Am J Hematol. 2025 Jul 2. doi: 10.1002/ajh.27756. Online ahead of print.

ABSTRACT

Hereditary hemorrhagic telangiectasia (HHT) is the second-most common inherited bleeding disorder worldwide, afflicting one in 4000-5000 people, and is the most morbid inherited bleeding disorder of women. HHT causes recurrent severe epistaxis, chronic gastrointestinal bleeding, heavy menstrual bleeding, and arteriovenous malformations in the lung, liver, and brain that cause serious bleeding and nonbleeding complications. There are no approved treatments worldwide, and the direct medical costs of HHT have not been well-characterized. We utilized the Komodo Healthcare Map claims database to create a large sample of US patients diagnosed with HHT, including a subgroup with anemia and a subgroup receiving hematologic support (iron infusions and/or red cell transfusions). We quantified mean per patient per year (PPPY) and total population inpatient, outpatient, and pharmacy costs in 2022 and 2023. The mean PPPY costs for all HHT patients (n = 24 407; n = 23 524), those with anemia (n = 13 856; n = 13 192) and those receiving hematologic support (n = 6191; n = 5818) were approximately $19 000, $27 000, and $40 000, respectively, across years, representing > $450 000 000 in annual healthcare costs in the sample. The leading cost drivers were related to treatment for bleeding and its consequences. While accounting for nearly 60% of HHT patients, those with anemia accounted for ~80% of direct medical costs. Across the majority of leading inpatient, outpatient, and pharmacy cost drivers, patients with anemia and anemia treatment accounted for 75%-100% of cost. The PPPY costs of HHT are comparable to, or exceed, those of other rare, resource-intensive serious diseases, including sickle cell disease, muscular dystrophy, and cystic fibrosis.

PMID:40600700 | DOI:10.1002/ajh.27756

Front Med (Lausanne). 2025 Jun 17;12:1577363. doi: 10.3389/fmed.2025.1577363. eCollection 2025.

ABSTRACT

PURPOSE: Burkholderia multivorans, a Gram-negative bacterium, often infect patients with severe immunocompromised and cystic fibrosis. B. multivorans infection is challenging to treat due to its ability to disrupt the action of multiple antimicrobial agents through intrinsic and acquired resistance mechanisms. A better understanding of the pulmonary microbial spectrum of B. multivorans infection is crucial for the prevention and treatment of B. multivorans.

CASE PRESENTATION: This case series reviewed the respiratory microbiome structure and alternations during the treatment of B. multivorans infection through metagenomic next-generation sequencing (mNGS). Analysis of mNGS data of 19 pharyngeal secretion samples collected from the 3 COVID-19 patients at different time points showed that the relative abundance of B. multivorans was fluctuated and eventually increased, indicating the possible development of drug resistance. A total of 40 antibiotic-resistant genes (ARGs) were detected. Significantly, the levels of CEOA, CEOB, and OPCM were consistent with the trends in the relative abundance of B. multivorans. Besides, we described nine previously uncharacterized non-synonymous mutations in PenA of B. multivorans. These mutations lead to amino acid changes Thr32Ala, Ala43Ser, Gln105Arg, Asn202Ser, Gln219Arg, Gly241Ala, Val259Ala, Thr279Ala, and Ser298Ile that may associate with resistance to β-lactam antibiotics.

CONCLUSION: This report shed light on the importance of rapidly diagnosis and treatment of B. multivorans infection. mNGS serve as a powerful microbial detection tool that provides a comprehensive, sensitive, and rapid method for pathogen detection and drug resistance analysis.

PMID:40600049 | PMC:PMC12209342 | DOI:10.3389/fmed.2025.1577363

Front Pharmacol. 2025 Jun 17;16:1528905. doi: 10.3389/fphar.2025.1528905. eCollection 2025.

ABSTRACT

Pseudomonas aeruginosa infection has become a widespread problem in patients with cystic fibrosis (CF). A safe and effective manufacturing method is required to produce antibiotic dry powder inhalations (DPIs) which can be effectively delivered to treat lung infections. In this study, an excipient-free tobramycin inhalable powder was prepared using spray freeze-drying (SFD) method. The mass median aerodynamic diameters (MMAD) of optimized inhalable powder prepared by SFD was 1.30 µm, and the fine particle fractions (FPF) reached 83.31%. In both in vitro and in vivo safety and activity studies, the inhalable powder showed excellent safety performance at both animal and cellular levels, with a minimum inhibitory concentration (MIC) of 0.5 μg/mL. Compared with intravenous injection, inhalation of excipient-free tobramycin inhalable powder had a better effect in the infected mouse model because of its amorphous state. This study demonstrates that excipient-free tobramycin inhalable powder with good delivery and deposition performance can be successfully obtained using the SFD method. Inhalation of excipient-free tobramycin inhalable powder has the potential to be a promising strategy for treating pulmonary infections caused by P. aeruginosa in patients with CF.

PMID:40599797 | PMC:PMC12208834 | DOI:10.3389/fphar.2025.1528905

J Nanobiotechnology. 2025 Jul 1;23(1):467. doi: 10.1186/s12951-025-03527-3.

ABSTRACT

Pancreatic cancer has the highest mortality rate among all major cancers, which highlights the urgent needs of non-invasive early detection. Circulating extracellular vesicles (EVs) have gained significant attention for discovering tumor biomarkers. However, isolating EVs with well-defined homogeneous populations from complex biological samples is challenging. Different methods have been found to derive different EV populations carrying different biomolecules, which significantly confound biomarker discovery for developing clinical diagnostics. Building a rigorous EV isolation and standardizing assessment platform associated with -omics is essential to overcome this challenge. We introduced a novel isolation approach using a pH-responsive peptide conjugated with NanoPom magnetic beads (ExCy) for homogeneous EV isolation. Additionally, we introduced the first statistical algorithm for EV quality assessment (ExoQuality Index, EQI), which enables multi-assay quantification to provide a consistent and accurate definition of EV purity and quality; ExoQuality's algorithm intakes multi-assay information to deconvolute complex EV heterogeneity. We performed the next generation sequencing on EV RNAs from pancreatic cancer patient plasma using four isolation methods; results highlighting ExCy's isolation and EQI assessment improved biomarker identification. We identified a novel EV biomarker for pancreatic tumor, ATP6V0b, validated with quantitative PCR (qPCR) by screening a pilot cohort of 22 plasma samples. 16 were from pancreatic cancer patients, 6 with matched tumor tissue, and 6 healthy plasma samples. Through modelling the ATP6V0B cycling threshold, we reported 3 models with AUCs between 0.86 and 0.88, showcasing an enabling and clinically translatable liquid biopsy approach for early detection of pancreatic cancer using circulating EVs.

PMID:40598203 | DOI:10.1186/s12951-025-03527-3

Nat Commun. 2025 Jul 1;16(1):5870. doi: 10.1038/s41467-025-61208-z.

ABSTRACT

With the rise of antibiotic-resistant bacteria, non-antibiotic therapies like gallium gain increasing attention. Intravenous gallium nitrate is under Phase II clinical trials to treat chronic Pseudomonas aeruginosa infections in cystic fibrosis patients. However, its clinical efficacy is constrained by the achievable peak concentration in human tissue. To address this limitation, we apply a genome-wide CRISPR interference approach (CRISPRi-seq) to identify potential synergistic targets with gallium. We classify the essential genes by response time and growth reduction, pinpointing the most vulnerable therapeutic targets in this species. In addition, we identify a highly conserved gene, fprB, encoding a ferredoxin-NADP⁺ reductase, whose deletion sensitizes P. aeruginosa to gallium, lowering its MIC by 32-fold and shifting mode of action from bacteriostatic to bactericidal. Further investigation reveals that FprB plays a critical role in modulating oxidative stress induced by gallium, via control of iron homeostasis and reactive oxygen species accumulation. Deleting fprB enhances gallium's efficacy against biofilm formation and improves outcomes in a murine lung infection model of P. aeruginosa, suggesting FprB is a promising drug target in combination with gallium. Overall, our data show CRISPRi-seq as a powerful tool for systematic genetic analysis of P. aeruginosa, advancing the identification of novel therapeutic targets.

PMID:40595632 | DOI:10.1038/s41467-025-61208-z

Nat Commun. 2025 Jul 1;16(1):5518. doi: 10.1038/s41467-025-60691-8.

ABSTRACT

The Endoplasmic Reticulum (ER)-Golgi Intermediate Compartment (ERGIC) is a network of tubules and vesicles known for producing COPI vesicles and receiving COPII vesicles from the ER. Much about its identity, stability, and regulation remains unknown. Here, we show that TUG (UBXN9, Aspscr1) protein, a central regulator of GLUT4 trafficking, localizes to the ERGIC, and that its deletion enhances anterograde flux of a model soluble cargo protein. TUG deletion redistributes ERGIC markers to the cis-Golgi and alters Golgi morphology. TUG forms biomolecular condensates in vitro and contains a central disordered region that mediates its recruitment to ERGIC membranes. A distinct N-terminal region mediates its oligomerization in cells. TUG deletion disrupts ERGIC-dependent processes, including autophagy and collagen secretion, and alters the targeting of the CFTR chloride channel. We conclude that TUG organizes and stabilizes ERGIC membranes to support their roles in diverse secretory and degradative membrane trafficking pathways.

PMID:40593538 | DOI:10.1038/s41467-025-60691-8

Nat Commun. 2025 Jul 1;16(1):5579. doi: 10.1038/s41467-025-60598-4.

ABSTRACT

Cystic fibrosis is a monogenetic disease complicated by recurrent bacterial lung infections that require chronic antibiotics. Pseudomonas aeruginosa is an increasingly antibiotic-resistant pathogen associated with cystic fibrosis morbidity and mortality. Here, we describe the development of a three-phage cocktail (BX004-A) designed to target a wide range of P. aeruginosa strains. We evaluated BX004-A in Part 1 of a first-in-human double-blind placebo-controlled phase 1b/2a clinical trial, which included nine adult cystic fibrosis patients chronically infected with P. aeruginosa (NCT05010577). BX004-A met the primary endpoints of safety and tolerability. Exploratory endpoints included pharmacokinetics and Pseudomonas aeruginosa sputum density reduction. Efficient phage delivery to the lower respiratory tract was observed, and a potential reduction in P. aeruginosa sputum burden was noted in the phage arm. However, due to the study's small sample size, definitive conclusions regarding efficacy are limited. These data pave the way toward further development of novel phage-based therapeutics in antibiotic-resistant pulmonary bacterial infections.

PMID:40593506 | DOI:10.1038/s41467-025-60598-4

Eur J Cancer Prev. 2025 Jun 26. doi: 10.1097/CEJ.0000000000000981. Online ahead of print.

ABSTRACT

INTRODUCTION: Cancer remains a leading cause of death in Europe, with over 1.2 million deaths recorded in the EU-27 in 2020.

METHODS: Using WHO death certification data for 33 European countries from 1990 to 2020, we analyzed mortality trends for all neoplasms and 24 cancer sites, stratified by sex and age. We computed age-standardized mortality rates (ASMR) and applied joinpoint regression models to evaluate temporal trends.

RESULTS: In 2020, the leading causes of cancer death in the EU-27 were lung (ASMR: 30.1/100 000), colorectal (14.6/100 000), and prostate (9.8/100 000) cancer in males and breast (13.8/100 000), lung (13.2/100 000), and colorectal (8.6/100 000) cancer in females. Pancreatic cancer was the fourth most common cause of cancer death in both sexes (ASMR: 8.2/100 000 males and 5.8/100 000 females). Most Central and Eastern European countries reported rates over two-fold higher compared to Western Europe. While overall cancer mortality declined since 1990 (average annual percent change: -1.3% in males and -0.8% in females in the EU-27), mortality from pancreatic (+0.2% in males and +0.8% in females) and female lung cancer (+1.9%) increased.

CONCLUSION: Declines in cancer mortality are attributable to reduced tobacco use, and improvements in organized screening programs and treatment. Pancreatic cancer mortality remains stable, while female lung cancer mortality continues to rise in some countries, largely due to later adoption of smoking and low cessation rates. Lower participation in screening programs and limited access to novel therapies in many Central and Eastern European countries contribute to poorer cancer outcomes, highlighting the need for equitable prevention, early detection, and treatment strategies across Europe.

PMID:40591447 | DOI:10.1097/CEJ.0000000000000981

Dis Model Mech. 2025 Jun 1;18(6):dmm052106. doi: 10.1242/dmm.052106. Epub 2025 Jul 1.

ABSTRACT

In the lung airways, multiple cell types facilitate airflow to alveoli, clearing out debris, particles and pathogens. These vital processes are impeded in chronic inflammatory respiratory diseases, in which the epithelium typically suffers from inflammation, infections and hypoxia. An increasing body of evidence highlights the critical role of modifier genes in responses and resistance against these pathogenic processes. Here, we sought to study the transcription factor EHF, suggested by previous studies as a putative modifier gene, yet its functional role remains ambiguous. To explore this question, we knocked out EHF in human induced pluripotent stem cell-derived lung cells and examined the subsequent phenotypic and functional impacts. Loss of EHF enhanced cystic fibrosis transmembrane conductance regulator activity, led to transcriptomic changes in basal cells, increased transepithelial electrical resistance and reduced HIF-1α-mediated response to hypoxia. Here, we show that variation in EHF expression can impact lung diseases through several mechanisms, thereby highlighting prospects for novel therapies.

PMID:40590703 | DOI:10.1242/dmm.052106

J Diabetes Sci Technol. 2025 Jul;19(4):937-949. doi: 10.1177/19322968251338754. Epub 2025 Jul 1.

ABSTRACT

BACKGROUND: Since the discovery of the life-saving hormone insulin in 1921 by Dr Frederick Banting in 1921, there have been many critical discoveries and technical breakthroughs that have enabled people living with type 1 diabetes (T1D) to live longer, healthier lives. The development of insulin pumps, continuous glucose monitoring (CGM) systems, and automated insulin delivery (AID) systems have enabled people living with T1D to safely manage their glucose, reduce their HbA1c, and improve their overall health and quality of life. Nevertheless, AID systems are not yet designed for all people with T1D, and they perform best during the overnight period when meals and exercise are not occurring. AID systems are not fully automated in that they require the person using the system to announce meals and exercise to the system to avoid dangerous hyper- or hypoglycemia, respectively.

METHODS: In this review, which is one of a collection of manuscripts to commemorate the 75th anniversary of the National Institute for Diabetes and Digestive and Kidney Diseases, we celebrate the commercialization of the AID and discuss the major challenges and research gaps that remain to be solved to enable single- and multi-hormone AID systems to more fully support glucose management in people living with T1D.

RESULTS: More research is required to design and evaluate more intelligent AID systems that do not require accurate carbohydrate estimations or announcements for meals and exercise. Current AID systems are also not designed to be used by older adults or pregnant people. Results are presented on new AID systems that can automatically respond to meals and exercise. Results are also presented on evaluations of AID systems in older adults and pregnant people.

CONCLUSIONS: Next-generation AID systems will need to support all people, including older adults, people during pregnancy, athletes, and people who may be too busy to announce carbohydrates or exercise to the system. Solutions are now becoming available that will enable AID systems to support a broader range of people living with T1D by leveraging the latest technologies in artificial intelligence and adaptive control.

PMID:40590464 | DOI:10.1177/19322968251338754

J Diabetes Sci Technol. 2025 Jul;19(4):908-923. doi: 10.1177/19322968251335685. Epub 2025 Jul 1.

ABSTRACT

The development of automated insulin delivery systems has seen tremendous improvements from individual components to interoperable system combinations of devices and new drugs besides insulin. The components have become progressively smaller, more accurate, and more user friendly. This article summarizes the history of the artificial pancreas from the earliest concepts to fully functional systems to research into further improvements in the future. The authors include many of the developers of this technology who received research support from the National Institute of Diabetes and Digestive and Kidney Diseases at various stages to develop these systems.

PMID:40590463 | DOI:10.1177/19322968251335685

ERJ Open Res. 2025 Jun 30;11(3):01001-2024. doi: 10.1183/23120541.01001-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: Cardiopulmonary exercise testing (CPET) provides prognostic information in people with advanced cystic fibrosis lung disease (pwACFLD). This project aimed to ascertain feasibility and inter-reporter variability in the identification of submaximal CPET outcomes for pwACFLD as potential predictors of prognosis where no peak exercise data are available.

METHODS: We utilised data from an international retrospective multicentre study involving pwACFLD, for whom raw CPET data were available. Two experienced operators independently reviewed and analysed CPET tests with a focus on three pre-defined measures: oxygen uptake (V'O2 ) at the anaerobic threshold (AT), the breathing reserve index at the AT (BRIAT), and the slope of the minute ventilation to carbon dioxide production ratio (V'E/V'CO2 -slope). We calculated intra-class correlation coefficients (ICCs) with their 95% confidence intervals (CI), and limits of agreement using the Bland-Altman method.

RESULTS: The original cohort included 174 pwACFLD. Among those, raw CPET data were available for 101 individuals, of which 89 tests were of sufficient technical quality for submaximal analysis. In 72 out of 89 technically acceptable tests (81%), the AT could be confidently identified by both operators. Furthermore, ICCs indicated good-to-excellent inter-reporter agreement for V'O2 at the AT (ICC 0.79, 95% CI 0.62-0.88), the V'E/V'CO2 -slope (0.95, 95% CI 0.93-0.97) and BRIAT (0.76, 95% CI 0.63-0.85).

CONCLUSIONS: Submaximal CPET data can be reliably obtained in most pwACFLD by trained CPET operators. Future studies may ascertain the prognostic value of submaximal CPET outcomes in pwACFLD.

PMID:40589908 | PMC:PMC12208563 | DOI:10.1183/23120541.01001-2024

Biochem Soc Trans. 2025 Jun 30;53(3):709-721. doi: 10.1042/BST20241029.

ABSTRACT

Short palate lung and nasal epithelial clone 1 (SPLUNC1; gene name BPIFA1) is a secreted protein that is highly expressed in the nasopharyngeal and pulmonary systems. By data mining, we found that SPLUNC1 is also expressed in other organs, including the kidneys and the pituitary gland. SPLUNC1 is an asthma and cystic fibrosis gene modifier that also inversely correlates with the severity of bronchiectasis. Orai1 is a plasma membrane Ca2+ channel that is an essential regulator of the immune system. We previously found that SPLUNC1 binds to Orai1, causing it to be ubiquitinated, internalized and trafficked to the lysosome for degradation, thus reducing Ca2+ signaling. Here, we discuss how dysregulation of SPLUNC1-Orai1 interactions may contribute to hyperinflammation in multiple pulmonary diseases. We, and others, have also targeted Orai1 therapeutically, and we will also discuss how Orai1 inhibition may overcome SPLUNC1 deficiency and be beneficial for the treatment of chronic lung disease.

PMID:40589325 | DOI:10.1042/BST20241029

Biofilm. 2025 Jan 20;9:100253. doi: 10.1016/j.bioflm.2025.100253. eCollection 2025 Jun.

ABSTRACT

Stenotrophomonas maltophilia is an emerging multidrug-resistant, Gram-negative opportunistic pathogen. It causes many healthcare-associated infections such as sepsis, endocarditis, meningitis, and catheter-related urinary tract infections. It also affects individuals with cystic fibrosis, exacerbating their lung condition. S. maltophilia often causes pathogenesis through the formation of biofilms. However, the molecular mechanisms S. maltophilia uses to carry out these pathogenic steps are unclear. The SMF-1 chaperone/usher pilus has been thought to mediate S. maltophilia attachment. To confirm this role, we created an isogenic deletion of the smf-1 pilin gene and observed a defect in biofilm compared to wild type. We also discovered an additional chaperone/usher pilus gene cluster: cbl. Mutation of cbl also affects biofilm levels. Intriguingly, through transmission electron microscopy studies, we found suggestive evidence that the mutation of one pilus (e.g. smf) is not phenotypically compensated by another (e.g. cbl). Additionally, infection of Galleria mellonella larvae revealed increased virulence of an smf-1 deletion mutant and an smf-1 cbl double deletion mutant. Together, these studies show that pili have an important role in switching between acute and chronic infections in conducting S. maltophilia virulence. Understanding their activity may help identify therapeutic targets for this pathogen.

PMID:40585315 | PMC:PMC12206331 | DOI:10.1016/j.bioflm.2025.100253

Res Sq [Preprint]. 2025 Jun 17:rs.3.rs-6890276. doi: 10.21203/rs.3.rs-6890276/v1.

ABSTRACT

The most common cystic fibrosis mutation is the F508del mutation in the human cystic fibrosis transmembrane conductance regulator (hCFTR), which causes misfolding of the first of two nucleotide binding domains (NBD1/2), preventing Mg/ATP-dependent NBD dimerization for normal function. Although folding correctors elexacaftor/VX-445 and lumacaftor/VX-809 have been combined to correct the NBD1 misfolding, the exact correction pathway is still unknown. In this study, the constrained tertiary noncovalent interaction networks or the thermoring structures of dimerized NBD1 in hCFTR/E1371Q with or without F508del were analyzed to identify the weakest noncovalent bridge as the final posttranslational tertiary folding of dimerized NBD1 in response to folding correctors. These computational analyses suggested that hCFTR may primarily use cooperative folding between α- and β-subdomains in dimerized NBD1 as the last step upon the binding of the potentiator ivacaftor/VX-770. However, the binding of folding correctors may allosterically protect the α-subdomain from misfolding until subsequent core formation. This thermodynamic protective mechanism, unlike the chaperone-based one in cotranslational NBD1 folding, may restore posttranslational NBD1 folding for tight Mg/ATP-mediated NBD dimerization in the F508del mutation, and also potentially apply to treating other cystic fibrosis patients with rare mutations.

PMID:40585202 | PMC:PMC12204354 | DOI:10.21203/rs.3.rs-6890276/v1

Mymensingh Med J. 2025 Jul;34(3):866-873.

ABSTRACT

Infection control in Cystic fibrosis (CF) patients plays a crucial role in improving the survival of patients with CF. Antimicrobial sensitivity patterns in these patient groups in our country are currently lacking. Therefore, the purpose of this observational study was to evaluate the microbiological cultures and antimicrobial susceptibility pattern of pediatric CF patients. A total of 50 respiratory samples were prospectively collected from the patients with CF got admitted in the Dhaka Shishu Hospital, Bangladesh from February 2021 to October 2021. Sputum and nasopharyngeal swabs were processed for culture and microbiological testing. Sample collection and evaluation were performed according to the Good Laboratory Practice guidelines (GLP). Informed written consent was ensured before participation. Statistical analysis was performed with SPSS v26.0. The median age of the children was 30 months (6-120) months, with a male predominance (66.0% vs. 34.0%). Single and two organisms were isolated in 72.0% (n=36) and 12.0% (n=6) of cases, respectively. During the study period, 36.0% of the patients harbored Pseudomonas aeruginosa, 18.0% harbored Klebsiella pneumoniae and both Staphylococcus aureus and Escherichia coli were detected in 16.0% of cases. Levofloxacin was found to be the most active antibiotic agent with 100.0% susceptibility. In contrast, nearly all isolates were resistant to amoxicillin, erythromycin and rifampicin. Levofloxacin is the most effective agent to treat CF patients. Active surveillance of the resistance pattern should always continue to be promoted.

PMID:40583680

Br J Nutr. 2025 Jun 30:1-27. doi: 10.1017/S0007114525103760. Online ahead of print.

ABSTRACT

The RDA for dietary protein is likely to be insufficient for individuals with cystic fibrosis (CF), whereas a higher daily intake of ≥1.2g·kg-1·day-1 may be more appropriate in view of the increased risk of sarcopenia and reduced muscle quality. This study sought to characterise protein intake and diet quality in adults with cystic fibrosis (awCF), before and after elexacaftor/tezacaftor/ivacaftor (ETI) therapy, compared to healthy controls. Dietary intake was assessed by diet diary in awCF at baseline (BL, n=40) and at follow-up >3 months post ETI therapy (FUP, n=40), and in age-matched healthy controls (CON, n=80) free from known disease at a single time point. Protein intake dose and daily distribution, protein quality, protein source and overall diet quality was calculated for each participant. Both CON (1.39±0.47g·kg-1·day-1) and CF (BL: 1.44±0.52g·kg-1·day-1, FUP: 1.12±0.32g·kg-1·day-1) had a higher mean daily protein intake than the protein RDA of 0.75g·kg-1·day-1. There was a significant reduction in daily protein intake in the CF group at FUP (P=0.0003, d=0.73), with levels below the alternative suggested dietary intake of ≥1.2g·kg-1·day-1. There were no sex differences or noticeable effects on protein quality or source following the commencement of ETI therapy when compared to CON (all P>0.05), although overall diet quality decreased between time points (P=0.027, d=0.57). The observed reduction in daily protein intake in the present cohort emphasises the importance of ensuring appropriate dietary protein intake to promote healthy ageing in adults with CF. More research is needed to evidence base dietary protein requirements in this at-risk population.

PMID:40583308 | DOI:10.1017/S0007114525103760

Ear Hear. 2025 Jun 30. doi: 10.1097/AUD.0000000000001693. Online ahead of print.

ABSTRACT

OBJECTIVES: Cystic fibrosis (CF) affects sinus and lung function, yet little is known about middle-ear function in relation to disease severity. Wideband (WB) absorbance measures are a more sensitive and specific metric of middle-ear function than traditional, single-frequency tympanometry. WB tympanometric measures were used to study middle-ear function in normal-hearing persons with CF and varying degrees of exposure to intravenous aminoglycoside (IV-AG) antibiotics as a proxy for disease severity compared with age-matched persons without CF.

METHODS: Middle-ear function was assessed in normal-hearing adult participants with (N = 57) and without CF (N = 29). Four groups were examined: (1) CF with a history of greater than 40 doses of IV-AGs (CF high IV-AG), (2) CF with fewer than 40 doses of IV-AGs (CF low IV-AG), (3) CF with no previous IV-AG exposures (CF no IV-AG), and (4) Healthy controls without CF or history of IV-AG exposure (non-CF). Clinical tests included pure-tone air (250 to 8000 Hz) and bone conduction audiometry (250 to 4000 Hz) and 226 Hz tympanometry. Experimental WB downswept tympanometry was also conducted for 250 to 8000 Hz. Hearing thresholds, air-bone gaps, and 226 Hz static acoustic admittance were compared between groups. WB tympanometric absorbance and peak-to-tail differences were compared between groups at half-octave frequencies, as was the tympanometric width (TW) of the low-frequency averaged absorbance tympanogram (from 380 to 2000 Hz) around its tympanometric peak pressure.

RESULTS: Air conduction thresholds were elevated for patients with CF for 250 to 2000 Hz compared with control participants. Broader absorbance TW was found for the CF participants relative to the non-CF control participants (p < 0.05). Specifically, non-CF controls demonstrated smaller TW compared with the CF no IV-AG (p = 0.015), CF low IV-AG (p = 0.011), and CF high IV-AG (p < 0.001) groups. WB peak-to-tail differences further revealed statistically significant group mean differences between the CF no IV-AG and CF high IV-AG groups from 500 to 1000 Hz (p < 0.05) and non-CF controls and CF high IV-AG group at 2000 and 5660 Hz (p < 0.05). There were no statistically significant differences at the p < 0.05 level for mean static acoustic admittance (Ytm) obtained from the 226 Hz tympanogram between non-CF controls and the three CF IV-AG exposure groups (p = 0.076).

CONCLUSIONS: Novel findings from this investigation revealed that participants with CF regardless of AG dosing had greater WB TW compared with non-CF controls. Greater WB TW along with poorer (elevated) low-frequency audiometric thresholds and lower absorbance peak-to-tail differences compared with non-CF controls suggest increased middle-ear stiffness in individuals with CF. These differences are subtle as reflected in the higher air conduction thresholds at low frequencies, despite absent air-bone gaps. Additional studies of middle-ear function in CF patients with a history of middle-ear disorders are needed to determine the clinical implications of these findings.

PMID:40583133 | DOI:10.1097/AUD.0000000000001693

J Vis Exp. 2025 Jun 13;(220). doi: 10.3791/68464.

ABSTRACT

Pseudomonas aeruginosa is a major human pathogen, particularly in chronic wound infections and chronic pulmonary infections (especially in patients with cystic fibrosis (CF)). Chronic bacterial infections are refractory to antibiotic treatments and there is an urgent need for in vivo chronic infection models amenable to drug screening to develop efficient therapies. Here, we describe a protocol of infection by a P. aeruginosa clinical isolate from a CF patient, expressing constitutively the Green Fluorescent Protein (GFP), for generating a persistent wound infection in zebrafish larvae. Tail fin-injured embryos are immersed in a bacterial suspension for 1.5 h, washed, and monitored for bacterial load for 3 days. The bacterial burden was quantified daily by counting fluorescent colony-forming units (CFU) from lysed infected larvae, which allowed a persistent infection. Moreover, persistent P. aeruginosa bacteria were refractory to antibiotic treatment. This novel in vivo model of persistent P. aeruginosa infection offers opportunities to evaluate the efficacy of innovative treatments against chronic infections.

PMID:40587407 | DOI:10.3791/68464

Ann Am Thorac Soc. 2025 Jun 30. doi: 10.1513/AnnalsATS.202411-1151OC. Online ahead of print.

ABSTRACT

In cystic fibrosis (CF), body composition alterations are observed. Prevalence of obesity in CF is increasing with evidence suggesting a subsequent increase in cardiometabolic risk. We sought to assess body composition using analytic morphomics (AM) from ultra-low dose thoracic CT scans in CF patients on the triple CFTR modulator therapy, Elexacaftor/Tezacaftor/Ivacaftor (ETI). Objective Our objective was to use analytical morphomics on routine ultra-low dose CTs to assess patterns of change in body composition in CF patients on ETI therapy. Methods Forty-two CF patients on ETI who had baseline and follow up ultra-low dose thoracic CT imaging were retrospectively analysed. The CTs were acquired at a radiation dose equivalent to 2 frontal chest x-rays using our previously published acquisition parameters. The Bhalla score was used as a marker of structural lung disease severity. AM variables including: cross sectional area (CSA) and attenuation of pectoralis muscle, visceral fat (epicardial and upper abdominal) and subcutaneous fat were extracted using the validated image segmentation software, CoreSlicer. Paired samples mean testing (Wilcoxon matched pairs signed rank test) and Spearman rank correlation analyses were performed. Results Total Bhalla scores significantly improved over time in patients on ETI (p < 0.0001). In addition, body composition also changed with an increase in the CSA of subcutaneous, and epicardial visceral fat (p values < 0.0001, and 0.0062, respectively). In those with a normal BMI at follow up, epicardial, and subcutaneous fat had also increased significantly in the interval (p = 0.0066, and 0.0002, respectively). Conclusion In CF, ETI produced a significant improvement in structural lung disease over time, however also resulted in an increase in visceral and subcutaneous fat. The AM methodology presented herein, may help identify those patients for aggressive primary prevention strategies and permit the creation of more personalised nutritional plans.

PMID:40587244 | DOI:10.1513/AnnalsATS.202411-1151OC