BMC Med Imaging. 2022 Aug 24;22(1):148. doi: 10.1186/s12880-022-00878-3.

ABSTRACT

Non-cystic fibrosis bronchiectasis is a clinically important disease with an estimated 340,000-522,000 persons living with the disease and 70,000 being diagnosed annually. The radiographic diagnosis remains a pivotal part of recognizing the disease due to its protean clinical manifestations. As physicians are sensitized to this disease, a greater proportion of patients are being diagnosed with mild to moderate bronchiectasis. Despite the established use of CT chest as the main tool for making a radiologic diagnosis of bronchiectasis, the literature supporting the process of making that diagnosis is somewhat sparse. Concurrently, there has been an increased trend to have Web-based radiologic tutorials due to its convenience, the ability of the learner to set the pace of learning and the reduced cost compared to in-person learning. The COVID-19 pandemic has accelerated this trend. We wanted to look carefully at the effect of a Web-based training session on interrater reliability. Agreement was calculated as percentages and kappa and prevalence adjusted kappa calculated. We found that a single Web-based training session had little effect on the variability and accuracy of diagnosis of bronchiectasis. Larger studies are needed in this area with multiple training sessions.

PMID:36002806 | DOI:10.1186/s12880-022-00878-3

J Cyst Fibros. 2022 Aug 21:S1569-1993(22)00646-4. doi: 10.1016/j.jcf.2022.08.009. Online ahead of print.

ABSTRACT

In 1872, Horace Dobell, a respected Victorian physician, described the key features of cystic fibrosis, with pancreatic insufficiency, pulmonary disease, and familial recurrence, plus effective treatment of steatorrhea with a pancreatic extract, and was aware of the combination of digestive and pulmonary disease in the pediatric population! This antedated modern descriptions of the full disorder by over 60 years.

PMID:36002377 | DOI:10.1016/j.jcf.2022.08.009

Ann Allergy Asthma Immunol. 2022 Aug 21:S1081-1206(22)00695-0. doi: 10.1016/j.anai.2022.08.015. Online ahead of print.

ABSTRACT

Human rhinovirus (HRV) is the most common causative agent for the common cold and its respiratory symptoms. For those with asthma, cystic fibrosis, or chronic obstructive pulmonary disease (COPD), HRVs can lead to severe and, at times, fatal complications. Furthermore, an array of innate and adaptive host immune responses leads to varying outcomes ranging from subclinical to severe. In this review, we discuss the viral pathogenesis and host immune responses associated with this virus. Specifically, we focus upon the immune responses that might skew a Th2 response, including alarmins, in those with allergic asthma. We also discuss the role of a poor innate immune response with interferons. Finally, we consider therapeutic options for HRV associated exacerbations of asthma, including biologics and intranasal sprays based on the current literature.

PMID:36002092 | DOI:10.1016/j.anai.2022.08.015

J Manag Care Spec Pharm. 2022 Sep;28(9):989-996. doi: 10.18553/jmcp.2022.28.9.989.

ABSTRACT

BACKGROUND: The approval of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) expanded highly effective cystic fibrosis transmembrane receptor modulator therapy to approximately 90% of persons aged 12 years and older with cystic fibrosis. Clinical pharmacists and pharmacy technicians played a key role in planning for ELX/TEZ/IVA initiation prior to US Food and Drug Administration approval as well as initiating therapy after approval. OBJECTIVE: To evaluate the impact of pharmacy services on time to ELX/TEZ/IVA initiation. METHODS: A retrospective chart review evaluated 146 patients aged at least 12 years with cystic fibrosis qualifying for ELX/TEZ/IVA at a single health system between October 21, 2019, and April 1, 2020. RESULTS: Patients filling ELX/TEZ/IVA at an integrated health system specialty pharmacy (HSSP) vs an outside specialty pharmacy (SP) started on therapy an average of 10.8 days sooner (10.8 days ± 14.0 vs 21.6 days ± 18.8, respectively; P = 0.006). More patients filling at an HSSP received ELX/TEZ/IVA within 14 days of the prescription being written compared with outside SPs (82.0% vs 41.4%, respectively; P = 0.001). Before ELX/TEZ/IVA initiation, patients were hospitalized for a cystic fibrosis-related complication for an average of 6.26 days (range = 0-183) compared with 1.16 days (range = 0-91) after ELX/TEZ/IVA initiation. Lastly, an estimated $134,810 was saved in hospitalization dollars in the 105 patients that were able to fill ELX/TEZ/IVA at an HSSP by initiating the drug an average of 10.8 days sooner than outside SPs. CONCLUSIONS: The results of this study demonstrate the value of an integrated HSSP model. The ability to fill specialty medications at an integrated HSSP may optimize medication access, control costs, and improve patient outcomes for patients receiving care within a health system. DISCLOSURES: Dr Loucks has accepted payment for reviewing content of Lexicomp through Wolters Kluwer Consulting and for presenting and attending the American Society of Health System Pharmacists (ASHP) Summer Meeting in June 2022. Dr Loucks is also a Workgroup Chair for the ASHP Pharmacist Section of Specialty Pharmacy Practitioners - Section Advisory Group on Outcomes and Value. Dr Simonsen was a participant in the Vertex Pharmaceuticals Advisory Board in April 2019 and accepted payment for travel and expenses. The remaining authors have no conflicts of interest or financial interests to disclose. This work is in part supported by the Statistical Expertise and Network (StatNet) Award of Cystic Fibrosis Foundation.

PMID:36001103 | DOI:10.18553/jmcp.2022.28.9.989

mSystems. 2022 Aug 24:e0036422. doi: 10.1128/msystems.00364-22. Online ahead of print.

ABSTRACT

Features of the airway microbiome in persons with cystic fibrosis (pwCF) are correlated with disease progression. Microbes have traditionally been classified for their ability to tolerate oxygen. It is unknown whether supplemental oxygen, a common medical intervention, affects the airway microbiome of pwCF. We hypothesized that hyperoxia significantly impacts the pulmonary microbiome in cystic fibrosis. In this study, we cultured spontaneously expectorated sputum from pwCF in artificial sputum medium under 21%, 50%, and 100% oxygen conditions using a previously validated model system that recapitulates microbial community composition in uncultured sputum. Culture aliquots taken at 24, 48, and 72 h, along with uncultured sputum, underwent shotgun metagenomic sequencing with absolute abundance values obtained with the use of spike-in bacteria. Raw sequencing files were processed using the bioBakery pipeline to determine changes in taxonomy, predicted function, antimicrobial resistance genes, and mobile genetic elements. Hyperoxia reduced absolute microbial load, species richness, and diversity. Hyperoxia reduced absolute abundance of specific microbes, including facultative anaerobes such as Rothia and some Streptococcus species, with minimal impact on canonical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. The effect size of hyperoxia on predicted functional pathways was stronger than that on taxonomy. Large changes in microbial cooccurrence networks were noted. Hyperoxia exposure perturbs airway microbial communities in a manner well tolerated by key pathogens. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting. IMPORTANCE The airway microbiome in persons with cystic fibrosis (pwCF) is correlated with lung function and disease severity. Supplemental oxygen use is common in more advanced CF, yet its role in perturbing airway microbial communities is unknown. By culturing sputum samples from pwCF under normal and elevated oxygen conditions, we found that increased oxygen led to reduced total numbers and diversity of microbes, with relative sparing of common CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus. Supplemental oxygen use may enable the growth of lung pathogens and should be further studied in the clinical setting.

PMID:36000724 | DOI:10.1128/msystems.00364-22

Pediatr Pulmonol. 2022 Aug 24. doi: 10.1002/ppul.26094. Online ahead of print.

ABSTRACT

Lobar atelectasis may be a complication of pulmonary exacerbations in cystic fibrosis (CF). There are no estabilished guidelines on the management of this condition in patients with CF. Therapeutic bronchoscopy with recombinant human deoxyribonuclease (rhDNase) instillation has been described to be successful in patients not responding to conservative measures. We describe a case of a young man with CF, with previously mildly impaired lung function, presenting with cough, desaturation and worsening dyspnea, persisting for over 6 weeks, despite conservative therapy. Thoracic imaging showed a right lower lobe atelectasis, which was successfully treated with bronchoscopy and instillation of rhDNase. Long-term resolution of the atelectasis was confirmed with chest MRI follow-up. This article is protected by copyright. All rights reserved.

PMID:36000266 | DOI:10.1002/ppul.26094

Med J Islam Repub Iran. 2022 Feb 12;36:7. doi: 10.47176/mjiri.36.7. eCollection 2022.

ABSTRACT

Background: Cystic Fibrosis (CF) is a life-threatening autosomal recessive disease. The purpose of this study was to evaluate the value of Polymerase Chain Reaction (PCR) in CF patients with Nontuberculous Mycobacteria (NTM) negative sputum culture. Methods: This is a descriptive cross-sectional study. The population included all children with CF, aged between 5 - 18 years old, with an NTM negative sputum culture. The patient's sputum samples were sent for smear and culture of NTM, RFLP PCR, and PCR sequence. Results: In total, 57 CF patients with negative NTM sputum culture were enrolled. Nine patients (15.78%) had positive sputum PCR for NTM. Among these strains, Mycobacterium simiae was the most common one with 5 cases (8.77% of total positive cases). Conclusion: PCR can be used as an alternative diagnostic method for NTM in CF patients with negative NTM sputum culture, always under clinical suspicion of the disease.

PMID:35999933 | PMC:PMC9386751 | DOI:10.47176/mjiri.36.7

Respir Res. 2022 Aug 23;23(1):214. doi: 10.1186/s12931-022-02132-4.

ABSTRACT

BACKGROUND: While there seems to be a consensus that a decrease in gut microbiome diversity is related to a decline in health status, the associations between respiratory microbiome diversity and chronic lung disease remain a matter of debate. We provide a systematic review and meta-analysis of studies examining lung microbiota alpha-diversity in patients with asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or bronchiectasis (NCFB), in which a control group based on disease status or healthy subjects is provided for comparison.

RESULTS: We reviewed 351 articles on title and abstract, of which 27 met our inclusion criteria for systematic review. Data from 24 of these studies were used in the meta-analysis. We observed a trend that CF patients have a less diverse respiratory microbiota than healthy individuals. However, substantial heterogeneity was present and detailed using random-effects models, which limits the comparison between studies.

CONCLUSIONS: Knowledge on respiratory microbiota is under construction, and for the moment, it seems that alpha-diversity measurements are not enough documented to fully understand the link between microbiota and health, excepted in CF context which represents the most studied chronic respiratory disease with consistent published data to link alpha-diversity and lung function. Whether differences in respiratory microbiota profiles have an impact on chronic respiratory disease symptoms and/or evolution deserves further exploration.

PMID:35999634 | DOI:10.1186/s12931-022-02132-4

Pediatr Pulmonol. 2022 Aug 23. doi: 10.1002/ppul.26100. Online ahead of print.

ABSTRACT

BACKGROUND: Consistently abnormal glucose levels on oral glucose tolerance test (OGTT) are the most effective screening tool for Cystic fibrosis-related diabetes (CFRD). However, some Cystic fibrosis (CF) patients demonstrate abnormal glucose profiles not reaching levels required for CFRD diagnosis and are therefore left untreated. Since CFRD is associated with disease deterioration, early diagnosis and treatment are desirable.

AIM: To explore the association between the area under the curve of glucose (G-AUC) obtained during a five-point two-hour standard OGTT and CF disease severity parameters.

METHODS: All CF patients referred for an annual routine OGTT at the Hadassah CF Center between 2002-and 2018, were included. Disease severity parameters were correlated with the G-AUC.

RESULTS: 242 OGTTs were performed in 81 patients (mean age 19.7±9.0 years); 54% were normal, 14% showed impaired glucose tolerance (IGT), 5% had values in the indeterminate range (INDET), 11% had both IGT and INDET and 16% were diagnosed with CFRD. A gradual increase in mean G-AUC was observed among the groups. In multivariate regression models, G-AUC ≥295mg h/dl was independently associated with an increased number of pulmonary exacerbations (PEx). Not all the patients having this value met the CFRD definition.

CONCLUSION: Patients who do not fulfill the criteria for CFRD may have abnormal glucose metabolism identifiable by abnormally high G-AUC values, which may be associated with more PEx. The potential advantage of treating these patients with insulin and the subsequent reduction in PEx needs further investigation. This article is protected by copyright. All rights reserved.

PMID:35999051 | DOI:10.1002/ppul.26100

Development. 2022 Oct 15;149(20):dev200955. doi: 10.1242/dev.200955. Epub 2022 Aug 23.

ABSTRACT

Complex organ development depends on single lumen formation and its expansion during tubulogenesis. This can be achieved by correct mitotic spindle orientation during cell division, combined with luminal fluid filling that generates hydrostatic pressure. Using a human 3D cell culture model, we have identified two regulators of these processes. We find that pleckstrin homology leucine-rich repeat protein phosphatase (PHLPP) 2 regulates mitotic spindle orientation, and thereby midbody positioning and maintenance of a single lumen. Silencing the sole PHLPP family phosphatase in Drosophila melanogaster, phlpp, resulted in defective spindle orientation in Drosophila neuroblasts. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) is the main channel regulating fluid transport in this system, stimulated by phosphorylation by protein kinase A and inhibited by the AMP-activated protein kinase AMPK. During lumen expansion, CFTR remains open through the action of PHLPP1, which stops activated AMPK from inhibiting ion transport through CFTR. In the absence of PHLPP1, the restraint on AMPK activity is lost and this tips the balance in the favour of channel closing, resulting in the lack of lumen expansion and accumulation of mucus.

PMID:35997536 | DOI:10.1242/dev.200955

Int J Neonatal Screen. 2022 Aug 3;8(3):46. doi: 10.3390/ijns8030046.

ABSTRACT

Pancreatitis-Associated Protein (PAP)-based Cystic Fibrosis (CF) newborn bloodspot screening (NBS) protocols detect less CFTR-Related Metabolic Syndrome (CRMS)/CF Screen Positive, Inconclusive Diagnosis (CFSPID). We prospectively evaluated the impact of PAP as the second step of the CF NBS protocol, before the CFTR genetic analysis, on NBS outcomes and CRMS/CFSPID detection in the Tuscany region, Italy. In parallel to the usual protocol (IRT/DNA, protocol 1), PAP was analyzed in IRT-positive infants (IRT/PAP/DNA, protocol 2) from 1 June 2020 until 31 May 2022. We defined an infant as NBS positive if PAP was >1.8 μg/L for IRT value 99th percentile-100 μg/L or >0.6 μg/L for IRT value >100 μg/L. To increase the positive predictive value (PPV) of protocol 2, we retrospectively lowered the upper IRT range value from 100 to 90 μg/L (modified protocol 2). We identified 8 CF and 13 CRMS/CFSPID with protocol 1, 5 CF and 5 CRMS/CFSPID with protocol 2 and 8 CF and 5 CRMS/CFSPID with modified protocol 2. With the PAP-based protocols, we observed a reduction of sweat tests, healthy carrier detection and a significant increase in PPV to 15.38%. Further data are needed in order to evaluate the outcomes of CRMS/CFSPID after a long follow-up.

PMID:35997436 | DOI:10.3390/ijns8030046

Nutr Clin Pract. 2022 Aug 23. doi: 10.1002/ncp.10899. Online ahead of print.

ABSTRACT

Advancements in respiratory and nutrition management have significantly improved the survival of patients with cystic fibrosis (CF). With the availability of several nutrition interventions such as oral/enteral nutrition supplements, enteric-coated pancreatic enzymes, and water-miscible CF-specific vitamin supplements, frank vitamin deficiencies-with the exception of vitamin D-are rarely encountered in current clinical practice. Whereas they were previously considered as micronutrients, our current understanding of fat-soluble vitamins and minerals as antioxidants, immunomodulators, and disease biomarkers has been evolving. The impact of highly effective modulators on the micronutrient status of patients with CF remains elusive. This narrative review focuses on the updates on the management of fat-soluble vitamins and other micronutrients in CF in the current era and identifies the gaps in our knowledge.

PMID:35997322 | DOI:10.1002/ncp.10899

Am J Physiol Lung Cell Mol Physiol. 2022 Aug 23. doi: 10.1152/ajplung.00455.2021. Online ahead of print.

ABSTRACT

Asthma is one of the most common chronic diseases. Mucus overproduction is consistently linked to asthma morbidity and mortality. Despite the knowledge of the importance of mucus, little data exists on how mucus is transported in asthma and the immediate effects of therapeutic intervention. We therefore used microscopic optical coherence tomography (mOCT) to study spontaneous and induced mucus transport in an interleukin-13 (IL-13) induced asthma mouse model and examined the effects of isotonic (0.9% NaCl) and hypertonic saline (7% NaCl) which are used to induce mucus transport in cystic fibrosis. Without intervention, no bulk mucus transport was observed by mOCT and no intraluminal mucus was detectable in the intrapulmonary airways by histology. Administration of ATP-g-S induced mucus secretion into the airway lumen, but did not result in bulk mucus transport in the trachea. Intraluminal secreted immobile mucus could be mobilized by administration of isotonic or hypertonic saline but hypertonic saline mobilized mucus more reliably than isotonic saline. Irrespective of saline concentration, the mucus was transported in mucus chunks. In contrast to isotonic saline solution, hypertonic saline solution alone was able to induce mucus secretion. In conclusion, mOCT is suitable to examine the effects of mucus-mobilizing therapies in vivo. Although hypertonic saline was more efficient in inducing mucus transport, it induced mucus secretion, which might explain its limited benefit in asthma patients.

PMID:35997279 | DOI:10.1152/ajplung.00455.2021

J Hum Nutr Diet. 2022 Aug 23. doi: 10.1111/jhn.13075. Online ahead of print.

ABSTRACT

Low serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with greater adiposity and an adverse cardiometabolic risk profile, yet findings are inconsistent and the role of vitamin D status in cardiovascular disease (CVD) remains uncertain. We aimed to examine the associations between serum 25(OH)D and CVD risk factors in the British population. We analysed data on 2842 subjects aged ≥40 years enrolled in the National Diet and Nutrition Survey (NDNS 2008-2018). Based on serum 25(OH)D concentrations, study subjects were grouped in three categories: vitamin D deficiency (<25 nmol/L), vitamin D insufficiency (25-49 nmol/L) and vitamin D sufficiency status (≥50 nmol/mL). Differences in CVD risk factors between vitamin D deficiency or insufficiency and vitamin D sufficiency status were expressed in standard deviation scores (SDSs) and estimated through weighted multiple linear regression models. We found that vitamin D deficiency was directly associated with BMI, waist circumference, triglycerides and inversely associated with high-density lipoprotein cholesterol (HDL) values. The strongest associations were found between vitamin D deficiency and triglycerides (0.50 SDS, 95% CI: 0.24, 0.77) among men, and vitamin D deficiency and waist circumference (0.70 SDS, 95% CI: 0.56, 0.94), BMI (0.63 SDS, 95% CI: 0.39, 0.88) and triglycerides (0.54 SDS, 95% CI: 0.30, 0.77) among women. When adjusting for BMI the association with triglyceride attenuated (from 0.50 SDS to 0.39 SDS among men and from 0.54 SDS to 0.30 SDS among women). Our data indicates a relationship between inadequate vitamin D status and an adverse CVD risk profile. However, interventional studies are needed to establish possible benefits of vitamin D supplementation on cardiovascular risk. This article is protected by copyright. All rights reserved.

PMID:35997254 | DOI:10.1111/jhn.13075

Pediatr Pulmonol. 2022 Aug 23. doi: 10.1002/ppul.26126. Online ahead of print.

ABSTRACT

BACKGROUND: Adherence to pulmonary medication is pivotal in delaying the progression of lung disease in Cystic Fibrosis (CF). Further exploring the consequences of poor adherence and its impact on disease severity may be valuable to personalize CF treatment strategy.

AIM: To evaluate indicators of disease severity among children and adults with CF and investigate which of them are related to pulmonary medication adherence.

METHODS: This is a retrospective cohort study. Data of children and adults followed up in one pediatric and one adult CF Unit was evaluated over four years. Disease severity was assessed by measuring Body Mass Index (BMI), lung function, history of pulmonary exacerbations, and medication complexity. Adherence was assessed by calculating a 12-month medication possession ratio (MPR) for each pulmonary medication and then averaged for a composite MPR (cMPR) for each patient. Regression analysis was performed to explore the association of adherence with disease severity.

RESULTS: Ninety-five patients were included in our study, 52 children and 43 adults. The overall cMPR was 0.74 (SD: 0.25); 0.68 (SD: 0.24) for children and 0.81 (SD: 0.24) for adults. Adults presented higher adherence, with overall mean cMPR 0.81 (SD: 0.24) compared to children with mean cMPR 0.68 (SD: 0.24) (p<0.05, 95% CI: -0.27 to -0.03). Adherence was inversely related to FEV1 % predicted (β=-0.002, 95%CI=-0.004 to 0, p=0.023) and FVC% predicted (β=-0.003, 95%CI=-0.005 to -0.001, p=0.006) in regression analysis. Adherence was not found to be associated with BMI, history of exacerbations and medication complexity. The analysis of each medication showed that adherence to Dornase-alpha, Tobramycin and Colomycin was significantly related to specific disease severity indicators.

CONCLUSION: An overall moderate to high level of adherence was found among our study population. Adults presented higher adherence compared to children. FEV1% and FVC% predicted were related to a significant decrease in adherence. Among our group of CF patients with an overall moderate to high level of adherence, adherence to pulmonary medication was inversely related to disease severity. This article is protected by copyright. All rights reserved.

PMID:35997065 | DOI:10.1002/ppul.26126

Pediatr Pulmonol. 2022 Aug 22. doi: 10.1002/ppul.26123. Online ahead of print.

ABSTRACT

INTRODUCTION: Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with Cystic Fibrosis (CF).

METHODS: A mathematical framework including Principal Component Analysis, data clustering and data completion was applied to a multi-center cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included Body Mass Index (BMI), number of days of antibiotics (ATB), Sweat Test (ST), Forced Expiratory Volume in 1 second expressed in percentage predicted (ppFEV1 ), Forced Vital Capacity (ppFVC), and Forced Expiratory Flow at 25-75% of FVC (ppFEF25-75 ).

RESULTS: Change in ppFEV1 was the most significant parameter in characterizing response heterogeneity among the 12-18 year-old patients. Patients with minimal changes in ppFEV1 were further separated by change in BMI and ATB course. In the 6-12 year-old children both BMI and ppFEV1 evolution were the most relevant. Sweat test change was not associated with a clinical response.

CONCLUSIONS: Change in ppFEV1 , BMI and ATB course are the most relevant outcomes to discriminate clinical response profiles in children treated with lumacaftor-ivacaftor. Prepubertal and pubertal children display different response profiles. This article is protected by copyright. All rights reserved.

PMID:35996214 | DOI:10.1002/ppul.26123

Sci Rep. 2022 Aug 22;12(1):14255. doi: 10.1038/s41598-022-18098-8.

ABSTRACT

Cystic fibrosis is an autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that can lead to terminal respiratory failure. Ultrafine carbonaceous particles, which are ubiquitous in ambient urban and indoor air, are increasingly considered as major contributors to the global health burden of air pollution. However, their effects on the expression of CFTR and associated genes in lung epithelial cells have not yet been investigated. We therefore evaluated the effects of carbon nanoparticles (CNP), generated by spark-ablation, on the human bronchial epithelial cell line 16HBE14o- at air-liquid interface (ALI) culture conditions. The ALI-cultured cells exhibited epithelial barrier integrity and increased CFTR expression. Following a 4-h exposure to CNP, the cells exhibited a decreased barrier integrity, as well as decreased expression of CFTR transcript and protein levels. Furthermore, transcriptomic analysis revealed that the CNP-exposed cells showed signs of oxidative stress, apoptosis and DNA damage. In conclusion, this study describes spark-ablated carbon nanoparticles in a realistic exposure of aerosols to decrease CFTR expression accompanied by transcriptomic signs of oxidative stress, apoptosis and DNA damage.

PMID:35995803 | DOI:10.1038/s41598-022-18098-8

J Cyst Fibros. 2022 Aug 19:S1569-1993(22)00645-2. doi: 10.1016/j.jcf.2022.08.007. Online ahead of print.

ABSTRACT

INTRODUCTION: While antibiotic eradication therapy (AET) of early Pseudomonas aeruginosa infection is considered standard of care, its long-term effect on the subsequent course of cystic fibrosis (CF) lung disease remains unclear.

METHODS: CF patients who were P. aeruginosa-free for at least a year and had a minimum of 10 years of pulmonary function measurements were included. Subjects were categorized as Never if they never had P. aeruginosa isolated from a respiratory tract sample. Subjects changed to the Eradicated group if they had a P. aeruginosa infection, were treated with AET, and subsequently cleared their infection. Subjects changed to the Chronic group if AET did not clear their P. aeruginosa infection. The primary outcome was absolute FEV1 decline over time, with age as the time variable. Mixed-effects linear regression models were used to account for the repeated lung function measurements over time within each patient.

RESULTS: 205 CF subjects (48% female) were included; the median (IQR) age at first infection was 9.6 (5.6, 14.6) years. The median (IQR) follow-up was 10.2 (5.7, 14.7) years for the Eradicated group, 8.8 (4.5, 14.9) years for the Chronic group and 2.8 (1.0, 5.7) years for the Never group was among those patients that had at least one P. aeruginosa infection over the study period, annual lung function decline of FEV1 was significantly less (-1.11% predicted/year; 95% CI: -1.18, -1.04) in the Eradication group compared to the Chronic group (-1.57%; -1.64, -1.50) (p<0.001).

CONCLUSIONS: AET against P. aeruginosa improves lung function trajectory in CF patients.

PMID:35995678 | DOI:10.1016/j.jcf.2022.08.007

Am J Physiol Cell Physiol. 2022 Aug 22. doi: 10.1152/ajpcell.00047.2022. Online ahead of print.

ABSTRACT

Na/K ATPase activity is essential for ion transport across epithelia. FXYD3, a ᵯE; subunit of the Na/K ATPase, is expressed in the airway, but its function remains undetermined. Single cell RNA sequencing and immunohistochemistry revealed that FXYD3 localizes within the basolateral membrane of all airway epithelial cells. To study FXYD3 function, we reduced FXYD3 expression using siRNA. After permeabilizing the apical membrane with nystatin, epithelia pretreated with FXYD3-targeting siRNA had lower ouabain-sensitive short-circuit currents than control epithelia. FXYD3-targeting siRNA also reduced amiloride-sensitive short-circuit currents and liquid absorption across intact epithelia. These data are consistent with FXYD3 facilitating Na+ and liquid absorption. FXYD3 may be needed to maintain the high rates of Na+ and fluid absorption observed for airway and other FXYD3-expressing epithelia.

PMID:35993520 | DOI:10.1152/ajpcell.00047.2022

Front Physiol. 2022 Aug 3;13:893862. doi: 10.3389/fphys.2022.893862. eCollection 2022.

ABSTRACT

The insulin secretion rate (ISR) contains information that can provide a personal, quantitative understanding of endocrine function. If the ISR can be reliably inferred from measurements, it could be used for understanding and clinically diagnosing problems with the glucose regulation system. Objective: This study aims to develop a model-based method for inferring a parametrization of the ISR and related physiological information among people with different glycemic conditions in a robust manner. The developed algorithm is applicable for both dense or sparsely sampled plasma glucose/insulin measurements, where sparseness is defined in terms of sampling time with respect to the fastest time scale of the dynamics. Methods: An algorithm for parametrizing and validating a functional form of the ISR for different compartmental models with unknown but estimable ISR function and absorption/decay rates describing the dynamics of insulin accumulation was developed. The method and modeling applies equally to c-peptide secretion rate (CSR) when c-peptide is measured. Accuracy of fit is reliant on reconstruction error of the measured trajectories, and when c-peptide is measured the relationship between CSR and ISR. The algorithm was applied to data from 17 subjects with normal glucose regulatory systems and 9 subjects with cystic fibrosis related diabetes (CFRD) in which glucose, insulin and c-peptide were measured in course of oral glucose tolerance tests (OGTT). Results: This model-based algorithm inferred parametrization of the ISR and CSR functional with relatively low reconstruction error for 12 of 17 control and 7 of 9 CFRD subjects. We demonstrate that when there are suspect measurements points, the validity of excluding them may be interrogated with this method. Significance: A new estimation method is available to infer the ISR and CSR functional profile along with plasma insulin and c-peptide absorption rates from sparse measurements of insulin, c-peptide, and plasma glucose concentrations. We propose a method to interrogate and exclude potentially erroneous OGTT measurement points based on reconstruction errors.

PMID:35991187 | PMC:PMC9384214 | DOI:10.3389/fphys.2022.893862