Int J Mol Sci. 2024 Oct 19;25(20):11244. doi: 10.3390/ijms252011244.

ABSTRACT

Findings accumulated over time show that neurophysiological, neuropathological, and molecular alterations are present in CMT1A and support the dysmyelinating rather than demyelinating nature of this neuropathy. Moreover, uniform slowing of nerve conduction velocity is already manifest in CMT1A children and does not improve throughout their life. This evidence and our previous studies displaying aberrant myelin composition and structure in adult CMT1A rats prompt us to hypothesize a myelin and axon developmental defect in the CMT1A peripheral nervous system. Peripheral myelination begins during the early stages of development in mammals and, during this process, chemical and structural features of myelinated fibers (MFs) evolve towards a mature phenotype; deficiencies within this self-modulating circuit can cause its blockage. Therefore, to shed light on pathophysiological mechanisms that occur during development, and to investigate the relationship among axonal, myelin, and lipidome deficiencies in CMT1A, we extensively analyzed the evolution of both myelin lipid profile and MF structure in WT and CMT1A rats. Lipidomic analysis revealed a delayed maturation of CMT1A myelin already detectable at P10 characterized by a deprivation of sphingolipid species such as hexosylceramides and long-chain sphingomyelins, whose concentration physiologically increases in WT, and an increase in lipids typical of unspecialized plasma membranes, including phosphatidylcholines and phosphatidylethanolamines. Consistently, advanced morphometric analysis on more than 130,000 MFs revealed a delay in the evolution of CMT1A axon and myelin geometric parameters, appearing concomitantly with lipid impairment. We here demonstrate that, during normal development, MFs undergo a continuous maturation process in both chemical composition and physical structure, but these processes are delayed in CMT1A.

PMID:39457026 | DOI:10.3390/ijms252011244

Int J Mol Sci. 2024 Oct 15;25(20):11081. doi: 10.3390/ijms252011081.

ABSTRACT

The measurement of cytokines in induced sputum and nasal lavage (NL) samples has been performed for years in people with cystic fibrosis (CF). The aim of this study was to directly compare sputum and NL samples and interpret results based on disease severity in patients who were categorized as having mild or severe lung disease. The categorization was based primarily on structural abnormalities detected on lung computed tomography and secondarily on lung function. The serum inflammatory markers neutrophil elastase (NE), IL-1β, 2, 6, 8, 10 and 17a were measured in each sputum and NL sample. Thirty-two sample pairs from 29 patients were included in this study (13 mild, 19 severe). In the patients classified as severe, many systemic inflammatory markers as well as sputum cytokines were significantly higher compared to those in the mild patients. However, all the markers measured in the NL were higher in the mild patients (p =< 0.05 for NE, IL-6 and IL-8). In addition, many cytokines in the NL correlated negatively with those in the sputum samples. Major differences in the cytokine levels were shown although the samples were obtained at the same time in the same patient. Advanced structural lung disease was closely related to systemic and lower airway inflammation, whereas preserved lung function was associated with higher levels in the NL. We hypothesize that the main part of the immune response takes place in the nasal mucosa in patients with minor pulmonary changes. Our results suggest that inflammation must be interpreted individually depending on the compartment in which it is measured. Further research is needed to accurately understand inflammatory markers measured in NL.

PMID:39456863 | DOI:10.3390/ijms252011081

Ital J Pediatr. 2024 Oct 25;50(1):220. doi: 10.1186/s13052-024-01792-w.

ABSTRACT

BACKGROUND: The use of mobile applications helps improving self-management in adolescents with asthma. However, no evidence is available for children with preschool wheezing. In addition, we have no data on the reliability of medical history collected at visits. The first aim was to assess the feasibility of a smartphone app in the management of preschool wheezing; secondly we aimed to evaluate the reliability of anamnestic data collected during face-to-face medical interviews.

METHODS: Children with recurrent wheezing, age between 25 and 72 months, were randomly assigned to the intervention group, provided with a smartphone app for symptoms monitoring and asthma attack treatment, or to the control group, with a written action plan. At follow-up medical history was collected and the asthma control test and a clinical questionnaire were completed. App acceptability was also explored. Respiratory symptoms, medication and utilization of healthcare resources were collected. Plus, medical information obtained from the paper questionnaires was compared with data daily recorded by the app.

RESULTS: We enrolled 85 preschool children with recurrent wheezing: 43 assigned to the intervention and 42 to the control group. The average (SD) adherence to e-Diary compilation was 60 (15)%. The acceptance and usability of the intervention was favorable as 70% and 93% of participants in the intervention arm described the app as ''simple and intuitive'' at Visit1 (after 3 months from enrollement) and Visit2 (3 months later than Visit1), respectively and 95% and 98% found it useful in symptoms management. There were no significant differences between the two groups in clinical outcomes. At Visit1, the cACT median score (IQR) was 23,5 (21-25) for the control group (42 patients) and 23 (21-24) for the intervention group (43 patients). At Visit2 (41 controls and 42 in the intervention group) it was 25 (24-25) and 24 (24-25), respectively. Secondary analysis of data from the intervention group showed higher incidence of daily symptoms recorded by the app in comparison with the paper questionnaire, suggesting that collection of retrospective medical history may not be completely reliable.

CONCLUSIONS: The smartphone app is usable and acceptable by families of preschool wheezers. Future controlled trial are needed to prove an impact on clinical outcomes or its efficacy in a telemedicine program. Finally a daily questionnaire could provide physicians with a more reliable clinical picture as reflected better daily asthma symptoms than the written retrospective questionnaire filled at clinical visit.

PMID:39456090 | DOI:10.1186/s13052-024-01792-w

Pathogens. 2024 Oct 7;13(10):875. doi: 10.3390/pathogens13100875.

ABSTRACT

Aspergillus fumigatus (Af) and Pseudomonas aeruginosa (Pa) are pathogens inhabiting the lungs of persons with cystic fibrosis (CF), or immune-compromised patients, causing or aggravating disease. We previously investigated their microbial interaction as well as susceptibility to anti-fungal drugs using RPMI medium (contains undetectable iron concentrations), as is standard for susceptibility testing. Here we investigated microbial interaction in synthetic sputum medium (SSPM), a complex mixture designed to mimic the milieu in CF lungs. SSPM contains Fe2+. Pa laboratory strain PA14 or PA14 siderophore mutant planktonic culture filtrate, prepared in RPMI or SSPM, were compared for inhibition of Af biofilm formation. SSPM enhanced bacterial and fungal growth and the production of the Pa molecules pyoverdine, phenazines, and rhamnolipids. Af was more susceptible to these molecules in SSPM (with the exception of pyoverdine). SSPM interfered with fungal susceptibility to pyoverdine. Studies with the mutant helped to reveal that the reduced anti-fungal activity of pyoverdine in SSPM appears to be compensated by higher production of other anti-fungal molecules, e.g., rhamnolipids, phenazines, and PQS, and higher Af sensitivity to these molecules. In summary, SSPM better defines Pa-Af intermicrobial competition in the milieu of CF lungs.

PMID:39452746 | DOI:10.3390/pathogens13100875

J Pers Med. 2024 Oct 17;14(10):1065. doi: 10.3390/jpm14101065.

ABSTRACT

BACKGROUND/OBJECTIVES: Elexacaftor, tezacaftor, and ivacaftor (ETI) have significantly improved lung function in people with cystic fibrosis (pwCF). Despite exceptional improvements in most cases, treatment-related inter-subject variability and drug-drug interactions that complicate modulator therapy have been reported.

METHODS: This retrospective analysis presents data on the serum concentration of ETI in our pwCF with full or reduced dosage from August 2021 to December 2023 via routine therapeutic drug monitoring (TDM). The data were compared with the maximum drug concentrations (Cmax) from the pharmaceutical company's summary of product characteristics.

RESULTS: A total of 786 blood samples from 155 pwCF (41% female, 59% male) were analyzed. The examinations were divided into four groups: full dose within the given tmax (38.5% of all measurements), full dose outside the tmax (29%), reduced dose within the tmax (19.2%), and reduced dose outside the tmax (13.2%). In pwCF receiving the full dose and blood taken within the tmax, 45.3% of serum concentrations of elexacaftor, 51.1% of serum concentrations of ivacaftor, and 8.9% of serum concentrations of tezacaftor were found to be above the Cmax, respectively. For those on reduced doses within the tmax, 24.5% had a serum concentration of elexacaftor, 23.2% had a serum concentration of ivacaftor, and 2.5% had a serum concentration of tezacaftor above the Cmax, respectively.

CONCLUSIONS: Many pwCF under ETI therapy have Cmax values for elexacaftor and ivacaftor above the recommended range, even on reduced doses or before the tmax was reached. This highlights the value of a TDM program. Further pharmacokinetic studies are necessary.

PMID:39452571 | DOI:10.3390/jpm14101065

Pediatr Pulmonol. 2024 Oct 25. doi: 10.1002/ppul.27342. Online ahead of print.

NO ABSTRACT

PMID:39451047 | DOI:10.1002/ppul.27342

Pediatr Pulmonol. 2024 Oct 25. doi: 10.1002/ppul.27363. Online ahead of print.

NO ABSTRACT

PMID:39451040 | DOI:10.1002/ppul.27363

Pediatr Pulmonol. 2024 Oct 25. doi: 10.1002/ppul.27358. Online ahead of print.

ABSTRACT

BACKGROUND: In the last decades none of the medical therapies investigated have shown clear efficacy in the treatment of bronchiolitis, and literature agrees on a general de-implementation of pharmacological therapies, recognizing an effective role only to nutritional support and oxygen therapy. High-flow nasal cannulas (HFNC) has become increasingly popular in the last decade, despite its lack of clear efficacy. Recent randomized controlled trials (RCT) comparing standard oxygen therapy (SOT) and HFNC did not demonstrate significant benefit of HFNC. To acquire more clinical data on HFNC efficacy we performed a retrospective, quasi-experimental analysis of patients admitted for bronchiolitis in the epidemic seasons 2021-2022 and 2022-2023.

METHODS: To assess the efficacy of SOT and HFNC we used a pragmatic approach, a fuzzy regression discontinuity design, which is a quasi-experimental test. Unlike RCTs, this process is not a true randomization, but may be interpreted as quasi-randomization in an observational setting.

RESULTS: HFNC did not reduce length of oxygen therapy (LOO) nor length of hospitalization (LOS) (respectively, p: 0.383 and p: 0.454). Treatment failure was not significantly different in the treatment groups (p: 0.354).

CONCLUSIONS: It is crucial to perform additional RCTs with uniform protocols to determine the efficacy of HFNC more accurately in the treatment of bronchiolitis. HFNC does not reduce LOO, suggesting that early use of HFNC does not change the course of disease in moderate bronchiolitis. In view of the greater complexity and higher cost, HFNC should not be routinely used as first-line treatment in children with moderate respiratory distress and mild hypoxemia.

PMID:39451018 | DOI:10.1002/ppul.27358

Expert Rev Respir Med. 2024 Oct 25. doi: 10.1080/17476348.2024.2421843. Online ahead of print.

ABSTRACT

INTRODUCTION: Excessive mucus secretion is pivotal in chronic obstructive pulmonary disease (COPD) pathophysiology, particularly in chronic bronchitis phenotypes. Cystic fibrosis transmembrane conductance regulator (CFTR), has been implicated in COPD-related hypersecretion with acquired dysfunction, and emerged as a therapeutic target. However, the clinical efficacy of CFTR-potentiators in COPD remains controversial.

METHODS: We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal (CSTJ) and Wanfang Database to retrieve eligible studies published before 28 May 2024.

RESULTS: 1172 COPD patients were included, meta-analysis showed that CFTR-potentiators significantly increased forced expiratory volume in 1 s (FEV1) and decreased sweat chloride and fibrinogen levels, with moderate-to-high quality evidence. However, no significant effects were observed on percentage of detected FEV1 to predicted FEV1 (FEV1% predicted), forced vital capacity (FVC), COPD assessment test (CAT) score, St. George's Respiratory Questionnaire (SGRQ) score or acute exacerbation times, with low-to-moderate quality evidence.Review registration PROSPERO Identifier: CRD42024538708.

CONCLUSION: Our meta-analysis demonstrated CFTR-potentiators' potential efficacy in increasing FEV1, decreasing sweat chloride and fibrinogen levels, despite limited impacts on FEV1% predicted, FVC, CAT score, SGRQ score and acute exacerbations, underscoring the necessity for future research to evaluate its effects on mucus hypersecretion, acute exacerbations, hospitalizations and mortality in COPD management.Review registration PROSPERO Identifier: CRD42024538708.

PMID:39450920 | DOI:10.1080/17476348.2024.2421843

Cureus. 2024 Oct 24;16(10):e72252. doi: 10.7759/cureus.72252. eCollection 2024 Oct.

ABSTRACT

This study aims to evaluate the therapeutic application of N-acetylcysteine (NAC) as a treatment or adjunct therapy for various medical conditions. While its efficacy in treating acetaminophen overdose, cystic fibrosis, and chronic obstructive pulmonary disease is well-established, emerging evidence suggests that NAC may also benefit a broader spectrum of illnesses due to its safety, simplicity, and affordability. A comprehensive review was conducted by searching PubMed, relevant books, and conference proceedings for publications discussing NAC about the specified health conditions. The clinically relevant data were analysed using the American Family Physician Evidence-Based Medicine Toolkit, following a standard integrated review methodology. NAC shows potential as an adjunctive treatment for a wide range of medical conditions, particularly chronic diseases. It may be beneficial for polycystic ovary syndrome, endometriosis, male infertility, cataracts, glaucoma, dry eye syndrome, parkinsonism, multiple sclerosis, Alzheimer's disease, stroke outcomes, non-acetaminophen-induced acute liver failure, Crohn's disease, ulcerative colitis, schizophrenia, bipolar disorder, and obsessive-compulsive disorder. Although evidence for some conditions is less robust, NAC's therapeutic potential warrants further investigation. Given the aging population and the decline in glutathione levels, the use of NAC should be considered across a variety of medical conditions. This paper suggests that NAC supplementation could play a significant role in reducing morbidity and mortality associated with numerous chronic diseases.

PMID:39450216 | PMC:PMC11499967 | DOI:10.7759/cureus.72252

PLoS One. 2024 Oct 24;19(10):e0312613. doi: 10.1371/journal.pone.0312613. eCollection 2024.

ABSTRACT

INTRODUCTION: Agenda-setting is a collaborative communication strategy used by a clinician before or at the start of a clinical encounter to work together with the patient to "elicit, propose, and organize" topics to be discussed during the encounter. While clinical visit agenda-setting has been acknowledged as an important element of patient-centered communication, the effectiveness of agenda-setting interventions in improving healthcare outcomes is unclear. To our knowledge, no systematic review has examined clinical visit agenda-setting interventions.

METHODS AND ANALYSIS: The primary aim of the systematic review will be to assess the effects of agenda-setting interventions on outcomes relating to the clinical encounter itself, patients, and clinicians, as well as any other study-specified outcomes. Our secondary aims will be to examine the characteristics and delivery attributes of agenda-setting interventions, as well as how agenda-setting has been operationalized and measured. We will search selected databases (APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature, MEDLINE via PubMed, ProQuest, Scopus, and Web of Science) and gray literature from inception until date of search. All studies comparing a clinical visit agenda-setting intervention with either usual care or another agenda-setting intervention will be included. Two independent reviewers will complete article screening and data extraction, with a third independent reviewer resolving any conflicts. We will assess all studies' methodological quality and the quality of their evidence using standardized criteria. If a sufficient number of studies report the same outcomes, we will pool their results and perform a meta-analysis of those outcomes. We will also synthesize all results qualitatively, regardless of whether we are able to complete a meta-analysis.

PROSPERO REGISTRATION NUMBER: CRD42023468045.

PMID:39446854 | DOI:10.1371/journal.pone.0312613

Mol Biotechnol. 2024 Oct 24. doi: 10.1007/s12033-024-01301-8. Online ahead of print.

ABSTRACT

Gene therapy has made substantial progress in the treatment of the genetic diseases, focussing on the reduction of characteristics of recessive/dominant disorders, as well as various cancers. Extensive research has been conducted in the past few decades to investigate the application of nanotechnology and CRISPR/Cas technology in gene therapy. Nanotechnology due to attributes such has targeted drug delivery, controlled release, scalability and low toxicity has gained attention of the medical world. CRISPR/Cas9 system is considered as an impactful genome editing tool in the area of next-generation therapeutics and molecular diagnostics. CRISPR technology emphasises on gene editing, gene regulation modulation, and formulation of defined genetic changes. Its applications in treatment of the genetic disorders are extended beyond traditional therapies. These techniques are being explored as treatment of several genetic disorders including Duchenne muscular dystrophy, cystic fibrosis, Alzheimer's disease, Parkinson's disease, and Huntington disease. Despite considerable therapeutic potential of gene therapy, several obstacles must be addressed before it can be widely adopted in clinical practice, particularly in terms of ensuring safety and effectiveness. As research advances in this captivating field, these therapies will become the primary treatments and will have significant beneficial effects on the lives of patients with genetic disorders.

PMID:39446301 | DOI:10.1007/s12033-024-01301-8

mBio. 2024 Oct 24:e0163424. doi: 10.1128/mbio.01634-24. Online ahead of print.

ABSTRACT

Trimethoprim-sulfamethoxazole (SXT) is commonly used to treat diverse Staphylococcus aureus infections, including those associated with cystic fibrosis (CF) pulmonary disease. Studies with Escherichia coli found that SXT impairs tetrahydrofolate production, leading to DNA damage, stress response induction, and accumulation of reactive oxygen species (ROS) in a process known as thymineless death (TLD). TLD survival can occur through the uptake of exogenous thymidine, countering the effects of SXT; however, a growing body of research has implicated central metabolism as another potentially important determinant of bacterial survival of SXT and other antibiotics. Here, we conducted studies to better understand the mechanisms of TLD survival in S. aureus. We found that thymidine abundances in CF sputum were insufficient to prevent TLD of S. aureus, highlighting the importance of alternative survival mechanisms in vivo. In S. aureus cultured in vitro with SXT and low thymidine, we frequently identified adaptive mutations in genes encoding carbohydrate, nucleotide, and amino acid metabolism, supporting reduced metabolism as a common survival mechanism. Although intracellular ROS levels rose with SXT treatment in vitro, survival was not improved in the presence of ROS scavengers, unlike in E. coli. SXT challenge induced the SOS response, which was alleviated by added thymidine. Finally, an inactivating mutation in the phosphotransferase gene ptsI conferred both limitation in cellular ATP and improved survival against TLD. Collectively, these results suggest that alterations in core metabolic functions, particularly those that reduce ATP levels, predominantly confer S. aureus survival and persistence during SXT treatment, potentially identifying novel targets for co-treatment.IMPORTANCEStaphylococcus aureus is a ubiquitous organism and one of the leading causes of human infections, many of which are difficult to treat due to persistence, antibiotic resistance, or antibiotic tolerance. As our arsenal of effective antibiotics dwindles, the need for improved treatments becomes increasingly urgent, necessitating a better understanding of the precise mechanisms by which pathogens evade our most critical antimicrobial agents. Here, we report a systematic characterization of the mechanisms of S. aureus survival to treatment with the first-line antistaphylococcal antibiotic trimethoprim-sulfamethoxazole, identifying pathways and candidate targets for enhancing the efficacy of available antimicrobial agents.

PMID:39445807 | DOI:10.1128/mbio.01634-24

Pediatr Allergy Immunol. 2024 Oct;35(10):e14261. doi: 10.1111/pai.14261.

ABSTRACT

BACKGROUND: Prematurity is associated with an increased risk of persistent wheezing but the underlying mechanisms are not well defined. The aim of this study was to identify blood transcriptional profiles associated with the development of wheezing in a cohort of moderate to late preterm infants and to define immune gene expression changes associated with wheezing.

MATERIALS AND METHODS: A convenience sample of a multicenter birth cohort (SAREPREM) of moderate-late preterm children followed during the first 3 years of life was analyzed. Children were enrolled in the first 2 weeks of life (Y0) and longitudinally evaluated at 1 (Y1), 2 (Y2), and 3 years (Y3) of age, for the presence of wheezing and to obtain samples for transcriptional profile analysis. Samples were processed on Illumina HT12 chips and genomic expression analyses performed with R programming, modular analysis for biological function, and QuSAGE for quantitative gene expression.

RESULTS: Seventy-six children were included in the study; 33 were classified as non-wheezing and 43 (56.6%) in the wheezing group. At Y0, children who developed wheezing had decreased expression of interferon genes and increased expression of B cell genes compared with the non-wheezing group. These changes in IFN and B cell gene expression were especially significant in children with late/persistent wheezing compared with transient wheezers.

CONCLUSIONS: Changes in IFN and B lymphocyte gene expression identified in early life suggest the existence of specific immunological mechanisms that play an important role in the development of wheezing in late-preterm infants.

PMID:39445663 | DOI:10.1111/pai.14261

ACS Sens. 2024 Oct 24. doi: 10.1021/acssensors.4c01669. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory, digestive, and reproductive systems. In the United States, approximately 32,000 individuals, spanning both children and adults, suffer from CF, and roughly 1,000 new cases are diagnosed annually. The current gold standard for CF diagnosis is the sweat test, yet this method is plagued by issues such as being time-consuming, expensive, challenging to replicate, and lacking treatment monitoring capabilities. In contrast, the emerging field of wearable sweat biosensors has gained significant attention due to their potential for noninvasive health monitoring. Despite this, there remains a conspicuous absence of a wearable sweat biosensor tailored specifically for CF diagnosis and monitoring. Here, this study introduces a flexible wearable sweat biosensor, named CFTrack, designed to address the unique challenges associated with CF. This proposed CFTrack biosensor not only facilitates CF diagnosis but also enables the monitoring of medication treatment effectiveness and tracks therapy activities. In addition, it operates in a self-powered and customized manner, ensuring seamless integration into the daily lives of individuals with CF. Given that sweat tests and fitness routines are the predominant methods for diagnosing and treating cystic fibrosis patients, respectively, the proposed CFTrack biosensor leverages ion concentration in sweat for diagnostic purposes. Additionally, it incorporates a motion-tracking function to monitor physical activity, providing a comprehensive approach to CF management. To evaluate the feasibility of the proposed CFTrack biosensor, a comprehensive evaluation has been performed including numerical simulations, theoretical analyses, and experimental tests. The results demonstrate the efficacy of the proposed CFTrack biosensor in diagnosing and monitoring CF conditions while also showcasing its ability to effectively track the progress of patients undergoing physical therapy. The proposed CFTrack biosensor resolves key issues associated with existing sweat sensors including high energy consumption, intricate fabrication procedures, and the absence of continuous monitoring capabilities. By addressing these challenges, the proposed sweat biosensor aims to revolutionize CF diagnosis and monitoring, offering a more efficient and user-friendly alternative to current methods.

PMID:39445573 | DOI:10.1021/acssensors.4c01669

Int J Cancer. 2024 Oct 24. doi: 10.1002/ijc.35227. Online ahead of print.

ABSTRACT

Cancer burden can be reduced by controlling modifiable risk factors, including diet. We provided an evidence-based assessment of cancer cases and deaths attributable to diet in Italy in 2020. We considered dietary factor-cancer type pairs for which the World Cancer Research Fund/American Institute for Cancer Research - Continuous Update Project reported either 'convincing' or 'probable' evidence of causal association. Relative risks were retrieved from recent meta-analyses and dietary intakes (around 2005) from a national food consumption survey. Sex-specific population attributable fractions (PAFs) were computed by comparing the distribution of dietary intakes in the Italian population against counterfactual scenarios based on dietary recommendations. Using data from national cancer and mortality registries in 2020, we estimated the number of attributable cancer cases and deaths, assuming ~15-year lag period. Unhealthy diet accounted for 6.3% (95% CI: 2.5%-9.9%) of all cancer cases in men and 4.5% (95% CI: 1.7%-7.4%) in women. PAFs of colorectal cancer were 10.5% and 7.0% for any intake of processed meat, 3.3% and 2.0% for high red meat, 4.8% and 4.3% for low dairy products, and 7.9% and 9.0% for low fiber intakes in men and women, respectively. PAFs for low intake of non-starchy vegetables and fruit ranged from 0.8% to 16.5% in men and 0.6%-17.8% in women for cancers of the aerodigestive tract. The estimated cancer burden associated with unfavorable dietary habits in Italy is considerable, but appears lower than for other high-income countries, reflecting the typically Mediterranean diet.

PMID:39445525 | DOI:10.1002/ijc.35227

Heliyon. 2024 Oct 5;10(19):e38895. doi: 10.1016/j.heliyon.2024.e38895. eCollection 2024 Oct 15.

ABSTRACT

Cystic Fibrosis (CF) airway disease is characterized by impaired mucociliary clearance, chronic, polymicrobial infections and robust, neutrophil-dominated inflammation. Pulmonary disease is the leading cause of morbidity and mortality in people with CF and is due to progressive airflow obstruction and ultimately respiratory failure. One of the earliest abnormalities in CF airway disease is the recruitment of neutrophils to the lungs. Neutrophil activation leads to the release of their intracellular content, including neutrophil elastase (NE), that damages lung tissues in CF. Our goal is to characterize a known bacterial NE inhibitor, ecotin, in the CF airway environment. Our results indicate that ecotins cloned from four Gram-negative bacterial species (Campylobacter rectus, Campylobacter showae, Escherichia coli and Pseudomonas aeruginosa) inhibit NE activity in CF sputum samples in a dose-dependent manner. Although we observed differences in the NE-inhibitory activity of the tested ecotins with the Campylobacter homologs being the most effective in NE inhibition in CF sputa, none of the ecotins impaired the ability of human neutrophils to kill major CF respiratory pathogens, P. aeruginosa or S. aureus, in vitro. Overall, we demonstrate that bacterial ecotins inhibit NE activity in CF sputa without compromising bacterial killing by neutrophils.

PMID:39444402 | PMC:PMC11497391 | DOI:10.1016/j.heliyon.2024.e38895

Sci Rep. 2024 Oct 23;14(1):25095. doi: 10.1038/s41598-024-76526-3.

ABSTRACT

Cystic fibrosis related diabetes (CFRD), the main co-morbidity in cystic fibrosis (CF), is associated with higher rates of lung function decline. We hypothesize that airway epithelial barrier function is impaired in CF and is further exacerbated under hyperglycemia, worsening pulmonary outcomes. Using 16HBE cells, we studied the effects of hyperglycemia in airway epithelial barrier function. Results show increased paracellular dye flux in CF cells in response to insulin under hyperglycemia. Gene expression experiments identified claudin-4 (CLDN4) as a key tight junction protein dysregulated in CF cells. CLDN4 protein localization by confocal microscopy showed that CLDN4 was tightly localized at tight junctions in WT cells, which did not change under hyperglycemia. ln contrast, CLDN4 was less well-localized in CF cells at normal glucose and localization was worsened under hyperglycemia. Treatment with highly effective modulator compounds (ETI) reversed this trend, and CFTR rescue was not affected by insulin or hyperglycemia. Bulk RNA sequencing showed differences in transcriptional responses in CF compared to WT cells under normal or high glucose, highlighting promising targets for future investigation. One of these targets is protein tyrosine phosphatase receptor type G (PTPRG), which has been previously found to play a role in defective Akt signaling and insulin resistance.

PMID:39443580 | DOI:10.1038/s41598-024-76526-3

J Pediatr Psychol. 2024 Oct 23:jsae081. doi: 10.1093/jpepsy/jsae081. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aims to describe the experience of implementing a psychosocial distress screening system for children with serious or chronic medical conditions.

METHODS: Achieving RoutIne Screening for Emotional health (ARISE) was developed to systematically evaluate psychosocial distress in children with serious medical or chronic medical illnesses, by integrating patient-reported outcome measures (PROM) into care delivery. ARISE was developed using a user-centered approach with extensive input from patients, families, and healthcare professionals to overcome barriers to routine PROM collection and integration into care as usual. It comprises a system to capture PROMs and then relay results to clinicians for changing care. We sought to implement ARISE at four subspecialty pediatric clinics caring for patients with cystic fibrosis, sickle cell disease, hemophilia, and neurological malignancy.

RESULTS: Problems with acceptability, appropriateness, and feasibility represented barriers to implementation which were overcome by modifying the intervention using stakeholder input during the planning phase, leading to broad program acceptance. ARISE was implemented in three of the four clinics, in which 79.8% of eligible children and their family completed PROMs.

CONCLUSION: The ARISE program demonstrated the feasibility and effectiveness of integrating psychosocial screenings into subspecialty pediatric clinics, thereby enhancing the identification and management of psychosocial issues in children with serious and chronic medical illnesses.

PMID:39441705 | DOI:10.1093/jpepsy/jsae081

Am J Respir Crit Care Med. 2024 Oct 23. doi: 10.1164/rccm.202311-2184OC. Online ahead of print.

ABSTRACT

RATIONALE: Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk.

OBJECTIVES: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD.

MEASUREMENTS AND MAIN RESULTS: Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV1% predicted, inhaled corticosteroids, and serum IgA.

RESULTS: The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations.

CONCLUSIONS: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.

PMID:39441116 | DOI:10.1164/rccm.202311-2184OC