J Cyst Fibros. 2024 Mar 8:S1569-1993(24)00033-X. doi: 10.1016/j.jcf.2024.03.005. Online ahead of print.

ABSTRACT

BACKGROUND: People living with cystic fibrosis (CF) experience a high symptom burden. Due to the changing landscape of CF in the era of modulator therapy, we sought to examine the epidemiology of symptoms and their association with quality of life, to help CF clinicians improve symptom screening in clinic.

METHODS: Using baseline data from a trial of specialist palliative care in adults with CF, we examined symptom prevalence, distress, and association with quality of life (measured with the Functional Assessment of Chronic Illness Therapy Total Score).

RESULTS: Among 262 participants, median age was 33, and 78% were on modulator therapy. The most common symptoms were lack of energy (n = 194, 74%) and cough (190, 73%), whereas the most distressing were difficulty sleeping (range 0-4, mean 2.19, SD 1.15) and pain (mean 2.04, SD 1.1). The symptoms that impaired quality of life the most were extrapulmonary: lack of energy (average quality of life score -29.8, 95% CI -36.8 to -22.8), feeling sad (-29.8, 95% CI -35.6 to -23.9) and worrying (-28.7, 95% CI -34.9 to -22.5).

CONCLUSIONS: The symptoms that were associated with the lowest quality of life were extrapulmonary. CF clinicians may consider screening for common symptoms that affect quality of life the most (lack of energy, worrying, difficulty sleeping, feeling irritable, pain, and shortness of breath). These symptoms may identify people living with CF who are most at risk for a decreased quality of life and may benefit from additional support.

PMID:38461123 | DOI:10.1016/j.jcf.2024.03.005

Prog Mol Biol Transl Sci. 2024;204:295-309. doi: 10.1016/bs.pmbts.2023.12.004. Epub 2024 Jan 24.

ABSTRACT

Diarrhea is caused by a variety of bacterial and viral agents, inflammatory conditions, medications, and hereditary conditions. Secretory diarrhea involves several ion and solute transporters, activation of the cyclic nucleotide and Ca2+ signaling pathways, as well as intestinal epithelial secretion. In many cases of secretory diarrhea, activation of Cl- channels, such as the cystic transmembrane conduction regulator and the Ca2+stimulated Cl- channel fibrosis, promote secretion while concurrently inhibiting Na+ transport expressing fluid absorption. Current diarrhea therapies include rehydration and electrolyte replacement via oral rehydration solutions, as well as medications that target peristalsis or fluid secretion. The rising understanding of RNA function and its importance in illness has encouraged the use of various RNAs to operate selectively on "untreatable" proteins, transcripts, and genes. Some RNA-based medications have received clinical approval, while others are currently in research or preclinical studies. Despite major obstacles in the development of RNA-based therapies, many approaches have been investigated to improve intracellular RNA trafficking and metabolic stability.

PMID:38458741 | DOI:10.1016/bs.pmbts.2023.12.004

Diabetes Res Clin Pract. 2024 Mar 6:111589. doi: 10.1016/j.diabres.2024.111589. Online ahead of print.

ABSTRACT

Many individuals with intermediate hyperglycaemia (IH), including impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT), as presently defined, will progress to type 2 diabetes (T2D). There is confirmatory evidence that T2D can be prevented by lifestyle modification and/or medications, in people with IGT diagnosed by 2-h plasma glucose (PG) during a 75-gram oral glucose tolerance test (OGTT). Over the last 40 years, a wealth of epidemiological data has confirmed the superior value of 1-h plasma glucose (PG) over fasting PG (FPG), glycated haemoglobin (HbA1c) and 2-h PG in populations of different ethnicity, sex and age in predicting diabetes and associated complications including death. Given the relentlessly rising prevalence of diabetes, a more sensitive, practical method is needed to detect people with IH and T2D for early prevention or treatment in the often lengthy trajectory to T2D and its complications. The International Diabetes Federation (IDF) Position Statement reviews findings that the 1-h post-load PG ≥ 155 mg/dL (8.6 mmol/L) in people with normal glucose tolerance (NGT) during an OGTT is highly predictive for detecting progression to T2D, micro- and macrovascular complications, obstructive sleep apnoea, cystic fibrosis-related diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and mortality in individuals with risk factors. The 1-h PG of 209 mg/dL (11.6 mmol/L) is also diagnostic of T2D. Importantly, the 1-h PG cut points for diagnosing IH and T2D can be detected earlier than the recommended 2-h PG thresholds. Taken together, the 1-h PG provides an opportunity to avoid misclassification of glycaemic status if FPG or HbA1c alone are used. The 1-h PG also allows early detection of high-risk people for intervention to prevent progression to T2D which will benefit the sizeable and growing population of individuals at increased risk of T2D. Using a 1-h OGTT, subsequent to screening with a non-laboratory diabetes risk tool, and intervening early will favourably impact the global diabetes epidemic. Health services should consider developing a policy for screening for IH based on local human and technical resources. People with a 1-h PG ≥ 155 mg/dL (8.6 mmol/L) are considered to have IH and should be prescribed lifestyle intervention and referred to a diabetes prevention program. People with a 1-h PG ≥ 209 mg/dL (11.6 mmol/L) are considered to have T2D and should have a repeat test to confirm the diagnosis of T2D and then referred for further evaluation and treatment. The substantive data presented in the Position Statement provides strong evidence for redefining current diagnostic criteria for IH and T2D by adding the 1-h PG.

PMID:38458916 | DOI:10.1016/j.diabres.2024.111589

J Cyst Fibros. 2024 Mar 7:S1569-1993(24)00025-0. doi: 10.1016/j.jcf.2024.02.010. Online ahead of print.

ABSTRACT

BACKGROUND: Despite translational evidences suggesting that cystic fibrosis-related abnormal glucose tolerance (CF-related AGT) may begin early in life and is known to be associated with increased morbidity and mortality, current guidelines recommend screening for AGT only from 10 years of age, thus missing the opportunity for early detection and intervention.

METHODS: A systematic review and meta-analysis (PROSPERO number: CRD42021282516) was conducted on studies that reported data on the prevalence of AGT or its subtypes in CF populations. Pooled proportions, risk, and odds ratios with 95 % confidence intervals (CI) were calculated. One-stage dose-response random-effect meta-analysis was used to assess the effect of age on CF-related diabetes (CFRD).

RESULTS: The quantitative analysis included 457 studies and data from 520,544 patients. Every third child with CF (chwCF) (0.31 [95 % CI 0.25-0.37]) and every second adult with CF (awCF) (0.51 [95 % CI 0.45-0.57]) were affected by AGT. Even in the 5-10 years of age subgroup, the proportion of AGT was 0.42 [95 % CI 0.34-0.51]. The prevalence of prediabetes remained unchanged (impaired glucose tolerance in chwCF:0.14 [95 % CI 0.10-0.18]) vs. awCF:0.19 [95 % CI 0.14-0.25]), whereas the proportion of CFRD increased with age (0-5: 0.005 [95 % CI 0.0001-0.15]; 5-10: 0.05 [95 % CI 0.01-0.27]; 10-18: 0.11 [95 % CI 0.08-0.14]; >18 years of age: 0.27 [95 % CI 0.24-0.30]).

CONCLUSION: CF-related AGT is common under 10 years of age. Our study suggests considering earlier AGT screening, starting from 5 years of age. This highlights the imperative for additional research for guideline adjustments and provides the opportunity for early intervention.

PMID:38458829 | DOI:10.1016/j.jcf.2024.02.010

BMJ Open. 2024 Mar 8;14(3):e075733. doi: 10.1136/bmjopen-2023-075733.

ABSTRACT

AIMS: The aim was to evaluate whether standardised exercise performance during the incremental shuttle walk test (ISWT) can be used to assess disease severity in children and young people (CYP) with chronic conditions, through (1) identifying the most appropriate paediatric normative reference equation for the ISWT, (2) assessing how well CYP with haemophilia and cystic fibrosis (CF) perform against the values predicted by the best fit reference equation and (3) evaluating the association between standardised ISWT performance and disease severity.

METHODS: A cross-sectional analysis was carried out using existing data from two independent studies (2018-2019) at paediatric hospitals in London,UK. CYP with haemophilia (n=35) and CF (n=134) aged 5-18 years were included. Published reference equations for standardising ISWT were evaluated through a comparison of populations, and Bland-Altman analysis was used to assess the level of agreement between distances predicted by each equation. Associations between ISWT and disease severity were assessed with linear regression.

RESULTS: Three relevant reference equations were identified for the ISWT that standardised performance based on age, sex and body mass index (Vardhan, Lanza, Pinho). A systematic proportional bias of standardised ISWT was observed in all equations, most pronounced with Vardhan and Lanza; the male Pinho equation was identified as most appropriate. On average, CYP with CF and haemophilia performed worse than predicted by the Pihno equation, although the range was wide. Standardised ISWT, and not ISWT distance alone, was significantly associated with forced expiratory volume in 1 s in CYP with CF. Standardised ISWT in CYP with haemophilia was slightly associated with haemophilia joint health score, but this was not significant.

CONCLUSIONS: ISWT performance may be useful in a clinic to identify those with worsening disease, but only when performance is standardised against a healthy reference population. The development of validated global reference equations is necessary for more robust assessment.

PMID:38458782 | DOI:10.1136/bmjopen-2023-075733

Expert Rev Pharmacoecon Outcomes Res. 2024 Mar 8. doi: 10.1080/14737167.2024.2328085. Online ahead of print.

ABSTRACT

OBJECTIVES: We aimed to develop a robust algorithm for accurately calculating 'daily complete dose counts' for inhaled medicine using electronically captured nebulizer data within the CFHealthHub Learning Health System.

METHODS: A multi-center cross-sectional study involved participants and clinicians reviewing inhaled medicine usage records and triangulating them with objective nebulizer data to establish a consensus on a 'daily complete dose counts.' An algorithm, which only used objective nebulizer data, was developed using a derivation dataset and evaluated using internal validation dataset. Agreement and accuracy between the algorithm-derived and consensus-derived 'daily complete dose counts' was examined with the consensus-derived count as the reference standard.

RESULTS: The algorithm derived a '"daily complete dose count"' by screening out 'invalid' doses (those <60s in duration or run in cleaning mode), combining all doses starting within 120s of each other, and then screening out all doses with duration < 480s which were interrupted by power supply failure. The kappa co-efficient was 0.85 (0.71-0.91) in the derivation and 0.86 (0.77-0.94) in the validation dataset.

CONCLUSIONS: The algorithm demonstrated strong agreement with participant-clinician consensus, enhancing confidence in CFHealthHub data. Publishing such algorithmic methods can encourage trust in digital endpoints and serve as an exemplar for other projects.

PMID:38458615 | DOI:10.1080/14737167.2024.2328085

Pediatr Pulmonol. 2024 Mar 8. doi: 10.1002/ppul.26953. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) treatment has increasingly focused on highly effective modulators. Despite measurable benefits of modulators, there is little guidance for CF care team members on providing education and support to patients regarding initiation of these therapies. We aimed to explore patient, caregiver, and clinician perceptions of modulators and influences on decisions about starting cystic fibrosis transmembrane regulator (CFTR) modulators.

METHODS: We conducted semistructured interviews with CF clinicians, adults with CF, and caregivers of children with CF. We reviewed audio recordings and coded responses to identify central themes.

RESULTS: We interviewed 8 CF clinicians, 9 adults with CF, and 11 caregivers of children with CF. Themes centered on emotional responses to modulator availability, influences on decision-making, concerns about side effects, impact of modulators on planning for the future, the benefits of the multidisciplinary CF care team in supporting treatment decisions, and the unique needs of people with CF who are not eligible for modulators. Clinicians described changes in conversations about modulators since the approval of elexacaftor/tezacaftor/ivacaftor, specifically greater willingness to prescribe with less nuanced conversations with patients and/or caregivers regarding their use.

CONCLUSION: Based on perspectives and experiences of CF clinicians, adults with CF, and caregivers of children with CF, we suggest clinicians approach conversations about CFTR modulators thoughtfully and thoroughly, utilizing the multidisciplinary model of CF care in exploring patient and caregiver emotions while filling in knowledge gaps, asking about treatment goals beyond potential clinical benefit, and having compassionate conversations with those who are ineligible for modulators.

PMID:38456611 | DOI:10.1002/ppul.26953

Arch Dis Child Educ Pract Ed. 2024 Mar 7:edpract-2023-326767. doi: 10.1136/archdischild-2023-326767. Online ahead of print.

ABSTRACT

Since screening for cystic fibrosis (CF) was incorporated into the newborn screening program, the number of recognised variants in the CF transmembrane conductance regulator (CFTR) gene has significantly increased. This has led to the discovery of combinations of gene variants with an uncertain prognosis. One outcome is the designation of 'cystic fibrosis screen positive inconclusive diagnosis' (CFSPID). While the majority of these children are expected to be unaffected by their CFTR variants, a small proportion have been seen to develop symptoms or increasing sweat chloride levels over time, which may reflect dysfunction of the CFTR protein.As the number of children with CFSPID increases, paediatricians and those working in primary care are more likely to encounter them in their practice. It is important that professionals have an understanding of CFSPID: what it is and, importantly, what it is not (ie, they do not have CF). In this article, we hope to explore this using some example cases, illustrating the ways in which these children may present symptomatically and how to manage them.

PMID:38453427 | DOI:10.1136/archdischild-2023-326767

Eur Respir J. 2024 Mar 7;63(3):2400328. doi: 10.1183/13993003.00328-2024. Print 2024 Mar.

NO ABSTRACT

PMID:38453247 | DOI:10.1183/13993003.00328-2024

Int J Pediatr Otorhinolaryngol. 2024 Feb 28;179:111898. doi: 10.1016/j.ijporl.2024.111898. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Olfactory dysfunction (OD) commonly occurs in patients with sinonasal dysfunction, but the prevalence and severity of olfactory issues in adolescents with cystic fibrosis (AwCF) is unclear. OD may contribute to dietary deficiencies and exacerbate nutritional challenges. We sought to review literature on the effectiveness of medical and surgical management of sinonasal symptoms in AwCF and the associated impact on olfactory function.

METHODS: We performed a systematic literature search of PubMed, Embase, Web of Science, and Ebsco CINAHL from 1980 to 2022 per PRISMA-ScR protocols to conduct a scoping review in an effort to compile data on study design, patient demographics, clinical characteristics and outcomes, along with risk of bias.

RESULTS: Of 368 abstracts, 3 articles exclusively evaluated AwCF for a total of 34 patients. Two studies evaluated endoscopic sinus surgery (ESS) and dornase alfa. An additional 6 articles were included for mixed pediatric and adult CF populations totaling 313 patients. Interventions included ESS, elexacaftor-tezacaftor-ivacaftor (ETI), ivacaftor, saline, dornase alfa, hyaluronic acid, and hyaluronic acid-tobramycin combination. Outcome measures included subjective assessment of OD using non-validated (4/9) and validated (4/9) surveys, and psychophysical (1/9) smell testing. Studies evaluating ESS, FESS, dornase alfa, ivacaftor, and both hypertonic and isotonic saline reported statistically significant improvement in OD, whereas ETI failed to improve OD despite improvement in other quality of life measures.

CONCLUSIONS: There is limited data regarding the impact of medical and surgical interventions on olfaction for AwCF. Assessment of olfaction was often limited to subjective and qualitative self-report. We suggest that tracking of olfactory outcomes with psychophysical testing is critical in this population with dietary challenges and weight management issues.

PMID:38452513 | DOI:10.1016/j.ijporl.2024.111898

Turk J Gastroenterol. 2024 Feb;35(2):150-157. doi: 10.5152/tjg.2024.22319.

ABSTRACT

BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma is an extremely deadly type of cancer with a high metastatic potential. Genetic factors in cellular events play an important role in the emergence of this situation. One of these factors is Aurora kinase family members, which play a role in migration, invasion, and cell cycle. In this study, the expression of vascular endothelial growth factor gene, which plays a role in migration, metastasis, and angiogenesis, on cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells of danusertib, a pan-Aurora kinase inhibitor, was examined.

MATERIALS AND METHODS: The half maximal inhibitory concentration (IC50) value (400 nM) of danusertib in cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells was determined by the wound-healing test depending on the dose and time and migration with CIM-Plate 16 in the xCELLingence system. In addition, the effect of danusertib on migration was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method and vascular endothelial growth factor gene expression.

RESULTS: When the dose- and time-dependent danusertib-applied cystic fibrosis human pancreatic ductal adenocarcinoma 1 cells were compared with the control group, it was observed that the wound formed did not close. In the xCELLigence system CIM-Plate 16 migration analysis, it was observed that migration was inhibited in the group administered danusertib in parallel with the wound dehiscence experiment. The gene expressions of vascular endothelial growth factor decreased 0.5-fold at the 24th hour and 0.3-fold at the 48th hour in the Danusertib-administered groups.

CONCLUSION: Danusertib, a pan-Aurora kinase inhibitor, is predicted to be used as a potential agent in pancreatic cancers due to its antitumor and anti-metastatic effect.

PMID:38454247 | DOI:10.5152/tjg.2024.22319

Int J Rheum Dis. 2024 Mar;27(3):e15074. doi: 10.1111/1756-185X.15074.

NO ABSTRACT

PMID:38450928 | DOI:10.1111/1756-185X.15074

Am J Physiol Renal Physiol. 2024 Mar 7. doi: 10.1152/ajprenal.00373.2023. Online ahead of print.

ABSTRACT

Resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and non-barrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2mg/kg Aristolochic acid (AA) injections i.p. to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at two weeks, six weeks, and six months after treatment. We identified a substantial population of TRMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single cell RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. While kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a non-antigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.

PMID:38450434 | DOI:10.1152/ajprenal.00373.2023

J Clin Transl Endocrinol. 2024 Feb 28;35:100332. doi: 10.1016/j.jcte.2024.100332. eCollection 2024 Mar.

ABSTRACT

OBJECTIVE: Patients with Cystic Fibrosis related diabetes [CFRD] are treated with insulin and high calorie diets to maintain body mass. The combined CFTR modulator elexacaftor/tezacaftor/ivacaftor [ETI] decreases pulmonary exacerbations and improves nutritional status. We reviewed the effects of ETI on BMI, HbA1c and diabetes regimen in patients with CFRD over a period of three years.

METHODS: Data of previously CFTR-modulator-naïve patients with CFRD and pancreatic insufficiency on ETI therapy were retrieved from an electronic health record database. Patients were followed for a mean duration of 2.7 ± 0.8 years after ETI initiation. Data pertaining to weight, BMI, HbA1c and diabetes regimen were collected at 6 months, 12 months, 2 years and at 3 years post-ETI initiation. Patients were then dichotomized based on their baseline BMI into a low BMI group and an "at target" BMI group. The effects of ETI on changes in weight, BMI, A1c and diabetes regimen were compared in both groups over a period of three years.

RESULTS: Twenty-seven patients with CFRD (15 men/12 women), age 30.6 ± 11.5 (SD) years, BMI 22.4 ± 4.0 kg/m2, were included. Fifteen patients had low BMI (<22 kg/m2 for women, <23 kg/m2 for men) and 12 patients had at target BMI (≥22 kg/m2for women, ≥BMI 23 kg/m2 for men). Patients with low BMI had an increase in their BMI from 19.5 ± 1.7 to 21.4 ± 2.2 kg/m2 at one year (p = 0.002), and 21.8 ± 1.8 kg/m2 at three years (p = 0.004) after ETI initiation. Four patients (out of 15) in the low BMI group had achieved normal BMI by the end of study follow up. There was no change in weight in the at target BMI group. HbA1c and basal insulin requirements did not change in either group. Five patients started non-insulin therapies.

CONCLUSION: BMI increased after ETI therapy in CFRD patients with low BMI, but not in those with at target BMI. The use of non-insulin therapies is increasing in CFRD and should be evaluated in future studies.

PMID:38449771 | PMC:PMC10915598 | DOI:10.1016/j.jcte.2024.100332

Heliyon. 2024 Feb 29;10(5):e26978. doi: 10.1016/j.heliyon.2024.e26978. eCollection 2024 Mar 15.

ABSTRACT

BACKGROUND: The upper airways of cystic fibrosis (CF) persons are an evolutionary niche where genetically adapted bacterial strains are selected for lung infection. The microbiological studies conducted up to now on the upper airways are not easily comparable.

METHODS: Using classical culture methods, we simultaneously studied the microbiological status of upper and lower airways in persons not chronically infected with P. aeruginosa. Each person had a single upper airways sampling and a concomitant lower airways sampling. Lower airways sampling was performed by oropharyngeal swab or sputum collection. Using a quasi-experimental design of study, we evaluated the performance of 2 different upper airways' sampling methods, nasal lavage according to method described by Mainz or nasal lavage with a rhino-set. Pain was measured with appropriate scales.

RESULTS: A total of 194 persons were enrolled in this study. Pathogenic flora was found in 128 (6.6%) of 194 upper airways samples and in 164 (84.6%) lower airways samples. A statistically significant difference between the upper airways and the lower airways was found in the isolation of S. aureus and non-fermenter gram negatives. Nasal lavage according to Mainz resulted in the isolation of more non-fermenter gramnegatives than the rhino-set (p < 0.05). No differences were found in the pain caused bythe two methods.

CONCLUSIONS: In our study population, cultures of the upper airway and lower airway differ in CF persons. In people sampled with nasal lavage according to Mainz more non-fermenter gram negatives were detected than with rhino-set. The two sampling methods were comparable with regard to the caused pain, nasal lavage according to Mainz method being quicker to perform.

PMID:38449646 | PMC:PMC10915376 | DOI:10.1016/j.heliyon.2024.e26978

Nat Biotechnol. 2024 Mar 6. doi: 10.1038/s41587-024-02165-8. Online ahead of print.

ABSTRACT

Programmable RNA pseudouridylation has emerged as a new type of RNA base editor to suppress premature termination codons (PTCs) that can lead to truncated and nonfunctional proteins. However, current methods to correct disease-associated PTCs suffer from low efficiency and limited precision. Here we develop RESTART v3, which uses near-cognate tRNAs to improve the readthrough efficiency of pseudouridine-modified PTCs. We show an average of ~5-fold (range: 2.1- to 9.5-fold) higher editing efficiency than RESTART v2 in cultured cells and achieve functional PTC readthrough in disease cell models of cystic fibrosis and Hurler syndrome. Furthermore, RESTART v3 enables accurate incorporation of the original amino acid for nearly half of the PTC sites, considering the naturally occurring frequencies of sense-to-nonsense codons, without affecting normal termination codons. Although off-target sites were detected, we did not observe changes to the coding information or the expression level of transcripts, and the overall natural tRNA abundance remained constant.

PMID:38448662 | DOI:10.1038/s41587-024-02165-8

J Cyst Fibros. 2024 Mar 6:S1569-1993(24)00029-8. doi: 10.1016/j.jcf.2024.02.015. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis associated liver disease (CFLD) carries a significant disease burden with no effective preventive therapies. According to the gut-liver axis hypothesis for CFLD pathogenesis, dysbiosis and increased intestinal inflammation and permeability permit pathogenic bacterial translocation into the portal circulation, leading to hepatic inflammation and fibrosis. Evaluating the effect of CFTR (cystic fibrosis transmembrane conductance regulator) modulation with elexacaftor/tezacaftor/ivacaftor (ETI) may help determine the role of CFTR in CFLD and increase understanding of CFLD pathogenesis, which is critical for developing therapies. We aimed to characterize the fecal microbiota in participants with CF with and without advanced CFLD (aCFLD) before and after ETI.

METHODS: This is an ancillary analysis of stool samples from participants ages ≥12 y/o enrolled in PROMISE (NCT04038047). Included participants had aCFLD (cirrhosis with or without portal hypertension, or non-cirrhotic portal hypertension) or CF without liver disease (CFnoLD). Fecal microbiota were defined by shotgun metagenomic sequencing at baseline and 1 and 6 months post-ETI.

RESULTS: We analyzed 93 samples from 34 participants (11 aCFLD and 23 CFnoLD). Compared to CFnoLD, aCFLD had significantly higher baseline relative abundances of potential pathogens Streptococcus salivarius and Veillonella parvula. Four of 11 aCFLD participants had an initially abnormal fecal calprotectin that normalized 6 months post-ETI, correlating with a significant decrease in S. salivarius and a trend towards decreasing V. parvula.

CONCLUSIONS: These results support an association between dysbiosis and intestinal inflammation in CFLD with improvements in both post-ETI, lending further support to the gut-liver axis in aCFLD.

PMID:38448281 | DOI:10.1016/j.jcf.2024.02.015

Antimicrob Agents Chemother. 2024 Mar 6:e0007524. doi: 10.1128/aac.00075-24. Online ahead of print.

ABSTRACT

Hydrogen sulfide (H2S) has been proposed to protect bacteria from antibiotics, pointing to H2S-producing enzymes as possible targets for the development of antibiotic adjuvants. Here, MIC assays performed with Pseudomonas aeruginosa mutants producing altered H2S levels demonstrate that H2S does not affect antibiotic resistance in this bacterium. Moreover, correlation analyses in a large collection of P. aeruginosa cystic fibrosis isolates argue against the protective role of H2S from antibiotic activity during chronic lung infection.

PMID:38445869 | DOI:10.1128/aac.00075-24

Front Pharmacol. 2024 Feb 20;15:1331637. doi: 10.3389/fphar.2024.1331637. eCollection 2024.

ABSTRACT

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

PMID:38444938 | PMC:PMC10912587 | DOI:10.3389/fphar.2024.1331637

ERJ Open Res. 2024 Mar 4;10(2):00699-2023. doi: 10.1183/23120541.00699-2023. eCollection 2024 Mar.

ABSTRACT

BACKGROUND: In 2016, nationwide cystic fibrosis newborn screening (CFNS) was newly implemented in Germany, using an immunoreactive trypsin/pancreatitis-associated protein/DNA screening algorithm that differs from most other nationwide screening programmes.

METHODS: We analysed real-life feasibility of the confirmation process with respect to our pre-specified procedural objectives. These included overall accuracy through false-negative and false-positive results, effectiveness of the Bavarian tracking system, and accuracy of Macroduct and Nanoduct sweat conductivity compared with quantitative chloride determination. All consecutive CFNS-positive newborns assigned to our CF centre and born between 1 September 2016 and 31 August 2021 (n=162) were included.

RESULTS: The German CFNS was feasible at our CF centre as all procedural objectives were met. The positive predictive value (PPV) of positive CFNS was low (0.23) and two initially negatively screened children were later diagnosed with CF. The tracking system was highly efficient with a 100% tracking rate. The Macroduct and Nanoduct systems had comparable success rates (93.2% versus 95.9%). Importantly, conductivity via Macroduct was more accurate than via Nanoduct (zero and four false-positive newborns, respectively).

CONCLUSIONS: CF confirmation diagnostics of neonates in a certified regional CF centre was well managed in daily routine. The PPV of the German CFNS needs to be improved, e.g. by extending the DNA analysis within the screening algorithm and by increasing the number of variants tested. The Bavarian tracking system can serve as a successful model for other tracking systems. We preferred the Macroduct system because of its more accurate sweat conductivity readings.

PMID:38444668 | PMC:PMC10910348 | DOI:10.1183/23120541.00699-2023