Beyond Borders of the Cell: How Extracellular Vesicles Shape COVID-19 for People with Cystic Fibrosis.

The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved in cell-cell communications in different physiological and pathological conditions, including inflammation and infection. The CF airway cells release EVs that differ from those released by healthy cells and may play an intriguing role in regulating the inflammatory response to SARS-CoV-2. On the one hand, EVs may activate neutrophils and exacerbate inflammation. On the other hand, EVs may block IL-6, a pro-inflammatory cytokine associated with severe COVID-19, and protect PwCF from adverse outcomes. EVs are regulated by TGF-ß signaling, essential in different disease states, including COVID-19. Here, we review the knowledge, identify the gaps in understanding, and suggest future research directions to elucidate the role of EVs in PwCF during COVID-19.

Insights into the Adolescent Cystic Fibrosis Airway Microbiome Using Shotgun Metagenomics.

Cystic fibrosis (CF) is an inherited genetic disorder which manifests primarily in airway disease. Recent advances in molecular technologies have unearthed the diverse polymicrobial nature of the CF airway. Numerous studies have characterised the genus-level composition of this airway community using targeted 16S rDNA sequencing. Here, we employed whole-genome shotgun metagenomics to provide a more comprehensive understanding of the early CF airway microbiome. We collected 48 sputum samples from 11 adolescents and children with CF over a 12-month period and performed shotgun metagenomics on the Illumina NextSeq platform. We carried out functional and taxonomic analysis of the lung microbiome at the species and strain levels. Correlations between microbial diversity measures and independent demographic and clinical variables were performed. Shotgun metagenomics detected a greater diversity of bacteria than culture-based methods. A large proportion of the top 25 most-dominant species were anaerobes. Samples dominated by Staphylococcus aureus and Prevotella melaninogenica had significantly higher microbiome diversity, while no CF pathogen was associated with reduced microbial diversity. There was a diverse resistome present in all samples in this study, with 57.8% agreement between shotgun metagenomics and culture-based methods for detection of resistance. Pathogenic sequence types (STs) of S. aureus, Pseudomonas aeruginosa, Haemophilus influenzae and Stenotrophomonas maltophilia were observed to persist in young CF patients, while STs of S. aureus were both persistent and shared between patients. This study provides new insight into the temporal changes in strain level composition of the microbiome and the landscape of the resistome in young people with CF. Shotgun metagenomics could provide a very useful one-stop assay for detecting pathogens, emergence of resistance and conversion to persistent colonisation in early CF disease.

Impact of 1-Year Supplementation with High-Rich Docosahexaenoic Acid (DHA) on Clinical Variables and Inflammatory Biomarkers in Pediatric Cystic Fibrosis: A Randomized Double-Blind Controlled Trial.

A randomized, double-blind, and placebo-controlled study was conducted to assess the effect of dietary supplementation with high-rich docosahexaenoic acid (DHA) (Tridocosahexanoin-AOX® 70%) at 50 mg/kg/day in pediatric patients with cystic fibrosis (CF) as compared with placebo. The duration of supplementation was 12 months. A total of 22 patients were included, with 11 in the DHA group and 11 in the placebo group. The mean age was 11.7 years. The outcome variables were pulmonary function, exacerbations, sputum cellularity, inflammatory biomarkers in sputum and peripheral blood, and anthropometric variables. In the DHA group, there was a significant increase in FVC (p = 0.004) and FVE1 expressed in liters (p = 0.044) as compared with placebo, and a lower median number of exacerbations (1 vs. 2). Differences in sputum cellularity (predominantly neutrophilic), neutrophilic elastase, and sputum and serum concentrations of resolvin D1 (RvD1), interleukin (IL)-8 (IL-8), and tumor necrosis factor alpha (TNF-α) between the study groups were not found. Significant increases in weight and height were also observed among DHA-supplemented patients. The administration of the study product was safe and well tolerated. In summary, the use of a highly concentrated DHA supplement for 1 year as compared with placebo improved pulmonary function and reduced exacerbations in pediatric CF.

The prevalence of developmental defects of enamel in people with cystic fibrosis: a systematic review.

BACKGROUND: Oral health impacts systemic health, individual well-being, and quality of life. It is important to identify conditions that may exacerbate oral disease to aid public health and policy development and promote targeted patient treatment strategies. Developmental defects can increase an individual's risk of dental caries, hypersensitivity, premature tooth wear, erosion, and poor aesthetics. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School and Hospital, a systematic review of available literature was conducted to assess the prevalence of enamel defects in people with cystic fibrosis. AIMS: To critically evaluate the literature to determine if the prevalence of developmental defects of enamel is higher in people with cystic fibrosis (PwCF). METHODS: Data Sources: Three online databases were searched Embase, Scopus, and Web of Science Core Collection. Studies that examined an association between cystic fibrosis and developmental defects of enamel were included in this systematic review. RESULTS: The initial search identified 116 publications from the following databases Embase, Web of Science Core Collection, and Scopus. Eleven studies were included for qualitative analysis. Nine studies concluded that PwCF had a higher prevalence of enamel defects than control people and one study found no difference in cystic fibrosis (CF) status. All studies had a risk of bias that may influence study results and their interpretation. CONCLUSIONS: The results of the systematic review show a consistent pattern that PwCF have a higher prevalence of DDE than people without CF. Genetic dysfunction, chronic systemic infections, and long-term antibiotic use are possible aetiological causes. This review highlights the need for future studies to investigate if DDEs are caused by the underlying CFTR mutation or as a consequence of disease manifestations and/or management.

PREFUL MRI for Monitoring Perfusion and Ventilation Changes after Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis: A Feasibility Study.

Purpose To assess the feasibility of monitoring the effects of elexacaftor-tezacaftor-ivacaftor (ETI) therapy on lung ventilation and perfusion in people with cystic fibrosis (CF), using phase-resolved functional lung (PREFUL) MRI. Materials and Methods This secondary analysis of a multicenter prospective study was carried out between August 2020 and March 2021 and included participants 12 years or older with CF who underwent PREFUL MRI, spirometry, sweat chloride test, and lung clearance index assessment before and 8-16 weeks after ETI therapy. For PREFUL-derived ventilation and perfusion parameter extraction, two-dimensional coronal dynamic gradient-echo MR images were evaluated with an automated quantitative pipeline. T1- and T2-weighted MR images and PREFUL perfusion maps were visually assessed for semiquantitative Eichinger scores. Wilcoxon signed rank test compared clinical parameters and PREFUL values before and after ETI therapy. Correlation of parameters was calculated as Spearman ρ correlation coefficient. Results Twenty-three participants (median age, 18 years [IQR: 14-24.5 years]; 13 female) were included. Quantitative PREFUL parameters, Eichinger score, and clinical parameters (lung clearance index = 21) showed significant improvement after ETI therapy. Ventilation defect percentage of regional ventilation decreased from 18% (IQR: 14%-25%) to 9% (IQR: 6%-17%) (P = .003) and perfusion defect percentage from 26% (IQR: 18%-36%) to 19% (IQR: 13%-24%) (P = .002). Areas of matching normal (healthy) ventilation and perfusion increased from 52% (IQR: 47%-68%) to 73% (IQR: 61%-83%). Visually assessed perfusion scores did not correlate with PREFUL perfusion (P = .11) nor with ventilation-perfusion match values (P = .38). Conclusion The study demonstrates the feasibility of PREFUL MRI for semiautomated quantitative assessment of perfusion and ventilation changes in response to ETI therapy in people with CF. Keywords: Pediatrics, MR-Functional Imaging, Pulmonary, Lung, Comparative Studies, Cystic Fibrosis, Elexacaftor-Tezacaftor-Ivacaftor Therapy, Fourier Decomposition, PREFUL, Free-Breathing Proton MRI, Pulmonary MRI, Perfusion, Functional MRI, CFTR, Modulator Therapy, Kaftrio Clinical trial registration no. NCT04732910 Supplemental material is available for this article. © RSNA, 2024.

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OBJECTIVES: To investigate the nutritional status of children with cystic fibrosis (CF) and understand the correlation between malnutrition and clinical characteristics as well as lung function. METHODS: A retrospective analysis was performed on clinical data of CF children admitted from January 2016 to June 2023. Clinical characteristics of CF children with different nutritional statuses were compared, and the correlation between malnutrition and lung function was analyzed. RESULTS: A total of 52 CF children were included, comprising 25 boys (48%) and 27 girls (52%), aged between 7 months and 17 years. Respiratory symptoms were the predominant clinical manifestations (96%, 50/52). The prevalence of malnutrition was 65% (34/52), with moderate/severe malnutrition being the most common (65%, 22/34). The malnutrition group had a longer duration of illness, higher proportion of digestive system symptoms, and lower levels of serum albumin (P<0.05). Pulmonary function parameters, including forced expiratory volume in one second as a percentage of the predicted value, ratio of forced expiratory volume in one second to forced vital capacity, forced expiratory flow at 25% of forced vital capacity exhaled, forced expiratory flow at 50% of forced vital capacity exhaled, forced expiratory flow at 75% of forced vital capacity exhaled, and maximum mid-expiratory flow as a percentage of the predicted value, were lower in the malnutrition group compared to the normal nutrition group (P<0.05). Correlation analysis showed body mass index Z-score was positively correlated with the above six pulmonary function parameters (P<0.05). CONCLUSIONS: The prevalence of malnutrition is high in CF children and is associated with decreased lung function. CF children with higher body mass index have better lung function. Therefore, screening and evaluation of nutritional status as well as appropriate nutritional intervention should be emphasized in CF children.

The effect of respiratory muscle training on children and adolescents with cystic fibrosis: a systematic review and meta-analysis.

BACKGROUND: Cystic fibrosis is a chronic genetic disease that can affect the function of the respiratory system. Previous reviews of the effects of respiratory muscle training in people with cystic fibrosis are uncertain and do not consider the effect of age on disease progression. This systematic review aims to determine the effectiveness of respiratory muscle training in the clinical outcomes of children and adolescents with cystic fibrosis. METHODS: Up to July 2023, electronic databases and clinical trial registries were searched. Controlled clinical trials comparing respiratory muscle training with sham intervention or no intervention in children and adolescents with cystic fibrosis. The primary outcomes were respiratory muscle strength, respiratory muscle endurance, lung function, and cough. Secondary outcomes included exercise capacity, quality of life and adverse events. Two review authors independently extracted data and assessed study quality using the Cochrane Risk of Bias Tool 2. The certainty of the evidence was assessed according to the GRADE approach. Meta-analyses where possible; otherwise, take a qualitative approach. RESULTS: Six studies with a total of 151 participants met the inclusion criteria for this review. Two of the six included studies were published in abstract form only, limiting the available information. Four studies were parallel studies and two were cross-over designs. There were significant differences in the methods and quality of the methodology included in the studies. The pooled data showed no difference in respiratory muscle strength, lung function, and exercise capacity between the treatment and control groups. However, subgroup analyses suggest that inspiratory muscle training is beneficial in increasing maximal inspiratory pressure, and qualitative analyses suggest that respiratory muscle training may benefit respiratory muscle endurance without any adverse effects. CONCLUSIONS: This systematic review and meta-analysis indicate that although the level of evidence indicating the benefits of respiratory muscle training is low, its clinical significance suggests that we further study the methodological quality to determine the effectiveness of training. TRIAL REGISTRATION: The protocol for this review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023441829.

Non-coding regulatory sRNAs from bacteria of the Burkholderia cepacia complex.

Small non-coding RNAs (sRNAs) are key regulators of post-transcriptional gene expression in bacteria. Hundreds of sRNAs have been found using in silico genome analysis and experimentally based approaches in bacteria of the Burkholderia cepacia complex (Bcc). However, and despite the hundreds of sRNAs identified so far, the number of functionally characterized sRNAs from these bacteria remains very limited. In this mini-review, we describe the general characteristics of sRNAs and the main mechanisms involved in their action as regulators of post-transcriptional gene expression, as well as the work done so far in the identification and characterization of sRNAs from Bcc. The number of functionally characterized sRNAs from Bcc is expected to increase and to add new knowledge on the biology of these bacteria, leading to novel therapeutic approaches to tackle the infections caused by these opportunistic pathogens, particularly severe among cystic fibrosis patients. KEY POINTS: •Hundreds of sRNAs have been identified in Burkholderia cepacia complex bacteria (Bcc). •A few sRNAs have been functionally characterized in Bcc. •Functionally characterized Bcc sRNAs play major roles in metabolism, biofilm formation, and virulence.

The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience.

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [- 3.86% (95% CI - 5.28-2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [- 3.46% (95% CI - 4.95-1.96)] and Pseudomonas aeruginosa [- 2.80%95% CI (- 4.26-1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (- 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

OrgaSegment: deep-learning based organoid segmentation to quantify CFTR dependent fluid secretion.

Epithelial ion and fluid transport studies in patient-derived organoids (PDOs) are increasingly being used for preclinical studies, drug development and precision medicine applications. Epithelial fluid transport properties in PDOs can be measured through visual changes in organoid (lumen) size. Such organoid phenotypes have been highly instrumental for the studying of diseases, including cystic fibrosis (CF), which is characterized by genetic mutations of the CF transmembrane conductance regulator (CFTR) ion channel. Here we present OrgaSegment, a MASK-RCNN based deep-learning segmentation model allowing for the segmentation of individual intestinal PDO structures from bright-field images. OrgaSegment recognizes spherical structures in addition to the oddly-shaped organoids that are a hallmark of CF organoids and can be used in organoid swelling assays, including the new drug-induced swelling assay that we show here. OrgaSegment enabled easy quantification of organoid swelling and could discriminate between organoids with different CFTR mutations, as well as measure responses to CFTR modulating drugs. The easy-to-apply label-free segmentation tool can help to study CFTR-based fluid secretion and possibly other epithelial ion transport mechanisms in organoids.

A RCT to explore the effectiveness of supporting adherence to nebuliser medication in adults with cystic fibrosis: fidelity assessment of study interventions.

BACKGROUND: A multi-component self-management intervention 'CFHealthHub' was developed to reduce pulmonary exacerbations in adults with Cystic Fibrosis (CF) by supporting adherence to nebuliser medication. It was evaluated in a randomized controlled trial (RCT) involving 19 CF centres, with 32 interventionists, 305 participants in the intervention group, and 303 participants in the standard care arm. Ensuring treatment fidelity of intervention delivery was crucial to ensure that the intervention produced the expected outcomes. METHODS: Fidelity of the CFHealthHub intervention and standard care was assessed using different methods for each of the five fidelity domains defined by the Borrelli framework: study design, training, treatment delivery, receipt, and enactment. Study design ensured that the groups received the intended intervention or standard care. Interventionists underwent training and competency assessments to be deemed certified to deliver the intervention. Audio-recorded intervention sessions were assessed for fidelity drift. Receipt was assessed by identifying whether participants set Action and Coping Plans, while enactment was assessed using click analytics on the CFHealthHub digital platform. RESULTS: Design: There was reasonable agreement (74%, 226/305) between the expected versus actual intervention dose received by participants in the CFHealthHub intervention group. The standard care group did not include focused adherence support for most centres and participants. Training: All interventionists were trained. Treatment delivery: The trial demonstrated good fidelity (overall fidelity by centre ranged from 79 to 97%), with only one centre falling below the mean threshold (> 80%) on fidelity drift assessments. Receipt: Among participants who completed the 12-month intervention, 77% (205/265) completed at least one action plan, and 60% (160/265) completed at least one coping plan. Enactment: 88% (268/305) of participants used web/app click analytics outside the intervention sessions. The mean (SD) number of web/app click analytics per participant was 31.2 (58.9). Additionally, 64% (195/305) of participants agreed to receive notifications via the mobile application, with an average of 53.6 (14.9) notifications per participant. CONCLUSIONS: The study demonstrates high fidelity throughout the RCT, and the CFHealthHub intervention was delivered as intended. This provides confidence that the results of the RCT are a valid reflection of the effectiveness of the CFHealthHub intervention compared to standard care. TRIAL REGISTRATION: ISRCTN registry: ISRCTN55504164 (date of registration: 12/10/2017).

Use of CFTR Modulators for Cystic Fibrosis in a Patient with Liver Transplant and ESRD on Hemodialysis.

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.

Airway commensal bacteria in cystic fibrosis inhibit the growth of P. aeruginosa via a released metabolite.

In cystic fibrosis (CF), Pseudomonas aeruginosa infection plays a critical role in disease progression. Although multiple studies suggest that airway commensals might be able to interfere with pathogenic bacteria, the role of the distinct commensals in the polymicrobial lung infections is largely unknown. In this study, we aimed to identify airway commensal bacteria that may inhibit the growth of P. aeruginosa. Through a screening study with more than 80 CF commensal strains across 21 species, more than 30 commensal strains from various species have been identified to be able to inhibit the growth of P. aeruginosa. The underlying mechanisms were investigated via genomic, metabolic and functional analysis, revealing that the inhibitory commensals may affect the growth of P. aeruginosa by releasing a large amount of acetic acid. The data provide information about the distinct roles of airway commensals and provide insights into novel strategies for controlling airway infections.

Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.

Experimentally evolved Staphylococcus aureus shows increased survival in the presence of Pseudomonas aeruginosa by acquiring mutations in the amino acid transporter, GltT.

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.

Surgical and medical management of chronic rhinosinusitis in pediatric cystic fibrosis patients: Impact on olfactory symptoms.

BACKGROUND AND PURPOSE: Olfactory dysfunction (OD) commonly occurs in patients with sinonasal dysfunction, but the prevalence and severity of olfactory issues in adolescents with cystic fibrosis (AwCF) is unclear. OD may contribute to dietary deficiencies and exacerbate nutritional challenges. We sought to review literature on the effectiveness of medical and surgical management of sinonasal symptoms in AwCF and the associated impact on olfactory function. METHODS: We performed a systematic literature search of PubMed, Embase, Web of Science, and Ebsco CINAHL from 1980 to 2022 per PRISMA-ScR protocols to conduct a scoping review in an effort to compile data on study design, patient demographics, clinical characteristics and outcomes, along with risk of bias. RESULTS: Of 368 abstracts, 3 articles exclusively evaluated AwCF for a total of 34 patients. Two studies evaluated endoscopic sinus surgery (ESS) and dornase alfa. An additional 6 articles were included for mixed pediatric and adult CF populations totaling 313 patients. Interventions included ESS, elexacaftor-tezacaftor-ivacaftor (ETI), ivacaftor, saline, dornase alfa, hyaluronic acid, and hyaluronic acid-tobramycin combination. Outcome measures included subjective assessment of OD using non-validated (4/9) and validated (4/9) surveys, and psychophysical (1/9) smell testing. Studies evaluating ESS, FESS, dornase alfa, ivacaftor, and both hypertonic and isotonic saline reported statistically significant improvement in OD, whereas ETI failed to improve OD despite improvement in other quality of life measures. CONCLUSIONS: There is limited data regarding the impact of medical and surgical interventions on olfaction for AwCF. Assessment of olfaction was often limited to subjective and qualitative self-report. We suggest that tracking of olfactory outcomes with psychophysical testing is critical in this population with dietary challenges and weight management issues.

Abnormal functional lymphoid tolerance and enhanced myeloid exocytosis are characteristics of resting and stimulated PBMCs in cystic fibrosis patients.

Introduction: Cystic Fibrosis (CF) is the commonest genetically inherited disease (1 in 4,500 newborns) and 70% of people with CF (pwCF) harbour the F508Del mutation, resulting in misfolding and incorrect addressing of the channel CFTR to the epithelial membrane and subsequent dysregulation of fluid homeostasis. Although studies have underscored the importance and over-activation of myeloid cells, and in particular neutrophils in the lungs of people with CF (pwCF), relatively less emphasis has been put on the potential immunological bias in CF blood cells, at homeostasis or following stimulation/infection. Methods: Here, we revisited, in an exhaustive fashion, in pwCF with mild disease (median age of 15, median % FEV1 predicted = 87), whether their PBMCs, unprimed or primed with a 'non specific' stimulus (PMA+ionomycin mix) and a 'specific' one (live P.a =PAO1 strain), were differentially activated, compared to healthy controls (HC) PBMCs. Results: 1) we analysed the lymphocytic and myeloid populations present in CF and Control PBMCs (T cells, NKT, Tgd, ILCs) and their production of the signature cytokines IFN-g, IL-13, IL-17, IL-22. 2) By q-PCR, ELISA and Luminex analysis we showed that CF PBMCs have increased background cytokines and mediators production and a partial functional tolerance phenotype, when restimulated. 3) we showed that CF PBMCs low-density neutrophils release higher levels of granule components (S100A8/A9, lactoferrin, MMP-3, MMP-7, MMP-8, MMP-9, NE), demonstrating enhanced exocytosis of potentially harmful mediators. Discussion: In conclusion, we demonstrated that functional lymphoid tolerance and enhanced myeloid protease activity are key features of cystic fibrosis PBMCs.

Evaluation of coping strategies of parents of children with cystic fibrosis.

This cross-sectional quantitative study was conducted to evaluate the coping strategies of parents of children with cystic fibrosis. The research sample is the parents (n: 112) who presented to Thoracic Medicine Department at Hacettepe University Pediatric Hospital between 3 April 2021 - 28 May 2021 and volunteered to participate in the study. Sociodemographic Data Form and Coping Orientation to Problems Experienced Inventory (COPE Inventory) were used in the collection of data. The study examined coping strategies according to children's characteristics such as age, sex, education, and parents' independent variables such as employment status, income status, number of individuals and children in the family, communication with other families, social and financial support. Data were analyzed using Mann-Whitney and Kruskal-Wallis tests. Research findings show that religious coping was the most frequently preferred coping strategy, and behavioral disengagement was the least commonly used coping strategy. Emotion-Focused Coping Strategies were also commonly used. Social work interventions and strategies play an important role in helping parents to adopt positive coping strategies and improve their skills.

Prevalence of common autosomal recessive mutation carriers in women in the Southern Vietnam following the application of expanded carrier screening.

The common autosomal recessive (AR) mutation carrier is still unknown in Vietnam. This study aims to identify the most common AR gene mutation carriers in women of reproductive age to build a Vietnamese-specific carrier screening panel for AR and X-linked disorders in the preconception and prenatal healthcare program. A cross-sectional study was conducted at University Medical Center-Branch 2 in Ho Chi Minh City from December 1st, 2020, to June 30th, 2023. 338 women have consented to take a 5 mL blood test to identify 540 recessive genes. The carrier screening panel was designed based on the American College of Medical Genetics and Genomics (ACMG)-recommended genes and suggestions from 104 clinical experts in Vietnam. Obstetricians and genetic experts counseled all positive testing results to discuss the possibility of recessive diseases in their offspring. The most common recessive disorders were defined at a prevalence of 1 in 60 or greater, and those were added to a Vietnamese-specific carrier screening panel. 338 non-pregnant and pregnant women underwent the expanded carrier screening (ECS). The carrier frequency was 63.6%, in which 215 women carried at least one AR gene mutation. GJB2 hearing impairment was identified as the most common chronic condition (1 in 5). The second most common AR disorder was beta-thalassemia (1 in 16), followed by cystic fibrosis (1 in 23), G6PD deficiency (1 in 28), Wilson's disease (1 in 31), Usher's syndrome (1 in 31), and glycogen storage disease (1 in 56). Seven common recessive genes were added in ethnic-based carrier screening. Women in the South of Vietnam have been carried for many recessive conditions at high frequency, such as hearing impairment, genetic anemia, and cystic fibrosis. It is necessary to implement a preconception and prenatal screening program by using seven widely popular AR genes in a Vietnamese-specific carrier screening panel to reduce the burden related to AR and X-linked disorders.