Expert Rev Respir Med. 2024 Feb 22. doi: 10.1080/17476348.2024.2323189. Online ahead of print.

NO ABSTRACT

PMID:38386416 | DOI:10.1080/17476348.2024.2323189

Clin Pharmacol Ther. 2024 Feb 22. doi: 10.1002/cpt.3214. Online ahead of print.

NO ABSTRACT

PMID:38385853 | DOI:10.1002/cpt.3214

Microbiol Spectr. 2024 Feb 22:e0315723. doi: 10.1128/spectrum.03157-23. Online ahead of print.

ABSTRACT

Chronic Pseudomonas aeruginosa lung infections are a feature of cystic fibrosis (CF) that many patients experience even with the advent of highly effective modulator therapies. Identifying factors that impact P. aeruginosa in the CF lung could yield novel strategies to eradicate infection or otherwise improve outcomes. To complement published P. aeruginosa studies using laboratory models or RNA isolated from sputum, we analyzed transcripts of strain PAO1 after incubation in sputum from different CF donors prior to RNA extraction. We compared PAO1 gene expression in this "spike-in" sputum model to that for P. aeruginosa grown in synthetic cystic fibrosis sputum medium to determine key genes, which are among the most differentially expressed or most highly expressed. Using the key genes, gene sets with correlated expression were determined using the gene expression analysis tool eADAGE. Gene sets were used to analyze the activity of specific pathways in P. aeruginosa grown in sputum from different individuals. Gene sets that we found to be more active in sputum showed similar activation in published data that included P. aeruginosa RNA isolated from sputum relative to corresponding in vitro reference cultures. In the ex vivo samples, P. aeruginosa had increased levels of genes related to zinc and iron acquisition which were suppressed by metal amendment of sputum. We also found a significant correlation between expression of the H1-type VI secretion system and CFTR corrector use by the sputum donor. An ex vivo sputum model or synthetic sputum medium formulation that imposes metal restriction may enhance future CF-related studies.IMPORTANCEIdentifying the gene expression programs used by Pseudomonas aeruginosa to colonize the lungs of people with cystic fibrosis (CF) will illuminate new therapeutic strategies. To capture these transcriptional programs, we cultured the common P. aeruginosa laboratory strain PAO1 in expectorated sputum from CF patient donors. Through bioinformatic analysis, we defined sets of genes that are more transcriptionally active in real CF sputum compared to a synthetic cystic fibrosis sputum medium. Many of the most differentially active gene sets contained genes related to metal acquisition, suggesting that these gene sets play an active role in scavenging for metals in the CF lung environment which may be inadequately represented in some models. Future studies of P. aeruginosa transcript abundance in CF may benefit from the use of an expectorated sputum model or media supplemented with factors that induce metal restriction.

PMID:38385740 | DOI:10.1128/spectrum.03157-23

iScience. 2024 Jan 9;27(3):108835. doi: 10.1016/j.isci.2024.108835. eCollection 2024 Mar 15.

ABSTRACT

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

PMID:38384849 | PMC:PMC10879674 | DOI:10.1016/j.isci.2024.108835

Radiol Case Rep. 2024 Feb 14;19(5):1753-1757. doi: 10.1016/j.radcr.2024.01.069. eCollection 2024 May.

ABSTRACT

Etiologies underlying the relatively infrequent third-trimester sonographic depiction of dilated fetal bowel include (functional or mechanical) bowel obstruction, intestinal atresia, volvulus, annular pancreas, intestinal malrotation, intussusception, gastrointestinal duplications, cystic fibrosis-associated meconium ileus, congenital chloride diarrhea, microvillus inclusion disease, intestinal neuronal dysplasia, and meconium plug syndrome. Fetal bowel obstruction may be associated with aneuploidy (mostly Trisomy 21 in association with esophageal or duodenal atresia), and rarely select microduplications or deletions. We present unusual sonographic findings associated with transient marked proximal fetal bowel dilatation in association with concurrent development of oligohydramnios, in a growth-restricted fetus at 35 weeks' gestation. This case supports that upon observation of dilated loops of fetal bowel, while not negating the potential need for delivery secondary to potential bowel compromise, consideration should be given for observation in anticipation of potential spontaneous resolution of this condition, especially among growth-restricted fetuses with decreased amniotic fluid volume in prematurity.

PMID:38384702 | PMC:PMC10877134 | DOI:10.1016/j.radcr.2024.01.069

Heliyon. 2024 Feb 2;10(4):e25403. doi: 10.1016/j.heliyon.2024.e25403. eCollection 2024 Feb 29.

ABSTRACT

BACKGROUND: Musculoskeletal (MSK) issues are common in the paediatric population and in people with CF. There is currently no MSK screening tool for children and adolescents with CF.

METHODS: The protocol to develop the pGALS (paediatric Gait, Arms, Legs, Spine) was followed to create this screening tool. Paediatric respiratory and MSK physiotherapists, and paediatric respiratory doctors at a large teaching hospital were involved in the creation of this tool. This was then reviewed by paediatric respiratory doctors and physiotherapists at a second large teaching hospital with amendments added. One year data of this screening tool used on children over 7 was collected and analysed as a secondary outcome of this project.

RESULTS: There were 81.8 % more positive screens for MSK issues in the newly developed screening tool compared to the year using Manchester MSK screening tool; there were also 6 more referrals all deemed as appropriate by the services referred to. Almost half of the population screened using the developed tool were positive for an MSK issue, this was commonly related to poor posture or correctable kyphosis. Kyphosis, as measured by plumb line, appeared to be associated with negative health outcomes in this population; pectoralis major length was also associated with kyphosis and these negative health outcomes.

CONCLUSION: The development of this tool has followed the protocol set out by the PGALs and has shown some promise with interesting initial results. This tool will need further validation before it is used in the wider paediatric CF population.

PMID:38384566 | PMC:PMC10878873 | DOI:10.1016/j.heliyon.2024.e25403

Mol Ther Nucleic Acids. 2024 Feb 2;35(1):102134. doi: 10.1016/j.omtn.2024.102134. eCollection 2024 Mar 12.

ABSTRACT

A "universal strategy" replacing the full-length CFTR cDNA may treat >99% of people with cystic fibrosis (pwCF), regardless of their specific mutations. Cas9-based gene editing was used to insert the CFTR cDNA and a truncated CD19 (tCD19) enrichment tag at the CFTR locus in airway basal stem cells. This strategy restores CFTR function to non-CF levels. Here, we investigate the safety of this approach by assessing genomic and regulatory changes after CFTR cDNA insertion. Safety was first assessed by quantifying genetic rearrangements using CAST-seq. After validating restored CFTR function in edited and enriched airway cells, the CFTR locus open chromatin profile was characterized using ATAC-seq. The regenerative potential and differential gene expression in edited cells was assessed using scRNA-seq. CAST-seq revealed a translocation in ∼0.01% of alleles primarily occurring at a nononcogenic off-target site and large indels in 1% of alleles. The open chromatin profile of differentiated airway epithelial cells showed no appreciable changes, except in the region corresponding to the CFTR cDNA and tCD19 cassette, indicating no detectable changes in gene regulation. Edited stem cells produced the same types of airway cells as controls with minimal alternations in gene expression. Overall, the universal strategy showed minor undesirable genomic changes.

PMID:38384445 | PMC:PMC10879780 | DOI:10.1016/j.omtn.2024.102134

Digit Health. 2024 Feb 20;10:20552076241232878. doi: 10.1177/20552076241232878. eCollection 2024 Jan-Dec.

ABSTRACT

OBJECTIVES: Sarcopenia and frailty have been associated with an increased risk of suffering health-related adverse events but the combination of both conditions results in worse health-related outcomes than either condition alone. Since both syndromes are reversible states, their early detection is fundamental. This study aims to validate a video analysis-based App to detect the presence of frailty or prefrailty plus sarcopenia syndromes and to analyze its construct validity with health-related risk factors.

METHODS: A total of 686 community-dwelling older adults (median-age: 72, 59% female) were enrolled. Muscle power generated during a sit-to-stand test using the App and calf circumference were considered the index test. The reference standards were the EWGSOP2 criteria (five-chair stand test plus appendicular skeletal mass or skeletal muscle index) and Fried's frailty phenotype. Area under the curve (AUC), sensitivity, specificity, positive and negative predictive values (PPV and NPV) were calculated.

RESULTS: The prevalence of both syndromes varied from 2.9% to 7.2% depending on the diagnostic criteria used for sarcopenia assessment. Excellent-to-outstanding AUC values were observed (range 0.80-0.92). Sensitivity and specificity ranged from 75% to 100% and 81.7% to 87.2%, respectively. PPV and NPV ranged from 12.1% to 37.5% and 97.9% to 100%, respectively. Individuals diagnosed by the App showed an increased risk of polypharmacy, depression, comorbidities, falls, hospitalization, low socioeconomical and educational levels, and smoking and poor self-perceived health compared to their healthy counterparts.

CONCLUSIONS: This App seems to be reliable to detect the simultaneous presence of both syndromes in community-dwelling older adults. Individuals diagnosed by the App showed more odds to have health-related risk factors.

PMID:38384370 | PMC:PMC10880523 | DOI:10.1177/20552076241232878

J Cyst Fibros. 2024 Feb 20:S1569-1993(24)00020-1. doi: 10.1016/j.jcf.2024.02.005. Online ahead of print.

ABSTRACT

Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation. The PRS values were significantly correlated with 25OHD concentrations, confirming our results in children with CF, and indicating that genetic factors play a role and have implications for therapy.

PMID:38383231 | DOI:10.1016/j.jcf.2024.02.005

Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2316673121. doi: 10.1073/pnas.2316673121. Epub 2024 Feb 21.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that regulates transepithelial salt and fluid homeostasis. CFTR dysfunction leads to reduced chloride secretion into the mucosal lining of epithelial tissues, thereby causing the inherited disease cystic fibrosis. Although several structures of CFTR are available, our understanding of the ion-conduction pathway is incomplete. In particular, the route that connects the cytosolic vestibule with the extracellular space has not been clearly defined, and the structure of the open pore remains elusive. Furthermore, although many residues have been implicated in altering the selectivity of CFTR, the structure of the "selectivity filter" has yet to be determined. In this study, we identify a chloride-binding site at the extracellular ends of transmembrane helices 1, 6, and 8, where a dehydrated chloride is coordinated by residues G103, R334, F337, T338, and Y914. Alterations to this site, consistent with its function as a selectivity filter, affect ion selectivity, conductance, and open channel block. This selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads us to propose a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer.

PMID:38381791 | DOI:10.1073/pnas.2316673121

J Gastrointest Cancer. 2024 Feb 21. doi: 10.1007/s12029-024-01032-8. Online ahead of print.

NO ABSTRACT

PMID:38381367 | DOI:10.1007/s12029-024-01032-8

J Biomed Mater Res A. 2024 Feb 21. doi: 10.1002/jbm.a.37680. Online ahead of print.

ABSTRACT

Pulmonary infections complicate chronic lung diseases requiring attention to both the pathophysiology and complexity associated with infection management. Patients with cystic fibrosis (CF) struggle with continuous bouts of pulmonary infections, contributing to lung destruction and eventual mortality. Additionally, CF patients struggle with airways that are highly viscous, with accumulated mucus creating optimal environments for bacteria colonization. The unique physiology and altered airway environment provide an ideal niche for bacteria to change their phenotype often becoming resistant to current treatments. Colonization with multiple pathogens at the same time further complicate treatment algorithms, requiring drug combinations that can challenge CF patient tolerance to treatment. The goal of this research initiative was to explore the utilization of a microparticle antibiotic delivery system, which could provide localized and sustained antibiotic dosing. The outcome of this work demonstrates the feasibility of providing efficient localized delivery of antibiotics to manage infection using both preclinical in vitro and in vivo CF infection models. The studies outlined in this manuscript demonstrate the proof-of-concept and unique capacity of polymerized cyclodextrin microparticles to provide site-directed management of pulmonary infections.

PMID:38380736 | DOI:10.1002/jbm.a.37680

Front Endocrinol (Lausanne). 2024 Feb 6;15:1293709. doi: 10.3389/fendo.2024.1293709. eCollection 2024.

ABSTRACT

INTRODUCTIONS: Cystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Onset is often insidious, so screening for early detection of glycemic abnormalities is important. Continuous glucose monitoring (CGM) has been validated in people with CF and has been shown to detect early glycemic variability otherwise missed on 2-hour oral glucose tolerance testing (OGTT). We previously reported that CGM measures of hyperglycemia and glycemic variability are superior to hemoglobin A1c (HbA1c) in distinguishing those with and without CFRD. However, little is known about the long-term predictive value of CGM measures of glycemia for both the development of CFRD and their effect on key clinical outcomes such as weight maintenance and pulmonary function. In addition, there have been no studies investigating advanced glycation endproducts (AGE) assessed by skin autofluorescence in people with CF.

METHODS: In this prospective observational study, CGM and HbA1c were measured at 2 to 3 time points 3 months apart in 77 adults with CF. Participants who did not have CFRD at the time of enrollment underwent OGTT at the baseline visit, and all participants had AGE readings at baseline. Follow up data including anthropometric measures, pulmonary function and CFRD status were collected by review of medical records 1- and 2-years after the baseline visits. We applied multivariable linear regression models correlating glycemic measures to change in key clinical outcomes (weight, BMI, FEV1) accounting for age, gender and elexacaftor/tezacaftor/ivacaftor (ETI) use. We also conducted logistic regression analyses comparing baseline glycemic data to development of CFRD during the 2-year follow up period.

RESULTS: Of the 77 participants, 25 had pre-existing CFRD at the time of enrollment, and six participants were diagnosed with CFRD by the OGTT performed at the baseline visit. When adjusting for age, gender, and ETI use, multiple CGM measures correlated with weight and BMI decline after one year but not after two years. CGM and HbA1c at baseline did not predict decline in FEV1 (p>0.05 for all). In the 46 participants without a diagnosis of CFRD at baseline, two participants were diagnosed with CFRD over the following two years, but CGM measures at baseline did not predict progression to CFRD. Baseline AGE values were higher in individuals with CFRD and correlated with multiple measures of dysglycemia (HbA1c, AG, SD, CV, TIR, % time >140, >180, >250) as well as weight. AGE values also correlated with FEV1 decline at year 1 and weight decline at year 1 and year 2.

CONCLUSIONS: Several key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD (n=2) during the follow up period and the initiation of ETI by many participants, affecting their trajectory in weight and pulmonary function. These results provide additional data supporting the potential role for CGM in identifying clinically significant dysglycemia in CF. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD and to understand the implications of AGE measures in this patient population.

PMID:38379863 | PMC:PMC10876871 | DOI:10.3389/fendo.2024.1293709

Nat Commun. 2024 Feb 20;15(1):1547. doi: 10.1038/s41467-024-45785-z.

ABSTRACT

Pseudomonas aeruginosa is a major nosocomial pathogen that causes severe disease including sepsis. Carbapenem-resistant P. aeruginosa is recognised by the World Health Organisation as a priority 1 pathogen, with urgent need for new therapeutics. As such, there is renewed interest in using bacteriophages as a therapeutic. However, the dynamics of treating pan-resistant P. aeruginosa with phage in vivo are poorly understood. Using a pan-resistant P. aeruginosa in vivo infection model, phage therapy displays strong therapeutic potential, clearing infection from the blood, kidneys, and spleen. Remaining bacteria in the lungs and liver displays phage resistance due to limiting phage adsorption. Yet, resistance to phage results in re-sensitisation to a wide range of antibiotics. In this work, we use phage steering in vivo, pre-exposing a pan resistant P. aeruginosa infection with a phage cocktail to re-sensitise bacteria to antibiotics, clearing the infection from all organs.

PMID:38378698 | DOI:10.1038/s41467-024-45785-z

MMW Fortschr Med. 2024 Feb;166(Suppl 1):50. doi: 10.1007/s15006-024-3640-x.

NO ABSTRACT

PMID:38376691 | DOI:10.1007/s15006-024-3640-x

Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2400674121. doi: 10.1073/pnas.2400674121. Epub 2024 Feb 20.

NO ABSTRACT

PMID:38377219 | DOI:10.1073/pnas.2400674121

PLoS One. 2024 Feb 20;19(2):e0292270. doi: 10.1371/journal.pone.0292270. eCollection 2024.

ABSTRACT

The objectives of the present study were to evaluate the discriminating power of spirometric and plethysmographic lung function parameters to differenciate the diagnosis of asthma, ACO, COPD, and to define functional characteristics for more precise classification of obstructive lung diseases. From the databases of 4 centers, a total of 756 lung function tests (194 healthy subjects, 175 with asthma, 71 with ACO, 78 with COPD and 238 with CF) were collected, and gradients among combinations of target parameters from spirometry (forced expiratory volume one second: FEV1; FEV1/forced vital capacity: FEV1/FVC; forced expiratory flow between 25-75% FVC: FEF25-75), and plethysmography (effective, resistive airway resistance: sReff; aerodynamic work of breathing at rest: sWOB), separately for in- and expiration (sReffIN, sReffEX, sWOBin, sWOBex) as well as static lung volumes (total lung capacity: TLC; functional residual capacity: FRCpleth; residual volume: RV), the control of breathing (mouth occlusion pressure: P0.1; mean inspiratory flow: VT/TI; the inspiratory to total time ratio: TI/Ttot) and the inspiratory impedance (Zinpleth = P0.1/VT/TI) were explored. Linear discriminant analyses (LDA) were applied to identify discriminant functions and classification rules using recursive partitioning decision trees. LDA showed a high classification accuracy (sensitivity and specificity > 90%) for healthy subjects, COPD and CF. The accuracy dropped for asthma (~70%) and even more for ACO (~60%). The decision tree revealed that P0.1, sRtot, and VT/TI differentiate most between healthy and asthma (68.9%), COPD (82.1%), and CF (60.6%). Moreover, using sWOBex and Zinpleth ACO can be discriminated from asthma and COPD (60%). Thus, the functional complexity of obstructive lung diseases can be understood, if specific spirometric and plethysmographic parameters are used. Moreover, the newly described parameters of airway dynamics and the central control of breathing including Zinpleth may well serve as promising functional marker in the field of precision medicine.

PMID:38377145 | DOI:10.1371/journal.pone.0292270

Pediatr Pulmonol. 2024 Feb 20. doi: 10.1002/ppul.26916. Online ahead of print.

ABSTRACT

Given extensive pertinent disease factors and evolving medical treatments, this systematic review explores qualitative and quantitative cystic fibrosis (CF) research surrounding self-concept, an overarching perception of self. Research methodologies, self-concept dimensions, prominent self-concept findings and clinical recommendations are identified. Preferred Reporting Items for Systematic Review and Meta-analyses guidelines were applied. PubMed, Scopus, Medline, Psycinfo, CINAHL (ebsco), and CENTRAL Cochrane electronic databases were searched from 2012 to 2022. Methodological quality was assessed using the critical appraisal skills program. Data-based convergent synthesis was applied to analyze and report on qualitative and quantitative studies in parallel. Thirty-seven publications met the inclusion criteria, most of which employed a cross-sectional, single-center design within an adolescent and adult population. Self-efficacy, self-esteem, and self-identity studies were dimensions of self-concept identified, with studies relating to self-efficacy surrounding physical health management most prevalent. All three dimensions were positively associated with improved treatment adherence and psychosocial health. Efficacy tested intervention programs to enhance self-concept are limited; however, an extensive range of clinical recommendations are offered, highlighting the importance of clinician self-concept awareness, quality clinician-patient conversations and online CF peer-support. Self-concept is an important mechanism to optimize patient outcomes. Further CF self-concept research is required, particularly multicenter, longitudinal, and interventional studies. Early childhood, post lung transplant and the older adult CF population in particular, lack research attention. Given the potential impact of rapidly evolving CF transmembrane conductance regulator modulator drugs on many aspects of self, future self-concept research beyond the dimension of self-efficacy may be beneficial.

PMID:38376009 | DOI:10.1002/ppul.26916

ERJ Open Res. 2024 Feb 19;10(1):00687-2023. doi: 10.1183/23120541.00687-2023. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Exercise capacity is an independent predictor of clinical worsening in cystic fibrosis (CF). There is limited evidence of the impact of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on exercise capacity in children with CF. The aim of the present study was to assess the impact of CFTR modulators on exercise capacity in a cohort of adolescents with CF.

METHODS: A prospective single-centre cohort study was carried out. Cardiopulmonary exercise testing (CPET) was performed at baseline, prior to starting Symkevi or Kaftrio and between 4 and 8 months after starting treatment.

RESULTS: 19 adolescents with CF had CPET performed prior to and after CFTR modulator treatment, between December 2019 and March 2022. Breathing reserve improved in the whole cohort, with greater improvement in the modulator-naïve patients after starting treatment with Kaftrio. There was no improvement in peak oxygen uptake and anaerobic threshold after 4 to 8 months of treatment with CFTR modulators.

CONCLUSION: Exercise testing with CPET can be used as an additional tool to monitor response to CFTR modulators. Breathing reserve on CPET may provide a surrogate marker to monitor the improvement in CF lung disease with CFTR modulator treatment.

PMID:38375430 | PMC:PMC10875456 | DOI:10.1183/23120541.00687-2023

Pflugers Arch. 2024 Feb 19. doi: 10.1007/s00424-024-02914-3. Online ahead of print.

ABSTRACT

The transport of bicarbonate across the enterocyte cell membrane regulates the intracellular as well as the luminal pH and is an essential part of directional fluid movement in the gut. Since the first description of "active" transport of HCO3- ions against a concentration gradient in the 1970s, the fundamental role of HCO3- transport for multiple intestinal functions has been recognized. The ion transport proteins have been identified and molecularly characterized, and knockout mouse models have given insight into their individual role in a variety of functions. This review describes the progress made in the last decade regarding novel techniques and new findings in the molecular regulation of intestinal HCO3- transport in the different segments of the gut. We discuss human diseases with defects in intestinal HCO3- secretion and potential treatment strategies to increase luminal alkalinity. In the last part of the review, the cellular and organismal mechanisms for acid/base sensing in the intestinal tract are highlighted.

PMID:38374228 | DOI:10.1007/s00424-024-02914-3