Pediatr Pulmonol. 2024 Dec 3:e27362. doi: 10.1002/ppul.27362. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) primarily affects Caucasian populations, with the highest prevalence in countries like Ireland, the UK, Australia, and Canada. Despite significant improvements in survival, pulmonary insufficiency remains the leading cause of death. Factors such as nutrition, chronic Pseudomonas aeruginosa (PsA) infection, genotype, pancreatic status, and cystic fibrosis-related diabetes affect pulmonary function across age groups.

OBJECTIVE: This review examines disparities in CF care and outcomes between high-income countries (HICs) and low-income countries (LICs), focusing on the impact of CFTR modulators like Elexacaftor/Tezacaftor/Ivacaftor (ETI) and challenges in accessing care in LICs.

METHODS: Data from the European CF Society Patient Registry and studies on CF outcomes across regions were reviewed to assess survival trends, pulmonary function, and infection rates among people with CF (pwCF). The effects of CFTR modulator therapies, particularly for F508del carriers, were also evaluated.

RESULTS: In HICs, improvements in survival rates and pulmonary function have been noted, especially with the use of CFTR modulators like ETI. However, in LICs, challenges like limited access to therapies, delayed diagnosis, poor nutrition, and high PsA infection rates lead to poorer outcomes. In regions with fewer F508del carriers, access to care and medications is further limited, exacerbating disparities.

CONCLUSION: Although CF treatment advancements have improved outcomes in many pwCF, these benefits are not evenly distributed globally. Efforts to improve CF care in LICs, such as increasing awareness, ensuring access to therapies, and establishing specialized clinics, are essential to bridging this gap.

PMID:39625248 | DOI:10.1002/ppul.27362

Front Pharmacol. 2024 Nov 18;15:1494327. doi: 10.3389/fphar.2024.1494327. eCollection 2024.

ABSTRACT

INTRODUCTION: Cystic Fibrosis (CF) is a genetic disease due to loss-of-function mutations of the CFTR channel. F508del is the most frequent mutation (70% of alleles in Italy), while other mutations have much lower frequency. Among them, G85E (0.4% frequency globally, 1.13% in Italy) emerges as a mutation characterized by a severe CFTR folding and trafficking defect.

METHODS: To investigate the pharmacological responsiveness of the G85E-CFTR variant, we performed a functional and biochemical characterization in heterologous expression systems and ex vivo models based on patient-derived human nasal epithelial cells (HNEC).

RESULTS: Our study demonstrated that treatment of primary airway cells with elexacaftor and tezacaftor causes a significant (although modest) rescue of CFTR function, that reaches 15%-25% of the activity measured in non-CF epithelia. A detrimental effect of chronic treatment with ivacaftor, further limiting G85E rescue, was also observed. A higher rescue of CFTR function, up to 25%-35% of the normal CFTR activity, with no evidence of negative effects upon chronic potentiator treatment, can be achieved by combining elexacaftor with ARN23765, a novel type 1 corrector endowed with very high potency. Importantly, dose-response relationships suggest that G85E might alter the binding of type 1 correctors, possibly affecting their affinity for the target.

DISCUSSION: In conclusion, our studies suggest that novel combinations of modulators, endowed with higher efficacy leading to increased rescue of G85E-CFTR, are needed to improve the clinical benefit in patients for this variant.

PMID:39624835 | PMC:PMC11608983 | DOI:10.3389/fphar.2024.1494327

Cureus. 2024 Nov 1;16(11):e72824. doi: 10.7759/cureus.72824. eCollection 2024 Nov.

ABSTRACT

Cystic fibrosis (CF) is a genetic disorder that primarily affects the respiratory and gastrointestinal systems, often leading to significant perioperative challenges due to compromised lung function, recurrent infections, and chronic respiratory failure. Managing anesthesia in patients with CF requires careful consideration, particularly because of the increased risk of respiratory complications with general anesthesia (GA). Neuraxial anesthesia, such as spinal anesthesia, presents an alternative that can reduce the likelihood of postoperative pulmonary issues, including respiratory depression, hypoxemia, and atelectasis. However, spinal anesthesia is not without risk, particularly in the presence of coagulation abnormalities, which must be considered. We present the case of a 26-year-old male with severe CF, complicated by chronic respiratory failure and recurrent infections, who presented with acute appendicitis. The patient, with a history of bronchiectasis and chronic colonization by multidrug-resistant organisms, had stable but significantly impaired respiratory function, with a forced expiratory volume in one second (FEV1) of 1.62 L (38% predicted). He had a history of multiple hospital admissions for exacerbations of lung disease, none of which required mechanical ventilation or intensive care, with the most recent admission occurring 13 months prior to this event. Preoperative coagulation studies revealed an elevated international normalized ratio (INR) of 1.52 (normal range 0.8-1.2) and an activated partial thromboplastin time (APTT) of 38.1 seconds (normal <29.4 seconds), for which the patient received vitamin K without improvement. Despite these abnormalities, a thorough preoperative assessment and multidisciplinary discussion led to the decision to proceed with spinal anesthesia, carefully weighing the risks and benefits. An initial spinal anesthetic attempt with 2.0 mL of hyperbaric bupivacaine 0.5% (10 mg) and 2.5 mcg of sufentanil was administered at the L3-L4 interspace using a 27G Whitacre needle. Despite confirmed cerebrospinal fluid flow before injection, no sensory or motor block occurred, requiring an additional spinal injection. A second dose of 2.0 mL of hyperbaric bupivacaine 0.5% was administered at the L2-L3 interspace without sufentanil. A satisfactory sensory block to the T6 level was eventually obtained, allowing the appendectomy to proceed without intraoperative complications. Postoperatively, the patient was closely monitored in a high-dependency unit. He maintained stable respiratory function and experienced a smooth recovery, with minimal opioid use to avoid respiratory depression. The patient was discharged on the fifth postoperative day without respiratory or other anesthesia-related complications. This case highlights the importance of individualized care in CF patients undergoing surgery. Neuraxial anesthesia, when carefully planned and executed, can offer a safer alternative to GA by minimizing respiratory risks. However, the presence of coagulation abnormalities requires a detailed risk-benefit analysis, multidisciplinary collaboration, and vigilant intraoperative and postoperative care to ensure patient safety and optimize outcomes.

PMID:39624565 | PMC:PMC11608909 | DOI:10.7759/cureus.72824

ERJ Open Res. 2024 Dec 2;10(6):00312-2024. doi: 10.1183/23120541.00312-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterised by inflammatory lung disease and large numbers of airways neutrophils. In health, neutrophils undergo apoptosis and removal from the airway. Since CF neutrophils are known to engage in apoptosis less efficiently, we wanted to assess whether alternative forms of neutrophil clearance such as NETosis were prominent in the CF airway.

METHODS: Sputum and blood were collected from 45 CF and 15 healthy control (HC) participants. Neutrophil morphology and biochemical properties were assessed in CF and HC sputum. Neutrophil extracellular traps (NETs) were measured by a novel histone-calprotectin ELISA. NET levels were compared with established measurements of airway inflammation. CF participants were followed up for 1 year and the number of exacerbations recorded. Neutrophil and macrophage co-culture experiments were undertaken with cells from CF and HC.

RESULTS: Neutrophil numbers were significantly higher in CF and associated with abnormal morphology. Several inflammatory mediators were elevated in CF sputum, as was cell-free DNA. This was highly correlated with sputum calprotectin, a known NET-associated protein. Using a histone-calprotectin NET ELISA, we demonstrated higher levels of NETs in the CF airway. CF participants treated with DNase had fewer sputum NETs, and in neutrophil/macrophage co-culture experiments, DNase effectively attenuated the pro-inflammatory potential of NETs, suggesting a previously unrecognised anti-inflammatory role for this treatment.

CONCLUSIONS: NETs in the CF airway are associated with increased levels of inflammatory mediators and more severe lung disease. NET effects on macrophages can be blocked by DNase, suggesting an anti-inflammatory role for this treatment in CF.

PMID:39624379 | PMC:PMC11610045 | DOI:10.1183/23120541.00312-2024

ERJ Open Res. 2024 Dec 2;10(6):00330-2024. doi: 10.1183/23120541.00330-2024. eCollection 2024 Nov.

ABSTRACT

Non-cystic fibrosis bronchiectasis (NCFBE) belongs to the spectrum of chronic suppurative lung diseases and is characterised by persistent wet/sputum-productive cough and airway dilatation. Morphological and structural changes in the airways lead to changes in airflow, impair breathing-induced mucus transport and sliding, and reduce the shear forces of cough. Moreover, mucus hyperviscosity contributes to compromised ciliary activity and the pathogenesis of the disease. This mini-review highlights the role of cough in NCFBE, especially with respect to mucus clearance. Cough is the principal backup mechanism when mucus clearance is impaired due to either reduced function of cilia- and breathing-induced mucus transport, or abnormal mucus, or both. The efficiency of cough in overcoming the cohesive and adhesive properties of mucus is determined by both the forces applied to mucus by airflow and the mucus-airway surface properties. In NCFBE, mucus hyperviscosity contributes to impaired mucus clearance and determines disease pathogenesis; therefore, it may be a therapeutic target. The primary objectives of physiotherapy regimens in NCFBE are mucus hydration and the establishment of an optimal expiratory airflow velocity, which exerts shearing forces on the mucus located on the airway surface. Modifying the rheological properties of mucus and enhancing its transport whenever possible (by breathing manoeuvres, ciliary activity and cough) represent prime goals in preventing disease progression and, indeed reversing, bronchiectasis in the early stages of the disease, as well as preventing pulmonary exacerbations.

PMID:39624376 | PMC:PMC11610066 | DOI:10.1183/23120541.00330-2024

J Biomed Sci. 2024 Dec 3;31(1):103. doi: 10.1186/s12929-024-01091-w.

ABSTRACT

BACKGROUND: Mycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, such as clarithromycin (CLR) or azithromycin (AZM), represent the cornerstone of antibiotherapy against the M. abscessus species. However, prolonged exposure to these macrolides can induce of Erm(41)-mediated resistance, limiting their spectrum of activity and leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility, thus increasing the rate of treatment success. In our previous study, the Erm(41) methyltransferase was identified as a possible target enzyme of Cyclipostins and Cyclophostin compounds (CyC).

METHODS: Herein, we exploited this feature to evaluate the in vitro activity of CLR and AZM in combination with different CyC via the checkerboard assay on macrolide-susceptible and induced macrolide-resistant M. abscessus strains selected in vitro following exposure CLR and AZM.

RESULTS: Our results emphasize the use of the CyC to prevent/overcome Erm(41)‑induced resistance and to restore macrolide susceptibility.

CONCLUSION: This work should expand our therapeutic arsenal in the fight against a antibioticresistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in patients, and particularly in erm(41)-positive strains.

PMID:39623375 | DOI:10.1186/s12929-024-01091-w

PLoS Pathog. 2024 Dec 2;20(12):e1012221. doi: 10.1371/journal.ppat.1012221. Online ahead of print.

ABSTRACT

Evolution of the highly successful and multidrug resistant clone ST111 in Pseudomonas aeruginosa involves serotype switching from O-antigen O4 to O12. How expression of a different O-antigen serotype alters pathogen physiology to enable global dissemination of this high-risk clone-type is not understood. Here, we engineered isogenic laboratory and clinical P. aeruginosa strains that express the different O-antigen gene clusters to assess the correlation of structural differences of O4 and O12 O-antigens to pathogen-relevant phenotypic traits. We show that serotype O12 is associated with enhanced adhesion, type IV pili dependent twitching motility, and tolerance to host defense molecules and serum. Moreover, we find that serotype O4 is less virulent compared to O12 in an acute murine pneumonia infection in terms of both colonization and survival rate. Finally, we find that these O-antigen effects may be explained by specific biophysical properties of the serotype repeat unit found in O4 and O12, and by differences in membrane stability between O4 and O12 expressing cells. The results demonstrate that differences in O-antigen sugar composition can affect P. aeruginosa pathogenicity traits, and provide a better understanding of the potential selective advantages that underlie serotype switching and emergence of serotype O12 ST111.

PMID:39621751 | DOI:10.1371/journal.ppat.1012221

Curr Opin Pulm Med. 2024 Nov 1;30(6):631-632. doi: 10.1097/MCP.0000000000001114. Epub 2024 Oct 3.

NO ABSTRACT

PMID:39620994 | DOI:10.1097/MCP.0000000000001114

Pediatr Pulmonol. 2024 Dec 2:e27431. doi: 10.1002/ppul.27431. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic Fibrosis (CF) is a multisystem autosomal recessive disease characterized by thick, sticky mucus which causes lung disease, pancreatic insufficiency, and many other manifestations. Constipation is a common complication in CF and few advances in treatment have been made until recent years. Linaclotide is a treatment approved for chronic idiopathic constipation and irritable bowel syndrome with constipation. This case series investigates the potential for use of this agent in adult people with CF (pwCF).

METHODS: A retrospective case series of 39 pwCF who are currently or previously prescribed linaclotide was completed at two adult Cystic Fibrosis Foundation (CFF) Accredited Care Centers. All patients 18 years and older were included with no exclusions. We reported results using descriptive statistics.

RESULTS: A total of 39 patients were identified for inclusion. The daily starting dose of linaclotide did vary with 18%, 72%, and 10% started on 72 mcg, 145 mcg, and 290 mcg respectively. Most patients (n = 30, 77%) reported experiencing no side effects. Of the total patients, 15% (n = 6) reported the medicine was not effective and 10% (n = 4) had to stop therapy due to adverse reactions. More than half of patients started on therapy were able to reduce baseline treatments for constipation.

CONCLUSION: While this case series shows compelling data that may indicate benefit and tolerability of linaclotide use in pw CF, more research is needed to fully evaluate safety and efficacy of linaclotide for treating constipation in pwCF.

PMID:39620387 | DOI:10.1002/ppul.27431

Pediatr Pulmonol. 2024 Dec 2:e27418. doi: 10.1002/ppul.27418. Online ahead of print.

ABSTRACT

BACKGROUND: Musculoskeletal problems are reported in the literature as a common problem for people with cystic fibrosis, with a range of aetiologies including an inflammatory arthritis. However, accurate data on the presentations and prevalence are lacking. The aim of this cohort study was to describe the scale and impact of musculoskeletal symptoms in CF.

METHODS: A collaboratively designed questionnaire was administered to adults attending two large UK CF centres. Data collected evaluated scale and impact of musculoskeletal symptoms.

RESULTS: Results were obtained from 489 patients (response rate 59%). Of these, 49% reported that musculoskeletal symptoms impacted their activities of daily living in the previous year. Back pain was common, occurring in 44% of participants in the preceding week. The knee was the most commonly affected painful peripheral joint, with 26% of participants reporting knee pain within the last week rising to 50% within the last year. Early morning stiffness and joint swelling were markedly less common, suggesting that the majority of musculoskeletal pain in CF is not due to an inflammatory arthritis but is due to other factors.

CONCLUSION: Musculoskeletal problems are common in CF and frequently affect activities of daily living. Symptoms of inflammatory arthritis occurred in only a small minority of individuals. A focused approach to characterising and clarifying the aetiology of musculoskeletal symptoms is needed to inform the management of these disabling symptoms.

PMID:39620372 | DOI:10.1002/ppul.27418

iScience. 2024 Oct 11;27(11):111153. doi: 10.1016/j.isci.2024.111153. eCollection 2024 Nov 15.

ABSTRACT

The care for cystic fibrosis (CF) has dramatically changed with the development of modulators, correctors, and potentiators of the CFTR molecule, which lead to improved clinical status of most people with CF (pwCF). The modulators influence phospholipids and ceramides, but not linoleic acid (LA) deficiency, associated with more severe phenotypes of CF. The LA deficiency is associated with upregulation of its transfer to arachidonic acid (AA). The AA release from membranes is increased and associated with increase of pro-inflammatory prostanoids and the characteristic inflammation is present before birth and bacterial infections. Docosahexaenoic acid is often decreased, especially in associated liver disease Some endogenously synthesized fatty acids are increased. Cholesterol and ceramide metabolisms are disturbed. The lipid abnormalities are present at birth, and before feeding in transgenic pigs and ferrets. This review focus on the lipid abnormalities and their associations to clinical symptoms in CF, based on clinical studies and experimental research.

PMID:39620135 | PMC:PMC11607544 | DOI:10.1016/j.isci.2024.111153

Chem Sci. 2024 Nov 25. doi: 10.1039/d4sc06893a. Online ahead of print.

ABSTRACT

CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), a naturally occurring anion channel essential for numerous biological processes, possesses a positively charged ion conduction pathway within its transmembrane domain, which serves as the core module for promoting the movement of anions across cell membranes. In this study, we developed novel artificial anion channels by rebuilding the positively charged ion permeation pathway of the CFTR in artificial systems. These synthetic molecules can be efficiently inserted into lipid bilayers to form artificial ion channels, which exhibit a preference for anions during the transmembrane transport process. More importantly, the positively charged amino acid residues located in the ion permeation pathway of these artificial channels can promote the transmembrane transport of anions through electrostatic interactions, which is consistent with the mechanism of anion transmembrane transport achieved by CFTR.

PMID:39620072 | PMC:PMC11605520 | DOI:10.1039/d4sc06893a

Int J Pediatr. 2024 Nov 21;2024:9184954. doi: 10.1155/ijpe/9184954. eCollection 2024.

ABSTRACT

Aim: The aim is to examine whether using a portable spring-infusor device to deliver antibiotics compared with a standard infusion pump (SIP) translated to (i) improve health outcomes, (ii) reduce the length of stay (LoS), and (iii) reduce cost for treatment of exacerbations of cystic fibrosis (CF). Methods: An observational cohort study was conducted between December 2020 and June 2022 with participants aged 8-19 years admitted for exacerbation of CF. An activity monitor was fitted to participants to measure physical activities for the final 5 days of hospital admission. LoS was measured (days). Group allocation was according to participant preference. Costs were compared between the two groups for LoS, pump cost, and preparation and administration of antibiotics. Results:Twenty-seven of 30 eligible participants were approached, and 22 consented. Data were captured for 16 participants (spring-infusor n = 9): 10 female; mean (SD) age 14.5 (2.1) years. Average step count was negatively associated with age (rho = 0.50), and greater overall in participants using spring-infusors (mean 5324 (SD 2873) steps) versus SIPs (4806 (3116) steps) - mean (95% CI) increase in the spring-infusor group of 3246 (54-6438) for participants of the same age. LoS was longer on average in the SIP group, (mean (SD) LoS: 16.1 (4.3) versus 12.4 (1.7)). The estimated cost saving for a child using a spring-infusor was AUS$12,000. Conclusion:Results from the study suggest that children hospitalised for exacerbations of CF are more active if they receive antibiotics via a spring-infusor device compared with a SIP, and have reduced hospital stay that results in cost saving to the hospital. What is already known? Spring-infusors are small, portable, and mechanical devices to deliver intravenous antibiotics to patients. Spring-infusors are preferred by patients with CF at Perth Children's Hospital Physical activity in children with CF is recommended, including during hospital admissions to promote wellbeing, quality of life, and health outcomes. What this paper adds? Children hospitalised for exacerbations of CF may be more active if they receive antibiotics via a portable spring-infusor device compared with a SIP. Children using spring-infusors had reduced hospital stays that results in cost saving to the hospital. Children hospitalised for exacerbations of CF step on average, fewer than 5000 steps per day, which is well below recommendations.

PMID:39618513 | PMC:PMC11606683 | DOI:10.1155/ijpe/9184954

Sci Rep. 2024 Dec 1;14(1):29840. doi: 10.1038/s41598-024-80933-x.

ABSTRACT

Impaired mucociliary transport is a distinguishing sign of cystic fibrosis, but current methods of evaluation are invasive or expose young patients to ionizing radiation. Contrast-enhanced ultrasound imaging may provide a feasible alternative. We formulated a cationic microbubble ultrasound contrast agent, to optimize adhesion to the respiratory mucus layer when inhaled. Potential toxicity was evaluated in human bronchial epithelial cell (hBEC) cultures following a 24-hour exposure, compared to positive and negative control conditions. In vivo tolerability and pulmonary image enhancement feasibility were evaluated in mice, comparing oropharyngeal administration of contrast agent to saline control. When induced to flow across mucus plated on microscope slides, cationic microbubbles demonstrated greater affinity for target samples than standard microbubbles. Cationic microbubbles elicited no proinflammatory or cytotoxic response in hBECs, nor were any cross-links to the cilia observed. Unlike standard microbubbles, cationic microbubbles mixed into the mucus layer, without epithelial absorption, and were observed to move with the mucus layer by the action of mucociliary transport. When administered to mice, cationic microbubbles enhanced sonographic visualization of the trachea, and were well-tolerated with no adverse effects. This developmental work supports the safety and feasibility of a mucus-targeting contrast agent that may be useful for pulmonary ultrasound applications.

PMID:39617759 | DOI:10.1038/s41598-024-80933-x

ACS Biomater Sci Eng. 2024 Dec 1. doi: 10.1021/acsbiomaterials.4c01377. Online ahead of print.

ABSTRACT

Inhaled therapy has become a crucial treatment option for respiratory diseases like asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD), delivering drugs directly to bronchial and alveolar tissues. However, traditional static in vitro cell models, while valuable for studying pharmacokinetics (PK) and pharmacodynamics (PD), fall short in replicating the dynamic nature of physiological breathing. In this study, we present a breathing lung chip model that integrates a dynamic breathing mechanism with an air-liquid interface (ALI) culture environment to overcome these limitations. The platform replicates key aspects of lung physiology, including a functional airway interface, cyclic breathing motion, and medium circulation. Using the Calu-3 cell line to model airway epithelium, our experiments show that the incorporation of breathing motion significantly enhances the efficacy of inhaled drug delivery and cellular uptake, resulting in improved treatment outcomes compared to direct exposure of the drug. While further research is needed to explore its full potential, this platform holds promise for advancing inhaled drug screening and respiratory disease research.

PMID:39616618 | DOI:10.1021/acsbiomaterials.4c01377

J Cyst Fibros. 2024 Nov 30:S1569-1993(24)01812-5. doi: 10.1016/j.jcf.2024.11.005. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a chronic condition that requires complex and long-term treatments. While substantial research has explored treatment burden associated with CF; its impact remains complex to quantify. This review aims to identify the different methods used in the literature to measure treatment burden in people with CF (pwCF).

METHOD: Five databases were searched for interventional and observational studies that focused primarily on treatment burden. The studies were presented using narrative synthesis structured around the perspective of treatment burden (subjective vs. objective).

RESULTS: This review synthesised 17 articles, which utilised subjective and objective measures separately or collectively. Twelve studies used subjective treatment burden measures (CF-specific and generic scales), while 14 studies used objective measures (treatment time, volume and complexity, and cost). Eight studies investigated treatment burden reported by proxy on behalf of children with CF. The most used measures were treatment time (9/17) and CF questionnaire-revised (CFQ-R) treatment burden subscale (6/17). Older age and lower lung function were associated with greater burden, treatment time, and complexity. Caregivers/parents reported worse treatment burden compared to children with CF (6-13 y/o) when completing the same measure.

CONCLUSION: No single measure used in the reviewed studies fully the multidimensional nature of treatment burden and summarised it in a single score. Given the rapidly evolving landscape of CF care a pragmatic approach to capture a broader array of treatment burden dimensions may be to routinely complement subjective measures with objective measures.

PMID:39616120 | DOI:10.1016/j.jcf.2024.11.005

Respir Med. 2024 Nov 28:107890. doi: 10.1016/j.rmed.2024.107890. Online ahead of print.

NO ABSTRACT

PMID:39615801 | DOI:10.1016/j.rmed.2024.107890

Neurobiol Dis. 2024 Nov 28:106756. doi: 10.1016/j.nbd.2024.106756. Online ahead of print.

ABSTRACT

The autosomal recessive disease ataxia-telangiectasia (A-T) presents with cerebellar degeneration, immunodeficiency, radiosensitivity, capillary dilatations, and pulmonary infections. Most symptoms outside the nervous system can be explained by failures of the disease protein ATM as a Ser/Thr-kinase to coordinate DNA damage repair. However, ATM in adult neurons has cytoplasmic localization and vesicle association, where its roles remain unclear. Here, we defined novel ATM protein targets in human neuroblastoma cells, and filtered initial pathogenesis events in ATM-null mouse cerebellum. Profiles of global proteome and phosphoproteomics - both direct ATM/ATR substrates and overall phosphorylation changes - confirmed previous findings for NBN, MRE11, MDC1, CHEK1, EIF4EBP1, AP3B2, PPP2R5C, SYN1 and SLC2A1. Even stronger downregulation of ATM/ATR substrate phosphopeptides after ATM-depletion was documented for CHGA, EXPH5, NBEAL2 and CHMP6 as key factors of protein secretion and endosome dynamics, as well as for CRMP5, DISP2, PHACTR1, PLXNC1, INA and TPX2 as neurite extension factors. Prominent effects on semaphorin-CRMP5-microtubule signals and ATM association with CRMP5 were validated. As a functional consequence, microtubules were stabilized, and neurite retraction ensued. The impact of ATM on secretory granules confirms previous ATM-null cerebellar transcriptome findings. This study provides the first link of A-T neural atrophy to growth cone collapse and aberrant microtubule dynamics.

PMID:39615799 | DOI:10.1016/j.nbd.2024.106756

Ann Allergy Asthma Immunol. 2024 Nov 28:S1081-1206(24)01711-3. doi: 10.1016/j.anai.2024.11.021. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma in children is a leading cause of missed school days, emergency department visits, and hospitalizations. Approximately 40% of children with asthma experience uncontrolled disease and annual exacerbations. There is a need for a validated composite tool for children like the Asthma Impairment and Risk Questionnaire (AIRQ®), which was developed to assess current control and predict exacerbations in adolescents and adults with asthma.

OBJECTIVE: To obtain feedback from children with asthma and their parents/caregivers to inform development of a version of the AIRQ for pediatric use (Peds-AIRQ).

METHODS: Children with asthma aged 5-11 years and their parents/caregivers participated in cognitive interviews to elicit language describing asthma symptoms and exacerbations and to assess understanding and relevance of draft Peds-AIRQ questions. Physicians and parents/caregivers provided clinical information and performed assessments relative to the children's asthma morbidity.

RESULTS: Sixty dyads participated: children's mean (SD) age=7.9 (1.9) years; 68% male, 45% non-White, 32% Hispanic, and 40% with public health insurance. Overall, 53% had well-controlled, 30% partly controlled, and 17% uncontrolled asthma based on the Global Initiative for Asthma symptom control questions. Oral or injected corticosteroids were used for asthma by 53% of the children in the prior year. Participants found draft Peds-AIRQ items understandable and relevant. Seven impairment and three risk questions were retained for validation, along with five additional items containing wording or control threshold variations.

CONCLUSION: This study supports the need for developing a composite (impairment and risk) control tool to assess children aged 5-11 years with asthma and identified suitable questions for the validation of a Peds-AIRQ.

PMID:39615584 | DOI:10.1016/j.anai.2024.11.021

Lung. 2024 Nov 30;203(1):9. doi: 10.1007/s00408-024-00768-1.

ABSTRACT

PURPOSE: In people with cystic fibrosis (pwCF), elexacaftor/tezacaftor/ivacaftor (ETI) therapy is associated with an average improvement in FEV1 of 10-14%. However, a subset of individuals fails to achieve a clinically meaningful increase in spirometric indicators. In this study, we aimed to assess whether the lung clearance index (LCI2.5), a more sensitive indicator of lung involvement, improves following ETI initiation in this population.

METHODS: We conducted a prospective observational study in a specialized CF center in Italy. PwCF performed a spirometry and a multiple breath nitrogen washout test the day they initiated ETI therapy and after 6 and 12 months. They were grouped according to the 12-month change in FEV1 into two groups: Individuals who experienced a change in FEV1 ≥ a minimal clinically important difference (MCID) of 3% and those who did not. Mean changes in LCI2.5 were estimated using generalized estimating equations.

RESULTS: The study included 129 pwCF who initiated ETI at our center (Age Range: 12-36 years). In 20 subjects (15.5%), the FEV1 change was < MCID. These individuals had better baseline pulmonary function than those with FEV1 changes ≥ MCID (Median FEV1: 102.5 vs 87.0%), with the majority (90%) having FEV1 values ≥ 90%. Mean changes in LCI2.5 at 12-month follow-up visit were - 1.44 units (95% CI: - 2.12; - 0.75) in individuals with changes in FEV1 < MCID and - 2.64 units (95% CI: -3.05; -2.23) in those with values ≥ MCID.

CONCLUSION: LCI2.5 is a useful measure to monitor the effectiveness of ETI in pwCF with normal spirometry and limited FEV1 change following treatment initiation.

PMID:39614886 | DOI:10.1007/s00408-024-00768-1