Am J Respir Crit Care Med. 2025 May 2. Online ahead of print.

ABSTRACT

RATIONALE: Hyper IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense.

OBJECTIVES: To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES.

METHODS: STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology; and bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR/Cas9), were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1β)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed.

MEASUREMENTS AND MAIN RESULTS: STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 mutations reduced CFTR mRNA and protein levels, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and post-IL1β exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a γ-secretase inhibitor restored HES6 expression, improved ciliogenesis in STAT3 R382W mutant cells.

CONCLUSIONS: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.

PMID:40315437

PLoS One. 2025 May 2;20(5):e0322911. doi: 10.1371/journal.pone.0322911. eCollection 2025.

ABSTRACT

BACKGROUND: The current study aimed to explore patient and provider perspectives of the impact of the pandemic on cystic fibrosis healthcare access and service delivery.

METHODS: We used Interpretive Description, a qualitative approach with the end-goal of informing decisions and actions in clinical practice by generating findings that are clinically meaningful and useful. Levesque et al.'s "Conceptual framework of access to health care" informed the development of our interview guides. Interviews were conducted via telephone or Zoom and confidentially transcribed verbatim. Data generation and analysis occurred concurrently to allow for iterative refinements of the interview guides. Analysis was informed by Braun and Clarke's six phases of reflexive thematic analysis. Strategies to enhance rigour and trustworthiness of the findings were utilized.

RESULTS: We completed 13 interviews: 8 with patients and 5 with providers. Three key themes were generated: (a) Tensions due to infection prevention at micro- meso-, and macro- levels; (b) Modifying aspects of person-focused care can bolster perceived quality of clinical encounters; and (c) Accessibility of appropriate healthcare services could improve efficiency of service delivery. Infection prevention at the individual level was not found to be burdensome. Society's compliance with public health measures, or lack thereof, impacted the level of stigma and anxiety experienced by patients with cystic fibrosis. A changed model of care reliant on patient self-report instead of clinician-led testing and in-person assessment due to the transition to virtual care was associated with mixed perceptions since patients with cystic fibrosis were comfortable making care decisions but many participants (patient and provider) felt challenged by the lack of objective data for decision-making. It was essential for patients with cystic fibrosis to feel known, heard, and seen by their providers in order to feel the care was effective. Finally, critical insights around the need for a balance of in-person and virtual care as well as the need for mental health supports were offered.

CONCLUSIONS: The learnings from this study could be translated into practical strategies for improving cystic fibrosis care during the pandemic and beyond. We recommend: (1) a hybrid approach to care moving forward, (2) each patient having a lead physician with others filling in as necessary when scheduling demands, and (3) a reallocation of resources to fund a mental health practitioner position.

PMID:40315223 | DOI:10.1371/journal.pone.0322911

Int J Mol Med. 2025 Jun;55(6):99. doi: 10.3892/ijmm.2025.5540. Epub 2025 May 2.

ABSTRACT

Cation channels have been extensively studied in the context of digestive disorders, but comparatively little attention has been given to anions and their associated channels. Chloride ions, the most abundant anions in the human body, act as signaling molecules, modulating cellular behavior and playing a key role in regulating multiorgan physiological and pathophysiological mechanisms. The intra‑ and extracellular distributions of chloride ions are primarily controlled by various chloride channels and transporters. Currently, these chloride channels are classified into several groups: The chloride channels family, cystic fibrosis transmembrane conductance regulator, calcium‑activated chloride channels, volume‑regulated anion channels, proton‑activated chloride channels and ligand‑gated anion channels. This review aims to summarize the roles of chloride ion channels and transporter proteins in digestive system diseases, providing a theoretical basis for future research and offering potential new strategies for disease treatment.

PMID:40314091 | DOI:10.3892/ijmm.2025.5540

Ulster Med J. 2025 Apr;94(1):28-30. Epub 2025 Apr 30.

NO ABSTRACT

PMID:40313987 | PMC:PMC12042854

Case Rep Med. 2025 Apr 23;2025:9935363. doi: 10.1155/carm/9935363. eCollection 2025.

ABSTRACT

This case report describes a 39-year-old phenotypically normal male patient of a married couple with primary infertility presenting as candidates for assisted reproductive techniques. The medical history of the couple is unremarkable, with both partners phenotypically normal. Semen analysis revealed oligoasthenzoospermia (OAT), 15% sperm DNA fragmentation and 4% aneuploidies in the sperm nuclei. Genetic analysis showed no Y chromosome of cystic fibrosis transmembrane conductance regulator gene mutations. Karyotype analysis in the male partner revealed a small supernumerary marker chromosome (sSMC) derived from chromosome 15, specifically inverted and duplicated (inv dup(15)) corresponding to the 15q11.2 region but lacking the Prader-Willi/Angelman syndrome critical region (PWACR). Further investigations revealed that 35% of the patient's spermatozoa carried the sSMC(15). This case study highlights the potential association between the presence of an inv dup(15) sSMC, without the involvement of the PWACR, and male infertility. sSMC(15) may disrupt spermatogenesis and contribute to oligoasthenozoospermia in males with primary infertility. Further research into the association of mechanism mechanisms of male infertility related to the 15q11.2 region is warranted.

PMID:40313645 | PMC:PMC12043387 | DOI:10.1155/carm/9935363

FEMS Microbiol Rev. 2025 May 1:fuaf018. doi: 10.1093/femsre/fuaf018. Online ahead of print.

ABSTRACT

The exquisite ability of bacteria to adapt to their environment is essential for their capacity to colonise hostile niches. In the cystic fibrosis (CF) lung, hypoxia is among several environmental stresses that opportunistic pathogens must overcome to persist and chronically colonise. Although the role of hypoxia in the host has been widely reviewed, the impact of hypoxia on bacterial pathogens has not yet been studied extensively. This review considers the bacterial oxygen-sensing mechanisms in three species that effectively colonise the lungs of people with CF, namely Pseudomonas aeruginosa, Burkholderia cepacia complex and Mycobacterium abscessus and draws parallels between their three proposed oxygen-sensing two-component systems: BfiSR, FixLJ, and DosRS, respectively. Moreover, each species expresses regulons that respond to hypoxia: Anr, Lxa, and DosR, and encode multiple proteins that share similar homologies and function. Many adaptations that these pathogens undergo during chronic infection, including antibiotic resistance, protease expression, or changes in motility, have parallels in the responses of the respective species to hypoxia. It is likely that exposure to hypoxia in their environmental habitats predispose these pathogens to colonisation of hypoxic niches, arming them with mechanisms than enable their evasion of the immune system and establish chronic infections. Overcoming hypoxia presents a new target for therapeutic options against chronic lung infections.

PMID:40312783 | DOI:10.1093/femsre/fuaf018

J Cyst Fibros. 2025 May 1:S1569-1993(25)01462-6. doi: 10.1016/j.jcf.2025.04.007. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled antibiotics are frequently used as chronic Pseudomonas aeruginosa (Pa) suppressive therapy among people with cystic fibrosis (PwCF). However, their use might increase the risk of developing treatment-emergent respiratory organisms. This study aimed to describe the proportion of PwCF utilizing inhaled antibiotics, determine factors associated with inhaled antibiotic prescription, and determine if chronic inhaled antibiotic use is associated with an increased risk of Aspergillus fumigatus, Stenotrophomonas maltophilia, or Achromobacter spp.

METHODS: This retrospective cohort study utilized Canadian CF Registry data. Pa status (chronic, intermittent, and negative) was defined per calendar year. The risk of developing A. fumigatus, S. maltophilia, or Achromobacter spp was compared between PwCF prescribed versus not prescribed inhaled antibiotics, adjusting for confounding by indication using inverse probability of treatment weighting.

RESULTS: This analysis included data from 2800 PwCF. >75 % of PwCF with chronic Pa were prescribed inhaled antibiotics, while up to 13 % of PwCF negative for Pa received inhaled antibiotics during the study period. There was an increased risk of developing A. fumigatus among PwCF with intermittent Pa (HR 1.43, 95 %CI; 1.08-1.88; p = 0.01) and who were Pa negative (HR 2.44, 95 %CI; 1.65-3.61; p < 0.001), but not for PwCF with chronic Pa (HR 1.36, 95 %CI; 0.94-1.95; p = 0.10). No association was seen between inhaled antibiotics and developing either S. maltophilia or Achromobacter spp.

CONCLUSIONS: Inhaled antibiotic use among Canadian PwCF was associated with an increased risk of A. fumigatus acquisition but not S. maltophilia or Achromobacter spp. Prospective studies are needed to better define this association.

PMID:40312233 | DOI:10.1016/j.jcf.2025.04.007

Respiration. 2025 Apr 24:1-22. doi: 10.1159/000546030. Online ahead of print.

ABSTRACT

BACKGROUND: bronchiectasis is an often underdiagnosed chronic respiratory disease in children and adolescents. Recent international guidelines highlighted the management of bronchiectasis in pediatric patients in comparison to adults. The purpose of this manuscript is to review the diagnostic, etiological work-up and follow-up in children and adolescents with bronchiectasis, using real-life clinical cases that highlight the multidisciplinary approach required for this complex condition.

SUMMARY: the diagnostic process requires both thoracic imaging and a clinical evaluation with the addition of pulmonary function tests and microbiological exams, when possible. Specific work-up should include past medical history (e.g. recurrent pneumonia, otitis or extra-respiratory infections), including family history, testing for genetic diseases (e.g. cystic fibrosis), evaluation of airways abnormalities and obstruction (e.g. bronchial foreign body), exclusion of concomitant immunodeficiencies and conditions associated to impaired mucociliary clearance. Main comorbidities and possible etiological conditions include chronic pulmonary aspiration and gastro-esophageal reflux, upper respiratory tract and otologic diseases, particularly rhinosinusitis, otitis, and asthma. Patients should be followed up every 3 to 6 months, with closer monitoring for those with severe disease; transition to adult care should be individualized, with emphasis on patient education, treatment adherence and multidisciplinary support.

KEY MESSAGES: the diagnostic work-up for children and adolescents with bronchiectasis is challenging and requires input from multiple experts. Early detection of bronchiectasis is crucial for establishing effective diagnostic and therapeutic strategies and may help prevent further progression.

PMID:40310989 | DOI:10.1159/000546030

Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2423842122. doi: 10.1073/pnas.2423842122. Epub 2025 May 1.

ABSTRACT

Mycobacterium abscessus is a rapidly growing nontuberculous Mycobacterium causing severe pulmonary infections, especially in immunocompromised individuals and patients with underlying lung conditions like cystic fibrosis (CF). While rifamycins are the pillar of tuberculosis treatment, their efficacy against M. abscessus lung disease is severely compromised by intrabacterial ADP-ribosylation. Additionally, rifamycins induce cytochrome P450 3A4 (CYP3A4), a major human drug-metabolizing enzyme, further limiting their use in patients with comorbidities that require treatment with CYP3A4 substrates such as CF and HIV coinfection. We chemically reengineered rifabutin to enhance its potency against M. abscessus by blocking intrabacterial inactivation and eliminate drug-drug interactions by removing induction of CYP3A4 gene expression. We have designed and profiled a series of C25-substituted derivatives resistant to intracellular inactivation and lacking CYP3A4 induction, while retaining excellent pharmacological properties. Against Mycobacterium tuberculosis, devoid of ADP-ribosyltransferase, the frontrunners are equipotent to rifabutin, suggesting superior clinical utility since they no longer come with the drug interaction liability typical of rifamycins. Prioritized compounds demonstrated superior antibacterial activity against a panel of M. abscessus clinical isolates, were highly bactericidal against replicating and drug-tolerant nonreplicating bacteria in caseum surrogate and were active against intracellular bacteria. As single agents, these rifamycins were as effective as a standard-of-care four-drug combination in a murine model of M. abscessus lung infection.

PMID:40310456 | DOI:10.1073/pnas.2423842122

J Glob Antimicrob Resist. 2025 Apr 28:S2213-7165(25)00082-7. doi: 10.1016/j.jgar.2025.04.010. Online ahead of print.

ABSTRACT

OBJECTIVES: Chronic Pseudomonas aeruginosa infections are a leading cause of acute pulmonary exacerbations in people with cystic fibrosis (pwCF). Intrinsic antibiotic resistance and biofilm formation complicate treatment. This study investigates the genomic diversity and cefiderocol efficacy against planktonic and biofilm-associated forms of P. aeruginosa isolates from pwCF.

METHODS: Eight P. aeruginosa clinical isolates and three laboratory strains underwent whole genome sequencing (WGS). Biofilm formation was assessed through biomass, cell count, metabolic activity, and extracellular DNA (eDNA). The minimum bactericidal concentration (MBC90) and biofilm eradication concentration (MBEC90) were also determined.

RESULTS: WGS revealed significant genomic diversity, identifying ten distinct sequence types (STs). Antibiotic susceptibility testing (AST) showed that 10/11 strains were susceptible to cefiderocol, with one isolate (MPA9) displaying resistance linked to the blaOXA486 gene. Adding the β-lactamase inhibitor avibactam (AVI) restored susceptibility in this resistant strain. Although iron metabolism genes were highly conserved across isolates, MPA9 lacked the fpvA iron receptor, potentially contributing to cefiderocol resistance. Biofilm formation significantly increased tolerance to cefiderocol, with an 8-fold rise in MBEC90 compared to MBC90.

CONCLUSION: These findings highlight the genomic diversity and adaptive potential of P. aeruginosa in pwCF. Cefiderocol shows promise against planktonic and biofilm-associated P. aeruginosa, and combining it with AVI may counteract β-lactamase-mediated resistance.

PMID:40306463 | DOI:10.1016/j.jgar.2025.04.010

Endocr Pract. 2025 Apr 28:S1530-891X(25)00129-6. doi: 10.1016/j.eprac.2025.04.011. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a multisystem autosomal recessive disease arising from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Dysfunction of the CFTR protein leads to progressive pulmonary disease, pancreatic exocrine insufficiency, and nutritional deficiencies. Survival has significantly increased over the last several decades due to improved pulmonary and nutritional management, including CFTR modulator therapy. The adult CF population now faces new challenges of aging, such as menopause-related symptoms and age-related osteoporosis superimposed on underlying CF-related bone disease. The menopausal transition and early post-menopause are characterized by rapid bone loss and represent a window of opportunity to preserve bone mass. Menopausal hormone therapy may alleviate vasomotor symptoms and improve bone density in appropriately selected people. This review will discuss the current knowledge of menopause and bone health in females with CF, address CF-specific considerations on osteoporosis and menopause treatment options, and explore opportunities for future areas of research.

PMID:40306365 | DOI:10.1016/j.eprac.2025.04.011

Med. 2025 Apr 25:100676. doi: 10.1016/j.medj.2025.100676. Online ahead of print.

ABSTRACT

BACKGROUND: Anti-melanoma differentiation-associated protein 5 dermatomyositis (MDA5+DM) is a potentially fatal subtype of dermatomyositis. The most severe cases are characterized by rapidly progressive interstitial lung disease (RPILD), the leading cause of death in these patients. There is currently no curative treatment for these patients, and indeed, MDA5+DM-RPILD is considered one of the most challenging pathologies in medicine. Nevertheless, the recent introduction of CD19 chimeric antigen receptor (CAR)-T cell therapies appears to offer a serious opportunity to develop solutions for complex autoimmune diseases refractory to multiple immunosuppressant treatments, mainly rheumatic diseases such as rheumatoid arthritis, dermatomyositis, and systemic lupus erythematosus.

METHODS: In this report, we describe the first use of a second-generation CD19 CAR-T cell therapy (ARI-0001) in a pediatric patient with severe MDA5+DM-RPILD.

FINDINGS: Conventional treatments stabilized MDA5+DM-RPILD before CAR-T cell inoculation (-34 days). The presence of CD19+ B lymphocytes that might serve as target cells in deeper tissues was suspected due to CAR-T cell expansion in a context of B cell aplasia. No fever or cytokine release syndrome/cell-associated neurotoxicity syndrome was evident. In global terms, B cell reconstitution and cutaneous, motor, respiratory, and neurological improvements were observed gradually in the patient in an immunosuppressant-free context (-7 to +325 days).

CONCLUSIONS: A pediatric patient with aggressive MDA5+DM-RPILD achieved progressive long-term improvement and immunosuppressant-free remission over 11 months after compassionate use of a CD19 CAR-T cell therapy (ARI-0001).

FUNDING: This work was supported by the Programa Investigo (PI_SEPE_APM) and grants from the ISC-III (PI22/01226) from the Comunidad de Madrid (S2022/BMD-7225) and from the CRIS Cancer Foundation.

PMID:40306284 | DOI:10.1016/j.medj.2025.100676

Methods Mol Biol. 2025;2908:51-64. doi: 10.1007/978-1-0716-4434-8_4.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel residing primarily at the apical membrane of epithelial cells, plays a major role in fluid secretion and the maintenance of epithelial surface hydration. Mutations in the CFTR gene lead to the fatal disease known as cystic fibrosis (CF). Drugs that improve mutant CFTR protein folding and channel function have dramatically improved CF patient outcomes. However, the current regimen only restores the function of the most common mutant, ΔF508, to ~62% of wildtype (WT). Notably, ~10% of patients harboring hundreds of less common CFTR mutations are not eligible or do not respond at all to treatment with current CFTR modulators. Better characterizing the WT and mutant CFTR protein interactomes could provide critical insight into how to treat patients with rarer mutations and thereby improve the druggability of this devastating disease. Here we describe how BioID (proximity-dependent biotin identification) can be used to map the CFTR interactome in a human airway model-bronchial epithelial cells grown at the air-liquid interface. Approximately 26% (>5500) of all human protein-coding genes are predicted to code for membrane proteins, which together account for ~30% of the druggable proteome. The methods described here could thus also be applied to improve our understanding of many additional respiratory, autoimmune, and metabolic diseases.

PMID:40304902 | DOI:10.1007/978-1-0716-4434-8_4

Pediatr Diabetes. 2023 Apr 17;2023:4395556. doi: 10.1155/2023/4395556. eCollection 2023.

ABSTRACT

BACKGROUND: In cystic fibrosis-related diabetes (CFRD) screening, oral glucose tolerance test (OGTT) thresholds for detecting prediabetes and diabetes are defined by the 2-hour glucose (2 hG). Intermediate OGTT glucoses, between 0 and 2 hours, that are ≥200 mg/dL are deemed "indeterminate," although lower 1-hour glucose (1 hG) thresholds identify those at increased risk of type 2 diabetes in other populations, and may also better predict clinical decline in CF. Studies of 1 hG thresholds <200 mg/dL in people with CF are limited.

METHODS: A single center, retrospective chart review was performed of patients with 1 hG available on OGTTs collected between 2010 and 2019. In patients with ≥2 OGTTs, Kaplan-Meier analysis estimated likelihood of progression to CFRD based on a high vs. low 1 hG. In patients with ≥1 OGTT, mixed-effects models tested whether baseline 1 hG and 2 hG predicted growth and lung function trajectories.

RESULTS: A total of 243 individuals with CF were identified with at least 1 OGTT including a 1 hG, and n = 177 had ≥2 OGTTs. Baseline age (mean ± SD) was 12.4 ± 2.6 years with 3.2 ± 1.4 years of follow-up. Twenty-eight developed CFRD. All who developed CFRD had a 1 hG ≥ 155 mg/dL prior to 2 hG > 140 mg/dL. The average 1 hG was 267 mg/dL when 2 hG ≥ 200 mg/dL. In a subset with baseline 2 hG < 140 mg/dL, 1 hG ≥ 140 mg/dL conferred an increased 5 years risk of CFRD (p=0.036). Baseline 2 hG predicted decline in FEV1%predicted, but 1 hG did not.

CONCLUSIONS: In youth with CF, 1 hG ≥ 140 mg/dl is an early indicator of CFRD risk. However, 2 hG, rather than 1 hG, predicted lung function decline.

PMID:40303238 | PMC:PMC12016879 | DOI:10.1155/2023/4395556

J Inflamm Res. 2025 Apr 25;18:5573-5586. doi: 10.2147/JIR.S516160. eCollection 2025.

ABSTRACT

PURPOSE: Macrophages play a pivotal role in the progression of atherosclerosis (AS), and targeting macrophage-associated pathological processes has emerged as a promising therapeutic strategy for AS. Flavonoids have demonstrated potent antioxidant properties with potential anti-atherosclerotic effects. This study aimed to investigate the therapeutic effects of the flavonoid calycosin-7-glucoside (CG) on AS and elucidate its underlying molecular mechanisms.

METHODS: Macrophages were differentiated from human monocytic THP-1 cells by treatment with phorbol-12-myristate-13-acetate (PMA). Foam cell formation was induced by exposing differentiated macrophages to oxidized low-density lipoprotein (ox-LDL). Protein and inflammatory cytokine expression levels were assessed using RT-qPCR, Western blot, and ELISA assays. Total cholesterol and free cholesterol levels were quantified using commercial kits, and lipid droplet accumulation was visualized using Nile red staining.

RESULTS: Activation of activating transcription factor 1 (ATF-1) was found to mediate CG-induced suppression of inflammatory responses and foam cell formation in ox-LDL-exposed THP-1-derived macrophages. CG treatment enhanced p38 MAPK activity, which was responsible for ATF-1 activation and subsequent inhibition of inflammation and foam cell formation. Mechanistically, ATF-1 facilitated CG-induced anti-atherosclerotic effects by upregulating liver X receptor beta (LXR-β) and cystic fibrosis transmembrane conductance regulator (CFTR), which are critical for lipid metabolism and inflammation regulation, respectively.

CONCLUSION: CG attenuates ox-LDL-induced foam cell formation and inflammatory responses in THP-1-derived macrophages by activating the p38 MAPK/ATF-1 signaling pathway, leading to the upregulation of LXR-β and CFTR. These findings highlight the potential of CG as a therapeutic agent for AS.

PMID:40303003 | PMC:PMC12039851 | DOI:10.2147/JIR.S516160

J Paediatr Child Health. 2025 Apr 29. doi: 10.1111/jpc.70072. Online ahead of print.

ABSTRACT

INTRODUCTION: Neonatal cholestasis is a group of disorders characterised by conjugated hyperbilirubinemia in the newborns and young infants. Advances in genetic testing have facilitated the identification of specific aetiology. This study examines the genetic and clinical profiles of neonates with cholestasis, focusing on genotype-phenotype correlations and diagnostic outcomes.

METHODS: A retrospective review of children with neonatal cholestasis treated between 1997 and 2024 was conducted. Extrahepatic causes were excluded, and genetic testing, including a targeted cholestasis panel and whole exome sequencing (WES), was employed. Clinical and biochemical data, including gamma-glutamyl transferase (GGT) levels, were collected.

RESULTS: Genetic disorders were identified in 28.0% of 378 cases, including mutations in ATP8B1, ABCB11, ABCB4, DCDC2, DGUOK, KIF12, USP53, and genes related to bile acid synthesis (HSD3B7, PEX1). GGT levels played a significant role in diagnosis: patients with low or normal GGT were frequently diagnosed with progressive familial intrahepatic cholestasis (PFIC)1 and 2, or bile acid synthesis defects, while high GGT levels were associated with PFIC3, alpha-1 antitrypsin deficiency, and cystic fibrosis. Consanguinity was noted in 56.0% of genetically diagnosed cases. After 2010, 35.5% of patients received a genetic diagnosis, compared to 18.2% before 2010.

CONCLUSION: Genetic diseases are a major cause of neonatal cholestasis, and GGT levels serve as a useful diagnostic tool in differentiating subtypes. The increasing availability of genetic testing has improved early diagnosis and personalised management. Expanded genetic testing in clinical practice is critical for timely and accurate diagnosis of these rare disorders.

PMID:40302296 | DOI:10.1111/jpc.70072

Orphanet J Rare Dis. 2025 Apr 29;20(1):205. doi: 10.1186/s13023-025-03714-3.

ABSTRACT

BACKGROUND: The high variety of mutations found in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene is responsible for the clinical heterogeneity observed in people with Cystic Fibrosis (CF) and the atypical manifestations in CFTR-related disorders (CFTR-RD). The intronic c.489+3A>G (c.621+3A>G) variant has been reported to have questionable pathogenicity, although its alleged severity was probably due to its co-segregation in cis with another undetected mutation, as previously reported from countries in the Mediterranean region. In the island of Cyprus, several rare CFTR variants have been previously identified, among them the c.489+3A>G in co-segregation with the pathogenic p.Cys1400Ter (cDNA name = c.4200_4201del or legacy name = 4332delTG) mutation. We aimed to investigate the prevalence of these variants in Cyprus and describe their clinical impact in patients and carriers.

RESULTS: The intronic variant c.489+3A>G has been so far identified to co-segregate with the pathogenic p.Cys1400Ter mutation in the same allele in six unrelated Cypriot families and in total of 20 subjects. Three of them were diagnosed with CF, presenting with persistent respiratory symptoms, pancreatic insufficiency and a second CF-causing mutation. Two were diagnosed with CFTR-RD, presenting with bronchiectasis, intermediate sweat test and a second mutation known to cause CFTR-RD. Also, four carriers had a high suspicion of CFTR-RD, with bronchiectasis or emphysema and intermediate sweat test, although due to the lack of another CFTR mutation and a second functional test, definite diagnosis has not been made. Haplotype analysis provided evidence of a common haplotype in all individuals with co-segregation of the c.489+3A>G variant with p.Cys1400Ter mutation.

CONCLUSION: The intronic c.489+3A>G variant co-segregates extensively with p.Cys1400Ter in Cyprus as an ancestral combination due to a possible founder effect. Before providing genetic counselling to subjects identified through population screening to harbour the c.489+3A>G variant, extensive analysis of CFTR including gene rearrangements should be performed to identify possible other mutations in cis, especially in Mediterranean countries where this complex allele is probably common. Further research is warranted to fully delineate the clinical implications of the in cis co-segregation of p.Cys1400Ter with c.489+3A>G, even in the absence of pathogenic variants in the other CFTR allele.

PMID:40301948 | DOI:10.1186/s13023-025-03714-3

Nat Med. 2025 Apr 29. doi: 10.1038/s41591-025-03678-8. Online ahead of print.

ABSTRACT

Bacteriophage (phage) therapy, which uses lytic viruses as antimicrobials, is a potential strategy to address the antimicrobial resistance crisis. Cystic fibrosis, a disease complicated by recurrent Pseudomonas aeruginosa pulmonary infections, is an example of the clinical impact of antimicrobial resistance. Here, using a personalized phage therapy strategy that selects phages for a predicted evolutionary trade-off, nine adults with cystic fibrosis (eight women and one man) of median age 32 (range 22-46) years were treated with phages on a compassionate basis because their clinical course was complicated by multidrug-resistant or pan-drug-resistant Pseudomonas that was refractory to prior courses of standard antibiotics. The individuals received a nebulized cocktail or single-phage therapy without adverse events. Five to 18 days after phage therapy, sputum Pseudomonas decreased by a median of 104 CFU ml-1, or a mean difference of 102 CFU ml-1 (P = 0.006, two-way analysis of variance with Dunnett's multiple-comparisons test), without altering sputum microbiome, and an analysis of sputum Pseudomonas showed evidence of trade-offs that decreased antibiotic resistance or bacterial virulence. In addition, an improvement of 6% (median) and 8% (mean) predicted FEV1 was observed 21-35 days after phage therapy (P = 0.004, Wilcoxon signed-rank t-test), which may reflect the combined effects of decreased bacterial sputum density and phage-driven trade-offs. These results show that a personalized, nebulized phage therapy trade-off strategy may affect clinical and microbiologic endpoints, which must be evaluated in larger clinical trials.

PMID:40301561 | DOI:10.1038/s41591-025-03678-8

Nat Commun. 2025 Apr 29;16(1):4021. doi: 10.1038/s41467-025-59136-z.

ABSTRACT

We present an efficient method for synthesizing cationic poly(ethylene imine) derivatives using the multicomponent split-Ugi reaction to create a library of functional ionizable lipopolymers. Here we show 155 polymers, formulated into polyplexes, to establish structure-activity relationships essential for endosomal escape and transfection. A lead structure is identified, and lipopolymer-lipid hybrid nanoparticles are developed to deliver mRNA to lung endothelium and immune cells, including T cells, with low in vivo toxicity. These nanoparticles show significant improvements in mRNA delivery to the lung compared to in vivo-JetPEI® and demonstrate effective delivery of therapeutic mRNA(s) of various sizes. IL-12 mRNA-loaded nanoparticles delay Lewis Lung cancer progression, while human CFTR mRNA restores CFTR protein function in CFTR knockout mice. Additionally, we demonstrate in vivo CRISPR-Cas9 mRNA delivery, achieving gene editing in lung tissue and successful PD-1 knockout in T cells in mice. These results highlight the platform's potential for systemic gene therapy delivery.

PMID:40301362 | DOI:10.1038/s41467-025-59136-z

Pharmacoeconomics. 2025 Apr 29. doi: 10.1007/s40273-025-01497-w. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a rare genetic condition requiring extensive medical care, which has a significant impact on people with CF. Advances in treatment have extended life expectancy, yet there remains a significant economic burden to manage CF. Cost-effectiveness analysis (CEA) is crucial for evaluating the economic value of treatments and screening for CF. This scoping review seeks to highlight the best practices and gaps in the current evidence base, contributing to robust and comparable CEAs in CF research.

METHODS: A scoping review was conducted using PubMed and Embase. Studies were included if they featured a CEA focused on CF treatment. Data extraction covered study characteristics, model inputs, and modeling assumptions. A qualitative synthesis was conducted to assess the inclusion of considerations for both healthcare and societal impacts.

RESULTS: In total, 11 studies were included. Of these, six focused on evaluations of supportive therapies for CF and five focused on evaluation of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Heterogeneity in comparators and drug costing methods complicated cross-study comparisons. A qualitative review revealed differences in the types of costs and outcomes considered. Studies captured long-term disease progression, health-related quality-of-life effects, and direct medical costs.

CONCLUSIONS: This review highlights the complexity of CEAs for CF treatment and underscores the need for standardized methodologies and comprehensive evaluations, including broader economic impacts, to support more robust analyses and better-informed decision-making in CF treatment.

PMID:40301297 | DOI:10.1007/s40273-025-01497-w