Am J Respir Crit Care Med. 2024 May 17. doi: 10.1164/rccm.202401-0201LE. Online ahead of print.

NO ABSTRACT

PMID:38760016 | DOI:10.1164/rccm.202401-0201LE

Respir Med. 2024 May 16:107664. doi: 10.1016/j.rmed.2024.107664. Online ahead of print.

ABSTRACT

BACKGROUND: Impaired glycemic control and the subsequent development of Cystic fibrosis Related Diabetes (CFRD) are prevalent complications, affecting up to 50% of adults with cystic fibrosis (CF). CFTR modulator (CFTRm) therapies improve pulmonary functions, reduce exacerbation rates, increase survival in people with CF (pwCF) and appear to have a positive effect on extrapulmonary manifestations, such as nutritional state, improvements in upper respiratory symptoms, and quality of life. Initial findings indicate that CFTRm may have a positive impact on short-term glycemic control; however, long-term effects remain uncertain at present.

METHODS: In this retrospective study, data were collected and analyzed on 15 pwCF, ages 13-37 years, started on CFTRm therapy. Oral Glucose Tolerance Test (OGTT) results were compared pre- and post-CFTRm therapy.

RESULTS: The 120-minute OGTT value decreased from 159.7 to 130.4 post-CFTRm (p = 0.047). The average time elapsed between the two OGTT tests was 49.87 months (ranging 9-157 months, median 38 months). Glycemic status improved in six pwCF (two CFRD to normal (NGT)/indeterminate (INDET) glucose tolerance; two impaired glucose tolerance (IGT) to INDET; two INDET to NGT) and worsened in one (IGT to CFRD). Six pwCF and NGT remained stable with no changes in glycemic statues throughout the follow-up period.

CONCLUSIONS: CFTRm therapy may decelerate the glycemic control deterioration in pwCF over an extended period. These findings indicate the need for periodic OGTTs following the initiation of CFTRm therapy to appropriately adjust insulin requirements and prevent hypoglycemia. Further larger cohorts are required to authenticate and substantiate these findings.

PMID:38759874 | DOI:10.1016/j.rmed.2024.107664

Protein Eng Des Sel. 2024 Jan 29;37:gzae007. doi: 10.1093/protein/gzae007.

ABSTRACT

With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead inhibitors. We also provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.

PMID:38757573 | DOI:10.1093/protein/gzae007

EMBO J. 2024 May 16. doi: 10.1038/s44318-024-00113-5. Online ahead of print.

ABSTRACT

Glycine-12 mutations in the GTPase KRAS (KRASG12) are an initiating event for development of lung adenocarcinoma (LUAD). KRASG12 mutations promote cell-intrinsic rewiring of alveolar type-II progenitor (AT2) cells, but to what extent such changes interplay with lung homeostasis and cell fate pathways is unclear. Here, we generated single-cell RNA-seq (scRNA-seq) profiles from AT2-mesenchyme organoid co-cultures, mice, and stage-IA LUAD patients, identifying conserved regulators of AT2 transcriptional dynamics and defining the impact of KRASG12D mutation with temporal resolution. In AT2WT organoids, we found a transient injury/plasticity state preceding AT2 self-renewal and AT1 differentiation. Early-stage AT2KRAS cells exhibited perturbed gene expression dynamics, most notably retention of the injury/plasticity state. The injury state in AT2KRAS cells of patients, mice, and organoids was distinguishable from AT2WT states via altered receptor expression, including co-expression of ITGA3 and SRC. The combination of clinically relevant KRASG12D and SRC inhibitors impaired AT2KRAS organoid growth. Together, our data show that an injury/plasticity state essential for lung repair is co-opted during AT2 self-renewal and LUAD initiation, suggesting that early-stage LUAD may be susceptible to interventions that target specifically the oncogenic nature of this cell state.

PMID:38755258 | DOI:10.1038/s44318-024-00113-5

Expert Rev Respir Med. 2024 May 16. doi: 10.1080/17476348.2024.2357210. Online ahead of print.

ABSTRACT

INTRODUCTION: 'Highly effective' modulator therapies (HEMTs) have radically changed the Cystic Fibrosis (CF) therapeutic landscape. These novel therapeutic approaches have permitted unprecedented opportunities for quality-of-life improvement and for enhancing people with CF's (pwCF) life expectancy.

AREAS COVERED: The aim of this review is to describe the current knowledge gaps. A comprehensive search strategy was undertaken to assess impact of HEMT in life of pwCF, treatment challenges in specific populations such as very young children, and research needs.

EXPERT OPINION: HEMTs are prescribed for pwCF with definite genotypes. The heterogeneity of variants complicates treatment possibilities and around 10% of pwCF worldwide remains ineligible. Genotype-specific treatments are prompting theratyping and personalized medicine strategies. Improvement in lung function and quality of life increase survival rates, shifting CF from a pediatric to an adult disease. This implies new studies addressing long-term efficacy, side effects, emergence of adult co-morbidities and possible drug-drug interactions. More sensitive and predictive biomarkers for both efficacy and toxicity are warranted. As HEMTs cross the placenta and are found in breast milk, studies addressing the potential consequences of treatment during pregnancy and breastfeeding are urgently needed. Finally, although the treatment and expected outcomes of CF have improved dramatically in high- and middle-income countries, lack of access in low-income countries to these lifesaving and life-changing medicines highlights inequity of care worldwide.

PMID:38755109 | DOI:10.1080/17476348.2024.2357210

PLoS One. 2024 May 16;19(5):e0303257. doi: 10.1371/journal.pone.0303257. eCollection 2024.

ABSTRACT

Patterns of single nucleotide polymorphisms (SNPs) in eukaryotic DNA are traditionally attributed to selective pressure, drift, identity descent, or related factors-without accounting for ways in which bias during de novo SNP formation, itself, might contribute. A functional and phenotypic analysis based on evolutionary resilience of DNA points to decreased numbers of non-synonymous SNPs in human and other genomes, with a predominant component of SNP depletion in the human gene pool caused by robust preferences during de novo SNP formation (rather than selective constraint). Ramifications of these findings are broad, belie a number of concepts regarding human evolution, and point to a novel interpretation of evolving DNA across diverse species.

PMID:38753830 | DOI:10.1371/journal.pone.0303257

J Pediatr Psychol. 2024 May 16:jsae034. doi: 10.1093/jpepsy/jsae034. Online ahead of print.

ABSTRACT

OBJECTIVE: Suboptimal nutritional adherence in adolescents with cystic fibrosis (awCF) has been associated with lower lung function. AwCF often have more independence in dietary decisions than younger children, yet little research has examined how adolescent decision-making relates to nutritional adherence. This study explored whether components of adolescent decision-making involvement facilitate enzyme and caloric adherence in awCF.

METHODS: 37 families participated and completed study procedures. AwCF and caregivers completed electronic surveys, including the Decision-Making Involvement Scale (DMIS). The DMIS evaluated awCF behaviors during nutrition-related decision-making/discussions with caregivers using DMIS subscales: Child Seek (asking for help/advice from caregivers), Child Express (awCF stating opinions) and Joint/Options (awCF participating in joint decision-making or caregiver providing options). AwCF completed 2, 24-hr diet recalls via videoconferencing/phone to estimate adherence. Chart reviews collected medical information. DMIS subscales were regressed onto enzyme and caloric adherence.

RESULTS: 43% of awCF met calorie recommendations; 48.6% took all enzymes as prescribed. Caloric adherence was positively correlated with adolescent- and parent-reported Child Seek (r = 0.53; r = 0.36) and adolescent-reported Joint/Options (r = 0.41). Per adolescent-report, the caloric adherence regression model was significant, with Child Seek contributing unique variance in caloric adherence (β = .62, p = .03). Parent-reported adolescent-decision-making involvement significantly predicted caloric adherence, but none of the subscales contributed unique variance. No other regressions were significant.

CONCLUSIONS: When awCF participated in nutrition-related discussions with a caregiver, especially with questions, caloric adherence was better. Future research should examine whether family factors influence these results. AwCF are encouraged to ask questions in nutrition discussions.

PMID:38752579 | DOI:10.1093/jpepsy/jsae034

Pediatr Pulmonol. 2024 May 15. doi: 10.1002/ppul.27041. Online ahead of print.

ABSTRACT

The aim was to gather an overview of the evidence of monoclonal antibody therapies in respiratory syncytial virus (RSV) prophylaxis in children. For this umbrella review of previous meta-analyses, we searched PubMed, Scopus, and Web of Science databases in August 2023. We included systematic reviews with meta-analyses of randomized controlled trials. One author extracted the data, and another author validated the data. We extracted all analyses focusing on clinical outcomes and comparing prophylaxis to placebo. Risk of bias in systematic reviews (ROBIS) tool was used to analyze the risk of bias in the included reviews. AMSTAR-2 was used to evaluate the quality of the included reviews. After screening of 323 abstracts and 22 full reports, a total of seven systematic reviews with meta-analyses were included. The risk of bias was rated to be low in four and high in three of these. Three reviews were of moderate quality, one low, and three very low quality according to AMSTAR-2 classification. Six of the meta-analyses were direct comparisons, and one was a network meta-analysis. Five of the reviews focused on palivizumab, one in nirsevimab, and one included all monoclonal antibodies. Six reviews focused on preterm neonates and consisted of 42 comparisons to placebo of which 21 showed efficacy, and 21 had no evidence of a difference. The positive effect was seen in all reviews against RSV infection and RSV hospitalization in palivizumab and nirsevimab groups compared to placebo. None of the mortality comparisons showed efficacy. One meta-analysis focused on cystic fibrosis patients and had eight comparisons, but it was underpowered to detect any results. The overall evidence from previous meta-analyses shows that monoclonal antibodies are effective in preventing RSV infections and RSV hospitalizations in preterm infants. However, no effect on mortality was seen in these studies. Evidence certainty has been ranked mainly from low to moderate.

PMID:38751021 | DOI:10.1002/ppul.27041

Pediatr Pulmonol. 2024 May 15. doi: 10.1002/ppul.27066. Online ahead of print.

NO ABSTRACT

PMID:38751016 | DOI:10.1002/ppul.27066

Sports Med Open. 2024 May 15;10(1):54. doi: 10.1186/s40798-024-00722-8.

ABSTRACT

BACKGROUND: This study aims to identify sports interventions for children and adolescents (CaA) with chronic diseases and evaluate their impact on physical, psychological, and social well-being. The findings of this study will contribute to our understanding of the potential benefits of sports interventions for CaA with chronic diseases and inform future interventions to promote their overall health and well-being.

METHODS: A systematic review was conducted in eight databases. This systematic review followed PRISMA guidelines and utilized a comprehensive search strategy to identify studies on sport-based interventions for CaA with chronic diseases. The review included randomized controlled trials and observational studies that focused on physical and psychosocial outcomes.

RESULTS: We screened 10,123 titles and abstracts, reviewed the full text of 622 records, and included 52 primary studies. A total of 2352 participants were assessed with an average of 45 ± 37 participants per study. Among the included studies involving CaA with chronic diseases with an age range from 3 to 18 years, 30% (n = 15) autism spectrum disorders, 21% (n = 11) cerebral palsy, 19% (n = 10) were attention deficit hyperactivity disorder, and 17% (n = 9) obesity. Other diseases included were cancer (n = 5), asthma (n = 1) and cystic fibrosis (n = 1). Interventions involved various sports and physical activities tailored to each chronic disease. The duration and frequency of interventions varied across studies. Most studies assessed physical outcomes, including motor performance and physical fitness measures. Psychosocial outcomes were also evaluated, focusing on behavioural problems, social competencies, and health-related quality of life.

CONCLUSION: Overall, sport-based interventions effectively improved physical and psychosocial outcomes in CaA with chronic diseases. Interventions are generally safe, and participants adhere to the prescribed protocols favorably. Despite that, there is little evidence that interventions are being implemented. Future studies should include interventions tailored to meet the common issues experienced by CaA with chronic conditions, providing a comprehensive understanding of the impact of sports interventions on those affected.

REGISTRATION: The methodology for this review was pre-determined and registered in the PROSPERO database (registration number: CRD42023397172).

PMID:38750266 | DOI:10.1186/s40798-024-00722-8

J Cyst Fibros. 2024 May 14:S1569-1993(24)00060-2. doi: 10.1016/j.jcf.2024.04.014. Online ahead of print.

ABSTRACT

BACKGROUND: The forskolin-induced swelling (FIS) assay measures CFTR function on patient-derived intestinal organoids (PDIOs) and may guide treatment selection for individuals with Cystic Fibrosis (CF). The aim of this study is to demonstrate the repeatability and reproducibility of the FIS assay following a detailed Standard Operating Procedure (SOP), thus advancing the validation of the assay for precision medicine (theranostic) applications.

METHODS: Over a 2-year period, FIS responses to CFTR modulators were measured in four European labs. PDIOs from six subjects with CF carrying different CFTR genotypes were used to assess the repeatability and reproducibility across the dynamic range of the assay.

RESULTS: Technical, intra-assay repeatability was high (Lin's concordance correlation coefficient (CCC) 0.95-0.98). Experimental, within-subject repeatability was also high within each lab (CCCs all >0.9). Longer-term repeatability (>1 year) showed more variability (CCCs from 0.67 to 0.95). The reproducibility between labs was also high (CCC ranging from 0.92 to 0.97). Exploratory analysis also found that between-lab percentage of agreement of dichotomized CFTR modulator outcomes for predefined FIS thresholds ranged between 78 and 100 %.

CONCLUSIONS: The observed repeatability and reproducibility of the FIS assay within and across different labs is high and support the use of FIS as biomarker of CFTR function in the presence or absence of CFTR modulators.

PMID:38749892 | DOI:10.1016/j.jcf.2024.04.014

J Cyst Fibros. 2024 May 14:S1569-1993(24)00064-X. doi: 10.1016/j.jcf.2024.05.002. Online ahead of print.

ABSTRACT

BACKGROUND: There is a paucity of knowledge on the longer-term effects of CF transmembrane conductance regulator (CFTR) modulator therapies upon the gut microbiome and associated outcomes. In a pilot study, we investigated longitudinal Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy on the gut microbiota, metabolomic functioning, and clinical outcomes in people with CF (pwCF).

STUDY DESIGN: Faecal samples from 20 pwCF were acquired before and then following 3, 6, and 17+ months of ETI therapy. Samples were subjected to microbiota sequencing and targeted metabolomics to profile and quantify short-chain fatty acid composition. Ten healthy matched controls were included for comparison. Clinical data, including markers of intestinal function were integrated to investigate relationships.

RESULTS: Extended ETI therapy increased core microbiota diversity and composition, which translated to gradual shifts in whole microbiota composition towards that observed in healthy controls. Despite becoming more similar over time, CF microbiota and functional metabolite compositions remained significantly different to healthy controls. Antibiotic treatment for pulmonary infection significantly explained a relatively large degree of variation within the whole microbiota and rarer satellite taxa. Clinical outcomes were not significantly different following ETI.

CONCLUSIONS: Whilst differences persisted, a positive trajectory towards the microbiota observed in healthy controls was found. We posit that progression was predominately impeded by pulmonary antibiotics administration. We recommend future studies use integrated omics approaches within a combination of long-term longitudinal patient studies and model experimental systems. This will deepen our understanding of the impacts of CFTR modulator therapy and respiratory antibiotic interventions upon the gut microbiome and gastrointestinal pathophysiology in CF.

PMID:38749891 | DOI:10.1016/j.jcf.2024.05.002

Transplant Proc. 2024 May 14:S0041-1345(24)00199-4. doi: 10.1016/j.transproceed.2024.03.034. Online ahead of print.

ABSTRACT

BACKGROUND: A 21-year-old woman diagnosed with cystic fibrosis developed cirrhosis, exocrine pancreatic insufficiency, and insulin-dependent diabetes mellitus. The patient qualified for double organ liver-pancreas transplantation beyond typical indications. The respiratory symptoms of cystic fibrosis were moderate and well-treated. The patient was endangered mainly by liver insufficiency and recurrent hypoglycemia, which was due to the treatment of diabetes with high doses of insulin. Computed tomography showed mild bronchiectasis, cirrhotic liver, splenomegaly, and atrophy of the pancreas. Pseudomonas aeruginosa colonized the upper respiratory tract. Gastrointestinal complications were sufficient for the patient to be qualified for combined liver-pancreas transplantation.

METHODS: First, a standard hepatectomy was performed. The liver was transplanted orthotopically. Subsequently, the team performed pancreas transplantation through a separate incision. The donor's duodenum was anastomosed to the recipient's jejunum, close to the ligament of Treitz.

RESULTS: No serious complications were noted during the postoperative period. Transplanted organs started functioning without delay. The patient was discharged after 6 weeks in general good condition. Twenty months later, the patient felt well, and the grafts kept functioning properly.

CONCLUSION: Combined liver-pancreas transplantation in patients with CF restores exocrine and endocrine pancreatic function and minimizes the risk of life-threatening complications associated with liver insufficiency. Improvement of life quality coincides with the possibility of discontinuing insulin and pancreatic enzyme supplementation. The combination of liver and pancreas transplantation may prevent advanced pulmonary complications, extend the prognosis of survival, and improve the long-term life quality.

PMID:38749862 | DOI:10.1016/j.transproceed.2024.03.034

Cien Saude Colet. 2024 May;29(5):e17652022. doi: 10.1590/1413-81232024295.17652022. Epub 2023 Jun 30.

ABSTRACT

The complexities referred to in the search for "accuracy" in the diagnosis of cystic fibrosis (CF) point to reflections around "what is needed" in the current situation of "precision medicine". We analyzed the discourses of 19 social actors belonging to the community of specialists in cystic fibrosis, exploring the semantic meanings of the word "precision", and the barriers to diagnosis and innovations in therapeutics. We adopted the critical discourse analysis (CDA) of Norman Fairclough in order to achieve the discursive constructions around the integrality of care, the guarantee and equitable supply of basic social needs. Access was identified as an emic category when in the social arenas of dispute are health needs and the right to life.

PMID:38747779 | DOI:10.1590/1413-81232024295.17652022

Protein Sci. 2024 Jun;33(6):e5021. doi: 10.1002/pro.5021.

ABSTRACT

While nickel-nitrilotriacetic acid (Ni-NTA) has greatly advanced recombinant protein purification, its limitations, including nonspecific binding and partial purification for certain proteins, highlight the necessity for additional purification such as size exclusion and ion exchange chromatography. However, specialized equipment such as FPLC is typically needed but not often available in many laboratories. Here, we show a novel method utilizing polyphosphate (polyP) for purifying proteins with histidine repeats via non-covalent interactions. Our study demonstrates that immobilized polyP efficiently binds to histidine-tagged proteins across a pH range of 5.5-7.5, maintaining binding efficacy even in the presence of reducing agent DTT and chelating agent EDTA. We carried out experiments of purifying various proteins from cell lysates and fractions post-Ni-NTA. Our results demonstrate that polyP resin is capable of further purification post-Ni-NTA without the need for specialized equipment and without compromising protein activity. This cost-effective and convenient method offers a viable approach as a complementary approach to Ni-NTA.

PMID:38747394 | DOI:10.1002/pro.5021

ERJ Open Res. 2024 May 13;10(3):00880-2023. doi: 10.1183/23120541.00880-2023. eCollection 2024 May.

ABSTRACT

The 2023 European Respiratory Society Congress took place on a hybrid platform, with participants joining online and in-person in Milan, Italy. The congress welcomed over 20 000 attendees, bringing together exciting updates in respiratory science and medicine from around the world. In this article, early career members of Assembly 10 (Respiratory Infections) summarise a selection of sessions across a broad range of topics, including presentations on bronchiectasis, nontuberculous mycobacteria, tuberculosis, cystic fibrosis and coronavirus disease 2019.

PMID:38746858 | PMC:PMC11089386 | DOI:10.1183/23120541.00880-2023

ERJ Open Res. 2024 May 13;10(3):00065-2024. doi: 10.1183/23120541.00065-2024. eCollection 2024 May.

ABSTRACT

BACKGROUND: Significant progress in the field of cystic fibrosis (CF) has substantially extended the life expectancy of patients with CF (pwCF). Consequently, the population of adult pwCF has outnumbered paediatric patients in most developed countries. Ageing is a new factor that can contribute to disease complexity and can require adaptation of CF units. Therefore, the necessity for standardised, specialised and multidisciplinary care is imperative. Concerns arise regarding the adequacy of current healthcare, therapeutic and educational offerings.

METHODS: To address these concerns, a multinational survey was conducted to assess the current state of care in specialised multidisciplinary adult and paediatric CF units and identify areas for improvement. Responses were collected from 44 centres providing regular care to CF patients.

RESULTS: The survey unveiled considerable disparities in the availability of critical resources, including diagnostic access, supplementary testing, treatment modalities, transplant and transition programmes, and healthcare professionals' training.

CONCLUSION: This study underscores the urgent need to standardise care across these centres in order to minimise disparities in terms of available resources and training with a particular emphasis on adult pwCF who are becoming more numerous and showing different needs with ageing. The changing landscape of CF in adulthood will require constant monitoring to ensure proper adaptation of the current model of care.

PMID:38746857 | PMC:PMC11089383 | DOI:10.1183/23120541.00065-2024

Sci Data. 2024 May 14;11(1):495. doi: 10.1038/s41597-024-03327-8.

ABSTRACT

Single amino acid substitutions can profoundly affect protein folding, dynamics, and function. The ability to discern between benign and pathogenic substitutions is pivotal for therapeutic interventions and research directions. Given the limitations in experimental examination of these variants, AlphaMissense has emerged as a promising predictor of the pathogenicity of missense variants. Since heterogenous performance on different types of proteins can be expected, we assessed the efficacy of AlphaMissense across several protein groups (e.g. soluble, transmembrane, and mitochondrial proteins) and regions (e.g. intramembrane, membrane interacting, and high confidence AlphaFold segments) using ClinVar data for validation. Our comprehensive evaluation showed that AlphaMissense delivers outstanding performance, with MCC scores predominantly between 0.6 and 0.74. We observed low performance on disordered datasets and ClinVar data related to the CFTR ABC protein. However, a superior performance was shown when benchmarked against the high quality CFTR2 database. Our results with CFTR emphasizes AlphaMissense's potential in pinpointing functional hot spots, with its performance likely surpassing benchmarks calculated from ClinVar and ProteinGym datasets.

PMID:38744964 | DOI:10.1038/s41597-024-03327-8

Mol Genet Genomics. 2024 May 14;299(1):52. doi: 10.1007/s00438-024-02119-4.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a rare multi-systemic recessive disorder. The spectrum and the frequencies of CFTR mutations causing CF vary amongst different populations in Europe and the Middle East. In this study, we characterised the distribution of CF-causing mutations (i.e. pathogenic variants in the CFTR gene) in a representative CF cohort from the Kingdom of Bahrain based on a three-decade-long analysis at a single tertiary centre. We aim to improve CF genetic diagnostics, introduce of CF neonatal screening and provide CFTR modulator therapy (CFTRm).

METHODS: CFTR genotyping and associated clinical information were drawn from a longitudinal cohort. We sequenced 56 people with CF (pwCF) that had one or both CFTR mutations unidentified and carried out comprehensive bioinformatic- and family-based segregation analyses of detected variants, including genotype-phenotype correlations and disease incidence estimates. The study methodology could serve as a basis for other non-European CF populations with a high degree of consanguinity.

RESULTS: Altogether 18 CF-causing mutations were identified, 15 of which were not previously detected in Bahrain, accounting for close to 100% of all population-specific alleles. The most common alleles comprise c.1911delG [2043delG; 22.8%], c.2988+1G > A [3120+1G>A; 16.3%], c.2989-1G>A [3121-1G>A; 14.1%], c.3909C>G [N1303K; 13.0%], and c.1521_1523delCTT [p.PheF508del; 7.6%]. Although the proportion of 1st cousin marriages has decreased to 50%, the frequency of homozygosity in our pwCF is 67.4%, thereby indicating that CF still occurs in large, often related, families. pwCF in Bahrain present with faltering growth, pancreatic insufficiency and classical sino-pulmonary manifestations. Interestingly, two pwCF also suffer from sickle cell disease. The estimated incidence of CF in Bahrain based on data from the last three decades is 1 in 9,880 live births.

CONCLUSION: The most commonCF-causing mutations in Bahraini pwCF were identified, enabling more precise diagnosis, introduction of two-tier neonatal screening and fostering administration of CFTRm.

PMID:38744777 | DOI:10.1007/s00438-024-02119-4

J Clin Invest. 2024 May 14:e174500. doi: 10.1172/JCI174500. Online ahead of print.

ABSTRACT

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that exhibits diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects are uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disrupted lung uptake of fatty acids yet enhanced uptake of arachidonic acid, a precursor of pro-inflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multi-organ metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue.

PMID:38743489 | DOI:10.1172/JCI174500