ERJ Open Res. 2024 Mar 25;10(2):00889-2023. doi: 10.1183/23120541.00889-2023. eCollection 2024 Mar.

ABSTRACT

This article summarises some of the outstanding sessions that were (co)organised by the Allied Respiratory Professionals Assembly during the 2023 European Respiratory Society International Congress. Two sessions from each Assembly group are outlined, covering the following topics: Group 9.01 focuses on respiratory physiology techniques, specifically on predicted values and reference equations, device development and novel applications of cardiopulmonary exercise tests; Group 9.02 presents an overview of the talks given at the mini-symposium on exercise training, physical activity and self-management at home and outlines some of the best abstracts in respiratory physiotherapy; Group 9.03 highlights the nursing role in global respiratory health and presents nursing interventions and outcomes; and Group 9.04 provides an overview of the best abstracts and recent advances in behavioural science and health psychology. This Highlights article provides valuable insight into the latest scientific data and emerging areas affecting the clinical practice of Allied Respiratory Professionals.

PMID:38529350 | PMC:PMC10962454 | DOI:10.1183/23120541.00889-2023

Signal Transduct Target Ther. 2024 Mar 25;9(1):74. doi: 10.1038/s41392-024-01753-z.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

PMID:38528022 | DOI:10.1038/s41392-024-01753-z

J Med Chem. 2024 Mar 25. doi: 10.1021/acs.jmedchem.3c01790. Online ahead of print.

ABSTRACT

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.

PMID:38527911 | DOI:10.1021/acs.jmedchem.3c01790

Allergy. 2024 Mar 25. doi: 10.1111/all.16104. Online ahead of print.

NO ABSTRACT

PMID:38525846 | DOI:10.1111/all.16104

Cureus. 2024 Feb 21;16(2):e54627. doi: 10.7759/cureus.54627. eCollection 2024 Feb.

ABSTRACT

Cystic fibrosis (CF) is a recessively inherited disease most commonly seen in Caucasians. The mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are responsible for the condition, and to date, more than 2000 mutations have been published in the literature. The most common mutation worldwide is F508del. Here, we reported a five-year-old child who presented to the clinic with a chronic cough. Her newborn screening for CF was negative, including 139 mutation panels done in India. The sweat chloride test was positive, and CF gene sequencing was reported as c.2489dup p. (Glu831GLYFS *5) homozygotes mutation in the CFTR gene (Online Mendelian Inheritance in Man (OMIM) *602421). To the best of our knowledge, this gene was first described and published in the literature.

PMID:38524055 | PMC:PMC10959411 | DOI:10.7759/cureus.54627

Microbiome. 2024 Mar 25;12(1):63. doi: 10.1186/s40168-024-01780-6.

ABSTRACT

BACKGROUND: Chronic infection and consequent airway inflammation are the leading causes of morbidity and early mortality for people living with cystic fibrosis (CF). However, lower airway infections across a range of chronic respiratory diseases, including in CF, do not follow classical 'one microbe, one disease' concepts of infection pathogenesis. Instead, they are comprised of diverse and temporally dynamic lung infection microbiota. Consequently, temporal dynamics need to be considered when attempting to associate lung microbiota with changes in disease status. Set within an island biogeography framework, we aimed to determine the ecological patterns and processes of temporal turnover within the lung microbiota of 30 paediatric and adult CF patients prospectively sampled over a 3-year period. Moreover, we aimed to ascertain the contributions of constituent chronic and intermittent colonizers on turnover within the wider microbiota.

RESULTS: The lung microbiota within individual patients was partitioned into constituent chronic and intermittent colonizing groups using the Leeds criteria and visualised with persistence-abundance relationships. This revealed bacteria chronically infecting a patient were both persistent and common through time, whereas intermittently infecting taxa were infrequent and rare; respectively representing the resident and transient portions of the wider microbiota. It also indicated that the extent of chronic colonization was far greater than could be appreciated with microbiological culture alone. Using species-time relationships to measure temporal turnover and Vellend's rationalized ecological processes demonstrated turnover in the resident chronic infecting groups was conserved and underpinned principally by the deterministic process of homogenizing dispersal. Conversely, intermittent colonizing groups, representing newly arrived immigrants and transient species, drove turnover in the wider microbiota and were predominately underpinned by the stochastic process of drift. For adult patients, homogenizing dispersal and drift were found to be significantly associated with lung function. Where a greater frequency of homogenizing dispersal was observed with worsening lung function and conversely drift increased with better lung function.

CONCLUSIONS: Our work provides a novel ecological framework for understanding the temporal dynamics of polymicrobial infection in CF that has translational potential to guide and improve therapeutic targeting of lung microbiota in CF and across a range of chronic airway diseases. Video Abstract.

PMID:38523273 | DOI:10.1186/s40168-024-01780-6

Respir Med. 2024 Mar 22:107606. doi: 10.1016/j.rmed.2024.107606. Online ahead of print.

ABSTRACT

INTRODUCTION: Despite concordant international recommendations, many surveys found disappointing rates of influenza vaccination in at-risk populations, ranging from 23% in overall COPD population to more than 70% in more severe COPD subjects. Therefore, we assessed the proportion of French COPD patients non-vaccinated for influenza and their clinical and socio-demographic factors.

MATERIEL AND METHODS: This was a national retrospective study based on the French health insurance database. We identified "diagnosed COPD", defined as subjects hospitalized at least once in 2017 with a principal or associated diagnosis of COPD, and "suspected COPD" as those who were prescribed at least thrice long-acting bronchodilators (LAB), after exclusion of patients with a principal diagnosis or secondary associated diagnosis of asthma or cystic fibrosis, patients deceased before the influenza season and patients hospitalized in long-term or in palliative care unit. Multivariate logistic regression was used to assess the association between patients' characteristics and the lack of influenza vaccination.

RESULTS: From the national database, 1 474 396 subjects were identified as "suspected COPD" of whom 528 114 were excluded because of previous diagnosis of asthma or cystic fibrosis, and 350 566 as "diagnosed COPD". Among the 1 296 848 patients included, 646 687 patients (53.3%) were vaccinated against influenza. Non-vaccinated subjects were significantly younger (62.1 vs 71.6 years old), more often women (47.9% vs 43.1%) and had fewer comorbidities assessed by Charlson's index (3.0 ± 2.2 vs 4.3 ± 2.1). Lack of vaccination was also associated with a lower LAB usage. Also, non-vaccinated subjects neither had severe exacerbation during the study period. Besides there was a significant heterogeneity in vaccination rate by geographic region, from 47% to 57%. In multivariate analysis, variables independently associated with the lack of influenza vaccination were female gender, younger age, fewer comorbidities and lower socio-economic level.

CONCLUSIONS: This study using the French exhaustive health insurance database shows that influenza vaccination among COPD patients remains dramatically low and must become a high-priority public-health strategy.

PMID:38522592 | DOI:10.1016/j.rmed.2024.107606

Tuberculosis (Edinb). 2024 Mar 20;147:102504. doi: 10.1016/j.tube.2024.102504. Online ahead of print.

ABSTRACT

Mycobacterium tuberculosis and opportunistic environmental non-tuberculous mycobacteria (NTM) can cause severe infection. Why latent tuberculosis infection advances to active disease, and why some individuals with cystic fibrosis (CF) develop pulmonary infections with NTM is still poorly understood. The aim of this study was to investigate the effector function of peripheral blood mononuclear cells (PBMC) from individuals with active or latent tuberculosis, individuals with CF with or without pulmonary NTM-infection and healthy controls, by measuring cytokine response to in vitro stimulation with different species of NTMs. The cytokine concentrations of IL-17A, IL-22, IL-23, IL-10, IL12p70 and IFN-γ were measured in PBMC-culture supernatants after stimulation with NTMs. PBMCs from individuals with latent tuberculosis infection showed strong IL-17A, IL-22, and IFN-γ responses compared to individuals with active tuberculosis or CF. IL-10 production was low in both tuberculosis groups compared to the CF groups and controls. This study suggests that IL-17A and IL-22 might be important to keep tuberculosis in a latent phase and that individuals with CF with an ongoing NTM infection seem to have a low cytokine response.

PMID:38522174 | DOI:10.1016/j.tube.2024.102504

Nat Commun. 2024 Mar 23;15(1):2611. doi: 10.1038/s41467-024-46825-4.

ABSTRACT

The dense O-glycosylation of mucins plays an important role in the defensive properties of the mucus hydrogel. Aberrant glycosylation is often correlated with inflammation and pathology such as COPD, cancer, and Crohn's disease. The inherent complexity of glycans and the diversity in the O-core structure constitute fundamental challenges for the analysis of mucin-type O-glycans. Due to coexistence of multiple isomers, multidimensional workflows such as LC-MS are required. To separate the highly polar carbohydrates, porous graphitized carbon is often used as a stationary phase. However, LC-MS workflows are time-consuming and lack reproducibility. Here we present a rapid alternative for separating and identifying O-glycans released from mucins based on trapped ion mobility mass spectrometry. Compared to established LC-MS, the acquisition time is reduced from an hour to two minutes. To test the validity, the developed workflow was applied to sputum samples from cystic fibrosis patients to map O-glycosylation features associated with disease.

PMID:38521783 | DOI:10.1038/s41467-024-46825-4

Chest. 2024 Mar 21:S0012-3692(24)00404-5. doi: 10.1016/j.chest.2024.03.033. Online ahead of print.

ABSTRACT

BACKGROUND: The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with CF (pwCF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, but predictors of FEV1 change after treatment are still missing.

RESEARCH QUESTION: Which ventilatory parameters are involved in the heterogeneity of FEV1 change after 12-month ETI treatment in pwCF with advanced lung disease?

STUDY DESIGN: AND METHODS: This was a multicenter, observational, prospective cohort study at two major CF centers in Italy. We enrolled 47 adults with CF and advanced lung disease (FEV1 <40% or actively listed for lung transplant) who started ETI treatment between December 2019 to December 2021. At treatment initiation and after 12 months, patients underwent body plethysmography. Values were compared at the two time points. To assess the relationship between baseline plethysmography measurements and treatment-induced changes in FEV1, we used the Spearman's rank correlation coefficient (r) and median quantile regressions.

RESULTS: After 12 months of ETI treatment, there was a significant increase in percent predicted FEV1 (ppFEV1) from a median (25th-75th percentiles) value of 36.0 (33 - 39) to 52 (43 - 61) (P<0.001). IC/TLC ratio also increased from 32.0 (28.6 - 36.9) to 36.3 (33.4 - 41.3) (P<0.001). sRaw decreased from 263 (182 - 405) to 207 (120 - 258) (P<0.001). FRC/TLC ratio decreased from 68.2 (63.3 - 71.9) to 63.9 (58.8 - 67.1) (P<0.001), and RV/TLC ratio decreased from 53.1 (48.3 - 59.4) to 45.6 (39.4 - 49.8) (P<0.001). Changes in ppFEV1 negatively correlated with baseline FRC/TLC ratio (r= -0.38, P= 0.009) and RV/TLC ratio (r= -0.42, P= 0.004). After adjustment for age at treatment initiation and CFTR genotype, we estimated that for each 10-unit increase in baseline RV/TLC ratio the expected median change in FEV1 decreased by 2.3 (95% CI: -5.8; -0.8).

INTERPRETATION: ETI was associated with improvements in both static and dynamic volumes in pwCF and advanced lung disease. Heterogeneity in ppFEV1 change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.

PMID:38521181 | DOI:10.1016/j.chest.2024.03.033

Microbiol Res. 2024 Mar 9;283:127680. doi: 10.1016/j.micres.2024.127680. Online ahead of print.

ABSTRACT

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.

PMID:38520837 | DOI:10.1016/j.micres.2024.127680

Med Sci (Paris). 2024 Mar;40(3):258-267. doi: 10.1051/medsci/2024014. Epub 2024 Mar 22.

ABSTRACT

Over time, cystic fibrosis has become a model of synergy between research in pathophysiology and cell biology, and clinical advances. Therapies targeting the CFTR protein, in particular CFTR modulators, have transformed the prognosis of patients, bringing the hope of a normal life with the possibility of starting a family and growing old, challenging established statistics. However, patients are not yet cured, and side effects remain insufficiently documented. Epidemiological changes create new challenges for the management of cystic fibrosis. Approximately 10 % of patients still lack a therapeutic option. The community of researchers, pharmaceutical industries, patient associations, and health authorities remains committed to monitor the long-term effects of these still poorly characterised treatments, and to explore new pharmacological approaches, such as gene therapies.

PMID:38520101 | DOI:10.1051/medsci/2024014

Kidney Int. 2024 Apr;105(4):663-665. doi: 10.1016/j.kint.2024.01.029.

ABSTRACT

In the current issue, Kuzmuk et al. offer a therapeutic option for patients with NPHS2 R138Q-associated nephrotic syndrome. For the first time in hereditary podocytopathies, this is offered by restoring the membrane targeting of a pathogenic protein. The idea that it is enough to liberate podocin from the trap of keratin 8, a key member of endoplasmic-reticulum-associated protein degradation complex, was brilliantly recognized based on former results obtained in cystic fibrosis.

PMID:38519231 | DOI:10.1016/j.kint.2024.01.029

Int J Biol Macromol. 2024 Mar 20:131027. doi: 10.1016/j.ijbiomac.2024.131027. Online ahead of print.

ABSTRACT

Lung infections, such as: pneumonia, chronic obstructive cystic fibrosis, tuberculosis are generally caused by viruses, bacteria and fungi. As these infections are very difficult to treat, new therapeutic approaches are investigated in order to maximize the efficiency of the treatment and to reduce the major complications that can occur. The main objective of this study was focused on the preparation of drug-loaded peptides-functionalized microcapsules, obtained by a double emulsion, based on carboxylated chitosan (CMCS), poly(vinyl alcohol) (PVA) and an activator [4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride] (DMT-MM), for the dual active targeting and treatment of pulmonary infections. The microcapsules were functionalized on the surface with both CGSPGWVRC and indolicidin (IN) peptides, as effective ligands for the active targeting of both alveolar capillary endothelial cells and bacterial cells. FTIR spectroscopy confirmed the formation of ester and amide bonds into the structure of prepared microcapsules. Microcapsules diameter varied between 893 and 965 nm. The swelling degree in PBS, at pH 7.4, ranged between 1760 %- 2100 %. All the analyzed samples showed hemolysis degrees lower than 2 %, which demonstrated their non-hemolytic character. Evaluation of the impact of microcapsules on WI-38 normal human lung cells and RAW 264.7 mouse macrophages revealed a non-toxic or slightly cytotoxic effect. Internalization assay proved that microcapsules were localized at intracellular level.

PMID:38518936 | DOI:10.1016/j.ijbiomac.2024.131027

Pediatr Pulmonol. 2024 Mar 22. doi: 10.1002/ppul.26962. Online ahead of print.

NO ABSTRACT

PMID:38517207 | DOI:10.1002/ppul.26962

J Hosp Med. 2024 Mar 22. doi: 10.1002/jhm.13322. Online ahead of print.

ABSTRACT

BACKGROUND: Young adults (YA) with childhood-onset chronic conditions-particularly YA with cystic fibrosis (CF), congenital heart disease (CHD), and sickle cell disease (SCD)-continue to have pediatric hospital admissions. Factors associated with this continued pediatric hospital use remain underexplored.

OBJECTIVE: To determine if pediatric hospital use by YA differed (1) across condition and (2) within each condition by sociodemographic factors.

METHODS: Conducted a cross-sectional analysis of admissions for YA 22-35 years with CF, CHD, and SCD from 2016 to 2020 in the National Inpatient Sample. Admissions for YA with CF, CHD, and SCD were identified by international classification of diseases, 10th revision-clinical modification diagnosis codes. To determine if conditions or sociodemographic factors were associated with YA pediatric hospital use, we used multivariable logistic regression with separate models for the different objectives.

RESULTS: YA with SCD had lower odds of pediatric hospital use compared to YA with CF. Relationships between sociodemographic factors and pediatric hospital use varied. Black YA with both CF and CHD had lower odds of pediatric hospital use than white YA with CF and CHD. For YA with SCD, despite 17,810 (6.5%) having rural residence, zero (0) had pediatric hospital use; whereas YA with CF living in a rural area had greater odds of pediatric hospital use compared to urban residents.

CONCLUSION: YA with SCD used pediatric hospitals less than YA with either CF or CHD. Coupled with our findings that Black YA with CF and CHD had less pediatric hospital use, these data may reflect systematic racial differences within pediatric to adult healthcare transition programs.

PMID:38517142 | DOI:10.1002/jhm.13322

Pediatr Pulmonol. 2024 Mar 22. doi: 10.1002/ppul.26980. Online ahead of print.

NO ABSTRACT

PMID:38517044 | DOI:10.1002/ppul.26980

Allergy. 2024 Mar 22. doi: 10.1111/all.16107. Online ahead of print.

NO ABSTRACT

PMID:38516981 | DOI:10.1111/all.16107

Genome Med. 2024 Mar 21;16(1):43. doi: 10.1186/s13073-024-01316-5.

ABSTRACT

BACKGROUND: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.

METHODS: We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes.

RESULTS: We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05].

CONCLUSIONS: We leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

PMID:38515211 | DOI:10.1186/s13073-024-01316-5

Curr Obes Rep. 2024 Mar 21. doi: 10.1007/s13679-024-00554-3. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: This study is to examine potential micronutrient deficiencies and any need for supplementation in children following specific diet plans in the first 1000 days of life.

RECENT FINDINGS: Optimal nutrition in the first 1000 days of life has a lifelong positive impact on child development. Specific intrauterine and perinatal factors, pathological conditions, and dietary restrictions can represent potential risk factors for micronutrient deficiencies in the first 1000 days of life, which can have negative systemic consequences. Preterm and low-birth-weight infants are intrinsically at risk because of immature body systems. Children affected by cystic fibrosis are prone to malnutrition because of intestinal malabsorption. The risk of micronutrient deficiency can increase in various situations, including but not limited to children following selective dietary regimens (vegetarian and vegan diets and children affected by specific neuropsychiatric conditions) or specific dietary therapies (children affected by food allergies or specific metabolic disorders and children following restricted diet as a part of therapeutic approach, i.e., ketogenic diet for epilepsy). In light of this situation, the micronutrient status in these categories of children should be investigated in order to tailor strategies specific to the individual's metabolic needs, with a particular focus on deficiencies which can impair or delay the physical and cognitive development of children, namely, vitamin B12, vitamin D and folic acid, as well as oligo-elements such as iron, zinc, calcium, sodium, magnesium, and phosphorus, and essential fatty acids such as omega-3. Identification of micronutrient deficiency in the first 1000 days of life and timely supplementation proves essential to prevent their long-term consequences.

PMID:38512555 | DOI:10.1007/s13679-024-00554-3