful to protect lung epithelial cells from oxidative stress, DNA damage, cell growth, and cell apoptosis. This effect might be exerted in lung diseases by the downregulation of IL-17A activities. Our results suggest a positive effect of the components of olive oil on human lung health.

PMID:38999871 | DOI:10.3390/nu16132123

J Clin Med. 2024 Jun 22;13(13):3652. doi: 10.3390/jcm13133652.

ABSTRACT

Background: Over the past decades, efforts have been made to improve the nutritional well-being of people with cystic fibrosis (pwCF). Due to the correlation observed between nutritional indices and lung function, prevailing recommendations consistently advocate for BMI percentile goals at or above the 50th percentile in pwCF. Recent global trends show a notable increase in overweight and obese statuses among pwCF. This study aims to explore the nutritional status of Italian pwCF. Methods: Data from the Italian CF Patient's Registry were analysed to assess the proportion of individuals categorized as underweight, target weight, overweight, and obese from 2010 to 2021. Patient-level comparison data from 2021 were also examined to identify the potential determinants of overweight and obesity. Results: Analysis spanning 2010 to 2021 reveals a decrease of approximately 40% in underweight status among adults, while the proportion of malnourished patients younger than 18 years remained stable. Conversely, there was a substantial increase of over 70% in overweight status and over 85% in obesity among adults, with minor fluctuations observed among children and adolescents. Patient factors associated with increased obesity incidence included age older than 45 years, male gender, pancreatic sufficiency, possession of at least one CFTR variant conferring residual function, ppFEV1 > 90, and lower prevalence of Pseudomonas aeruginosa colonization. Conclusions: Our study confirms the evolving nutritional status landscape among Italian adult pwCF, with a significant shift towards overweight and obesity over the past decade. These trends highlight the need for proactive measures within CF standards of care to adapt and address the changing needs of patients.

PMID:38999218 | DOI:10.3390/jcm13133652

J Cyst Fibros. 2024 Jul 11:S1569-1993(24)00776-8. doi: 10.1016/j.jcf.2024.06.007. Online ahead of print.

ABSTRACT

INTRODUCTION: Insulin remains the only recommended medical treatment for cystic fibrosis related diabetes (CFRD) Whilst there is an established role for orally bioavailable incretin mimetic agents such as the dipeptidyl peptidase-4 inhibitors (DPP4-I) in Type 2 diabetes mellitus, there exists little data on their utility in CFRD.

AIM: To examine the use of DPP4-I therapy in patients with CFRD at a single large adult cystic fibrosis center.

METHOD: People with CFRD prescribed a DPP4-I were identified from our specialist CFRD clinic and records were retrospectively examined for indication for therapy, tolerability and effectiveness. Analysis of continuous glucose monitoring data Libre 2 was done for these patients (CGM) pre and at least 3 months post therapy was performed.

RESULTS: 23 people with CF (PwCF) with a mean (SD) age of 35.0 ± 2.4 years were included in this analysis . In 21 patients DPP4-I was prescribed as a monotherapy and it was given in combination with insulin in 2 others. Indications for therapy included reactive hypoglycaemia (n = 10) post prandial hyperglycaemia (8), insulin avoidance (3), metformin intolerance (1) and unclear (1). Therapy was well tolerated with no discontinuations due to adverse effects. Significant improvements were noted in Time in Range- Pre vs Post: 78.0 [67.5 - 84.0] vs 89.0 [79.8 - 96.0]%, p = 0.005, Time above Range -Pre vs Post: 19.5 [12.5 - 30.8] vs 6.0 [2.5 - 16.5]%, p = 0.006 and glucose variability Pre versus Post: 28.3 [25.4 - 31.1] vs 26.9 [23.1 - 31.3], p = 0.021, Of the 10 subjects who initiated therapy for hypoglycaemia, 7 reported an improvement in symptoms. No significant difference was found in weight pre and post: 61.5 ± 15.0 kg vs 62.5 ± 15.3 kg, p = 0.326 or Hba1c pre vs post: 41.0 [36.0 - 53.3] mmol/mol versus 40.5 [36.8 - 47.3], p = 0.727.

CONCLUSION: DPP4-I is well tolerated in CFRD and can lead to an improved glycaemic control in these patients with significant improvement in validated CGM metrics.

PMID:38997826 | DOI:10.1016/j.jcf.2024.06.007