bioRxiv [Preprint]. 2025 Jan 14:2025.01.14.632786. doi: 10.1101/2025.01.14.632786.

ABSTRACT

Pf bacteriophages, lysogenic viruses that infect Pseudomonas aeruginosa (Pa), are implicated in the pathogenesis of chronic Pa infections; phage-infected (Pf+) strains are known to predominate in people with cystic fibrosis (pwCF) who are older and have more severe disease. However, the transmission patterns of Pf underlying the progressive dominance of Pf+ strains are unclear. In particular, it is unknown whether phage transmission commonly occurs horizontally between bacteria within the airway via viral particles or if Pf+ bacteria are mostly acquired via new Pseudomonas infections. Here, we have studied Pa genomic sequences from 3 patient cohorts totaling 663 clinical isolates from 105 pwCF. We identify Pf+ isolates and analyze transmission patterns of Pf within patients between genetically similar groups of bacteria called "clone types". We find that Pf is predominantly passed down vertically within Pa lineages and rarely via horizontal transfer between clone types within the airway. Conversely, we find extensive evidence of Pa superinfection by a new, genetically distinct Pa that is Pf+. Finally, we find that clinical isolates show reduced activity of the type IV pilus and reduced susceptibility to Pf in vitro. These results cast new light on the transmission of virulence-associated phages in the clinical setting.

PMID:39868244 | PMC:PMC11761399 | DOI:10.1101/2025.01.14.632786

Biofilm. 2024 Dec 30;9:100252. doi: 10.1016/j.bioflm.2024.100252. eCollection 2025 Jun.

ABSTRACT

Antibiotics are central to managing airway infections in cystic fibrosis (CF), yet current treatments often fail due to the presence of Pseudomonas aeruginosa biofilms, settling down the need for seeking therapies targeting biofilms. This study aimed to investigate the antibiofilm activity of aspartic acid and its potential as an adjuvant to tobramycin against P. aeruginosa biofilms formed by mucoid and small colony variant (SCV) tobramycin tolerant strain. We assessed the effect of aspartic acid on both surface-attached and suspended P. aeruginosa biofilms within CF artificial mucus and investigated the synergistic impact of combining it with non-lethal tobramycin concentrations. Our findings showed that aspartic acid inhibited planktonic P. aeruginosa without affecting its viability and prevented biofilm formation by hindering bacterial adhesion or interfering with EPS production, depending on the experimental conditions. In CF mucus, aspartic acid significantly reduced bacterial growth, with the highest inhibition observed when combined with tobramycin, showing notable effects against the mucoid and tolerant SCV strain. Despite these reductions, P. aeruginosa repopulated the mucus within 24 h of stress withdrawal. Additional strategies, including delayed tobramycin application and a second dose of co-application of aspartic acid and tobramycin were explored to address bacterial survival and recovery. Although none of the strategies eradicated P. aeruginosa, the second co-application resulted in slower bacterial recovery rates. In conclusion, this study highlighted aspartic acid as an effective antibiofilm agent and demonstrated for the first time its potential as an adjuvant to tobramycin. The combined use of aspartic acid and tobramycin offers a promising advancement in CF therapeutics, particularly against P. aeruginosa biofilms formed by mucoid and SCV strains, mitigating their antibiotic resistance.

PMID:39866543 | PMC:PMC11759549 | DOI:10.1016/j.bioflm.2024.100252

Heliyon. 2025 Jan 7;11(1):e41716. doi: 10.1016/j.heliyon.2025.e41716. eCollection 2025 Jan 15.

ABSTRACT

BACKGROUND: Cystic fibrosis is a heterogeneous disease whose severity and symptoms largely depend on the functional impact of mutations in the cystic fibrosis transmembrane conductance regulator gene. Other genes may also modulate the clinical manifestations and complications associated with cystic fibrosis. Genetic variants of the bitter taste receptor TAS2R38 have been shown to contribute to the susceptibility and severity of chronic rhinosinusitis. This study aims to elucidate the role of TAS2R38 as a novel modifier gene influencing sinonasal disease severity and pulmonary Pseudomonas Aeruginosa colonization in children with cystic fibrosis.

METHODS: This retrospective observational case-control study evaluated sinus clinical features, quality of life, and the occurrence of Pseudomonas Aeruginosa pulmonary colonization in 69 children with cystic fibrosis. Propylthiouracil testing and TAS2R38 genotyping were performed to characterize patients based on receptor functionality.

RESULTS: The non-taster genetic variant of bitter taste receptor TAS2R38 was associated with greater severity of chronic rhinosinusitis, as measured by endoscopic and radiological scores, compared to the taster variant (p = 0.031 and p = 0.03, respectively). Furthermore, an inverse correlation was observed between the age at first Pseudomonas Aeruginosa infection and chronic rhinosinusitis severity assessed by endoscopic score (r = -0.3388, p = 0.0302).

CONCLUSIONS: The findings highlight the role of TAS2R38 as a potential genetic modifier influencing the severity of chronic rhinosinusitis in children with cystic fibrosis. The clinical implications include the potential development of T2R38-targeted topical therapies and the use of taste testing or genotyping to predict susceptibility to infection. In addition, these results may pave the way for novel, tailored therapeutic approaches in the era of precision medicine.

PMID:39866409 | PMC:PMC11761314 | DOI:10.1016/j.heliyon.2025.e41716

Otolaryngol Head Neck Surg. 2025 Jan 26. doi: 10.1002/ohn.1143. Online ahead of print.

ABSTRACT

OBJECTIVE: Cystic fibrosis (CF) is a clinical entity defined by aberrant chloride (Cl-) ion transport causing downstream effects on mucociliary clearance (MCC) in sinonasal epithelia. Inducible deficiencies in transepithelial Cl- transport via CF transmembrane conductance regulator (CFTR) has been theorized to be a driving process in recalcitrant chronic rhinosinusitis (CRS) in patients without CF. We have previously identified that brief exposures to bacterial lipopolysaccharide (LPS) in mammalian cells induces an acquired dysfunction of CFTR in vitro and in vivo. The objective of the current study is to evaluate whether LPS generates a model of acquired CFTR dysfunction murine nasal airways.

STUDY DESIGN: Basic science.

SETTING: Laboratory.

METHODS: CFTR+/+ murine nasal airways were irrigated with 2 µg/mL LPS or control vehicle twice daily for 1 week and transepithelial Cl- transport assessed with the nasal potential difference (NPD) assay. Histopathologic evaluation included the number of lymphoid aggregates, as well as the epithelial and subepithelial heights.

RESULTS: Transepithelial Cl- secretion by NPD was markedly reduced in mice exposed to LPS (in mV, -0.14 ± 7.7 vs control, -6.98 ± 7.15, P < .05), while amiloride-sensitive voltage was preserved (6.38 ± 5.09 vs control, 7.36 ± 2.87, P = .99). Histopathology demonstrated significantly higher lymphoid aggregates per high-power field (2.3 ± 0.9 vs 1.1 ± 0.7, control, P < .01) and increased epithelial height (in µm, 40.88 ± 13.9 vs control, 25.32 ± 6.26, P < .05).

CONCLUSION: Twice daily irrigation with LPS in murine nasal airways over 1 week led to acquired defects in transepithelial Cl- transport. This animal model provides an excellent means to test the contributions of acquired CFTR dysfunction to CRS and test CFTR correctors and potentiators that might improve MCC.

PMID:39865444 | DOI:10.1002/ohn.1143

J Cyst Fibros. 2025 Jan 25:S1569-1993(25)00009-8. doi: 10.1016/j.jcf.2025.01.009. Online ahead of print.

ABSTRACT

BACKGROUND: A previous Australia-wide pilot study identified pain as a significant burden in people with CF (pwCF). However, the prevalence, frequency and severity have not been evaluated using validated tools.

METHODS: Australian adults, pwCF and healthy controls (HC) were invited to complete an online questionnaire from July 2023 - February 2024, consisting of four validated tools: Brief Pain Inventory, Pain Catastrophising Scale, PAGI-SYM and PAC-SYM. The questionnaire, disseminated via Cystic Fibrosis Australia, CF Together and online social media groups, explored experiences surrounding pain and its management using closed and free text entries.

RESULTS: There were 206 respondents, consisting of 117 CF patients and 89 HC. Over 70 % (n = 69) of pwCF reported pain compared to 28 % (n = 21) of HC (p = <0.001). Further, significantly higher pain frequency per month was reported for pwCF than HC (40 % vs. 10 %; p < 0.001). Symptom clustering was also observed where at least three other locations of pain were reported, and pain was reported to trigger other physiological and psychological symptoms. Notably, there was no significant difference in the locations, occurrence, frequency or severity of pain between those on a CFTR modulator or not (p = 0.625). PwCF also reported significantly lower relief from over-the-counter therapies (p = 0.002) and expressed themes of unmet symptom and management needs.

CONCLUSIONS: This study identified a high prevalence of pain affecting multiple body parts in pwCF compared to HC and suggests that pain is sub-optimally managed, impairing their quality of life. Increased awareness and early recognition within the CF clinics and the development of clinical pathways are critically needed to better manage and monitor pain in pwCF, leading to improved quality of life and health outcomes.

PMID:39864974 | DOI:10.1016/j.jcf.2025.01.009

Microb Pathog. 2025 Jan 24:107332. doi: 10.1016/j.micpath.2025.107332. Online ahead of print.

ABSTRACT

Burkholderia contaminans SK875, a member of Burkholderia cepacia complex (Bcc), are known to cause lung infections in cystic fibrosis patients. To gain deeper insights into its quorum sensing (QS)-mediated pathogenicity, we employed a transposon (Tn) insertion-based random mutagenesis approach. A Tn mutant library comprising of 15,000 transconjugants was generated through conjugation between wild-type (WT) recipient B. contaminans SK875 and the donor E. coli BW20767 carrying pRL27 plasmid. From this library, 26 mutants were initially screened using the reporter strain Agrobacterium tumefaciens NT1, identified as blue-colored indicator colonies. These mutants were further analyzed for phenotypic variations related to autoinducer (AI) production, morphological changes, motility, biofilm formation, protease activity, and virulence in Caenorhabditis elegans. The Tn insertion sites in the mutants were sequenced and aligned with the reference genome of B. contaminans SK875 (PRJNA439184). Sequence analysis revealed the Tn5 insertion in genes encoding Ribonuclease P protein, a hypothetical protein, gamma-glutamyltranspeptidase 1, GCN5-related N-acetyltransferase (DUF1311), cytochrome C oxidase assembly protein, glutamyl-Q tRNA synthetase, AFG1-like ATPase, chorismate synthase, and aldehyde oxidase. Compared to wild-type (WT) strain B. contaminans SK875, the mutants (SK1917, SK1925, SK1926, SK1927, SK1935) exhibited attenuated AI production, impaired swimming and swarming motility, reduced biofilm formation and protease activity, and decreased virulence in C. elegans. We suggest that these genes are likely involved in the QS-dependent pathogenicity of B. contaminans. This study also introduces a visual color-screening method for identifying novel gene functions related to QS-dependent pathogenicity in Burkholderia species.

PMID:39864765 | DOI:10.1016/j.micpath.2025.107332

Respiration. 2025 Jan 24:1-16. doi: 10.1159/000543009. Online ahead of print.

ABSTRACT

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) has shown significant improvements in pulmonary and nutritional status in persons with cystic fibrosis (pwCF). Less is known about the extrapulmonary impact of ETI and effects on airway microbiology, lung clearance index (LCI) and fraction of exhaled nitric oxide (FeNO).

METHODS: A multicentre prospective observational trial, including 79 pwCF ≥ 18 years eligible for ETI. Assessments were done at the initiation of, and 3 and 6 months into treatment with ETI. Outcomes included forced expiratory volume in 1 second (FEV1), LCI, FeNO, sputum or cough swab culture, body mass index (BMI), cystic fibrosis questionnaire-revised respiratory domain (CFQ-R RD), sinonasal outcome test-22 (SNOT-22), general anxiety disorder-7 (GAD-7), patient health questionnaire-9 (PHQ-9), fecal elastase-1 (FE-1), adherence to baseline therapies, exacerbation rate and adverse events.

RESULTS: Our cohort included 79 pwCF (31±11(SD) years) with a baseline ppFEV1 of 68±23. Forty-two (53%) pwCF were previously treated with a CFTR modulator. In the entire study group, there were significant improvements from baseline in ppFEV1, LCI, FeNO, annualized exacerbation rate, BMI, CFQ-R RD and SNOT-22 (p<0.05 for all). Airway culture positivity for methicillin-susceptible Staphylococcus aureus and Pseudomonas aeruginosa also decreased during the study period. There was no significant change in FE-1, GAD-7 or PHQ-9. Adherence to dornase alfa and hypertonic saline decreased.

CONCLUSION: ETI treatment led to significant improvements in respiratory and nutritional status, alongside a decrease in adherence to chronic supportive therapies. We did not observe any significant changes in exocrine pancreas function or in questionnaire scores for depression and anxiety.

PMID:39864420 | DOI:10.1159/000543009

Lancet. 2025 Jan 25;405(10475):314-328. doi: 10.1016/S0140-6736(24)02560-1.

ABSTRACT

BACKGROUND: In the UK, booster COVID-19 vaccinations have been recommended biannually to people considered immune vulnerable. We investigated, at a population level, whether the absence of detectable anti-SARS-CoV-2 spike protein IgG antibody (anti-S Ab) following three or more vaccinations in immunosuppressed individuals was associated with greater risks of infection and severity of infection.

METHODS: In this prospective cohort study using UK national disease registers, we recruited participants with solid organ transplants (SOTs), rare autoimmune rheumatic diseases (RAIRDs), and lymphoid malignancies. All participants were tested for anti-S Ab using a lateral flow immunoassay, completed a questionnaire on sociodemographic and clinical characteristics, and were followed up for 6 months using linked data from the National Health Service in England. SARS-CoV-2 infection was primarily defined using UK Health Security Agency data and supplemented with hospitalisation and therapeutics data, and hospitalisation due to SARS-CoV-2 was defined as an admission within 14 days of a positive test.

FINDINGS: Between Dec 7, 2021, and June 26, 2022, we recruited 21 575 participants. Anti-S Ab was detected in 6519 (77·0%) of 8466 participants with SOTs, 5594 (85·9%) of 6516 with RAIRDs, and 5227 (79·3%) of 6593 with lymphoid malignancies. COVID-19 infection was recorded in 3907 (18·5%) participants, with 556 requiring a COVID-19-related hospital admission and 17 dying within 28 days of infection. Rates of infection varied by sociodemographic and clinical characteristics but, in adjusted analysis, having detectable anti-S Ab was independently associated with a reduced incidence of infection, with incident rate ratios (IRRs) of 0·69 (95% CI 0·65-0·73) in the SOT cohort, 0·57 (0·49-0·67) in the RAIRD cohort, and 0·62 (0·54-0·71) in the lymphoid malignancy cohort. In adjusted analysis, having detectable anti-S Ab was also associated with a reduced incidence of hospitalisation, with IRRs of 0·40 (0·35-0·46) in the SOT cohort, 0·32 (0·22-0·46) in the RAIRD cohort, and 0·41 (0·29-0·58) in the lymphoid malignancy cohort.

INTERPRETATION: All people with immunosuppression require ongoing access to COVID-19 protection strategies. Assessment of anti-S Ab responses, which can be performed at scale, can identify people with immunosuppression who remain most at risk, providing a mechanism to further individualise protection approaches.

FUNDING: UK Research and Innovation, Kidney Research UK, Blood Cancer UK, Vasculitis UK, and Cystic Fibrosis Trust.

PMID:39863371 | DOI:10.1016/S0140-6736(24)02560-1

J Biol Chem. 2025 Jan 23:108220. doi: 10.1016/j.jbc.2025.108220. Online ahead of print.

ABSTRACT

Carboxyl-terminus of Hsp70-Interacting Protein (CHIP) is an E3 ubiquitin ligase that marks misfolded substrates for degradation. Hyper-activation of CHIP has been implicated in multiple diseases, including cystic fibrosis and cancer, suggesting that it may be a potential drug target. However, there are few tools available for exploring this possibility. Moreover, the best ways of inhibiting CHIP's function are not obvious, as this complex protein is composed of a tetratricopeptide repeat (TPR) domain, a U-box domain, and a coiled-coil domain that mediates homodimerization. To probe the structure and function of CHIP, we report an antibody panning campaign that yielded six recombinant Fabs with affinity for CHIP. Interestingly, these antibodies varied in their binding site(s) and impact on CHIP function, such as inhibiting TPR interactions, autoubiquitination, and/or substrate ubiquitination. Of particular interest, antibody 2F1 nearly eliminated substrate binding (IC50 = 2.7 μM) and limited ubiquitination and autoubiquitination. Cryo-electron microscopy of the 2F1:CHIP complex revealed a 2:1 binding mode (Fab:CHIP dimer), with 2F1 bound to the U-box domain and simultaneously displacing the TPR domain. Together, these studies provide insight into ways of inhibiting CHIP's activity and provide a series of new probes for exploring the function of this important E3 ubiquitin ligase.

PMID:39863102 | DOI:10.1016/j.jbc.2025.108220

Int J Pharm. 2025 Jan 23:125241. doi: 10.1016/j.ijpharm.2025.125241. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is characterized by abnormal mucus hydration due to a defective CF Transmembrane Regulator (CFTR) protein, leading to the production of difficult-to-clear mucus. This causes airflow obstruction, recurrent infections, and respiratory complications. Chronic lung infections are the leading cause of death for CF patients and inhaled tobramycin is the first-in-line antibiotic treatment against these infections, mainly caused by Pseudomonas aeruginosa in adult patients. KuDa-tob, a nanoformulation of tobramycin (tob) as the active ingredient and dextran single chain nanoparticles, a drug carrier platform (KuDa) as an excipient, has been developed. The neutralization of the positive charges of the drug by KuDa nanoparticles facilitates its diffusion through the mucus and biofilm, reaching the bacteria. The polar interactions existing between tobramycin and KuDa have been thoroughly characterized by electrophoresis (ζ-potential) and diffusion experiments (diffusion ordered spectroscopy and Taylor dispersion analysis) demonstrating that up to 40 wt% tobramycin could be loaded into the KuDa-tob nanoformulation. The drug product was developed following Quality by Design (QbD) principles. Critical quality attributes (CQAs), critical process parameters (CPPs) and critical material attributes (CMAs) have been defined to obtain a robust production process that was then scaled-up to 40 g, allowing the production of KuDa-tob for further preclinical evaluation. Finally, the final pharmaceutical form of KuDa-tob was defined based on stability studies, and nebulization assays showed that the aerosols generated by reconstituted KuDa-tob were in the ideal range size for lung deposition (Median Mass Aerodynamic Diameter - MMAD - 2.2 μm).

PMID:39863028 | DOI:10.1016/j.ijpharm.2025.125241

Pharmaceutics. 2025 Jan 15;17(1):111. doi: 10.3390/pharmaceutics17010111.

ABSTRACT

This paper presents a comprehensive review of the current literature, clinical trials, and products approved for the delivery of antibiotics to the lungs. While there are many literature reports describing potential delivery systems, few of these have translated into marketed products. Key challenges remaining are the high doses required and, for powder formulations, the ability of the inhaler and powder combination to deliver the dose to the correct portion of the respiratory tract for maximum effect. Side effects, safety concerns, and disappointing clinical trial results remain barriers to regulatory approval. In this review, we describe some possible approaches to address these issues and highlight prospects in this area.

PMID:39861758 | DOI:10.3390/pharmaceutics17010111

Int J Mol Sci. 2025 Jan 8;26(2):471. doi: 10.3390/ijms26020471.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that is dysfunctional in individuals with cystic fibrosis (CF). The permeability of CFTR can be experimentally manipulated though different mechanisms, including activation via inducing the phosphorylation of residues in the regulatory domain as well as altering the gating/open probability of the channel. Phosphorylation/activation of the channel is achieved by exposure to compounds that increase intracellular cAMP, with forskolin and IBMX commonly used for this purpose. Cact-A1 is a unique CFTR activator that does not increase intracellular cAMP, and VX-770 (ivacaftor) is a CFTR potentiator that is used experimentally and therapeutically to increase the open probability of the channel. Using primary human nasal epithelial cell (HNEC) cultures and Fischer rat thyroid (FRT) epithelial cells exogenously expressing functional CFTR, we examined the impact of VX-770, Cact-A1, and forskolin/IBMX on CFTR activity during analysis in an Ussing chamber. Relative contributions of these compounds to maximal CFTR activity were dependent on order of exposure, the presence of chemical and electrical gradients, the level of constitutive CFTR function, and the cell model tested. Increasing intracellular cAMP appeared to change cellular functions outside of CFTR activity that resulted in alterations in the drive for chloride through CFTR. These results demonstrate that one can utilize combinations of small-molecule CFTR activators and potentiators to provide detailed characterization of CFTR-mediated ion transport in primary HNECs and properties of these modulators in both primary HNECs and FRT cells. Future studies using these approaches may assist in the identification of novel defects in CFTR function and the identification of modulators with unique impacts on CFTR-mediated ion transport.

PMID:39859187 | DOI:10.3390/ijms26020471

Int J Mol Sci. 2025 Jan 7;26(2):437. doi: 10.3390/ijms26020437.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. Currently, CFTR modulators are the most effective treatment for CF; however, they may not be suitable for all patients. A representative and convenient in vitro model is needed to screen therapeutic agents under development. This study, on the most common mutation, F508del, investigates the efficacy of human induced pluripotent stem cell-derived lung organoids (hiLOs) from NKX2.1+ lung progenitors and airway basal cells (hiBCs) as a 3D model for CFTR modulator response assessment by a forskolin-induced swelling assay. Weak swelling was observed for hiLOs from NKX2.1+ lung progenitors and hiBCs in response to modulators VX-770/VX-809 and VX-770/VX-661, whereas the VX-770/VX-661/VX-445 combination resulted in the highest swelling response, indicating superior CFTR function restoration. The ROC analysis of the FIS assay results revealed an optimal cutoff of 1.21, with 65.9% sensitivity and 71.8% specificity, and the predictive accuracy of the model was 76.4%. In addition, this study compared the response of hiLOs with the clinical response of patients to therapy and showed similar drug response dynamics. Thus, hiLOs can effectively model the CF pathology and predict patients' specific response to modulators.

PMID:39859153 | DOI:10.3390/ijms26020437

Biomedicines. 2025 Jan 1;13(1):82. doi: 10.3390/biomedicines13010082.

ABSTRACT

Background: The potentiator VX-770 (ivacaftor) has been approved as a monotherapy for over 95 cystic fibrosis (CF)-causing variants associated with gating/conductance defects of the CF transmembrane conductance regulator (CFTR) channel. However, despite its therapeutic success, VX-770 only partially restores CFTR activity for many of these variants, indicating they may benefit from the combination of potentiators exhibiting distinct mechanisms of action (i.e., co-potentiators). We previously identified LSO-24, a hydroxy-1,2,3-triazole-based compound, as a modest potentiator of p.Arg334Trp-CFTR, a variant with a conductance defect for which no modulator therapy is currently approved. Objective/Methods: We synthesized a new set of LSO-24 structure-based compounds, screened their effects on p.Arg334Trp-CFTR activity, and assessed the additivity of hit compounds to VX-770, ABBV-974, ABBV-3067, and apigenin. After validation by electrophysiological assays, the most promising hits were also assessed in cells expressing other variants with defective gating/conductance, namely p.Pro205Ser, p.Ser549Arg, p.Gly551Asp, p.Ser945Leu, and p.Gly1349Asp. Results: We found that five compounds were able to increase p.Arg334Trp-CFTR activity with similar efficacy, but slightly greater potency promoted by LSO-150 and LSO-153 (EC50: 1.01 and 1.26 μM, respectively). These two compounds also displayed a higher rescue of p.Arg334Trp-CFTR activity in combination with VX-770, ABBV-974, and ABBV-3067, but not with apigenin. When tested in cells expressing other CFTR variants, LSO-24 and its derivative LSO-150 increased CFTR activity for the variants p.Ser549Arg, p.Gly551Asp, and p.Ser945Leu with a further effect in combination with VX-770 or ABBV-3067. No potentiator was able to rescue CFTR activity in p.Pro205Ser-expressing cells, while p.Gly1349Asp-CFTR responded to VX-770 and ABBV-3067 but not to LSO-24 or LSO-150. Conclusions: Our data suggest that these new potentiators might share a common mechanism with apigenin, which is conceivably distinct from that of VX-770 and ABBV-3067. The additive rescue of p.Arg334Trp-, p.Ser549Arg-, p.Gly551Asp-, and p.Ser945Leu-CFTR also indicates that these variants could benefit from the development of a co-potentiator therapy.

PMID:39857666 | DOI:10.3390/biomedicines13010082

Vaccines (Basel). 2024 Dec 29;13(1):19. doi: 10.3390/vaccines13010019.

ABSTRACT

Safeguarding patients from emerging infectious diseases demands strategies that prioritise patient well-being and protection. Immunobridging is an established trial methodology which has been increasingly employed to ensure patient protection and provide clinicians with swift access to vaccines. It uses immunological markers to infer the effectiveness of a new drug through a surrogate measure of efficacy. Recently, this method has also been employed to authorise novel drugs, such as COVID-19 vaccines, and this article explores the concepts behind immunobridging trials, their advantages, issues, and significance in the context of COVID-19 and other infectious diseases. Our goal is to improve awareness among clinicians, patient groups, regulators, and health leaders of the opportunities and issues of immunobridging, so that fewer patients are left without protection from infectious diseases, particularly from major pathogens that may emerge.

PMID:39852798 | PMC:PMC11768488 | DOI:10.3390/vaccines13010019

BMJ Open. 2025 Jan 23;15(1):e092209. doi: 10.1136/bmjopen-2024-092209.

ABSTRACT

OBJECTIVES: To determine the diagnostic yield of cystic fibrosis (CF) using a two-tiered genetic testing approach. Although newborn screening includes CF, this typically only covers a selection of common genetic variants, and with over 2000 reported in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, we hypothesised that patients will be missed and present clinically later in life.

DESIGN: A retrospective study over a 5-year period (January 2018-December 2022).

SETTING: A single pathology service in South Australia.

PARTICIPANTS: A total of 1909 CF test referrals from patients with clinical suspicion indicated by respiratory and gastrointestinal manifestations, foetal echogenic bowel and male infertility and asymptomatic CF requests for reproductive carrier screening.

PRIMARY AND SECONDARY OUTCOME MEASURES: The number and type of CFTR gene variants detected in symptomatic and asymptomatic testing referrals.

RESULTS: A total of 25 patients were diagnosed with CF or CF-related disorders (2.5%) with gastrointestinal symptoms yielding the highest diagnostic rate of 4.4%. Additionally, a total of 79 carriers (4.1%) were identified uncovering a carrier frequency of 1 in 24, which is consistent with the 1 in 25 reported in the Caucasian population. CF was found to be causative of foetal echogenic bowel in 0.83% of cases.

CONCLUSIONS: This study highlights the importance of considering CF in symptomatic patients, even in a nation with >99% of newborns screened for CF. Additionally, the identification of CF in this population supports the recommendation for CF genetic testing in reproductive healthcare.

PMID:39855646 | DOI:10.1136/bmjopen-2024-092209

PLoS One. 2025 Jan 24;20(1):e0317775. doi: 10.1371/journal.pone.0317775. eCollection 2025.

ABSTRACT

The Cystic Fibrosis (CF) Impact Questionnaire (CF-IQ) was qualitatively developed to assess the impact of CF in the context of treatment advancements and increased longevity. This study reports the CF-IQ validation. In this noninterventional validation study, people with CF completed the 40-item CF-IQ and validating patient-reported outcome measures (PROMs) via electronic diaries at enrollment (baseline) and at the 4-week follow-up. Validation consisted of modern methods and focus groups to finalize structural validity, and classical methods to assess internal consistency [1-3], test-retest reliability [4,5], concurrent validity [5], and known-groups validity [5] of the CF-IQ. At baseline, 214 adults completed the survey; 193 completed the follow-up survey. Unidimensional item response theory (IRT) models were separately fit to 5 prespecified domains (Control and Burden of CF Treatment Impacts, Physical Activity Impacts, Social Activity Impacts, Emotional Impacts, and Work/School Limitation Impacts). IRT local dependence (LD) statistics identified 17 redundant items. Two independent CF-patient focus groups (14 total patients) confirmed these findings, and the 17 items were dropped. Each domain defined on the final 23 items achieved the criterion of exact model fit as measured by the root mean squared error of approximation (RMSEA, values = 0), Internal consistency (Cronbach's α) values ranged from 0.81 to 0.89, 4 of 5 domains achieved acceptable test-retest reliability, with intraclass correlation coefficient (ICC) values ≥ 0.7, acceptable concurrent validity was achieved for all domains, and known-groups validity was established. The novel CF-IQ is a psychometrically robust PROM capturing patient-centric impacts of CF in the context of the current standard of care.

PMID:39854524 | DOI:10.1371/journal.pone.0317775

Indian J Pediatr. 2025 Jan 24. doi: 10.1007/s12098-025-05428-7. Online ahead of print.

NO ABSTRACT

PMID:39853622 | DOI:10.1007/s12098-025-05428-7

Mol Biol Rep. 2025 Jan 24;52(1):155. doi: 10.1007/s11033-025-10258-z.

ABSTRACT

BACKGROUND: Pathogenic mutations in the CFTR gene disrupt the normal function of the chloride ion channel CFTR protein, resulting in Cystic Fibrosis (C.F.). Pakistan's situation regarding C.F. mutation is largely unknown, complicating the disease management and treatment. This study is designed to identify the disease-causing CFTR mutations in the Pakistani C.F. cohort and perform an in silico analysis of rare/novel variants.

METHODOLOGY: Ninety-five C.F. patients were recruited from pediatric healthcare facilities in different regions of Pakistan. Initially, we investigated ∆F508 mutation in all patients, followed by whole exome sequencing (W.E.S.) of nineteen patients and in silico analysis of identified rare/novel mutations.

RESULTS AND DISCUSSION: Initial screening revealed that ∆F508 mutation was absent in 73.74% of cases. W.E.S. identified three novel variants (c.3036del/Q1012Hfs*11, c.488 A > T/p.K163M, c.2384del/S795Yfs*8), one rare variant (c.489 + 2T > C) previously reported in two Pakistani residing in U.K. and one (c.164 + 1G > T/p.?) extremely rare in other populations. Additionally, c.1705T > G/p.Y569D, c.653T > A/p.L218X, c.2125 C > T/p.R709X, and c.3484 C > T/p.R1162X were also identified. Most variants in our cohort are either frameshift or nonsense, while only two are missense variants. Alarmingly, most of these variants, except ∆F508, are non-responsive to modulator drugs, while the responsiveness of c.488 A > T/p.K163M is yet to be determined. High consanguinity (73.40%) and homozygous status of all mutations, except c.3036del/Q1012Hfs*11, are indicative of a high ratio of C.F. carriers in Pakistan.

CONCLUSION: These findings represent the diverse pattern of CFTR mutations within the Pakistani population, highlighting the imperative need to improve earlier C.F. diagnostic and management facilities and to conduct research on treatment strategies other than modulator therapies.

PMID:39853500 | DOI:10.1007/s11033-025-10258-z

Microb Genom. 2025 Jan;11(1). doi: 10.1099/mgen.0.001332.

ABSTRACT

Bacteria from the Stenotrophomonas maltophilia complex (Smc) are important multidrug-resistant pathogens that cause a broad range of infections. Smc is genomically diverse and has been classified into 23 lineages. Lineage Sm6 is the most common among sequenced strains, but it is unclear why this lineage has evolved to be dominant. Antagonistic interactions can significantly affect the evolution of bacterial populations. These interactions may be mediated by secreted contact-dependent proteins, which allow inhibitor cells to intoxicate adjacent target bacteria. Contact-dependent inhibition (CDI) requires three proteins: CdiA, CdiB and CdiI. CdiA is a large, filamentous protein exported to the surface of inhibitor cells through the pore-like CdiB. The CdiA C-terminal domain (CdiA-CT) is toxic when delivered into target cells of the same species or genus. CdiI immunity proteins neutralize the toxicity of cognate CdiA-CT toxins. We found that all complete Smc genomes from the Sm6 lineage harbour at least one CDI locus. By contrast, less than a quarter of strains from other lineages have CDI genes. Smc CdiA-CT domains are diverse and have a broad range of predicted functions. Most Sm6 strains harbour non-cognate cdiI genes predicted to provide protection against foreign toxins from other strains. Finally, we demonstrated that an Smc CdiA-CT toxin has antibacterial properties and is neutralized by its cognate CdiI.

PMID:39853206 | DOI:10.1099/mgen.0.001332