Adv Respir Med. 2025 Jun 17;93(3):20. doi: 10.3390/arm93030020.

ABSTRACT

Poor sleep quality and excessive daytime sleepiness are commonly reported by individuals with cystic fibrosis. The potential impact of comorbid sleep-disordered breathing (SDB), particularly obstructive sleep apnea (OSA), has not been extensively studied in the CF population. At present, there are no specific recommendations available to help clinicians identify patients with CF who are at increased risk of sleep disorders. Home sleep apnea testing using a validated peripheral arterial tonometry (PAT) device may offer an accurate diagnosis of OSA in a more convenient and low-cost method than in-lab polysomnography. In this single-center study of 19 adults with CF, we found an increased prevalence of OSA among individuals with CF compared to general population estimates. Although associations with an FEV < 70% predicted and a modified Mallampati score ≥ 3 were observed, these odds ratios did not reach statistical significance, likely reflecting limited power in this small pilot sample. There was no association found between the self-reported presence of nocturnal cough or snoring and OSA. We also found no association between OSA and abnormal scores on commonly used, validated sleep questionnaires, suggesting that CF-specific scales may be needed for effective screening in the CF clinic.

PMID:40558119 | DOI:10.3390/arm93030020

Front Cell Infect Microbiol. 2025 Jun 10;15:1582339. doi: 10.3389/fcimb.2025.1582339. eCollection 2025.

ABSTRACT

Pseudomonas aeruginosa is a major opportunistic pathogen that causes chronic infections, particularly in patients with cystic fibrosis and chronic obstructive pulmonary disease (COPD). The type VI secretion system (T6SS) is a primary virulence factor of P. aeruginosa in chronic infections. The objective of this study was to elucidate the regulatory mechanisms and pathogenic effects of the T6SS during P. aeruginosa infection, utilizing transcriptome sequencing and functional assays. We found that T6SS expression is elevated in P. aeruginosa isolated from chronically infected patients. Deletion of the retS gene activates P. aeruginosa PAO1 T6SS while repressing T3SS in vitro. Bacterial and cellular transcriptome sequencing analyses showed that T6SS genes were upregulated, while T3SS genes were downregulated in the ΔretS mutant. Additionally, the expression levels of the fimbriae gene cupC, the histidine phosphotransfer protein hptC (PA0033), and the transcription factor PA0034 were significantly increased. Subsequent experiments revealed that adhesion mediated by cupC enhances the contact-killing activity of the T6SS. Deletion of the hptC-PA0034 operon results in the down-regulation of cupC expression. The ΔretSΔcupC and ΔretSΔhptC-PA0034 mutants exhibited reduced cytotoxicity compared to the ΔretS mutant, similar to the ΔretSΔclpV1ΔclpV2 mutant. The ΔretS infection increased cell death, inflammatory factors (IL-1β, IL-6, TNF-α), and reactive oxygen species compared to a T6SS-inactive strain. Importantly, our study demonstrates that the T6SS activates the PDE4C pathway in epithelial cells, leading to significant cellular alterations. The application of PDE inhibitors effectively mitigates cell damage and inflammatory responses. These findings highlight the critical role of T6SS in modulating host cell signaling and suggest potential therapeutic strategies for conditions associated with T6SS-mediated inflammation.

PMID:40557319 | PMC:PMC12185982 | DOI:10.3389/fcimb.2025.1582339

Calcif Tissue Int. 2025 Jun 24;116(1):88. doi: 10.1007/s00223-025-01400-x.

ABSTRACT

Familial dysautonomia (FD) is characterized by skeletal morbidity, including osteoporosis and increased fracture risk. We aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) in individuals with FD, and to explore correlations with disease severity. This retrospective study included all the patients with FD who performed at least one dual-energy X-ray absorptiometry (DXA) scan at our institution during 2015-2023. Demographic and clinical data obtained from medical records included: medical treatment, anthropometric measurements, Functional Severity Scale (FuSS) score, balance assessment, the Brief Ataxia Rating Scale score, ambulation ability, blood test results and fracture history. Forty-one patients (21 males) had at least one DXA scan. The median age at the first scan was 25 years (range 7-47). The mean BMD Z-score was - 1.2 ± 1.5 at the lumbar spine and - 1.3 ± 1.1 at the bilateral proximal femur. The mean TBS Z-score was - 1.8 ± 1.6. The bilateral proximal femur BMD Z-score correlated with better scores of balance (r = 0.612, p = 0.001), ambulation (r = 0.627, p = 0.001) and ataxia (r = - 0.470, p = 0.015). For 67% of the patients, C-terminal telopeptides of type I collagen (CTX) was above the normal range for age. Both CTX and procollagen type I N-terminal propeptide (P1NP) correlated negatively with FuSS (r = - 0.515, p = 0.10 and r = - 0.619, p = 0.042, respectively) and with L1-4 Z-scores (r = - 0.681, p = 0.03 and r = - 0.700, p = 0.02, respectively). Individuals with FD had low BMD and TBS Z-scores. These parameters were correlated to disease severity, specifically to balance and ambulation. The bone resorption marker was high and negatively correlated with disease severity.

PMID:40555858 | DOI:10.1007/s00223-025-01400-x

J Dent. 2025 Jun 22:105847. doi: 10.1016/j.jdent.2025.105847. Online ahead of print.

ABSTRACT

OBJECTIVES: To adapt the supranational European Federation for Periodontology (EFP) S3-Level Clinical Practice Guideline for treatment of very severe periodontitis (stage IV) to a UK healthcare environment, considering views of a broad range of stakeholders, and patients.

SOURCES: This UK version is based on the supranational EFP guideline published in the Journal of Clinical Periodontology. The source guideline was developed using the S3-level methodology, combining assessment of formal evidence from 13 systematic reviews with a moderated consensus process of a representative group of dental discipline stakeholders, accounting for health equality, environmental factors and clinical effectiveness. This guideline encompasses 47 clinical recommendations for the treatment of stage IV periodontitis, based on a step-wise process mapped to the 2018 periodontal and peri-implant diseases and conditions classification and UK classification implementation.

METHODOLOGY: The UK version was developed from the source guideline using a formal process called the GRADE ADOLOPMENT framework. The adoption allows (unmodified acceptance) adaptation (acceptance with modifications) and the de novo development of clinical recommendations. Using this framework and following the S3-process, the underlying evidence was updated and a representative guideline group of 101 delegates from 19 stakeholder organisations was assembled into three working groups. Following the formal S3-process, all clinical recommendations were formally assessed for their applicability to the UK and adoloped accordingly.

RESULTS AND CONCLUSION: Using the ADOLOPMENT protocol, a UK version of the EFP S3-level Stage IV clinical practice guideline was developed. This guideline delivers evidence- and consensus-based clinical recommendations of direct relevance to the UK dental community.

PMID:40555302 | DOI:10.1016/j.jdent.2025.105847

J Infect Chemother. 2025 Jun 17:102756. doi: 10.1016/j.jiac.2025.102756. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) patients experience chronic lung inflammation and decline. Azithromycin (AZM), a macrolide antibiotic, offers potential anti-inflammatory and antimicrobial benefits. We aim to evaluate the safety and efficacy of AZM therapy in patients with CF. A comprehensive search was conducted across PubMed, Scopus, Web of Science, and Cochrane on 22 December 2023. We included all relevant randomized controlled trials (RCTs) and cohort studies. Meta-analysis was conducted using R Studio software (version: 2023.12.1). Continuous outcomes were expressed as weighted mean differences with standard deviation (SD), and dichotomous variables were reported as relative risks with a 95% confidence interval (CI). A total of 18 studies comprising 2877 patients were included, with 11 studies meeting the criteria for inclusion in the meta-analysis. AZM significantly reduced the need for new oral antibiotics (RR = 0.77; 95% CI: [0.66, 0.89]). No significant increase in adverse events was observed. However, lung function (FEV1, FVC, FEF), inflammatory markers, and pulmonary exacerbations remained unchanged. Azithromycin holds promise for managing CF, but further research is needed to fully understand its long-term impact on lung health and resistance patterns.

PMID:40554009 | DOI:10.1016/j.jiac.2025.102756

Gastroenterology. 2025 Jun 17:S0016-5085(25)00896-0. doi: 10.1053/j.gastro.2025.06.011. Online ahead of print.

ABSTRACT

BACKGROUND: Tasty&Healthy (T&H) is a whole-food diet for Crohn's disease (CD), which excludes processed food, gluten, red meat, and dairy, without requiring formula or mandatory ingredients. TASTI-MM was a clinician-blinded, randomized-controlled trial comparing tolerability and effectiveness of T&H vs. exclusive enteral nutrition (EEN).

METHODS: Patients with biologic-naive mild-moderate CD aged 6-25 years were randomized to either T&H or EEN for 8 weeks, receiving weekly dietary support. Tolerability was evaluated by weekly interviews, questionnaires and intake diaries. Other outcomes included symptomatic remission, Mucosal-Inflammation Non-Invasive (MINI) index, calprotectin, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Fecal microbiome was analyzed by metagenomics at baseline, week-4 and week-8. Data were analyzed by the intention-to-treat approach unless specified otherwise.

RESULTS: Among 83 included patients (41 T&H, 42 EEN; mean age 14.5±3.7 years), 88% tolerated T&H vs. 52% for EEN (aOR 7.7 [95%CI 2.4-25]; p<0.001). Calprotectin, CRP and ESR decreased significantly in both groups, with no between-group differences. Symptomatic remission was achieved in 56% of T&H group vs. 38% of the EEN group (aOR 2.5 [0.98-6.3], p=0.1; per-protocol: 67% vs. 76%; p=0.47). Calprotectin <250μg/g was achieved in 34% vs. 33% (aOR 0.97 [0.37-2.6], p=0.84) and MINI<8 in 44% vs. 31% (aOR 1.8 [0.7-4.5]; p=0.33). Microbiome α-diversity improved in the T&H arm and declined in the EEN arm, showing superior species richness at both week-4 and week-8. Species associated with bowel inflammation, such as Ruminococcus gnavus, decreased in T&H and increased in EEN (q<0.001).

CONCLUSIONS: T&H demonstrated better tolerability than EEN for inducing remission in mild-to-moderate CD, while positively affecting the microbiome (TASTI-MM, NCT#04239248).

PMID:40553742 | DOI:10.1053/j.gastro.2025.06.011

J Pediatr (Rio J). 2025 Jun 16:S0021-7557(25)00098-1. doi: 10.1016/j.jped.2025.05.007. Online ahead of print.

ABSTRACT

OBJECTIVE: Cystic fibrosis (CF) treatment has evolved significantly with the development of CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI). This study aimed to evaluate in a real-life context, the efficacy, safety and tolerability of ETI in children and adolescents with CF at a national reference center in Brazil.

METHODS: A cohort of 39 patients (mean age: 11.7 years) who had been using ETI for at least three months were evaluated. Anthropometric data, pulmonary function, sweat chloride concentration, pulmonary exacerbations, antibiotic use, and liver function were assessed over a follow-up period of up to 17 months.

RESULTS: Significant improvements were observed in weight Z-score at three months (p = 0.046) and six months (p = 0.018), as well as absolute weight gain (p < 0.001). Height showed absolute growth, but no significant changes in Z-scores. Sweat chloride concentration decreased by 52.8 mmol/L (p < 0.001). Pulmonary exacerbations and antibiotic use significantly declined (p < 0.001 for both). Despite limitations in spirometry data collection, FEV1 values showed a median increase of 6 percentage points. Oropharyngeal swab cultures for Pseudomonas aeruginosa positivity dropped from 43.6 % to 5.1 %. Safety assessments showed a transient rise in alkaline phosphatase (p = 0.011), but no significant hepatotoxicity. The most common adverse events were increased respiratory secretions (25.6 %) and abdominal pain (15.4 %). One temporary treatment suspension and one dose reduction occurred, but no patient required permanent discontinuation.

CONCLUSIONS: ETI demonstrated effectiveness in improving weight gain, reducing pulmonary exacerbations, and significantly lowering sweat chloride concentration. The treatment was well-tolerated, with a favorable safety profile. These findings align with existing literature, supporting ETI's role as a transformative therapy in pediatric CF management.

PMID:40553696 | DOI:10.1016/j.jped.2025.05.007

Endocr Pract. 2025 May 12:S1530-891X(25)00105-3. doi: 10.1016/j.eprac.2025.04.001. Online ahead of print.

ABSTRACT

OBJECTIVE: Despite recent revisions of Medicare coverage guidelines for continuous glucose monitoring (CGM) in 2023, the policy change has been slow to disseminate to providers and patients. This quality improvement project aimed to increase CGM prescriptions and utilization amongst qualifying Medicare patients with diabetes on insulin.

METHODS: An interprofessional study team used process mapping to define the baseline state of CGM ordering and opportunities for improvement at a single diabetes specialty clinic. Several interventions were trialed through Plan-Do-Study-Act (PDSA) cycles, including general and targeted provider education, provider-facing technology support documents, a formulary guide, and patient-facing education about the new coverage requirements. The primary outcome was percentage of eligible patients using CGM. Process measures included the number of CGM orders started monthly. Demographic and socioeconomic factors in patients using and not using CGM were measured to assess for differences in prescribing practices.

RESULTS: Over 8 months of intervention, the percentage of eligible Medicare patients using CGM increased from 49.6% to 62.6%. The median number of CGM orders started monthly increased from 34 to 60. Both pre- and postintervention, compared to patients not using CGM, patients using CGM were younger, had lower A1c, and were more often enrolled in the electronic health record patient portal. There were no differences in other demographic factors between the groups.

CONCLUSION: Quality improvement interventions targeting providers and patients can help translate policy changes into clinical practice. Creating interventions with all patients in mind can prevent new differences in care as innovations are adopted.

PMID:40553031 | DOI:10.1016/j.eprac.2025.04.001

Pharm Stat. 2025 Jul-Aug;24(4):e70023. doi: 10.1002/pst.70023.

ABSTRACT

In this study, we present an innovative approach for tailoring treatment selection on an individualized basis in the presence of correlated multiple responses, particularly those measured on ordinal scales, including binary responses. Our methodology involves the utilization of rank lists for treatments, generated from probabilities of observing responses of higher order than each level of the ordinal outcome, conditional on patient covariate measurements. We introduce a rank aggregation technique designed to amalgamate multiple lists of ranks, allowing for correlations both within these lists and among elements within each list. Our approach is versatile, accommodating any number of treatments and responses, and is applicable across a wide range of models. Our method offers flexibility by allowing the integration of response weights, enabling customization based on patient and clinician preferences on an individual case basis for optimal treatment decisions. To evaluate the performance of our proposed method in finite samples, we conducted a simulation study. Furthermore, we provide two illustrative examples using data from clinical trials on Cystic Fibrosis and Alzheimer's Disease, demonstrating the application of our proposed procedure in real-world scenarios.

PMID:40552707 | DOI:10.1002/pst.70023

Pediatr Pulmonol. 2025 Jun;60(6):e71164. doi: 10.1002/ppul.71164.

ABSTRACT

OBJECTIVE: This study aimed to examine the preliminary psychometric characteristics of the Cystic Fibrosis Coping Self-Efficacy Scale (CF-CSE), a new measure of coping self-efficacy assessing confidence in one's ability to cope with challenges of living with cystic fibrosis (CF).

METHODS: Measure development included cognitive testing with people with CF who participated in a pilot trial of CF-CBT, a CF-specific cognitive behavioral therapy skills-based intervention. Data were then collected from a baseline assessment in a multi-center randomized-controlled trial of CF-CBT for adults with mild symptoms of depression and/or anxiety (N = 60). Multitrait analysis was used to evaluate how individual CF-CSE items loaded on five hypothesized subscales, followed by assessment of subscale internal consistency and construct validity.

RESULTS: Multitrait analysis supported retention of four subscales (21 items total; 4-7 items each) reflecting coping skill domains: Acceptance-Based Strategies/Self-Compassion, Cognitive Coping, Active Stress Management, and Coping with Daily Self-Care. Each scale had excellent internal consistency (Cronbach ⍺ = 0.81 to 0.90). Medium to large effect-size (ES) correlations were found for all CF-CSE subscales with self-reported Perceived Stress Scale scores, and medium to large ES correlations for all subscales with Cystic Fibrosis Questionnaire-Revised (CFQ-R) Emotional Functioning. There were medium ES correlations between the Coping with Daily Self-Care subscale and CFQ-R Social and Role Functioning and Health Perceptions.

CONCLUSION: CF-CSE is a new CF-specific measure of coping self-efficacy with preliminary evidence of reliability and construct validity. It offers a promising strengths-based patient-reported outcome measure identifying targets for clinical intervention and evaluating outcomes in CF mental health care.

PMID:40552690 | DOI:10.1002/ppul.71164

Pediatr Pulmonol. 2025 Jun;60(6):e71180. doi: 10.1002/ppul.71180.

ABSTRACT

BACKGROUND: The lung clearance index (LCI) is a sensitive measure of global ventilation inhomogeneity but does not describe the gas mixing mechanisms that lead to inhomogeneity. Multiple breath washout normalized phase III slope (SnIII) metrics may complement LCI when assessing lung disease; Scond describes convection-dependent inhomogeneity and Sacin reflects diffusion convection-interaction-dependent inhomogeneity respectively. We aim to determine the feasibility and utility of Scond and Sacin in preschool children with CF.

METHODS: We retrospectively assessed Scond and Sacin in successful MBW tests performed on preschool children. Scond and Sacin were calculated by visual breath-by-breath analysis according to ATS/ERS MBW consensus statement, with the exception that minimum SnIII was at least 30% of expired volume rather than between 65% and 95% of expired volume.

RESULTS: We analyzed MBW tests for 40 healthy controls and 40 participants with CF, with a mean (range) baseline age of 4.1 years (2.6-5.9). Of the 372 successful MBW tests analyzed, 77% had reportable SnIII indices. Scond was elevated in CF relative to controls (∆ 0.037; 95% CI: 0.026-0.047; p < 0.001). Both within- and between-test variability was higher for Scond and Sacin than for LCI. More clinically stable test occasions were above the upper limit of normal for Scond than for LCI (64% vs. 50%, p = 0.02).

CONCLUSIONS: MBW metrics Scond and Sacin are feasible in young children. While they differentiate preschool children with CF from healthy controls, SnIII indices are more variable than LCI, limiting their interpretability.

PMID:40552665 | DOI:10.1002/ppul.71180

Front Immunol. 2025 Jun 9;16:1553013. doi: 10.3389/fimmu.2025.1553013. eCollection 2025.

ABSTRACT

Pulmonary diseases, such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and ventilator-associated pneumonia (VAP), are attributed to the prolonged infection of the airway and hypersecretion of mucus. Pseudomonas aeruginosa (PA) is one of the most common nosocomial pathogens in these diseased airways, secreting a wide spectrum of metabolites and volatile organic compounds (VOCs) that significantly impact the respiratory epithelium, including disruption of mucus homeostasis and inflammatory responses of the diseased lungs. In this review, we highlighted the major metabolites and VOCs produced by PA and the mechanisms by which they modulate inflammation, cellular injury, and mucus hypersecretion in respiratory epithelium.

PMID:40552284 | PMC:PMC12183278 | DOI:10.3389/fimmu.2025.1553013

ERJ Open Res. 2025 Jun 23;11(3):00987-2024. doi: 10.1183/23120541.00987-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Multiple-breath washout (MBW) is an established outcome measure of lung disease in cystic fibrosis (CF). However, data on its sensitivity to detect lung function impairment in bronchiectasis across age groups remain limited. The aim of this study was therefore to determine the feasibility, validity and sensitivity of MBW compared with spirometry in people with bronchiectasis.

METHODS: We performed MBW and spirometry in 94 people with bronchiectasis (aged 0.2 to 79.3 years), 168 healthy controls, and 128 people with CF and 76 with asthma as disease controls.

RESULTS: The overall success rate of MBW in all 466 participants was 96.1%. People with bronchiectasis had an elevated lung clearance index (LCI) and a reduced forced expiratory volume in 1 s (FEV1) compared with healthy controls and people with asthma (all p<0.001). Comparing bronchiectasis and CF, there was no difference in LCI, but FEV1 was reduced in bronchiectasis (p=0.032). Within the bronchiectasis group, LCI correlated strongly with FEV1 (r= -0.69, p<0.001). However, 34.3% of people with bronchiectasis presented with an elevated LCI but normal FEV1, while none had a reduced FEV1 combined with a normal LCI (p<0.001). LCI was superior to FEV1 in detecting lung function impairment in bronchiectasis (area under the curve: 0.95 versus 0.86).

CONCLUSION: LCI is more sensitive than FEV1 to detect lung function impairment in bronchiectasis. These findings support further evaluation of LCI for clinical monitoring and as a sensitive outcome measure in clinical trials in people with bronchiectasis.

PMID:40551806 | PMC:PMC12183715 | DOI:10.1183/23120541.00987-2024

ERJ Open Res. 2025 Jun 23;11(3):01115-2024. doi: 10.1183/23120541.01115-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: The extent to which changes in lung function are due to natural variability in patients with primary ciliary dyskinesia (PCD) is unknown. We aimed to assess intra-individual variability in forced expiratory volume in 1 s (FEV1) derived from spirometry to define the extent to which the observed changes were due to test variability in clinically stable PCD patients.

METHODS: PROVALF-PCD (Prospective Observational Multicentre Study on Variability of Lung Function in Stable PCD Patients) was a large international prospective cohort conducted in 2017-2019. We included patients aged ≥5 years who were clinically stable at two or more consecutive visits and provided spirometry-derived lung function measurements. To calculate the upper limit of normal (ULN), we fitted an unadjusted multilevel mixed-effect model, and to determine the absolute change in FEV1 z-scores, we calculated the coefficient of repeatability (CR). We performed sensitivity analyses by stratifying relative change by age (adults versus children), number of measurements (at least four), and time between measurements (<4 months apart).

RESULTS: We included 252 participants from 12 countries with confirmed or highly likely PCD. We included 1028 FEV1 measurements from patients in stable state. The ULN for relative change between two measurements of FEV1 was 25%. Test variability remained high in all sensitivity analyses. The CR was 1.88 FEV1 z-score.

CONCLUSIONS: Changes in intra-individual FEV1 >25% between visits in stable PCD patients lie beyond the expected test variability and therefore could be considered physiologically relevant. These findings inform the selection of end-points for pulmonary intervention trials in PCD, as they suggest that FEV1 is not a sensitive test for monitoring lung health in PCD.

PMID:40551797 | PMC:PMC12183702 | DOI:10.1183/23120541.01115-2024

ERJ Open Res. 2025 Jun 23;11(3):01071-2024. doi: 10.1183/23120541.01071-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by dysfunction of motile cilia. Symptoms include recurrent and chronic airway infections which can lead to deteriorating lung function and inflammatory destructive lung disease in the form of persistent atelectasis and bronchiectasis. Routine blood testing may be used as a tool for disease monitoring and management. However, currently there are no consensus-based guidelines within the field of PCD. BEAT-PCD together with the ERN-LUNG PCD-Clinical Trial Network aimed to develop an international expert consensus statement on which routine blood tests should be conducted in patients with PCD.

METHODS: An international panel of 33 PCD experts from 17 countries was established to generate consensus on routine blood testing in PCD. A modified Delphi technique with three e-survey rounds was used to reach consensus, which was defined as ≥80% agreement for each statement. Two patient representatives were included in the consensus process.

RESULTS: The expert panel reached consensus on 51 out of 101 statements (50%) on routine blood testing in children and adults with PCD to be performed at diagnosis, annually and on exacerbation. The statements include biomarkers for inflammation, haemoglobin, iron status, vitamin D, immune function, inhalant allergies, liver and kidney function, and allergic bronchopulmonary aspergillosis.

CONCLUSIONS: This is the first international consensus on routine blood testing in PCD. It highlights blood tests that may be relevant to perform at diagnosis, annually and on exacerbation in people with PCD. Further research on the clinical usefulness of routine blood testing in PCD is needed.

PMID:40551794 | PMC:PMC12183740 | DOI:10.1183/23120541.01071-2024

ERJ Open Res. 2025 Jun 23;11(3):00709-2024. doi: 10.1183/23120541.00709-2024. eCollection 2025 May.

ABSTRACT

INTRODUCTION: Real-world data on children with severe asthma is scarce. We report characteristics of children with severe asthma already on biologics, enrolled in the Severe Paediatric Asthma Collaborative in Europe, a clinical research collaboration of the European Respiratory Society.

METHODS: We describe patient's characteristics including asthma control assessed with Global Initiative for Asthma (GINA) criteria, composite asthma severity index (CASI), exacerbations, unscheduled medical attendances, lung function and quality of life in children on biologic treatment because of severe asthma. We also assessed previous biologics use. Forced expiratory volume in 1 s, CASI, GINA, Paediatric Asthma Quality of Life Questionnaire score, exacerbations, unscheduled medical attendance and hospital admission comparisons in patients treated with different biologics were adjusted by age, sex and biologic therapy duration.

RESULTS: Among the 250 children (median age 13.2 years) recruited, 56.8% used omalizumab, 21.6% mepolizumab and 21.6% dupilumab. At enrolment, the dupilumab group was older (median 15.0 years), while the omalizumab group had been on biologic treatment the longest (median 622 days). Overall, 27% and 8% had partly controlled and uncontrolled asthma respectively, according to GINA. In the last 12 months, 52% and 29% had at least one and two exacerbations, respectively; airflow obstruction was found in 33%. 10% were admitted to hospital due to exacerbation. A previous switch from another biologic was recorded in 16%, predominantly due to nonresponse.

CONCLUSIONS: Most children on biologics obtained good symptom control, but many still experienced asthma attacks. Switching between biologics was substantial. There is still an unmet need in severe paediatric asthma.

PMID:40551791 | PMC:PMC12183703 | DOI:10.1183/23120541.00709-2024

Front Nutr. 2025 Jun 9;12:1579957. doi: 10.3389/fnut.2025.1579957. eCollection 2025.

ABSTRACT

Vitamin D₃ (cholecalciferol) is a fat-soluble secosteroid with essential roles in calcium-phosphorus metabolism, bone health, and an expanding range of extraskeletal processes. Upon synthesis in the skin via ultraviolet B exposure or ingestion from dietary sources, cholecalciferol is hydroxylated in the liver and kidneys to form its active metabolite, calcitriol (1,25-dihydroxyvitamin D), which exerts pleiotropic effects through vitamin D receptor (VDR)-mediated genomic and non-genomic pathways. This narrative review synthesizes evidence on the systemic effects of high-dose cholecalciferol on bone health, metabolism, cardiovascular and immune function, and its emerging roles in neurological, gastrointestinal, reproductive, oncologic, and psychiatric disorders. High-dose vitamin D₃ has demonstrated benefits in specific populations, including improved bone mineral density, immune homeostasis, glycemic control, and reduced inflammation. In patients with chronic kidney disease, cystic fibrosis, and inflammatory bowel disease, targeted supplementation has been associated with clinical improvements. Preclinical models support calcitriol's antiproliferative and neuroprotective functions, and its synergistic effects with chemotherapy, although large-scale randomized controlled trials (RCTs) have yielded mixed or inconclusive results, particularly in cancer, cardiovascular events, and cognitive decline. Methodological variability-such as inconsistent dosing regimens, baseline vitamin D status, and heterogeneous populations-limits definitive conclusions. While vitamin D supplementation is generally safe within recommended limits, excessive intake may cause hypercalcemia or nephrolithiasis, emphasizing the need for personalized strategies. Food fortification and targeted screening remain underutilized yet cost-effective public health interventions. Overall, vitamin D₃ represents a promising but complex therapeutic agent, necessitating further rigorously designed clinical trials to establish evidence-based guidelines for its use in diverse pathological conditions.

PMID:40551736 | PMC:PMC12183072 | DOI:10.3389/fnut.2025.1579957

Drugs R D. 2025 Jun 23. doi: 10.1007/s40268-025-00514-9. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Lumacaftor is an active ingredient in the US Food and Drug Administration-approved combination medication Orkambi®, which is used for treating cystic fibrosis. Experimental evidence suggests that lumacaftor can be used as a monotherapy to improve brain perfusion and memory in heart failure. To clinically assess this therapeutic intervention, a formulation with demonstrated bioequivalence to the currently approved combination product is required.

METHODS: This comparative bioavailability and food-effect study compared lumacaftor pharmacokinetics in healthy patients following: (i) oral administration of lumacaftor (400 mg; Test Product) or Orkambi® (lumacaftor 400 mg/ivacaftor 250 mg; Reference Product) in the fed state and (ii) oral administration of lumacaftor (400 mg; Test Product) in the fasted to fed state. Plasma lumacaftor concentrations were measured with a standard liquid chromatography with tandem mass spectrometry approach.

RESULTS: The "Test-to-Reference ratio" of the geometric least-square means for maximum plasma concentration and area under the curve met the Food and Drug Administration-defined criteria for bioequivalence; median times to maximum plasma concentration values were not statistically different. The "Fed to Fasted ratio" of the geometric least-square means for maximum plasma concentration and area under the curve indicated a clear food effect on bioavailability. Lumacaftor exposure was approximately two times higher when administered with fatty foods than when taken in a fasting state. The monosubstance formulation was well tolerated.

CONCLUSIONS: We conclude that the lumacaftor monosubstance formulation delivers lumacaftor exposure that is not meaningfully different than the currently approved combination product.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05968612.

PMID:40551045 | DOI:10.1007/s40268-025-00514-9

PLoS One. 2025 Jun 23;20(6):e0325347. doi: 10.1371/journal.pone.0325347. eCollection 2025.

ABSTRACT

BACKGROUND: Non-tuberculous mycobacteria (NTM) are pulmonary pathogens with increasing incidence and prevalence worldwide, with people with cystic fibrosis (pwCF) traditionally considered at high risk of disease development. The imaging assessment of NTM-pulmonary disease (NTM-PD) relies heavily on high-resolution computed tomography (HRCT). However, due to lengthy treatment regimens and the need for long-term follow-up, serial HRCT's result in progressive exposure to ionizing radiation; a particular concern in younger people.

METHODS: We performed a retrospective cohort study of patients who had undergone serial thoracic magnetic resonance imaging (tMRI) scans to monitor NTM-PD as a novel tool to image the lung with a view to creating an algorithm for the utility of tMRI in the management of NTM-PD.

RESULTS: Thirty-six patients, of which twenty-four had a diagnosis of CF, with suspected or confirmed NTM-PD underwent serial tMRI between 1st January 2013 and 30th June 2018. A total of 117 serial tMRI's were performed (mean number per patient 3.25; range 2-6). The associated clinical impact that each serial MRI had on management, deemed as the utility of tMRI, found that all tMRI's were classified as aiding management with 60 (51.3%) altering management. tMRI's were more likely to alter management in the non-CF cohort than the CF cohort (69.4% vs. 43.2%). No imaging-related adverse events were reported across the 117 tMRI's.

CONCLUSION: This study highlights that tMRI may hold promise as a monitoring tool in NTM-PD and should be prospectively evaluated in the monitoring of individuals with NTM-PD.

PMID:40549769 | DOI:10.1371/journal.pone.0325347

Access Microbiol. 2025 Jun 20;7(6):000979.v3. doi: 10.1099/acmi.0.000979.v3. eCollection 2025.

ABSTRACT

Non-typeable Haemophilus influenzae (NTHi) is an early pathogen isolated from the lungs of children with cystic fibrosis (CF). However, its role in the progression of CF lung infection is poorly understood. Additionally, whether it forms biofilms in the lungs of people with CF is an open question. The development of synthetic CF sputum media (SCFM) has given key insights into the microbiology of later CF pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, through replicating the chemical composition of CF sputum. However, the growth of NTHi in these media has not previously been reported. We show that NTHi grows poorly in three variants of SCFM commonly used to induce in vivo-like growth of P. aeruginosa and S. aureus (SCFM1, SCFM2 and SCFM3). The addition of NAD and haemin to SCFM1 and SCFM2 promoted the planktonic growth and biofilm formation of both laboratory and clinical NTHi isolates, and we were able to develop a modified variant of SCFM2 that allows culture of NTHis. We show that NTHi cannot be identified in an established ex vivo model of CF infection, which uses SCFM and porcine bronchiolar tissue. This may in part be due to the presence of endogenous bacteria on the pig lung tissue, which outcompete NTHi, but the lack of selective agar to isolate NTHi from endogenous bacteria, and the fact that NTHi is an exclusively human pathogen, makes it hard to conclude that this is the case. Through spiking modified SCFM2 with filter-sterilized lung homogenate, biofilm growth of clinical NTHi isolates was enhanced. Our results highlight that there are crucial components present in the lung tissue, which NTHi require for growth, which are not present in any published variant of SCFM from the Palmer et al. Endres and Konstan in JAMA (2022;137:191-1) lineage. Our results may inform future modifications to SCFM recipes to truly mimic the environment of CF lung sputum and thus, to facilitate the study of a wide range of CF pathogens.

PMID:40548129 | PMC:PMC12181625 | DOI:10.1099/acmi.0.000979.v3