Emerg Infect Dis. 2023 Nov;29(11):2229-2237. doi: 10.3201/eid2911.230493.

ABSTRACT

Pandoraea spp. are gram-negative, nonfermenting rods mainly known to infect patients with cystic fibrosis (CF). Outbreaks have been reported from several CF centers. We report a Pandoraea spp. outbreak comprising 24 non-CF patients at a large university hospital and a neighboring heart center in Germany during July 2019-December 2021. Common features in the patients were critical illness, invasive ventilation, antimicrobial pretreatment, and preceding surgery. Complicated and relapsing clinical courses were observed in cases with intraabdominal infections but not those with lower respiratory tract infections. Genomic analysis of 15 isolates identified Pandoraea commovens as the genetically most similar species and confirmed the clonality of the outbreak strain, designated P. commovens strain LB-19-202-79. The strain exhibited resistance to most antimicrobial drugs except ampicillin/sulbactam, imipenem, and trimethoprim/sulfamethoxazole. Our findings suggest Pandoraea spp. can spread among non-CF patients and underscore that clinicians and microbiologists should be vigilant in detecting and assessing unusual pathogens.

PMID:37877517 | DOI:10.3201/eid2911.230493

Br J Haematol. 2023 Oct 24. doi: 10.1111/bjh.19134. Online ahead of print.

ABSTRACT

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

PMID:37876306 | DOI:10.1111/bjh.19134

Sci Rep. 2023 Oct 24;13(1):18138. doi: 10.1038/s41598-023-45273-2.

ABSTRACT

Recurrent pulmonary exacerbation due to infection and inflammation remain the major cause of mortality and morbidity in patients with cystic fibrosis (CF). Increased levels of BPI-ANCA have been linked to Pseudomonas colonization and pulmonary exacerbations in patients with CF. The majority of these studies were done in Europe, and it is unclear whether similar findings are true in CF patients who lives in United States. In our single center study of 47 patients with CF, the prevalence of BPI-ANCA was 19% at baseline and 15% at annual follow-up visit. Overall, there were no statistical differences noted in FEV1 and frequency of pulmonary exacerbations in CF patients who were positive for BPI-ANCA compared to those who were negative for BPI-ANCA. The role of BPI-ANCA in patients with CF still remains unclear.

PMID:37875496 | DOI:10.1038/s41598-023-45273-2

Diabetes Care. 2023 Oct 24:dc231411. doi: 10.2337/dc23-1411. Online ahead of print.

ABSTRACT

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) affects up to 50% of adults with cystic fibrosis and adds significant morbidity and treatment burden. We evaluated the safety and efficacy of automated insulin delivery with the iLet bionic pancreas (BP) in adults with CFRD in a single-center, open-label, random-order, crossover trial.

RESEARCH DESIGN AND METHODS: Twenty participants with CFRD were assigned in random order to 14 days each on the BP or their usual care (UC). No restrictions were placed on diet or activity. The primary outcome was the percent time sensor-measured glucose was in target range 70-180 mg/dL (time in range [TIR]) on days 3-14 of each arm, and key secondary outcomes included mean continuous glucose monitoring (CGM) glucose and the percent time sensor-measured glucose was in hypoglycemic range <54 mg/dL.

RESULTS: TIR was significantly higher in the BP arm than the UC arm (75 ± 11% vs. 62 ± 22%, P = 0.001). Mean CGM glucose was lower in the BP arm than in the UC arm (150 ± 19 vs. 171 ± 45 mg/dL, P = 0.007). There was no significant difference in percent time with sensor-measured glucose <54 mg/dL (0.27% vs. 0.36%, P = 1.0), although self-reported symptomatic hypoglycemia episodes were higher during the BP arm than the UC arm (0.7 vs. 0.4 median episodes per day, P = 0.01). No episodes of diabetic ketoacidosis or severe hypoglycemia occurred in either arm.

CONCLUSIONS: Adults with CFRD had improved glucose control without an increase in CGM-measured hypoglycemia with the BP compared with their UC, suggesting that this may be an important therapeutic option for this patient population.

PMID:37874987 | DOI:10.2337/dc23-1411

PLoS One. 2023 Oct 24;18(10):e0293367. doi: 10.1371/journal.pone.0293367. eCollection 2023.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease hallmarked by aberrant ion transport that results in delayed mucus clearance, chronic infection, and progressive lung function decline. Several animal models have been developed to study the airway anatomy and mucus physiology in CF, but they are costly and difficult to maintain, making them less accessible for many applications. A more available CFTR-/- rat model has been developed and characterized to develop CF airway abnormalities, but consistent dosing of pharmacologic agents and longitudinal evaluation remain a challenge. In this study, we report the development and characterization of a novel ex vivo trachea model that utilizes both wild type (WT) and CFTR-/- rat tracheae cultured on a porcine gelatin matrix. Here we show that the ex vivo tracheae remain viable for weeks, maintain a CF disease phenotype that can be readily quantified, and respond to stimulation of mucus and fluid secretion by cholinergic stimulation. Furthermore, we show that ex vivo tracheae may be used for well-controlled pharmacological treatments, which are difficult to perform on freshly excised trachea or in vivo models with this degree of scrutiny. With improved interrogation possible with a durable trachea, we also established firm evidence of a gland secretion defect in CFTR-/- rat tracheae compared to WT controls. Finally, we demonstrate that the ex vivo tracheae can be used to generate high mucus protein yields for subsequent studies, which are currently limited by in vivo mucus collection techniques. Overall, this study suggests that the ex vivo trachea model is an effective, easy to set up culture model to study airway and mucus physiology.

PMID:37874846 | DOI:10.1371/journal.pone.0293367

Pulm Ther. 2023 Oct 24. doi: 10.1007/s41030-023-00241-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a life-limiting genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a CFTR modulator (CFTRm) that targets the underlying cause of CF. Based on safety and efficacy demonstrated in clinical trials, ELX/TEZ/IVA is approved in the US for the treatment of CF in people aged ≥ 2 years who have ≥ 1 F508del-CFTR mutation or a CFTR mutation that is responsive to ELX/TEZ/IVA based on in vitro data. While ELX/TEZ/IVA demonstrated unprecedented improvements in lung function and dramatic reductions in pulmonary exacerbations (PEx) and associated hospitalizations in clinical trials, a limited number of studies have examined the impact of ELX/TEZ/IVA on healthcare resource utilization (HCRU) and associated costs in a real-world setting. The aim of this retrospective study was to evaluate changes in PEx, HCRU, and associated non-CFTRm healthcare costs following initiation of ELX/TEZ/IVA among people with CF aged ≥ 12 years in the US.

METHODS: We evaluated the rates of PEx, HCRU, and associated costs before and after initiation of ELX/TEZ/IVA in people with CF aged ≥ 12 years using data from the Merative MarketScan® Commercial Claims and Encounters Database and the Merative Multi-State Medicaid Database from April 21, 2019 to December 31, 2020. Because the study period included time following the onset of the COVID-19 pandemic, we limited our primary analysis to the period prior to the pandemic (October 21, 2019 to March 12, 2020). Outcomes following the onset of the pandemic (March 13 to December 31, 2020) were examined in an exploratory analysis.

RESULTS: In both commercially insured and Medicaid-insured people with CF, ELX/TEZ/IVA was associated with reductions in PEx, hospitalizations, and associated costs prior to the COVID-19 pandemic, and these reductions were maintained following the onset of the pandemic.

CONCLUSIONS: These findings suggest that ELX/TEZ/IVA reduces the burden and costs associated with PEx and hospitalizations in people with CF.

PMID:37874528 | DOI:10.1007/s41030-023-00241-z

Int J Neonatal Screen. 2023 Oct 11;9(4):57. doi: 10.3390/ijns9040057.

ABSTRACT

Determining the scope of a newborn screening program is a challenging health policy issue. Our study aimed to explore the attitudes of specialists in pediatrics, neonatology, medical genetics, and biochemistry regarding the prospects for expanding the panel of diseases for universal newborn screening in Bulgaria. We conducted an online survey in March-May 2022. The questionnaire listed 35 disorders that could potentially be included in the Bulgarian panel for universal newborn screening. If endorsing a specific condition, participants had to justify their position by judging its performance against the ten principles of Wilson and Jungner. We found a high degree of knowledge about the current universal newborn screening program in Bulgaria. An overwhelming majority (97.4%) supported the expansion of the panel to include more conditions. Four disorders obtained more than 50% approval for inclusion: cystic fibrosis (87.0%), thalassemia (72.7%), spinal muscular atrophy (65.6%), and classical galactosemia (59.1%). The perception of the condition as an important health problem was the most significant factor in this support. The costs of diagnosis and treatment appeared to be the main source of concern. We recommend country-specific economic evaluations and research on the views of other stakeholders, including the government, payers, and patient organizations, to better understand and manage the complex nature of newborn screening policymaking.

PMID:37873848 | DOI:10.3390/ijns9040057

bioRxiv. 2023 Oct 9:2023.10.05.561147. doi: 10.1101/2023.10.05.561147. Preprint.

ABSTRACT

Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) result in cystic fibrosis - a lethal genetic disease. Missense mutations that alter a single amino acid in the CFTR protein are among the most common cystic fibrosis mutations. AlphaMissense (AM) is a new technology that predicts the pathogenicity of missense mutations based on dual learned protein structure and evolutionary features. We evaluated the ability of AM to predict the pathogenicity of CFTR missense variants. AM predicted a high pathogenicity for CFTR residues overall, resulting in a high false positive rate and fair classification performance on CF variants from the CFTR2.org database. AM pathogenicity score correlated modestly with pathogenicity metrics from persons with CF including sweat chloride level, pancreatic insufficiency rate, and pseudomonas infection rate. Correlation was also modest with CFTR trafficking and folding competency in vitro . By contrast, the AM score correlated well with CFTR functional data in vitro - demonstrating the dual structure and evolutionary training approach learns important functional information despite lacking such data during training. Different performance across metrics indicated AM may determine if polymorphisms in CFTR are recessive CF variants yet cannot differentiate mechanistic effects or the nature of pathophysiology. Finally, AM predictions offered limited utility to inform on the pharmacological response of CF variants i.e., theratype. The development of new approaches to differentiate the biochemical and pharmacological properties of CF variants is therefore still needed to refine the targeting of emerging precision CF therapeutics.

PMID:37873426 | PMC:PMC10592606 | DOI:10.1101/2023.10.05.561147

Respir Res. 2023 Oct 24;24(1):251. doi: 10.1186/s12931-023-02554-8.

ABSTRACT

Interstitial lung diseases (ILDs) are complex and heterogeneous diseases. The use of traditional diagnostic classification in ILD can lead to suboptimal management, which is worsened by not considering the molecular pathways, biological complexity, and disease phenotypes. The identification of specific "treatable traits" in ILDs, which are clinically relevant and modifiable disease characteristics, may improve patient's outcomes. Treatable traits in ILDs may be classified into four different domains (pulmonary, aetiological, comorbidities, and lifestyle), which will facilitate identification of related assessment tools, treatment options, and expected benefits. A multidisciplinary care team model is a potential way to implement a "treatable traits" strategy into clinical practice with the aim of improving patients' outcomes. Multidisciplinary models of care, international registries, and the use of artificial intelligence may facilitate the implementation of the "treatable traits" approach into clinical practice. Prospective studies are needed to test potential therapies for a variety of treatable traits to further advance care of patients with ILD.

PMID:37872563 | DOI:10.1186/s12931-023-02554-8

Nat Commun. 2023 Oct 23;14(1):6604. doi: 10.1038/s41467-023-41907-1.

ABSTRACT

Soft materials in nature are formed through reversible supramolecular assembly of biological polymers into dynamic hierarchical networks. Rational design has led to self-assembling peptides with structural similarities to natural materials. However, recreating the dynamic functional properties inherent to natural systems remains challenging. Here we report the discovery of a short peptide based on the tryptophan zipper (trpzip) motif, that shows multiscale hierarchical ordering that leads to emergent dynamic properties. Trpzip hydrogels are antimicrobial and self-healing, with tunable viscoelasticity and unique yield-stress properties that allow immediate harvest of embedded cells through a flick of the wrist. This characteristic makes Trpzip hydrogels amenable to syringe extrusion, which we demonstrate with examples of cell delivery and bioprinting. Trpzip hydrogels display innate bioactivity, allowing propagation of human intestinal organoids with apical-basal polarization. Considering these extensive attributes, we anticipate the Trpzip motif will prove a versatile building block for supramolecular assembly of soft materials for biotechnology and medicine.

PMID:37872151 | DOI:10.1038/s41467-023-41907-1

J Nat Prod. 2023 Oct 23. doi: 10.1021/acs.jnatprod.3c00536. Online ahead of print.

ABSTRACT

Through genome mining efforts, two lasso peptide biosynthetic gene clusters (BGCs) within two different species of Achromobacter, a genus that contains pathogenic organisms that can infect patients with cystic fibrosis, were discovered. Using gene-refactored BGCs in E. coli, these lasso peptides, which were named achromonodin-1 and achromonodin-2, were heterologously expressed. Achromonodin-1 is naturally encoded by certain isolates from the sputum of patients with cystic fibrosis. The NMR structure of achromonodin-1 was determined, demonstrating that it is a threaded lasso peptide with a large loop and short tail structure, reminiscent of previously characterized lasso peptides that inhibit RNA polymerase (RNAP). Achromonodin-1 inhibits RNAP in vitro and has potent, focused activity toward Achromobacter pulmonis, another isolate from the sputum of a cystic fibrosis patient. These efforts expand the repertoire of antimicrobial lasso peptides and provide insights into how Achromobacter isolates from certain ecological niches interact with each other.

PMID:37870195 | DOI:10.1021/acs.jnatprod.3c00536

Singapore Med J. 2023 Sep 19. doi: 10.4103/singaporemedj.SMJ-2022-093. Online ahead of print.

ABSTRACT

INTRODUCTION: : Asian children with cystic fibrosis (CF) managed in Malaysia have significant morbidity with limited access to life-sustaining treatments. We determined the morbidity and treatment cost of CF in a resource-limited country.

METHODS: This cross-sectional study included all children diagnosed with CF in our centre. Data on clinical presentation, genetic mutation, serial spirometry results and complications were collected. Out-of-pocket (OOP) and healthcare costs over 1 year were retrieved for patients who were alive. Cohen's d and odds ratio (OR) were used to determine the effect size.

RESULTS: Twenty-four patients were diagnosed with CF. Five patients died at a median (range) age of 18 (0.3-22) years. F508deletion (c. 1521_1523delCTT) was found in 20% of the alleles, while 89% of the variants were detected in nine patients. Body mass index (BMI) Z score was >-1.96 in 70.6% of patients. Two thirds (68%) were colonised with Pseudomonas aeruginosa, and this was associated with lower weight (P = 0.009) and BMI (P = 0.02) Z scores. Only 18% had FEV1 Z scores >-1.96. Early symptom onset (d = 0.74), delayed diagnosis (d = 2.07), a low FEF25-75 Z score (d = 0.82) and a high sweat conductance (d = 1.19) were associated with death. Inpatient cost was mainly from diagnostic tests, while medications contributed to half of the outpatient cost.

Healthcare utilisation cost was catastrophic, amounting to 20% of the total income.

CONCLUSION: Asian children with CF suffer significant complications such as low weight, low lung function and shortened lifespan. P. aeruginosa colonisation was frequent and associated with poor growth. Healthcare cost to parents was catastrophic.

PMID:37870036 | DOI:10.4103/singaporemedj.SMJ-2022-093

J Pediatr. 2023 Oct 20:113800. doi: 10.1016/j.jpeds.2023.113800. Online ahead of print.

ABSTRACT

OBJECTIVES: To test the utility of various biomarkers as indicators of gut dysfunction in cystic fibrosis (CF) and determine whether intra-individual variations in these measures are repeatable over short intervals and whether inter-individual variations correlate with clinical outcomes.

STUDY DESIGN: We performed a cross-sectional, limited longitudinal study of children with CF aged 1-21 years who provided blood and stool samples at 2 or 3 visits, 2 weeks and 3 months apart, which were assayed for markers of intestinal inflammation (fecal calprotectin [fCal], lipocalin-2 [fLcn2], neopterin [fNeo]) and permeability (plasma lipopolysaccharide [LPS] antibodies, LPS-binding protein) by enzyme immunoassays. Control specimens were obtained from children without CF who had undergone esophagogastroduodenoscopy and had no evidence of gut inflammation.

RESULTS: Twenty-six of 29 participants with CF completed the study. Sixty-nine stools (57 case/12 control) and 76 plasmas (60 case/16 control) were analyzed. LPS antibody had reliable intra-individual stability. fCal, fLcn2, and fNeo were significantly greater in CF than in control samples. fCal was negatively correlated with 3-month interval change (Δ) in weight-for-age z-score, body mass index/weight-for-length z-score (BMIZ/WLZ), and FEV1. fLcn2 was negatively correlated with FEV1 but not with anthropometrics. No marker correlated with ΔBMIZ/WLZ or ΔFEV1.

CONCLUSIONS: Lcn2 is elevated in people with CF and might predict worse interval pulmonary function. Expanded studies are warranted to test if fLcn2 correlates with changes in additional outcomes.

PMID:37866678 | DOI:10.1016/j.jpeds.2023.113800

J Cyst Fibros. 2023 Oct 20:S1569-1993(23)00928-1. doi: 10.1016/j.jcf.2023.10.009. Online ahead of print.

ABSTRACT

BACKGROUND: In times of genotype guided therapy options, a total of 3.2 % of people with CF (pwCF) in the German CF Registry[1] only have one or no CFTR-variant detected after genetic analysis. Additionally, genetic data in the Registry can be documented as free text and can therefore be prone to error. In order to allow the greatest possible amount of pwCF access to modern therapies, we conducted a re-evaluation of free text entries and established a custom-whole-CFTR-locus NGS-approach for all pwCF who remained without genetic confirmation afterwards.

METHODS: To this end, we assembled 731 free text variants of 655 pwCF in the German CF Registry. All variants were evaluated using ClinVar, HGMD and CFTR1/2, corrected in the Registries' database and uploaded to ClinVar. PwCF whose diagnosis remained uncertain as well as additional pwCF or pwCFTR-RD that were assembled through a nationwide call for testing of unclear cases were offered genetic analysis. Samples were analysed using a target-capture based NGS-custom-design-panel covering the entire CFTR-locus.

RESULTS: Evaluation of free text variants led to the discovery of 43 variants not formerly reported in the context of CF. The Registries' dropdown list was extended by 497 variants and over 500 pwCF were provided with their most up-to-date genotype. Samples of 47 pwCF/pwCFTR-RD were sequenced via NGS with an overall success rate of 61.7 %, resulting in implementation of entire CFTR-genotyping into routine diagnostics.

CONCLUSION: Entire CFTR-genotyping can greatly increase the genetic diagnostic rate of pwCF/pwCFTR-RD and should be considered after inconspicuous CFTR screening panels in CFTR-diagnostics.

PMID:37867076 | DOI:10.1016/j.jcf.2023.10.009

J Cyst Fibros. 2023 Oct 20:S1569-1993(23)00145-5. doi: 10.1016/j.jcf.2023.05.015. Online ahead of print.

NO ABSTRACT

PMID:37867075 | DOI:10.1016/j.jcf.2023.05.015

Stem Cell Res. 2023 Oct 18;72:103232. doi: 10.1016/j.scr.2023.103232. Online ahead of print.

ABSTRACT

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel defective in cystic fibrosis (CF). Several CFTR mutations are causative of CF, among which G542X is a nonsense mutation introducing a premature stop codon which prevents CFTR protein synthesis. We generated a new iPSC line from nasal cells carrying G542X homozygous mutation for CFTR: IGGi002A. This cell line has normal female karyotype, express pluripotency markers and could differentiate into three germ layers in vitro. This iPSC line may be used for disease modeling (cell differentiation and organoid formation) and development of personalized treatments by genome editing or pharmacological screening.

PMID:37865062 | DOI:10.1016/j.scr.2023.103232

J Pediatr Nurs. 2023 Oct 18;73:211-220. doi: 10.1016/j.pedn.2023.10.014. Online ahead of print.

ABSTRACT

PURPOSE: To explore young children's (age 3-6 years) own experiences and perceptions of treatment and care when living with a chronic illness.

DESIGN AND METHODS: The study employed a qualitative research design using a narrative and play-based interview approach. Individual face-to-face, narrative and play-based interviews were conducted with eight young children age 3-6 years with type 1 diabetes or cystic fibrosis. The play sessions took place at the home of the children and were video recorded. Interpretative phenomenological analysis was used to analyse the data and frame the study.

RESULTS: Our analysis identified six main themes: 1. Children understood illness through their bodily experience of treatment and care, 2. Children's experience of care and treatment ranged from a feeling of powerlessness to a sense of agency, 3. Children depended on their parents to provide comfort, advocacy and protection, 4. Children's perceptions of treatment and care were inherently related to their experiences of familiarity, interpersonal relationships and trust, 5. Children with type 1 diabetes did not perceive that they played an active role during consultations, and 6. Children associated medical treatment with receiving tangible rewards or positive feedback.

CONCLUSION: Children expressed a need to feel safe and build agency. They experienced this through participation and interpersonal relationships with healthcare professionals.

PRACTICE IMPLICATIONS: We should prioritize the establishment and implementation of age-appropriate psychosocial care practices that support young children in participating, forming relationships, and building trust.

PMID:37862851 | DOI:10.1016/j.pedn.2023.10.014

Evolution. 2023 Oct 20:qpad189. doi: 10.1093/evolut/qpad189. Online ahead of print.

ABSTRACT

Genetic background has the potential to influence both the tempo and trajectory of adaptive change: different genotypes of a given species may adopt varied solutions to the same environmental challenge, or they may approach the same solution at different rates. Laboratory selection has been used widely to experimentally examine the evolutionary consequences of variation in genetic background, although largely using genotypes differing by only a few mutations. Here, we leverage natural variation in the bacterium Pseudomonas aeruginosa to investigate whether different adaptive solutions are accessible from distant points of departure on an adaptive landscape. We evolved seventeen diverse genotypes in a laboratory medium that partially mimics the lung sputum of cystic fibrosis patients, and we measured changes in ten phenotypes as well as in fitness. Using phylogenetically-informed analyses, we found that genetic background impacted the tempo, but not the trajectory, of phenotypic evolution: different starting genotypes converged towards similar phenotypes, but at varying rates. Our findings add to a growing body of evidence supporting widespread diminishing returns epistasis during adaptation. The importance of genetic background towards the trajectory of adaptation remains inconsistent across experimental systems and conditions.

PMID:37862583 | DOI:10.1093/evolut/qpad189

J Magn Reson Imaging. 2023 Oct 20. doi: 10.1002/jmri.29041. Online ahead of print.

ABSTRACT

BACKGROUND: Lung magnetic resonance imaging (MRI) with ultrashort echo-times (UTE-MRI) allows high-resolution and radiation-free imaging of the lung structure in cystic fibrosis (CF). In addition, the combination of elexacaftor/tezacaftor/ivacaftor (ETI) has improved CF clinical outcomes such as need for hospitalization. However, the effect on structural disease still needs longitudinal evaluation at high resolution.

PURPOSE: To analyze the effects of ETI on lung structural alterations using UTE-MRI, with a focus on bronchiectasis reversibility.

STUDY TYPE: Retrospective.

POPULATION: Fifty CF patients (mean age 24.3 ± 9.2; 23 males).

FIELD STRENGTH/SEQUENCE: 1.5 T, UTE-MRI.

ASSESSMENT: All subjects completed both UTE-MRI and pulmonary function tests (PFTs) during two annual visits (M0 and M12), and 30 of them completed a CT scan. They initiated ETI treatment after M0 within a maximum of 3 months from the annual examinations. Three observers scored a clinical MRI Bhalla score on UTE-MRI. Bronchiectasis reversibility was defined as a reduction in both outer and inner bronchial dimensions. Correlations were searched between the Bhalla score and PFT such as the forced expiratory volume in 1 second percentage predicted (FEV1%p).

STATISTICAL TESTS: Comparison was assessed using the paired t-test, correlation using the Spearman correlation test with a significance level of 0.05. Concordance and reproducibility were assessed using intraclass correlation coefficient (ICC).

RESULTS: There was a significant improvement in MRI Bhalla score after ETI treatment. UTE-MRI demonstrated bronchiectasis reversibility in a subgroup of 18 out of 50 CF patients (36%). These patients with bronchiectasis reversibility were significantly younger, with lower severity of wall thickening but no difference in mucus plugging extent (P = 0.39) was found. The reproducibility of UTE-MRI evaluations was excellent (ICC ≥ 0.95), was concordant with CT scan (N = 30; ICC ≥ 0.90) and significantly correlated to FEV1% at PFT at M0 (N = 50; r = 0.71) and M12 (N = 50; r = 0.72).

DATA CONCLUSION: UTE-MRI is a reproducible tool for the longitudinal follow-up of CF patients, allowing to quantify the response to ETI and demonstrating the reversibility of some structural alterations such as bronchiectasis in a substantial fraction of this study population.

LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

PMID:37861357 | DOI:10.1002/jmri.29041

Oncoimmunology. 2023 Oct 16;12(1):2271693. doi: 10.1080/2162402X.2023.2271693. eCollection 2023.

ABSTRACT

BCL2 robustly preserves mitochondrial integrity, hence inhibiting innate immune signaling and apoptotic cell death in several cell types. Here, we comment on our recent data demonstrating that BCL2 also limits the ability of dendritic cells to elicit adaptive immune responses, lending support to a universal immunosuppressive function for the mitochondrial immune checkpoint.

PMID:37860277 | PMC:PMC10583618 | DOI:10.1080/2162402X.2023.2271693