Cureus. 2025 Feb 3;17(2):e78408. doi: 10.7759/cureus.78408. eCollection 2025 Feb.

ABSTRACT

Cystic fibrosis liver disease (CFLD) is a common complication of cystic fibrosis (CF), typically emerging within the first two decades of life. It significantly impacts both short- and long-term prognosis, being the third leading cause of mortality in this population. We present the case of a child with a rare CF mutation who was diagnosed with CFLD, portal hypertension, esophageal varices, and early-onset CF-related diabetes at the age of 6. This case provides valuable insights into the early onset and progression of CF liver disease, highlighting the importance of timely diagnosis and management.

PMID:40046358 | PMC:PMC11880950 | DOI:10.7759/cureus.78408

Phage (New Rochelle). 2024 Dec 18;5(4):203-222. doi: 10.1089/phage.2024.0011. eCollection 2024 Dec.

ABSTRACT

Rising antibiotic resistance among bacterial pathogens has become a substantial health issue for human civilization. The emergence of these pathogens in high-risk diseases such as cystic fibrosis (CF) has led to financial and nonfinancial losses, necessitating alternative therapies. This study presents an overview of such approaches, including phage therapy, antimicrobial peptides (AMPs), nanotechnology, monoclonal antibodies (mAbs), microbial therapies (probiotic therapy), clustered regularly interspaced short palindromic repeats technology (CRISPR), and aptamers focusing on their mechanisms of action and exploring the impact of combining phage and phage derivatives with the mentioned approaches. Although alternative approaches and their combinations with phages show promise, the phage-antibiotic combination has been the subject of most studies, and It has been proven to be highly effective in combating antibiotic-resistant infections. Other combinations also appear promising, but further studies are needed to determine their effectiveness. This emphasizes the need for more thorough research into different phage combination treatments beyond the well-established phage-antibiotic strategy.

PMID:40045937 | PMC:PMC11876824 | DOI:10.1089/phage.2024.0011

J Pediatr Orthop. 2025 Mar 6. doi: 10.1097/BPO.0000000000002947. Online ahead of print.

ABSTRACT

BACKGROUND: Although cystic fibrosis (CF) mainly affects the respiratory and gastrointestinal systems, it may frequently present with musculoskeletal manifestations including bone fractures, low bone mineral density, and spinal pathologies. Assessment of spinal pathologies in CF patients is of vital importance because the effects on lung capacity and spinal posture are clearly defined.

QUESTIONS/PURPOSES: The frequency of vertebral pathologies in CF patients has yet to be determined. The aim of this study was to investigate the frequency of scoliosis and hyperkyphosis and the relationship of coronal, sagittal, and spinopelvic parameters with disease severity in CF patients.

METHODS: Patients were tested with forced expiratory volume in 1 second (FEV1), dual-energy x-ray absorptiometry (DEXA), and full spine radiographs. Measurements were taken of the major coronal curve in the coronal plane, cervical and lumber lordosis, thoracic kyphosis, and C7 plumb line values. Patients were categorized into 3 groups based on the FEV1 values (severity) from respiratory function tests (severe: group 1 FEV 1≤40, moderate: group 2 FEV1 40 to 80, mild: group).

RESULTS: This cross-sectional study included 208 CF patients aged 5 to 21 years. The rates of scoliosis and thoracic hyperkyphosis were 31% (n=64) and 24% (n=50), respectively. The highest rates of scoliosis (63%) and thoracic hyperkyphosis (56%) were found in the severe CF group (P=0.016 and P=0.006, respectively). FEV1 and thoracic kyphosis were weakly and inversely but significantly correlated (rho: -0.200 and P=0.004). There was no difference in BMD between patients with and without scoliosis and between patients with and without hyperkyphosis. There was no significant difference in DEXA Z-score between patients with and without hyperkyphosis. The L1-L4 DEXA Z-score of patients without scoliosis was significantly higher (P=0.017).

CONCLUSIONS: Scoliosis and hyperkyphosis were more prevalent in the severe CF patients group, although the proportion of patients requiring treatment was relatively low. Understanding the relationship between disease severity and coronal and sagittal spinal balance, and spinopelvic parameters is crucial, as it guides the early detection and management of scoliosis in CF patients.

LEVEL OF EVIDENCE: Level II.

PMID:40045563 | DOI:10.1097/BPO.0000000000002947

Nat Commun. 2025 Mar 5;16(1):2214. doi: 10.1038/s41467-025-57520-3.

ABSTRACT

Putting pancreatic adenocarcinoma (PAAD) screening into perspective for high-risk individuals could significantly reduce cancer morbidity and mortality. Previous studies have profiled somatic mutations in PAAD. In contrast, the prevalence of mutations in PAAD predisposition genes has not been defined, especially in the Asian population. Using a multi-tier cohort design and whole genome/exome sequencing, we create a comprehensive germline mutation map of PAAD in 1,123 Chinese cancer patients in comparison with 11 pan-ethnic studies. For well-known pathogenic/likely pathogenic germline variants, Chinese patients exhibit overlapping but distinct germline mutation patterns comparing with Western cohorts, highlighted by lower mutation rates in known PAAD genes including BRCA1, BRCA2, ATM, CDKN2A, and CHEK2, and distinct mutations in CFTR, RAD51D, FANCA, ERCC2, and GNAS exclusive to Chinese patients. CFTR emerges as a top candidate gene following loss of heterozygosity analysis. Using an integrative multi-omics and functional validation paradigm, we discover that deleterious variants of uncertain significance may compromise CFTR's tumor suppressor function, and demonstrate the clinical relevance by using patient derived organoids for drug screen. Our multifaceted approach not only deepens the knowledge of population differences in PAAD germline mutations but also unveils potential avenues for targeted therapeutic interventions.

PMID:40044664 | DOI:10.1038/s41467-025-57520-3

Int J Pharm. 2025 Mar 3:125424. doi: 10.1016/j.ijpharm.2025.125424. Online ahead of print.

ABSTRACT

Lipoplexes are non-viral lipid vectors that effectively form complexes with genetic material, positioning them as promising alternatives to viral vectors in gene therapy. Their advantages include lower toxicity, reduced immunogenicity, improved targetability, and ease of large-scale production. A typical lipoplex is composed of cationic lipids, neutral lipids, and anionic nucleic acids (e.g., DNA, mRNA, miRNA, siRNA, shRNA). Neutral lipids play an auxiliary role and are often used as transfection enhancers. Enhancing lipoplex efficiency often involves modifying the cationic lipid structure through functional groups like PEG polymers and targeting ligands. The assembly of lipoplexes occurs spontaneously. This process involves the binding of the positively charged polar head group of the cationic lipid to the negatively charged DNA spontaneously as a result of electrostatic interaction, then irreversible rearrangement and condensation of the lipoplex occurs to form either lamellar or hexagonal structures. The transfection process encompasses several steps: cellular entry, endosomal escape and cargo release, cytoplasmic trafficking, and nuclear entry. The physicochemical and biological properties of lipoplexes are influenced by factors such as lipid structure, charge ratio, and environmental conditions. Despite certain limitations like low gene transfer efficiency and rapid clearance by serum proteins, lipoplexes show promise for clinical applications. They can be administered through various routes, offering potential treatments for diseases such as cancer, bone damage, infection, and cystic fibrosis. The study aims to examine the potential of lipoplexes as a promising vehicle for delivering therapeutic agents and their progression from theoretical concepts to practical clinical applications.

PMID:40043964 | DOI:10.1016/j.ijpharm.2025.125424

Ann Am Thorac Soc. 2025 Jan;22(1):39-40. doi: 10.1513/AnnalsATS.202411-1148ED.

NO ABSTRACT

PMID:40043192 | DOI:10.1513/AnnalsATS.202411-1148ED

Ann Am Thorac Soc. 2025 Mar 5. doi: 10.1513/AnnalsATS.202408-831OC. Online ahead of print.

ABSTRACT

RATIONALE: Since the approval of elexacaftor/tezacaftor/ivacaftor (ETI), data suggests there have been changes in the management of pulmonary exacerbations (PEx) of Cystic Fibrosis (CF).

OBJECTIVE: Given the subjective nature of PEx diagnosis and management, we sought to characterize provider PEx management practices in people with CF (pwCF) prescribed highly effective modulator therapy (HEMT) and to identify practice changes that may impact clinical outcomes.

METHODS: We conducted semi-structured qualitative interviews amongst clinicians in the United States (US) in late 2021 to 2022 to investigate changes in the management of PEx in pwCF prescribed ETI. Inductive coding of transcripts was utilized in a thematic analysis.

RESULTS: We conducted 19 qualitative interviews with providers at 15 CF centers. Thematic analysis identified five themes regarding the presentation, diagnosis, and management of PEx in pwCF prescribed ETI: (1) PEx have changed in the era of HEMT to become a more subtle pathology that may result in providers questioning PEx diagnosis; (2) providers feel less anxious about clinical outcomes after PEx; (3) providers are expanding their assessment of PEx in the era of HEMT to identify more subtle PEx phenotypes; (4) pwCF are driving their care during PEx more than in the pre-HEMT era, with interviewees reporting that some "patients don't really contact us [with mild PEx symptoms]…we hear about it in retrospect." Interviewees expressed concern that this may result in more severe PEx; (5) provider management is less aggressive in the post-HEMT era, reflecting reduced PEx severity. Participants emphasized that their approach to PEx in general is unchanged and that "[providers] treat depending on severity…and the background of the patient." Interviewees reported they increasingly recommend maintenance therapies for PEx treatment before prescribing antibiotics.

CONCLUSIONS: Participants report that PEx in pwCF prescribed ETI appear milder, resulting in less anxiety about outcomes and a more conservative approach to management. Providers express uncertainty regarding the diagnosis of PEx given its evolving presentation and reduced in-person evaluation. Further research is necessary to identify sensitive markers of PEx and to assess the impact of conservative management on clinical outcomes.

PMID:40042492 | DOI:10.1513/AnnalsATS.202408-831OC

mBio. 2025 Mar 5:e0388324. doi: 10.1128/mbio.03883-24. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in CFTR protein dysfunction. CFTR dysfunction has multi-organ consequences, leading to dehydrated mucus that is adherent to epithelia. In the lungs, this leads to recalcitrant infections with bacteria such as Pseudomonas aeruginosa. In the gut, mucus-laden feces can adhere to the intestines, resulting in distal intestinal obstruction syndrome (DIOS). There is limited information on how lung colonization and DIOS are correlated in people with CF (pwCF). In this novel work, we describe the development of spontaneous lung colonization of CF pathogens in young (<3 months old) CF rats, preceding the development of DIOS. Once DIOS is established, the lung microbiome becomes predominated by taxa also observed in the feces. Induced infection with P. aeruginosa in the CF rats reflects data found in pwCF, as once CF rats are infected, they retain a higher relative abundance of P. aeruginosa than their healthy agemates. Finally, we found that ivacaftor treatment favors a healthier gut microbiome in CF rats, decreasing the relative abundance of Escherichia coli. These results indicate that the CF rat model is recapitulative of human CF disease with the spontaneous lung colonization of traditional CF pathogens and maintenance of P. aeruginosa after induced infection. Furthermore, these results indicate a possible role for the gut-lung axis in lung colonization and DIOS in CF.IMPORTANCEThese data describe for the first time the development of spontaneous lung colonization in the cystic fibrosis (CF) rat model, a hallmark aspect of human CF disease. We also find that CF rats infected with Pseudomonas aeruginosa maintain higher relative abundance following chronic infection as compared to healthy rats, similar to those is seen in people with CF. Additionally, we describe the possible contribution of the gut-lung axis linking lung health with distal intestinal obstruction syndrome, a relationship largely unexplored in the context of CF.

PMID:40042272 | DOI:10.1128/mbio.03883-24

Pediatr Pulmonol. 2025 Mar;60(3):e71035. doi: 10.1002/ppul.71035.

NO ABSTRACT

PMID:40042147 | DOI:10.1002/ppul.71035

Pediatr Pulmonol. 2025 Mar;60(3):e71024. doi: 10.1002/ppul.71024.

ABSTRACT

BACKGROUND: Systemic antibiotics can impact all microbes inhabiting patients, regardless of the intended target organism(s). We studied the simultaneous effects on respiratory and fecal microbiomes of β-lactam antibiotics administered for respiratory symptoms in infants with cystic fibrosis (IWCF).

OBJECTIVE: To compare the magnitude and duration of intended (respiratory) and unintended (fecal) antimicrobial action by analyzing oropharyngeal (OP) and fecal microbiota in IWCF.

DESIGN: Shotgun metagenomic sequencing and qPCR were performed on OP and fecal samples collected longitudinally from 14 IWCF (ages 1-17 months) during ("On Antibiotics") and after ("Off Antibiotics") β-lactam therapy, and from 5 IWCF (3-16 months) never treated with antibiotics.

RESULTS: Total bacterial loads (TBL) for On Antibiotics samples were lower than for both Never (OP and fecal) and Off Antibiotics samples (fecal only). α-diversities (within-sample) for OP On Antibiotics samples were lower than for Never and Off Antibiotics samples but did not differ between fecal sample groups. β-diversity (between-sample) differed between all OP sample groups and between fecal On and Never Antibiotics and Off and Never antibiotics samples; however, fecal On and Off Antibiotics sample β-diversities did not differ. Patterns of change in antibiotic resistance gene abundances reflected shifts in microbial community composition.

CONCLUSIONS: β-lactam antibiotic exposure was followed by marked alterations in both OP and fecal microbiota. While microbiota appeared to rebound after treatment in both sample types, our results suggest that fecal microbiota recovered less than OP. The clinical consequences of these findings should be studied in IWCF and other populations frequently treated with antibiotics.

PMID:40042126 | DOI:10.1002/ppul.71024

Afr J Thorac Crit Care Med. 2024 Dec 11;30(4):e1899. doi: 10.7196/AJTCCM.2024.v30i4.1899. eCollection 2024.

ABSTRACT

BACKGROUND: Bronchiectasis, a chronic suppurative lung condition, is a largely neglected disease, especially in low- to middle-income countries (LMICs), from which there is a paucity of data. Post-infectious causes are more common in LMICs, while in high-income countries, inborn errors of immunity (IEIs), recurrent aspiration, primary ciliary dyskinesia (PCD) and cystic fibrosis are more common. Children living with HIV (CLWH), especially those who are untreated, are at increased risk of bronchiectasis. Data on risk factors, diagnosis and follow-up of children with bronchiectasis are required to inform clinical practice and policy.

OBJECTIVES: To describe the demographics, medical history, aetiology, clinical characteristics and results of special investigations in children with bronchiectasis.

METHODS: We undertook a retrospective descriptive study of children aged <16 years with chest computed tomography (CT) scan-confirmed bronchiectasis in Johannesburg, South Africa, over a 10-year period. Demographics, medical history, aetiology, clinical characteristics and results of special investigations were described and compared according to HIV status.

RESULTS: A total of 91 participants (51% male, 98% black African) with a median (interquartile range) age of 7 (3 - 12) years were included in the study. Compared with HIV-uninfected children, CLWH were older at presentation (median 10 (6 - 13) years v. 4 (3 - 9) years; p<0.01), and more likely to be stunted (p<.01), to have clubbing (p<0.01) and hepatosplenomegaly (p=0.03), and to have multilobar involvement on the chest CT scan (p<0.01). All children had a cause identified, and the majority (86%) of these were presumed to be post-infectious, based on a previous history of a severe lower respiratory tract infection. This group included all 38 CLWH. Only a small proportion of the participants had IEIs, secondary immune deficiencies or PCD.

CONCLUSION: A post-infectious cause for bronchiectasis was the most common aetiology described in children from an LMIC in Africa, especially CLWH. With improved access to diagnostic techniques, the aetiology of bronchiectasis in LMICs is likely to change.

STUDY SYNOPSIS: What the study adds. In this retrospective descriptive study of children aged <16 years with chest computed tomography scan-confirmed bronchiectasis in Johannesburg, South Africa (SA), over a 10-year period, we report that a post-infectious cause for bronchiectasis was the most commonly described, and that HIV was an important contributor. A large proportion of children with bronchiectasis in low- and middle-income countries such as SA do not benefit from an extensive work-up for the non-infectious causes of bronchiectasis.Implications of the findings. With improved access to diagnostic techniques, including improvements in early diagnosis and access to treatment for children living with HIV, the aetiology of bronchiectasis is likely to change in the coming years.

PMID:40041419 | PMC:PMC11874181 | DOI:10.7196/AJTCCM.2024.v30i4.1899

Afr J Thorac Crit Care Med. 2024 Dec 11;30(4):e2884. doi: 10.7196/AJTCCM.2024.v30i4.2884. eCollection 2024.

NO ABSTRACT

PMID:40041417 | PMC:PMC11874178 | DOI:10.7196/AJTCCM.2024.v30i4.2884

ERJ Open Res. 2025 Mar 3;11(2):00701-2024. doi: 10.1183/23120541.00701-2024. eCollection 2025 Mar.

ABSTRACT

CFTR modulators may be valuable therapy for patients with ABCA3 pathogenic variants https://bit.ly/3TMWKK9.

PMID:40040902 | PMC:PMC11874218 | DOI:10.1183/23120541.00701-2024

iScience. 2025 Feb 1;28(3):111942. doi: 10.1016/j.isci.2025.111942. eCollection 2025 Mar 21.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening disease affecting >160,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the p.Phe508del variant that causes the CF transmembrane conductance regulator (CFTR) protein to misfold and be targeted for premature degradation by the endoplasmic reticulum (ER) quality control (ERQC), thus preventing its plasma membrane (PM) traffic. Despite the recent approval of a "highly effective" drug rescuing p.Phe508del-CFTR, maximal lung function improvement is ∼14%. To identify global modulators of p.Phe508del traffic, we performed a high-content small interfering RNA (siRNA) microscopy-based screen of >9,000 genes and monitored p.Phe508del-CFTR PM rescue in human airway cells. This primary screen identified 227 p.Phe508del-CFTR traffic regulators, of which 35 could be validated by additional siRNAs. Subsequent mechanistic studies established GRK5 as a robust regulator whose inhibition rescues p.Phe508del-CFTR PM traffic and function in primary and immortalized cells, thus emerging as a novel potential drug target for CF.

PMID:40040803 | PMC:PMC11876911 | DOI:10.1016/j.isci.2025.111942

Genome Med. 2025 Mar 4;17(1):19. doi: 10.1186/s13073-025-01443-7.

ABSTRACT

BACKGROUND: Non-tuberculous mycobacteria (NTM) are a diverse group of environmental bacteria that are increasingly associated with human infections and difficult to treat. Plasmids, which might carry resistance and virulence factors, remain largely unexplored in NTM.

METHODS: We used publicly available complete genome sequence data of 328 NTM isolates belonging to 125 species to study gene content, genomic diversity, and clusters of 196 annotated NTM plasmids. Furthermore, we analyzed 3755 draft genome assemblies from over 200 NTM species and 5415 short-read sequence datasets from six clinically relevant NTM species or complexes including M. abscessus, M. avium complex, M. ulcerans complex and M. kansasii complex, for the presence of these plasmids.

RESULTS: Between one and five plasmids were present in approximately one-third of the complete NTM genomes. The annotated plasmids varied widely in length (most between 10 and 400 kbp) and gene content, with many genes having an unknown function. Predicted gene functions primarily involved plasmid replication, segregation, maintenance, and mobility. Only a few plasmids contained predicted genes that are known to confer resistance to antibiotics commonly used to treat NTM infections. Out of 196 annotated plasmid sequences, 116 could be grouped into 31 clusters of closely related sequences, and about one-third were found across multiple NTM species. Among clinically relevant NTM, the presence of NTM plasmids showed significant variation between species, within (sub)species, and even among strains within (sub)lineages, such as dominant circulating clones of Mycobacterium abscessus.

CONCLUSIONS: Our analysis demonstrates that plasmids are a diverse and heterogeneously distributed feature in NTM bacteria. The frequent occurrence of closely related putative plasmid sequences across different NTM species suggests they may play a significant role in NTM evolution through horizontal gene transfer at least in some groups of NTM. However, further in vitro investigations and access to more complete genomes are necessary to validate our findings, elucidate gene functions, identify novel plasmids, and comprehensively assess the role of plasmids in NTM.

PMID:40038805 | DOI:10.1186/s13073-025-01443-7

Mol Cell Biochem. 2025 Mar 4. doi: 10.1007/s11010-025-05243-w. Online ahead of print.

ABSTRACT

Emerging evidence indicates that chloride channels (ClCs) significantly affect the pathogenesis of inflammatory bowel disease (IBD) through their regulatory roles in mast cell function and epithelial integrity. IBD, encompassing conditions such as Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract, where channels influence immune responses, fluid balance, and cellular signalling pathways essential for maintaining mucosal homeostasis. This review examines the specific roles of ClC in mast cells, focussing on the regulation of mast cell activation, degranulation, cytokine release, and immune cell recruitment in inflamed tissues. Key channels, including Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and ClC-2, are discussed in detail because of their involvement in maintaining intestinal epithelial barrier function, a critical factor disrupted in IBD. For example, CFTR facilitates chloride ion transport across epithelial cells, which is essential for mucosal hydration and maintenance of the intestinal barrier. Reduced CFTR function can compromise this barrier, permitting microbial antigens to penetrate the underlying tissues and triggering excessive immune responses. ClC-2, another chloride channel expressed in mast cells and epithelial cells, supports tight junction integrity, contributes to barrier function, and reduces intestinal permeability. Dysregulation of these channels is linked to altered mast cell activity and excessive release of pro-inflammatory mediators, exacerbating IBD symptoms, such as diarrhoea, abdominal pain, and tissue damage. Here, we review recent pharmacological strategies targeting ClC, including CFTR potentiators and ClC-2 activators, which show the potential to mitigate inflammatory responses. Additionally, experimental approaches for selective modulation of chloride channels in mast cells have been explored. Although targeting ClC offers promising therapeutic avenues, challenges remain in achieving specificity and minimizing side effects. This review highlights the therapeutic potential of Cl channel modulation in mast cells as a novel approach for IBD treatment, aiming to reduce inflammation and restore intestinal homeostasis in affected patients.

PMID:40038149 | DOI:10.1007/s11010-025-05243-w

Eur J Prev Cardiol. 2025 Mar 4:zwaf122. doi: 10.1093/eurjpc/zwaf122. Online ahead of print.

ABSTRACT

AIM: To assess the impact of antimicrobial resistance (AMR) on major adverse cardiovascular event (MACE) risk in patients with bronchiectasis.

METHODS: This retrospective study utilized data from the TriNetX research network, analysing patients with bronchiectasis categorized by the presence or absence of AMR. Primary outcomes included the risk of MACE (myocardial infarction, stroke and systemic thromboembolism, and cardiac arrest) and all-cause death. Cox regression analysis with 1:1 propensity score matching (PSM) was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the primary outcomes. Subgroup analyses were conducted to validate results in clinically relevant subgroups.

RESULTS: Prior to PSM, patients with AMR (n=6,543, 61.0±22.0 years, 55.8% female) were younger, more often male, and presented a higher prevalence of cardiovascular risk factors than those without AMR (n=154,685, 67.3±16.0 years, 59.4% female). After PSM, no significant differences were found between groups. However, AMR patients showed a higher risk of MACE (HR 1.29, 95% CI 1.17-1.41) and all-cause death (HR 1.49, 95% CI 1.38-1.61) compared to non-AMR patients. The MACE risk was notably elevated among AMR patients without prior cardiovascular events (HR 1.56, 95% CI 1.34-1.81). Similar MACE risks were observed in cystic fibrosis (HR 1.24, 95% CI 0.86-1.78) and non-cystic fibrosis subgroups (HR 1.28, 95% CI 1.16-1.41), with consistent findings across different AMR types.

CONCLUSIONS: In patients with bronchiectasis, AMR is associated with an increased risk of MACE and all-cause death, suggesting that controlling AMR spread may confer broader health benefits, particularly in reducing cardiovascular risk.

PMID:40037796 | DOI:10.1093/eurjpc/zwaf122

PLoS One. 2025 Mar 4;20(3):e0318085. doi: 10.1371/journal.pone.0318085. eCollection 2025.

ABSTRACT

BACKGROUND: Current diagnostic tools are limited in their ability to diagnose cystic fibrosis liver disease (CFLD) as disease is often focal in nature. Magnetic resonance extracellular volume quantification (MRI ECV) in the liver may have diagnostic utility in CFLD as a more selective liver volume is assessed and can be performed using equipment readily available in clinical practice on a standard MRI protocol.

METHODS: Healthy volunteers (HV), CF participants with no liver disease (CF-noLD) and CF participants with cirrhosis (CF-C) aged 18 years and above had MRI ECV measured using a 3T Siemens scanner. An additional retrospective analysis was performed to calculate MRI ECV in individuals who had available images obtained using a 1.5T Siemens scanner from a previous study.

RESULTS: 16 individuals had MRI ECV measured using a 3T Siemens scanner. Mean (SD) MRI ECV was 0.316 (0.058) for HV (n = 5), 0.297 (0.034) for CF-noLD (n = 5) and 0.388 (0.067) for CF-C (n = 6 ). Post-hoc analysis showed a significant difference between CF-noLD and CF-C (p = 0.046). Of 18 individuals with available images using a 1.5T scanner, mean (SD) MRI ECV was 0.269 (0.048) in HV (n = 8), 0.310 (0.037) in CF-noLD (n = 8) and 0.362 (0.063) in CF-C (n = 2).

CONCLUSIONS: Liver MRI ECV quantification was feasible in adults with CF with no significant difference in results between 1.5T and 3T obtained images suggesting applicability across different types of MRI scanner. A higher MRI ECV was demonstrated in CF participants with cirrhosis suggesting potential utility as a diagnostic tool for those with advanced CFLD. Further evaluation in larger cohorts is warranted.

PMID:40036270 | DOI:10.1371/journal.pone.0318085

Appl Environ Microbiol. 2025 Mar 4:e0240224. doi: 10.1128/aem.02402-24. Online ahead of print.

ABSTRACT

Quorum sensing (QS) plays a crucial role in regulating key traits, including the upregulation of phage receptors, which leads to heightened phage susceptibility in Pseudomonas aeruginosa. As a result, higher cell densities typically increase the risk of phage invasions. This has led to speculation that bacteria may have evolved strategies to counterbalance this increased susceptibility. Additionally, non-synonymous mutations in LasR, the master regulator of QS, are common among cystic fibrosis patients, but the impact of these mutations on phage interactions remains poorly understood. Here, we systematically investigated the role of QS in shaping these interactions using bacterial strains with functional or altered QS systems. In the QS-functional strain ZS-PA-35, disruption of the Las system reduces cell susceptibility to the type IV pili-dependent phage phipa2, delaying bacterial lysis during the early logarithmic growth phase. At high cell densities, Las-induced dormancy further inhibits phage proliferation despite enhanced phage adsorption. Notably, nutrient supplementation fully restores phage proliferation in the strains with a functional Las system. In contrast, the QS-deficient strain ZS-PA-05, carrying a LasR mutation, fails to regulate phage-host interactions via QS. Moreover, our findings reveal that within mixed microbial populations, cells benefit from the presence of closely related kin, which collectively reduce prey density and limit phage-host interaction frequencies under nutrient-rich conditions. These results underscore the flexibility of QS-regulated defense strategies, highlighting their critical role in optimizing bacterial resilience against phage predation, particularly in heterogeneous communities most vulnerable to phages.IMPORTANCEBacteria have developed various strategies to combat phage infection, posing challenges to phage therapy. In this study, we demonstrate that Pseudomonas aeruginosa strains with functional or altered quorum sensing (QS) systems may adapt different survival tactics for prolonged coexistence with phages, contingent upon bacterial population dynamics. The dynamics of phage infection highlight the influence of intrinsic heterogeneity mediated by QS, which leads to the emergence of different phage-host outcomes. These variants may arise as a result of coevolutionary processes or coexistence mechanisms of mutational and non-mutational defense strategies. These insights enhance our comprehension of how bacteria shield themselves against phage attacks and further underscore the complexity of such approaches for successful therapeutic interventions.

PMID:40035599 | DOI:10.1128/aem.02402-24

Res Sq [Preprint]. 2025 Feb 17:rs.3.rs-5938603. doi: 10.21203/rs.3.rs-5938603/v1.

ABSTRACT

BACKGROUND: In a healthy lung, the airway epithelium regulates glucose transport to maintain low glucose concentrations in the airway surface liquid (ASL). However, hyperglycemia and chronic lung diseases, such as cystic fibrosis (CF), can result in increased glucose in bronchial aspirates. People with CF are also at increased risk of lung infections caused by bacterial pathogens, including methicillin-resistant Staphylococcus aureus. Yet, it is not known how increased airway glucose availability affects bacteria in chronic CF lung infections or impacts treatment outcomes.

METHODS: To model the CF airways, we cultured immortalized CF (CFBE41o-) and non-CF (16HBE) human bronchial epithelial cells at air liquid interface (ALI). Glucose concentrations in the basolateral media were maintained at 5.5 mM or 12.5 mM, to mimic a normal and hyperglycemic milieu respectively. 2-deoxyglucose was added to high glucose culture media to restrict glucose availability. We collected ASL, basolateral media, and RNA from ALI cultures to assess the effects of elevated glucose. We also inoculated S. aureus onto the apical surface of normal or high glucose ALI cultures and observed the results of antibiotic treatment post-inoculation. S. aureus growth was measured by enumerating viable colony forming units (CFU) and with fluorescence microscopy. The effects of elevated glucose on in vitro growth and antibiotic treatment were also evaluated in standard bacterial culture medium and synthetic CF medium (SCFM).

RESULTS: We found that glucose concentrations in the ASL of ALI cultures maintained in normal or high glucose mimicked levels measured in breath condensate assays from people with CF and hyperglycemia. Additionally, we found hyperglycemia increased S. aureus aggregation and antibiotic resistance during infection of cells maintained in high glucose compared to normal glucose conditions. Heightened antibiotic tolerance or resistance as not observed during in vitro growth with elevated glucose. Limiting glucose with 2-deoxyglucose both decreased aggregation and reduced antibiotic resistance back to levels comparable to non-hyperglycemic conditions.

CONCLUSIONS: These data indicate hyperglycemia alters S. aureus growth during infection and may reduce efficacy of antibiotic treatment. Glucose restriction is a potential option that could be explored to limit bacterial growth and improve treatment outcomes in chronic airway infections.

PMID:40034435 | PMC:PMC11875303 | DOI:10.21203/rs.3.rs-5938603/v1