Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S36-S43. doi: 10.1002/ppul.26870.

ABSTRACT

People with CF (pwCF) are at high risk for malnutrition, making nutritional management a critical aspect of CF care. Over the past several decades, optimal nutritional status for pwCF has been defined by body mass index (BMI) based on evidence linking suboptimal BMI to decreased lung function and life expectancy, although more recent changes in CF care may also bring changes to how nutritional health is defined. The historical focus on weight, BMI, and nutrition as key parts of multidisciplinary CF care starting at an early age places pwCF at increased risk for body image concerns and disordered eating. The landscape of CF care is evolving with the approval of highly effective modulator therapies (HEMT) and resulting improvements in growth; however, issues related to body image and eating remain important to consider, especially as past difficulties gaining weight may shift to discomfort with one's weight gain and/or physical appearance. This review aims to describe how body image concerns and disordered eating occur in pwCF across the lifespan; to discuss evidence-based approaches to addressing these concerns; and to identify future directions for research and clinical practice in assessing and treating eating disorders and body image concerns in this population.

PMID:39105343 | DOI:10.1002/ppul.26870

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S98-S106. doi: 10.1002/ppul.26869.

ABSTRACT

Hepatobiliary complications of Cystic Fibrosis (CF) constitute a significant burden for persons with CF of all ages, with advanced CF liver disease in particular representing a leading cause of mortality. The causes of the heterogeneity of clinical manifestations, ranging from steatosis to focal biliary cholestasis and biliary strictures, are poorly understood and likely reflect a variety of environmental and disease-modifying factors in the setting of underlying CFTR mutations. This review summarizes the current understanding of the pathophysiology of hepatobiliary manifestations of CF, and discusses emerging disease models and therapeutic approaches that hold promise to impact this important yet incompletely addressed aspect of CF care.

PMID:39105342 | DOI:10.1002/ppul.26869

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S6-S16. doi: 10.1002/ppul.26806.

ABSTRACT

Advances in cystic fibrosis (CF) diagnostics and therapeutics have led to improved health and longevity, including increased body weight and decreased malnutrition in people with CF. Highly effective CFTR modulator therapies (HEMT) are associated with increased weight through a variety of mechanisms, accelerating trends of overweight and obesity in the CF population. Higher body mass index (BMI) is associated with improved pulmonary function in CF, yet the incremental improvement at overweight and obese BMIs is not clear. Improvements in pulmonary health with increasing BMI are largely driven by increases in fat-free mass (FFM), and impact of HEMT on FFM is uncertain. While trends toward higher weight and BMI are generally seen as favorable in CF, the increased prevalence of overweight and obesity has raised concern for potential risk of traditional age- and obesity-related comorbidities. Such comorbidities, including impaired glucose tolerance, hypertension, cardiac disease, hyperlipidemia, fatty liver, colon cancer, and obstructive sleep apnea, may occur on top of pre-existing CF-related comorbidities. CF nutrition recommendations are evolving in the post-modulator era to more individualized approaches, in contrast to prior blanket high-fat, high-calorie prescriptions for all. Ultimately, it will be essential to redefine goals for optimal weight and nutritional status to allow for holistic health and aging in people with CF.

PMID:39105341 | DOI:10.1002/ppul.26806

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S107-S114. doi: 10.1002/ppul.26892.

ABSTRACT

Cystic fibrosis-related hepatobiliary involvement (CFHBI) is a term used to describe a spectrum of hepatobiliary involvement ranging from a transient elevation of transaminase levels to advanced cystic fibrosis-associated liver disease (aCFLD). While CFHBI is common among people with cystic fibrosis (PwCF), aCFLD is rare impacting only approximately 5%-10% of the CF population. After respiratory/cardiorespiratory issues and transplant-related complications, aCFLD is now the 4th leading cause of mortality among PwCF. Additionally, aCFLD is an independent predictor of all-cause mortality and is associated with significant morbidity. Despite this recognition, our ability to predict those patients at greatest risk for aCFLD, identify early aCFLD, and monitor the incremental progression of CFHBI is lacking. Here, we review the strengths and weaknesses of the common biomarkers and imaging modalities used in the evaluation and monitoring of CFHBI, as well as the current understanding of genetic modifiers related to aCFLD.

PMID:39105338 | DOI:10.1002/ppul.26892

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S91-S97. doi: 10.1002/ppul.27060.

ABSTRACT

Advances in treatment for cystic fibrosis (CF), including cystic fibrosis transmembrane conductor regulator (CFTR) modulators, have ushered in an era where patients with CF have much longer life expectancies. This shift in life expectancy demands increased attention to diseases of aging in patients with CF. A notable complication of CF is early-onset colorectal cancer (CRC), which is especially prevalent in patients with severe mutations and after transplant. CFTR acts as a tumor suppressor gene based on knockout models. Lack of CFTR expression promotes carcinogenic processes such as intestinal inflammation and deleterious gut microbiome changes. The consensus Cystic Fibrosis Foundation recommendations advocate treating this population as a high-risk group, using a colonoscopy-only screening strategy starting at age 40 in patients without transplant and at age 30 after transplant. Screening should be considered every 5 years if negative and every 3 years or sooner for patients with adenomatous polyps. Future research will determine the role of noninvasive CRC screening tools in this population, as well as the effects of CFTR modulators on the risk of developing CRC.

PMID:39105336 | DOI:10.1002/ppul.27060

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S17-S26. doi: 10.1002/ppul.26871.

ABSTRACT

Cystic fibrosis (CF) results in chronic pulmonary infections, inflammation, pancreatic insufficiency, and multiple gastrointestinal manifestations. Malnutrition and poor growth are hallmarks of CF, and strongly associated with poor outcomes. Through newborn screening, many infants can be diagnosed within a few days of life, which allows for early initiation of nutritional counseling and close clinical follow-up. Obstacles to growth for infants with CF start in utero, as newborns with CF can have a lower birth weight than the general population. Improving infant growth has been linked to improved clinical outcomes and survival. It remains a top priority and challenge for caregivers and healthcare teams. An interdisciplinary approach, including registered dietitian and social work support, is essential to optimize health for infants with CF. Remaining barriers to normalcy include deficits in linear growth, lack of accurate nutrition biomarkers, persistence of inequities related to social determinant of health, particularly in the global CF community.

PMID:39105334 | DOI:10.1002/ppul.26871

Pediatr Pulmonol. 2024 Sep;59 Suppl 1:S61-S69. doi: 10.1002/ppul.27123.

ABSTRACT

The aerodigestive organs share a kindred embryologic origin that allows for a more complete explanation as to how the foregut can remain a barrier to normalcy in people with cystic fibrosis (pwCF). The structures of the aerodigestive tract include the nasopharynx, the oropharynx, the hypopharynx, the esophagus, the stomach, as well as the supraglottic, glottic, and subglottic tubular airways (including the trachea). Additional gastrointestinal (GI) luminal/alimentary organs of the foregut include the duodenum. Extraluminal foregut structures include the liver, the gall bladder, the biliary tree, and the pancreas. There are a variety of neurologic controls within these complicated anatomic compartments to separate the transit of food and liquid from air. These structures share the same origin from the primitive foregut/mesenchyme. The vagus nerve is a critical structure that unites respiratory and digestive functions. This article comments on the interconnected nature of cystic fibrosis and the GI tract. As it relates to the foregut, this has been typically treated as simple "reflux" as the cause of worsened lung function in pwCF. That terms like gastroesophageal reflux (GER), gastroesophageal reflux disease (GERD), heartburn, and regurgitation are used interchangeably to reflect pathology further complicates matters; we offer a more physiologically accurate term called "GI-related aspiration" or "GRASP." Broadly, this term reflects that aspiration of foregut contents from the duodenum through the stomach to the esophagus, into the pharynx and the respiratory tree in pwCF. As a barrier to normalcy in pwCF, GRASP is fundamentally two disease processes-GERD and gastroparesis-that likely contribute most to the deterioration of lung disease in pwCF. In the modulator era, successful GRASP management will be critical, particularly in those post-lung transplantation (LTx), only through successful management of both GERD and gastroparesis. Standardization of clinical management algorithms for GRASP in CF-related GRASP is a key clinical and research gap preventing normalcy in pwCF; what exists nearly exclusively addresses surgical evaluations or offers guidance for the management of GI symptoms alone (with unclear parameters for respiratory disease considerations). We begin first by describing the result of GRASP damage to the lung in various stages of lung disease. This is followed by a discussion of the mechanisms by which the digestive tract can injure the lungs. We summarize what we anticipate future research directions will be to reduce the impact of GRASP as a barrier to normalcy in pwCF.

PMID:39105333 | DOI:10.1002/ppul.27123

Front Physiol. 2024 Jul 22;15:1401774. doi: 10.3389/fphys.2024.1401774. eCollection 2024.

ABSTRACT

INTRODUCTION: Sex-specific patterns in respiratory conditions, such as asthma, COPD, cystic fibrosis, obstructive sleep apnea, and idiopathic pulmonary fibrosis, have been previously documented. Animal models of acute lung injury (ALI) have offered insights into sex differences, with male mice exhibiting distinct lung edema and vascular leakage compared to female mice. Our lab has provided evidence that the chemoreflex is sensitized in male rats during the recovery from bleomycin-induced ALI, but whether sex-based chemoreflex changes occur post-ALI is not known. To bridge this gap, the current study employed the bleomycin-induced ALI animal model to investigate sex-based differences in chemoreflex activation during the recovery from ALI.

METHODS: ALI was induced using a single intra-tracheal instillation of bleomycin (bleo, 2.5 mg/Kg) (day 1). Resting respiratory frequency (fR) was measured at 1-2 days pre-bleo, day 7 (D7) post-bleo, and 1 month (1 mth) post-bleo. The chemoreflex responses to hypoxia (10% O2, 0% CO2) and normoxic-hypercapnia (21% O2, 5% CO2) were measured before bleo administration (pre-bleo) and 1 mth post-bleo using whole-body plethysmography. The apnea-hypopnea Index (AHI), post-sigh apneas, and sighs were measured at each time point.

RESULTS: There were no significant differences in resting fR between male and female rats at the pre-bleo time point or in the increase in resting fR at D7 post-bleo. At 1 mth post-bleo, the resting fR was partially restored in both sexes but the recovery towards normal ranges of resting fR was significantly lower in male rats. The AHI, post-sigh apneas, and sighs were not different between male and female rats pre-bleo and 1 mth post-bleo. However, at D7 post-bleo, the male rats exhibited a higher AHI than female rats. Both male and female rats exhibited a sensitized chemoreflex in response to hypoxia and normoxic-hypercapnia with no significant differences between sexes.

CONCLUSION: A sex difference in resting ventilatory parameters occurs post ALI with a prolonged increase in resting fR and larger AHI in male rats. On the other hand, we did not find any sex differences in the chemoreflex sensitization that occurs at 1 mth post-bleo. This work contributes to a better understanding of sex-based variations in lung disorders.

PMID:39105084 | PMC:PMC11298475 | DOI:10.3389/fphys.2024.1401774

ERJ Open Res. 2024 Aug 5;10(4):00989-2023. doi: 10.1183/23120541.00989-2023. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare multisystem genetic disease caused by dysfunctional motile cilia. Despite PCD being the second most common inherited airway disease after cystic fibrosis, PCD continues to be under-recognised globally owing to nonspecific clinical features and the lack of a gold standard diagnostic test. Commonly repeated prevalence estimates range from one in 10 000 to one in 20 000, based on regional epidemiological studies with known limitations. The purpose of this scoping review was to appraise the PCD literature, to determine the best available global PCD prevalence estimate and to inform the reader about the potential unmet health service needs in PCD. The primary objective of the present study was to systematically review the literature about PCD prevalence estimates.

METHODS: A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) methodology. Included studies estimated PCD prevalence and used cohort, clinical or genomic data. Case reports, conference abstracts, review articles, animal studies or non-English articles were excluded.

RESULTS: A literature review identified 3484 unique abstracts; 34 underwent full-text review and eight met the inclusion/exclusion criteria. Seven articles were based on epidemiological studies of specific geographical regions and provided prevalence estimates that ranged from approximately one to 44.1 in 100 000. Only one study estimated global prevalence, using two large genomic databases, and calculated it to be ∼13.2 in 100 000 (based on pathogenic variants in 29 disease-causing genes).

CONCLUSIONS: A population-based genomic approach for estimating global prevalence has found that PCD is much more prevalent than previously cited in the literature. This highlights the potential unmet health service needs of people living with PCD.

PMID:39104959 | PMC:PMC11299005 | DOI:10.1183/23120541.00989-2023

Am J Physiol Gastrointest Liver Physiol. 2024 Aug 6. doi: 10.1152/ajpgi.00211.2022. Online ahead of print.

ABSTRACT

Increased intestinal permeability is a manifestation of cystic fibrosis (CF) in people with CF (pwCF) and in CF mouse models. CF transmembrane conductance regulator knockout (Cftr KO) mouse intestine exhibits increased proliferation and Wnt/β-catenin signaling relative to wild-type mice (WT). Since the Rho GTPase Cdc42 plays a central role in intestinal epithelial proliferation and tight junction remodeling, we hypothesized that Cdc42 may be altered in the Cftr KO crypts. Immunofluorescence showed distinct tight junction localization of Cdc42 in Cftr KO fresh crypts and enteroids, the latter indicating an epithelial-autonomous feature. Quantitative PCR and immunoblots revealed similar expression of Cdc42 in the Cftr KO crypts/enteroids relative to WT, whereas pull-down assays showed increased GTP-bound (active) Cdc42 in proportion to total Cdc42 in Cftr KO enteroids. Cdc42 activity in the Cftr KO and WT enteroids could be reduced by inhibition of the Wnt transducer Disheveled 2. Using a dye permeability assay, Cftr KO enteroids exhibited increased paracellular permeability to 3kD dextran relative to WT. In Cftr KO relative to WT enteroids, leak permeability and Cdc42 tight junction localization were reduced to a greater extent by inhibition of Wnt/β-catenin signaling with Endo-IWR1. Increased proliferation or inhibition of Cdc42 activity with ML141 had no effect on WT enteroid permeability. In contrast, inhibition of Cdc42 with ML141 increased permeability to both 3kD dextran and tight-junction impermeant 500 kD dextran in Cftr KO enteroids. These data suggest that increased constitutive Cdc42 activity may alter the stability of paracellular permeability in Cftr KO crypt epithelium.

PMID:39104325 | DOI:10.1152/ajpgi.00211.2022

Am J Physiol Lung Cell Mol Physiol. 2024 Aug 6. doi: 10.1152/ajplung.00010.2024. Online ahead of print.

ABSTRACT

Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [68Ga] tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.

PMID:39104314 | DOI:10.1152/ajplung.00010.2024

Vestn Otorinolaringol. 2024;89(3):29-35. doi: 10.17116/otorino20248903129.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a severe hereditary disease with a multisystem lesion. Manifestations of CF include severe infectious purulent lesions of all parts of the respiratory tract, including purulent rhinosinusitis with nasal polyps. The involvement of the sinonasal region and the need for systemic use of ototoxic drugs (primarily aminoglycosides to treat resistant bacterial infection) potentially create a risk of both conductive and sensorineural hearing loss (SNHL). The available data on the epidemiology of hearing disorders in CF is contradictory. Currently, genetic determinants of the development of aminoglycoside SNHL have been identified.

MATERIAL AND METHODS: For 136 CF patients (75 girls, 61 boys) aged 3 to 17 (9.4±3.9) years were performed audiological examination: tympanometry, transient-evoked otoacoustic emission and the pure tone threshold audiometry (standard frequency range) (n=126). History of systemic therapy with aminoglycosides was evaluated for each patient. Sequencing of c.35delG mutations in the GJB2 gene (nuclear DNA) and A1555G in the 12S rRNA gene (mitochondrial DNA) was performed in 215 patients with cystic fibrosis (the group partially overlaps with the audiological group), and as a control - 106 children with bronchial asthma and 103 healthy children, their age ranged from 3 to 17 (8.8±3.8) years.

RESULTS: Audiological examination of CF children reveled a prevalence of conductive hearing loss comparable to the general population (2.4%). The frequency of SNHL was 1.6%, wich exceeds that of non-CF children. A genetic study revealed one case of heterozygous carriage of the c.35delG mutation in the GJB2 gene in a patient with bronchial asthma. In the group of patients with CF (n=215), mutations in the connexin 26 gene were not detected. No A1555G mutation was detected either in the group of patients with CF or in the control groups.

CONCLUSIONS: Children with CF are at risk for the development of sensorineural, but not conductive hearing loss. Routine total screening for A1555G and c.35delG mutations probably seems not to be recommended.

PMID:39104270 | DOI:10.17116/otorino20248903129

Transplantation. 2024 Aug 6. doi: 10.1097/TP.0000000000005162. Online ahead of print.

ABSTRACT

The term "chronic lung allograft dysfunction" has emerged to describe the clinical syndrome of progressive, largely irreversible dysfunction of pulmonary allografts. This umbrella term comprises 2 major clinical phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome. Here, we discuss the clinical manifestations, diagnostic challenges, and potential therapeutic avenues to address this major barrier to improved long-term outcomes. In addition, we review the immunologic mechanisms thought to propagate each phenotype of chronic lung allograft dysfunction, discuss the various models used to study this process, describe potential therapeutic targets, and identify key unknowns that must be evaluated by future research strategies.

PMID:39104003 | DOI:10.1097/TP.0000000000005162

Proc Natl Acad Sci U S A. 2024 Aug 13;121(33):e2406234121. doi: 10.1073/pnas.2406234121. Epub 2024 Aug 5.

ABSTRACT

Laboratory models are central to microbiology research, advancing the understanding of bacterial physiology by mimicking natural environments, from soil to the human microbiome. When studying host-bacteria interactions, animal models enable investigators to examine bacterial dynamics associated with a host, and in the case of human infections, animal models are necessary to translate basic research into clinical treatments. Efforts toward improving animal infection models are typically based on reproducing host genotypes/phenotypes and disease manifestations, leaving a gap in how well the physiology of microbes reflects their behavior in a human host. Understanding bacterial physiology is vital because it dictates host response and bacterial interactions with antimicrobials. Thus, our goal was to develop an animal model that accurately recapitulates bacterial physiology in human infection. The system we chose to model was a chronic Pseudomonas aeruginosa respiratory infection in cystic fibrosis (CF). To accomplish this goal, we leveraged a framework that we recently developed to evaluate model accuracy by calculating the percentage of bacterial genes that are expressed similarly in a model to how they are expressed in their infection environment. We combined two complementary models of P. aeruginosa infection-an in vitro synthetic CF sputum model (SCFM2) and a mouse acute pneumonia model. This combined model captured the chronic physiology of P. aeruginosa in CF better than the standard mouse infection model, showing the power of a data-driven approach to refining animal models. In addition, the results of this work challenge the assumption that a chronic infection model requires long-term colonization.

PMID:39102545 | DOI:10.1073/pnas.2406234121

Acta Clin Belg. 2024 Aug 5:1-7. doi: 10.1080/17843286.2024.2386216. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to evaluate an expanded matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MALDI-TOF MS) database for the identification of Haemophilus species other than H. influenzae (Hi).

METHODS: A total of 144 Haemophilus species, cultured from respiratory samples from people (living) with cystic fibrosis, were identified with MALDI-TOF MS and 16S rRNA sequencing. Of these, 99 Haemophilus strains showed >99% similarity with the best matching strain in the National Center for Biotechnology Information (NCBI) database and were assigned to a single Haemophilus subspecies using both MALDI-TOF MS and 16S rRNA sequencing. The MS profiles of a subset of strains (n = 58/99) were added to the Bruker MALDI-TOF MS database. Subsequently, 270 different strains that were analyzed previously in a routine setting were re-analyzed.

RESULTS: 16S rRNA sequencing reliably identified 99/144 Haemophilus strains (>99% similarity). H. haemolyticus 16S rRNA identification was suboptimal since only 3/21 H. haemolyticus strains attained a similarity of >99% with H. haemolyticus 16S rRNA sequence in the NCBI database. Expansion of the MALDI-TOF MS database improved the number of reliable identifications only moderately for H. haemolyticus, H. influenzae and H. paraphrohaemolyticus (<10%). By contrast, improved identification was more outspoken for H. parahaemolyticus, H. parainfluenzae, H. sputorum and H. pittmaniae (>85%).

CONCLUSION: 16S rRNA sequencing is a valuable method for the identification of Haemophilus sp. other than Hi. Expansion of the MALDI-TOF MS database, based on 16S rRNA sequencing results, increased the proportion of reliable identifications and in this study resulted in an increase of 10% of Haemophilus sp. other than Hi strain identifications.

PMID:39101268 | DOI:10.1080/17843286.2024.2386216

ACS Omega. 2024 Jul 17;9(30):32873-32880. doi: 10.1021/acsomega.4c03626. eCollection 2024 Jul 30.

ABSTRACT

The most prevalent comorbidity among cystic fibrosis (CF) patients is cystic fibrosis-related diabetes (CFRD). CFRD has been linked to one of the worse clinical outcomes and a higher mortality. Improved clinical results have been related to earlier diagnosis and treatment of CFRD. Therefore, the present study aimed to investigate the metabolome of human serum of patients with CFRD. This might aid in identifying novel biomarkers linked with the pathophysiology of CFRD and its diagnosis. The liquid chromatography-high-resolution mass spectrometry (LC-HRMS) metabolomics approach was utilized for serum samples from patients with CF (n = 36) and healthy controls (n = 36). Nine patients in the CF group had CFRD, and 27 were non-CFRD patients (nCFRD). A total of 2328 metabolites were significantly altered in CF compared with the healthy control. Among those, 799 significantly dysregulated metabolites were identified between CFRD and nCFRD. Arachidonic acid (AA), ascorbate, and aldarate metabolism were the most common metabolic pathways dysregulated in CF. l-Homocysteic acid (l-HCA) levels were significantly reduced in CF and CFRD compared to the control and nCFRD, respectively. In addition, gamma-glutamylglycine and l-5-hydroxytryptophan (5-HTP) had the highest discrimination between CFRD and nCFRD with AUC (0.716 and 0.683, respectively). These biomarkers might serve as diagnostic biomarkers and aid in understanding potential metabolic changes linked to CF and CFRD.

PMID:39100315 | PMC:PMC11292812 | DOI:10.1021/acsomega.4c03626

Pediatr Allergy Immunol. 2024 Aug;35(8):e14210. doi: 10.1111/pai.14210.

NO ABSTRACT

PMID:39099145 | DOI:10.1111/pai.14210

J Cyst Fibros. 2024 Aug 3:S1569-1993(24)00803-8. doi: 10.1016/j.jcf.2024.07.018. Online ahead of print.

ABSTRACT

BACKGROUND: CF-related diabetes (CFRD) is a common, life-expectancy limiting complication of CF. While Black race and Hispanic ethnicity in youth-onset type 1 and type 2 diabetes are well-recognized risk factors for worse diabetes complications, the potential for racial/ethnic disparities in CFRD has received limited attention.

METHODS: We conducted a retrospective cohort study utilizing the CF Foundation Patient Registry from 2010 to 2019 to determine the prevalence and incidence of CFRD by race/ethnicity. Three age cohorts were identified at baseline in 2010 (11-20y, 21-30y, and 31-40y). Logistic regression and Cox regression stratified by age group were used to determine the prevalence and incidence, respectively, among Hispanic, non-Hispanic Blacks (NHB), and non-Hispanic whites (NHW) after adjustment for relevant confounders, including demographics, socioeconomic status, clinical factors, and chronic medication use.

RESULTS: Among 14,660 registry participants, 510 were NHB and 890 Hispanic. NHB associated with higher odds of CFRD baseline prevalence in all age cohorts (11-20y: OR 2.53 (95 % CI: 1.88-3.41, P < 0.05), 21-30y: OR 1.80 (1.25-2.59, P < 0.05), and 31-40y: OR 1.93 (1.00-3.73, P < 0.05)) relative to NHW. In the 11-20y cohort, the hazard of new-onset CFRD was 40 % higher in NHB (HR 1.40 (1.09-1.8, P < 0.05)) and 19 % higher in Hispanics (HR 1.19 (1.01-1.41, P < 0.05)).

CONCLUSION: NHB had a higher prevalence of CFRD across all age groups, with NHB and Hispanics showing higher incidence of CFRD in the youngest group. Multicenter studies performed in diverse CF populations are warranted to identify modifiable factors influencing earlier CFRD development in minoritized groups and their potential contribution to diabetes complication disparities.

PMID:39098507 | DOI:10.1016/j.jcf.2024.07.018

J Cyst Fibros. 2024 Aug 3:S1569-1993(24)00802-6. doi: 10.1016/j.jcf.2024.07.017. Online ahead of print.

ABSTRACT

Nonsense mutations account for 12 % of cystic fibrosis (CF) cases. The presence of a premature termination codon (PTC) leads to gene inactivation, which can be countered by the use of drugs stimulating PTC readthrough, restoring production of the full-length protein. We recently identified a new readthrough inducer, TLN468, more efficient than gentamicin. We measured the readthrough induced by these two drugs with different cystic fibrosis transmembrane conductance regulator (CFTR) PTCs. We then determined the amino acids inserted at the S1196X, G542X, W846X and E1417X PTCs of CFTR during readthrough induced by gentamicin or TLN468. TLN468 significantly promoted the incorporation of one specific amino acid, whereas gentamicin did not greatly modify the proportions of the various amino acids incorporated relative to basal conditions. The function of the engineered missense CFTR channels corresponding to these four PTCs was assessed with and without potentiator. For the recoded CFTR, except for E1417Q and G542W, the PTC readthrough induced by TLN468 allowed the expression of CFTR variants that were correctly processed and had significant activity that was enhanced by CFTR modulators. These results suggest that it would be relevant to assess the therapeutic benefit of TLN468 PTC suppression in combination with CFTR modulators in preclinical assays.

PMID:39098506 | DOI:10.1016/j.jcf.2024.07.017

Thorax. 2024 Aug 3:thorax-2024-221939. doi: 10.1136/thorax-2024-221939. Online ahead of print.

NO ABSTRACT

PMID:39097411 | DOI:10.1136/thorax-2024-221939