J Clin Ultrasound. 2024 Oct 28. doi: 10.1002/jcu.23884. Online ahead of print.

ABSTRACT

Fetal liver calcifications (FLCs) are isolated or multiple areas of increased echogenicity in the fetal liver, with an estimated prevalence of 5-10 per 10 000 births. However, their clinical importance remains still unclear. Although they are often linked to infections, chromosomal disorders, thrombotic events, or tumors, isolated FLCs generally have a favorable outcome. This article aims to present a case of a 29-year-old pregnant woman with a low-risk cfDNA test, who presented for the first trimester screening scan at our hospital at 12 weeks of pregnancy. The morphology scan at 20 weeks and 5 days revealed a normal fetal size with areas of increased echogenicity in the liver. No other fetal issues were identified. The patient was monitored throughout her pregnancy at our center, receiving genetic counseling and tests for detecting cystic fibrosis, STORCH (syphilis, cytomegalovirus, herpes virus 1;2, rubella, and toxoplasma), fetal echocardiography, and MRI, all of which were normal. At 35 weeks and 6 days, the patient gave birth to a healthy male, and all subsequent postnatal examinations confirmed the baby's health. This article aims to offer comprehensive insights into the management and postnatal outcomes of isolated FLCs, based on a review of the literature.

PMID:39467273 | DOI:10.1002/jcu.23884

Laryngoscope. 2024 Oct 28. doi: 10.1002/lary.31869. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (BCC) is a rare pathogen typically causing respiratory illnesses in immunocompromised individuals. We present a novel case of BCC manifesting as a laryngeal abscess, mimicking a laryngeal malignancy in an immunocompetent patient. A 74-year-old male presented to the emergency department with acute respiratory failure and was emergently intubated, revealing abnormal supraglottic tissue. ENT consultation post-extubation and flexible laryngoscopy suggested malignancy in the right supraglottis. A subsequent CT neck showed an expansive paraglottic mass, again consistent with an advanced malignancy. During direct laryngoscopy with biopsy, purulence was encountered, and cultures were obtained. Biopsy results showed benign mucosa with inflammation, and cultures identified BCC. The patient received 7 days of Levofloxacin and Ampicillin-Sulbactam before culture results. Follow-up 2 weeks later showed near-complete symptom resolution, normal supraglottic mucosa on flexible laryngoscopy, and interval CT neck showed resolution of the "mass." This case involves an unusual presentation of an acute paraglottic BCC infection initially mistaken for a laryngeal mass. BCC is typically a threat to individuals with cystic fibrosis (CF) or other immunocompromised states due to its intrinsic antibiotic resistance. However, BCC is rarely implicated in paraglottic infections or abscess formation. This is the first reported case of a laryngeal BCC infection mimicking a laryngeal mass. It underscores the importance of maintaining an open differential diagnosis until pathologic confirmation, even when imaging and clinical examination suggest malignancy. Laryngoscope, 2024.

PMID:39466957 | DOI:10.1002/lary.31869

JAMA Pediatr. 2024 Oct 28. doi: 10.1001/jamapediatrics.2024.4435. Online ahead of print.

NO ABSTRACT

PMID:39466261 | DOI:10.1001/jamapediatrics.2024.4435

Pediatr Pulmonol. 2024 Oct 28. doi: 10.1002/ppul.27355. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) airway disease is characterized by chronic infection and neutrophil-driven inflammation, leading to progressive airway damage and early mortality. Infection with Pseudomonas aeruginosa significantly impacts morbidity and mortality, requiring early detection and aggressive antibiotic treatment. Controlling inflammation remains difficult due to the limited availability of effective anti-inflammatory treatments. CFTR modulators show potential in reducing inflammation, but further research is needed. Effective management of CF lung disease requires a comprehensive approach addressing both infection and inflammation.

PMID:39465651 | DOI:10.1002/ppul.27355

J Pediatr Gastroenterol Nutr. 2024 Oct 28. doi: 10.1002/jpn3.12389. Online ahead of print.

ABSTRACT

OBJECTIVE: Acid blocker therapy (ABT) has become common in cystic fibrosis (CF), despite insufficient evidence for benefits and studies showing potentially negative effects. We examined associations between ABT usage and growth, gut microbiome (GM), and early-onset lung disease in young children with CF.

METHODS: One hundred forty-five infants with CF born during 2012-2017, diagnosed through newborn screening by age 3 months and followed to 36 months of age at six CF centers were evaluated. Longitudinal data on growth, pancreatic functional status, pulmonary symptoms, and acid blocker medications were prospectively collected. Early-onset lung disease severity was evaluated by a clinical scoring system. GM composition was assessed by 16S rRNA methodology.

RESULTS: ABT use before age 3 years was frequent, with 81 (56%) of patients on H2 receptor antagonist (H2RA) or proton pump inhibitor (PPI), and higher among pancreatic insufficient (60%) versus pancreatic sufficient (26%) children. H2RA was commonly prescribed in infancy before transitioning to PPI. Growth improvements were not significantly greater, while GM α-diversity at 3 years of age was significantly lower and early-onset lung disease more severe, in persistent ABT users compared to nonusers of ABT.

CONCLUSION: In our cohort of young children with CF, early and persistent ABT use was not associated with significant growth benefits and instead showed associations with reduced GM diversity and negative effects on early-onset lung disease. Consequentially, there is a critical need for systematic evaluation and comprehensive risk-benefit analysis of ABT to ensure proper guidelines for children with CF.

PMID:39465618 | DOI:10.1002/jpn3.12389

BMC Infect Dis. 2024 Oct 27;24(1):1209. doi: 10.1186/s12879-024-10050-7.

ABSTRACT

BACKGROUND: Haemophilus influenzae is prevalent within the airways of persons with cystic fibrosis (pwCF). H. influenzae is often associated with pulmonary exacerbations (PEx) in pediatric cohorts, but in adults, studies have yielded conflicting reports around the impact(s) on clinical outcomes such as lung function decline. Accordingly, we sought to discern the prevalence, natural history, and clinical impact of H. influenzae in adult pwCF.

METHODS: This single-centre retrospective cohort study reviewed all adult pwCF with H. influenzae sputum cultures between 2002 and 2016. From this cohort, persistently infected subjects (defined as: ≥2 samples with the same pulsotype and > 50% sputum culture-positive for H. influenzae in each year) were matched (1:2) to controls without H. influenzae. Demographic and clinical status (baseline health or during periods of PEx) were obtained at each visit that H. influenzae was cultured. Yearly biobank isolates were typed using pulsed-field gel electrophoresis (PFGE) to assess relatedness.

RESULTS: Over the study period, 30% (n = 70/240) of pwCF were culture positive for H. influenzae, of which 38 (54%) were culture-positive on multiple occasions and 12 (17%) had persistent infection. One hundred and thirty-seven isolates underwent PFGE, with 94 unique pulsotypes identified. Two (1.5%) were serotype f with the rest non-typeable (98.5%). H. influenzae isolation was associated with an increased risk of PEx (RR = 1.61 [1.14-2.27], p = 0.006), however, this association was lost when we excluded those who irregularly produced sputum (i.e. only during a PEx). Annual lung function decline did not differ across cohorts.

CONCLUSIONS: Isolation of H. influenzae was common amongst adult pwCF but often transient. H. influenzae infection was not associated with acute PEx or chronic lung function decline.

PMID:39465381 | DOI:10.1186/s12879-024-10050-7

Antimicrob Steward Healthc Epidemiol. 2024 Oct 25;4(1):e189. doi: 10.1017/ash.2024.445. eCollection 2024.

ABSTRACT

OBJECTIVE: We sought to compare patient outcomes between carbapenem-resistant Enterobacterales (CRE) and carbapenem-susceptible Enterobacterales (CSE) infections at our academic medical center.

DESIGN: We conducted a retrospective cohort study of adult patients with a positive culture of E. coli, E. cloacae, K. aerogenes, K. oxytoca, and/or K. pneumoniae admitted at UK HealthCare (January 1, 2010-December 31, 2019). Based on the type of pathogen on the date of the first culture (index date), patients were included in the CRE (i.e., exposed) group, or the CSE (comparator) group. Exclusion criteria were age < 18 years old, pregnancy, endocarditis, osteomyelitis, necrotizing fasciitis, or cystic fibrosis. We evaluated the impact of CRE vs CSE on a composite outcome of 30-day of all-cause mortality or discharge to hospice using Kaplan-Meier survival curves and Cox proportional hazard regression with inverse probability of treatment weights (IPTW).

RESULTS: Of 17,839 hospitalized patients, 128 and 6,953 patients were included in the CRE and CSE groups, respectively. Baseline differences existed in sex-assigned-at-birth, admission source, time-to-index culture, and infection type/severity. Most CRE index cultures observed (76%) only exhibited resistance to ertapenem. IPTW-adjusted HR [95% CI] of composite outcome was 0.99 [0.65, 1.51] after 30 days. Follow-up analysis in patients with carbapenem-non-susceptible Enterobacteralesbloodstream infections on index yielded an HR of 1.38 [0.85, 2.24].

CONCLUSIONS: Risk of composite outcome was not estimated to differ between patients with CRE and CSE in the overall analysis. Although follow-up analysis identified an increased risk, we cannot statistically distinguish this from a null effect.

PMID:39465213 | PMC:PMC11504081 | DOI:10.1017/ash.2024.445

In Silico Pharmacol. 2024 Oct 24;12(2):93. doi: 10.1007/s40203-024-00271-8. eCollection 2024.

ABSTRACT

Antibiotic resistance in bacteria leads to high mortality rates and healthcare costs, a significant concern for public health. A colonizer of the human respiratory system, Stenotrophomonas maltophilia is frequently associated with hospital-acquired infections in individuals with cystic fibrosis, cancer, and other chronic illnesses. The importance of this study is underscored by its capacity to meet the critical demand for effective preventive strategies against this pathogen, particularly among susceptible groups of cystic fibrosis and those undergoing cancer treatment. In this study, we engineered a multi-epitope vaccine targeting S. maltophilia through genomic analysis, reverse vaccination strategies, and immunoinformatic techniques by examining a total of 81 complete genomes of S. maltophilia strains. Our investigation revealed 1945 core protein-coding genes alongside their corresponding proteomic sequences, with 191 of these genes predicted to exhibit virulence characteristics. Out of the filtered proteins, three best antigenic proteins were selected for epitope prediction while seven epitopes each from CTL, HTL, and B cell were chosen for vaccine development. The vaccine was refined and validated, showing highly antigenic and desirable physicochemical features. Molecular docking assessments revealed stable binding with TLR-4. Molecular dynamic simulation demonstrated stable dynamics with minor alterations. The originality of this investigation is rooted in the thorough techniques aimed at designing a vaccine that directly targets S. maltophilia, a microorganism of considerable clinical relevance that currently lacks an available vaccine. This study not only responds to a pressing public health crisis but also lays the groundwork for subsequent research endeavors focused on the prevention of S. maltophilia outbreaks. Further evidence from studies in mice models is needed to confirm immune protection against S. maltophilia.

PMID:39464855 | PMC:PMC11499521 | DOI:10.1007/s40203-024-00271-8

ACS Omega. 2024 Oct 10;9(42):43184-43192. doi: 10.1021/acsomega.4c07394. eCollection 2024 Oct 22.

ABSTRACT

The concentration of nonesterified fatty acids (NEFAs) in biological media is associated with metabolic and cardiovascular disorders (e.g., diabetes, cancer, and cystic fibrosis) and in food products is indicative of their quality. Therefore, the early identification of NEFAs is crucial for both medical diagnosis and food quality assessment. However, the development of a portable and scalable sensor capable of detecting these compounds at a low cost presents challenges due to their considerable chemical and physical stability. This research endeavors to illustrate the viability of detecting linoleic acid using a chemiresistive bienzymatic sensor constructed with cotton thread. The sensor's design incorporates the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrenesulfonate (PEDOT:PSS) within the thread, alongside the enzymes horseradish peroxidase (HRP) and lipoxygenase (LOX). By implementing this technology, a sensitive detection range spanning from 161 nM to 16.1 μM is achieved when the PEDOT:PSS/HRP/LOX system is integrated into a single thread. The sensor exhibits exceptional selectivity toward linoleic acid, owing to the specific enzymatic reaction between LOX and linoleic acid. This selectivity is upheld even in the presence of other unsaturated fatty acids. This system can be used for future designs with the capability to detect polyunsaturated fatty acids and other intricate biomolecules.

PMID:39464462 | PMC:PMC11500365 | DOI:10.1021/acsomega.4c07394

Sci Rep. 2024 Oct 28;14(1):25689. doi: 10.1038/s41598-024-76722-1.

ABSTRACT

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

PMID:39463434 | DOI:10.1038/s41598-024-76722-1

Mycoses. 2024 Oct;67(10):e13810. doi: 10.1111/myc.13810.

ABSTRACT

OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) is a complex lung disease associated with significant morbidity. The ABPA Working Group (AWG) of the International Society for Human and Animal Mycology (ISHAM) revised their management guidelines in 2024, but there is currently no standardised tool to assess adherence to these recommendations.

METHODS: We extracted key recommendations from the updated 2024 ISHAM-AWG guidelines, focusing on critical areas: screening and diagnosis of ABPA, managing acute and treatment-dependent ABPA, and monitoring treatment response. Each item was assigned a score ranging from zero to three. We assigned negative scores to interventions not recommended by the guidelines.

RESULTS: We identified 38 items indicative of optimal clinical care for patients with ABPA. The score for screening asthmatics for ABPA was set at three points. For diagnosing ABPA, 16 items were included, with a score ranging from 12 to 16 points, depending on the specific components used (predisposing conditions, serum A. fumigatus-specific IgE and IgG, serum total IgE, blood eosinophil count and chest computed tomography). The management of acute ABPA comprised 11 items, with a maximum score of three points. For treatment-dependent ABPA, there were nine items (scores ranging from -3 to 6). Follow-up care comprised 10 items with a maximum score of 10-13 points, covering imaging, spirometry, testing serum total IgE levels and therapeutic drug monitoring.

CONCLUSIONS: The EQUAL ABPA score has been developed as a comprehensive tool to quantify guideline adherence. Future studies will evaluate to which extent guideline adherence is associated with improved clinical outcomes for patients with ABPA.

PMID:39462638 | DOI:10.1111/myc.13810

Sci Rep. 2024 Oct 26;14(1):25555. doi: 10.1038/s41598-024-76482-y.

ABSTRACT

The TMEM16A chloride channel is proposed as a therapeutic target in cystic fibrosis, where activation of this ion channel might restore airway surface hydration and mitigate respiratory symptoms. While TMEM16A is associated with increased mucin production under stimulated or pro-inflammatory conditions, its role in baseline mucin production, secretion and/or maturation is less well understood. Here, we use the Xenopus tadpole skin mucociliary surface as a model of human upper airway epithelium to study Tmem16a function in mucus production. We found that Xenopus tropicalis Tmem16a is present at the apical membrane surface of tadpole skin small secretory cells that express canonical markers of mammalian "goblet cells" such as Foxa1 and spdef. X. tropicalis Tmem16a functions as a voltage-gated, calcium-activated chloride channel when transfected into mammalian cells in culture. Depletion of Tmem16a from the tadpole skin results in dysregulated mucin maturation post-secretion, with secreted mucins having a disrupted molecular size distribution and altered morphology assessed by sucrose gradient centrifugation and electron microscopy, respectively. Our results show that in the Xenopus tadpole skin, Tmem16a is necessary for normal mucus barrier formation and demonstrate the utility of this model system to discover new biology relevant to human mucosal biology in health and disease.

PMID:39461969 | DOI:10.1038/s41598-024-76482-y

Chest. 2024 Oct 24:S0012-3692(24)05400-X. doi: 10.1016/j.chest.2024.06.3843. Online ahead of print.

ABSTRACT

INTRODUCTION: Aspergillus sp. cause diverse clinical manifestations in bronchiectasis including Allergic bronchopulmonary aspergillosis (ABPA), Aspergillus sensitization (AS) and raised IgG indicating exposure or infection with Aspergillus.

RESEARCH QUESTION: What is the prevalence and clinical significance of Aspergillus-associated conditions in individuals with bronchiectasis?

METHODS: Bronchiectasis patients enrolled into the EMBARC registry from 2015 to 2022 with laboratory testing for Aspergillus lung disease (total IgE, specific IgE to Aspergillus or Aspergillus skin test, IgG to Aspergillus and blood eosinophil counts) were included for analysis. Modified-ISHAM-ABPA working group criteria (2021) were used to define ABPA.

RESULTS: 9953 patients were included. 608 (6.1%) were classified as having ABPA, 570 (5.7%) showed Aspergillus sensitization, 806 (8.1%) had raised Aspergillus-specific IgG without sensitisation, 184 (1.8%) were both sensitised to Aspergillus and had raised Aspergillus-specific IgG and 619 (6.2%) had eosinophilic bronchiectasis (elevated eosinophil counts without evidence of Aspergillus lung disease). The remaining 72.0% had negative Aspergillus serology. Patients with ABPA, Aspergillus sensitization, and raised Aspergillus-specific IgG had more severe disease, with worse lung function and more frequent exacerbations at baseline. During long-term follow-up, patients with raised Aspergillus-specific IgG had higher exacerbation frequency and more severe exacerbations. Aspergillus sensitization associated with increased exacerbations and hospitalisations only in patients not receiving inhaled corticosteroids.

INTERPRETATION: Aspergillus lung disease is common in bronchiectasis. Raised IgG to Aspergillus is associated with significantly worse outcomes while ABPA and Aspergillus sensitization are associated with severe disease and exacerbations with a risk that is attenuated by inhaled corticosteroid use.

PMID:39461553 | DOI:10.1016/j.chest.2024.06.3843

Crit Rev Microbiol. 2024 Oct 25:1-13. doi: 10.1080/1040841X.2024.2418130. Online ahead of print.

ABSTRACT

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens ubiquitous in the environment. Mycobacteroides abscessus is a relatively new pathogen associated with underlying lung chronic pathologies, accounting for most of the pulmonary infections linked to the rapidly growing mycobacteria group. This includes chronic obstructive pulmonary disease, bronchiectasis, or cystic fibrosis. Patient outcomes from M. abscessus infections are poor due to complicated treatments and other factors. Intrinsic drug resistance plays an important role. The M. abscessus toolbox of resistance is varied leading to complex strategies for treatment. Mechanisms include waxy cell walls, drug export mechanisms, and acquired resistance. Many studies have also shown the impact of extracellular DNA found in the biofilm matrix during early infection and its possible advantage in pathogenicity. In this review, we discuss the current knowledge of early infection focusing on biofilm formation, an environmental strategy, and which treatments prevent its formation improving current antibiotic treatment outcomes in preliminary studies.

PMID:39460453 | DOI:10.1080/1040841X.2024.2418130

Life (Basel). 2024 Oct 16;14(10):1309. doi: 10.3390/life14101309.

ABSTRACT

INTRODUCTION: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial.

AIM: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population.

MATERIALS AND METHODS: A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T3mo), 6 months (T6mo) and 12 months (T12mo) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del).

RESULTS: Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T3mo and T6mo, but not at T12mo, whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly.

CONCLUSION: We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

PMID:39459609 | DOI:10.3390/life14101309

Microorganisms. 2024 Oct 12;12(10):2059. doi: 10.3390/microorganisms12102059.

ABSTRACT

Clostridioides difficile infection (CDI) is generally treated with vancomycin, metronidazole or fidaxomicin, although fecal microbiota transplantation (FMT) represents a promising therapeutic option for antibiotic-resistant recurrent C. difficile infections (rCDIs) in adults. In pediatric cystic fibrosis (CF) patients, CDIs are generally asymptomatic and respond to treatment. Here, we present the case of an 8-year-old female, initially diagnosed as "CFTR-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis" (CMRS/CFSPID), who then progressed to CF at 12 months. In the absence of CF-related symptoms, she presented multiple and disabling episodes of bloody diarrhoea with positive tests for C. difficile antigen and A/B toxin. After conventional treatments failed and several CDI relapses, FMT was proposed. Donor screening and GM donor-receiver matching identified her mother as a donor. Metataxonomy and targeted metabolomics provided, through a pre- and post-FMT time course, gut microbiota (GM) profiling to assess GM engraftment. At first, the GM map revealed severe dysbiosis, with a prevalence of Bacteroidetes and Proteobacteria (i.e., Klebsiella spp., Escherichia coli), a reduction in Firmicutes, a GM nearly entirely composed of Enterococcaceae (i.e., Enterococcus) and an almost complete depletion of Verrucomicrobia and Actinobacteria, mostly represented by Veillonella dispar. Post FMT, an increment in Bifidobacterium spp. and Collinsella spp. with a decrease in V. dispar restored intestinal eubiosis. Consistently, four weeks after FMT treatment, the child's gut symptoms cleared, without CDI recurrence.

PMID:39458368 | DOI:10.3390/microorganisms12102059

Microorganisms. 2024 Oct 11;12(10):2051. doi: 10.3390/microorganisms12102051.

ABSTRACT

Cystic fibrosis (CF) is a life-threatening genetic disease characterised by chronic lung infections sustained by opportunistic pathogens such as Pseudomonas aeruginosa. During the chronic long-lasting lung infections, P. aeruginosa adapts to the host environment. Hypermutability, mainly due to defects in the DNA repair system, resulting in an increased spontaneous mutation rate, represents a way to boost the rapid adaptation frequently encountered in CF P. aeruginosa isolates. We selected 609 isolates from 51 patients with CF chronically colonised by P. aeruginosa to study, by full-length genome sequencing, the longitudinal evolution of the bacterium. We recovered at least one hypermutable (mutator) isolate in 57% of patients. By combining genomic information and phenotypic analyses, we followed the evolutionary pathways of the P. aeruginosa mutator strains, identifying their contribution to multi-drug resistance and the emergence of new sub-lineages. By implementing patient clinical data, we observed that mutators preferentially follow a specific evolutionary trajectory in patients with a negative clinical outcome and that maintenance antibiotic polytherapy, based on alternating molecules, apparently reduces the occurrence of hypermutability. Finally, we draw attention to the possibility that modulator-induced changes in the pulmonary environment may be associated with the onset of hypermutability.

PMID:39458360 | DOI:10.3390/microorganisms12102051

J Clin Med. 2024 Oct 18;13(20):6210. doi: 10.3390/jcm13206210.

ABSTRACT

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with 'rare' CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have 'rare' CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority.

PMID:39458161 | DOI:10.3390/jcm13206210

J Clin Med. 2024 Oct 15;13(20):6146. doi: 10.3390/jcm13206146.

ABSTRACT

Background/Objectives: High-flow nasal therapy (HFNT) has been shown to reduce exacerbations of COPD and some evidence displays benefits in non-cystic fibrosis bronchiectasis (NCFB) patients. The present study aimed to compare the effectiveness of 12 months of home HFNT on the annual exacerbation rate between mild/moderate and severe NCFB patients, classified by the bronchiectasis severity index (BSI). Secondary outcomes were the evaluation of the dyspnea, pulmonary function, and sputum cultures in both groups. Methods: The study population included NCFB adult patients, with at least one severe exacerbation in the previous year on optimized therapy. NCFB exacerbations, dyspnea (mMRC score), pulmonary function test, and sputum cultures were assessed at baseline and after 12 months of HFNT. Results: A total of 86 NCFB patients were enrolled: 36 in the mild/moderate (BSI < 9) and 50 in the severe (BSI ≥ 9) group. A significant improvement in the annual exacerbation rate was found in both BSI ≥ 9 (p < 0.0001) and BSI < 9 cohorts (p < 0.0001), with a between-group difference of -1 (95% CI: -2 to 0) exacerbations per year (p = 0.0209). The change in the annual exacerbation rate was significantly correlated with BSI (ρ = -0.26, p = 0.0151) and with HFNT daily use (ρ = -0.22, p = 0.0460). The mMRC score significantly improved by -2 points (95% CI: -2 to -1) after treatment in both groups (p < 0.0001). The percentage of patients with P. aeruginosa colonization decreased from 34.9% to 27.9%. Conclusions: Long-term HFNT reduces the annual exacerbation rate in NCFB patients and its effectiveness increases alongside disease severity and daily use of HFNT.

PMID:39458096 | DOI:10.3390/jcm13206146

Genes (Basel). 2024 Oct 17;15(10):1335. doi: 10.3390/genes15101335.

ABSTRACT

BACKGROUND/OBJECTIVES: Cystic fibrosis (CF) is one of the most common autosomal-recessive disorders worldwide. The incidence of CF depends on the prevalence of cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations in the population, which is determined by genetic diversity and ethnicity.

METHODS: The search for the causes of mutations in the transmembrane conductance regulator gene (CFTR) was carried out using targeted next-generation sequencing (NGS) on the Illumina platform in patients with cystic fibrosis from the Republic of Bashkortostan (Russia), taking into account the ethnic structure of the sample.

RESULTS: A total of 35 distinct causal variants were found in 139 cases from 129 families. Five (F508del, E92K, 3849+10kbC>T, CFTRdele2.3, L138ins) explain 78.7% of identified CF causal alleles. Variants N13103K and 394delTT were found in four families each. Variants 2143delT, S1196X, W1282X, Y84X, G194R, and 1525-1G>A, as well as the two previously described complex alleles-c. [S466X; R1070Q] and str.[G509D;E217G]-were found in two or three families each. Twenty additional variants occurred only once. Variant c.3883_3888dup has not been described previously. Thus, regional and ethnic features were identified in the spectrum of frequencies of pathogenic variants of the CFTR gene in the three major sub-groups of patients-Russians, Tatars, and Bashkirs.

CONCLUSIONS: Taking into account these results, highlighting the genetic specificity of the region, a more efficient search for CFTR mutations in patients can be performed. In particular it is possible to choose certain test kits for quick and effective genetic screening before use of NGS sequencing.

PMID:39457459 | DOI:10.3390/genes15101335