Am J Physiol Gastrointest Liver Physiol. 2024 Dec 6. doi: 10.1152/ajpgi.00066.2024. Online ahead of print.

ABSTRACT

Membrane proteins, such as the Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), play a crucial role in gastrointestinal functions and heath. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins' processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3ΔIEC). EMC3ΔIEC mice were viable but notable smaller compared to their wildtype littermates. While intestinal structure was generally maintained, EMC3ΔIEC crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3ΔIEC enteroids. CFTR-mediated organoid swelling in EMC3ΔIEC mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC.

PMID:39641142 | DOI:10.1152/ajpgi.00066.2024

Mol Ther Nucleic Acids. 2024 Oct 28;35(4):102375. doi: 10.1016/j.omtn.2024.102375. eCollection 2024 Dec 10.

ABSTRACT

For cystic fibrosis patients, a lung-targeted gene therapy would significantly alleviate pulmonary complications associated with morbidity and mortality. However, mucus in the airways and cell entry pose huge delivery barriers for local gene therapy. Here, we used phage display technology to select for and identify mucus- and cell-penetrating peptides against primary human bronchial epithelial cells from cystic fibrosis patients cultured at the air-liquid interface. At the air-liquid interface, primary human bronchial epithelial cells produce mucus and reflect cystic fibrosis disease pathology, making it a clinically relevant model. Using this model, we discovered a lead candidate peptide and incorporated it into lipid nanoparticles to deliver mRNA to primary human bronchial epithelia in vitro and mouse lungs in vivo. Compared to lipid nanoparticles without our peptide, peptide-lipid nanoparticles demonstrated up to 7.8-fold and 3.4-fold higher reporter luciferase bioactivity in vitro and in vivo, respectively. Importantly, these peptides facilitated higher specific uptake of nanoparticles into lung epithelia relative to other cell types. Since gene delivery to primary human bronchial epithelia is a significant challenge, we are encouraged by these results and anticipate that our peptide could be used to successfully deliver cystic fibrosis gene therapies in future work.

PMID:39640013 | PMC:PMC11617931 | DOI:10.1016/j.omtn.2024.102375

J Magn Reson Imaging. 2024 Dec 6. doi: 10.1002/jmri.29669. Online ahead of print.

ABSTRACT

Lung MRI is an important tool in the assessment and monitoring of pediatric and neonatal lung disorders. MRI can provide both similar and complementary image contrast to computed tomography for imaging the lung macrostructure, and beyond this, a number of techniques have been developed for imaging the key functions of the lungs, namely ventilation, perfusion, and gas exchange, through the use of free-breathing proton and hyperpolarized gas MRI. Here, we review the state-of-the-art in MRI methods that have found utility in pediatric and neonatal lung imaging, the structural and physiological information that can be gleaned from such images, and strategies that have been developed to deal with respiratory (and cardiac) motion, and other technological challenges. The application of lung MRI in neonatal and pediatric lung conditions, in particular bronchopulmonary dysplasia, cystic fibrosis, and asthma, is reviewed, highlighting our collective experiences in the clinical translation of these methods and technology, and the key current and future potential avenues for clinical utility of this methodology. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

PMID:39639777 | DOI:10.1002/jmri.29669

United European Gastroenterol J. 2024 Dec 5. doi: 10.1002/ueg2.12674. Online ahead of print.

ABSTRACT

Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below the level that allows the normal digestion of nutrients. Pancreatic disease and surgery are the main causes of PEI. However, other conditions and upper gastrointestinal surgery can also affect the digestive function of the pancreas. PEI can cause symptoms of nutritional malabsorption and deficiencies, which affect the quality of life and increase morbidity and mortality. These guidelines were developed following the United European Gastroenterology framework for the development of high-quality clinical guidelines. After a systematic literature review, the evidence was evaluated according to the Oxford Center for Evidence-Based Medicine and the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted on using the Delphi method. The diagnosis of PEI should be based on a global assessment of symptoms, nutritional status, and a pancreatic secretion test. Pancreatic enzyme replacement therapy (PERT), together with dietary advice and support, are the cornerstones of PEI therapy. PERT is indicated in patients with PEI that is secondary to pancreatic disease, pancreatic surgery, or other metabolic or gastroenterological conditions. Specific recommendations concerning the management of PEI under various clinical conditions are provided based on evidence and expert opinions. This evidence-based guideline summarizes the prevalence, clinical impact, and general diagnostic and therapeutic approaches for PEI, as well as the specifics of PEI in different clinical conditions. Finally, the unmet needs for future research are discussed.

PMID:39639485 | DOI:10.1002/ueg2.12674

Farm Hosp. 2024 Dec 4:S1130-6343(24)00136-3. doi: 10.1016/j.farma.2024.07.011. Online ahead of print.

ABSTRACT

OBJECTIVE: Inhaled therapy is essential in cystic fibrosis; however, inhalers have a significant environmental impact due to the greenhouse gases (GHGs) emitted. The environmental impact of a product is estimated by its carbon footprint (CF). Pressurized metered-dose inhalers (pMDIs) have a higher CF than dry powder inhalers (DPIs) and soft mist inhalers (SMIs) due to the incorporation of GHGs. The objectives are to analyze the consumption of inhalers (β2-adrenergic agonist bronchodilators, anticholinergics, and/or corticosteroids) in a cystic fibrosis unit and estimate the generated CF.

METHOD: Retrospective determination (January 2018-December 2023) of consumption and CF (tCO2eq) by type of inhaler was conducted. Consumption and CF trends were evaluated using lineal regression.

RESULTS: Annually, 1,529 (1,279-1,613) pMDIs, 1,055 (855-1,333) DPIs, and 28 (20-42) SMIs were dispensed, representing 55.97%, 42.33%, and 1.70%, respectively. A statistically significant positive trend in the consumption of SMIs was observed. The median annual CF was: pMDI 38.3 (31.2-40.3) tCO2eq, DPIs 0.8 (0.6-0.9) tCO2eq, and SMIs 0.02 (0.02-0.03) tCO2eq, representing 97.86, 2.04, and 0.10%, respectively.

CONCLUSIONS: pMDIs were the inhalers with the highest consumption and CF, although their consumption appears to be decreasing, with an increase in the consumption of SMIs.

PMID:39638699 | DOI:10.1016/j.farma.2024.07.011

Clin Nutr. 2024 Nov 26;44:76-85. doi: 10.1016/j.clnu.2024.11.039. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: The relation between various types of plant-based diets and cancer risk is still unclear. We examined the association of the overall plant-based diet index (PDI) and healthy (hPDI) and unhealthy plant-based diet indices (uPDI) with the risk of selected digestive cancers.

METHODS: We used data from a network of hospital-based case-control studies including 942 oral/pharyngeal, 304 esophageal, 230 stomach, 1953 colorectal, and 326 pancreatic cancer cases. We calculated PDI, hPDI, and uPDI from a validated food frequency questionnaire. We used multivariable logistic regression models to estimate the odds ratios (OR) of selected digestive cancers across the three indices (in quintiles, Q, or tertiles, T, and in continuous).

RESULTS: The PDI was significantly inversely associated with oral/pharyngeal (ORQ5 vs Q1=0.63, 95% confidence interval, CI, 0.47-0.84) and esophageal cancer risk (ORT3 vs T1=0.47, 95% CI 0.31-0.72). The inverse associations appeared stronger for the hPDI (oral cavity/pharynx: ORQ5 vs Q1=0.52; 95% CI 0.39-0.70; esophagus: ORT3 vs T1=0.59, 95% CI 0.39-0.91; stomach: ORT3 vs T1=0.42, 95% CI 0.27-0.67; colorectum: ORQ5 vs Q1=0.69; 95% CI 0.57-0.84; pancreas: ORT3 vs T1=0.60; 95% CI 0.41-0.89). In contrast, the uPDI was directly associated with the risk of oral/pharyngeal (ORQ5 vs Q1=1.43, 95% CI 1.06-1.94), colorectal (ORQ5 vs Q1=2.28, 95% CI 1.86-2.81), and pancreatic cancer (ORT3 vs T1=1.74, 95% CI 1.14-2.65). Esophageal and stomach cancer risks were non-significantly increased by 34% and 46% respectively in the highest uPDI quantile.

CONCLUSION: A plant-based diet, especially a healthy plant-based diet, may reduce the risk of various digestive cancers, whereas an unhealthy plant-based diet may increase the risk. The quality of plant-based diets is important for digestive cancer risk evaluation and prevention.

PMID:39637750 | DOI:10.1016/j.clnu.2024.11.039

PLoS One. 2024 Dec 5;19(12):e0292568. doi: 10.1371/journal.pone.0292568. eCollection 2024.

ABSTRACT

BACKGROUND: The duration of time a person with cystic fibrosis (pwCF) spends on the lung transplant waitlist is dependent on waitlist and post-transplant survival probabilities and can extend up to 2 years. Understanding the characteristics involved with lung transplant and survival prognoses may help guide decision making by the patient, the referring CF Center and the transplant team.

METHODS: This study seeks to identify clinical predictors of lung transplant and survival of individuals with CF using 29,847 subjects from 2003-2014 entered in the Cystic Fibrosis Foundation Patient Registry (CFFPR).

RESULTS: Predictors significant (p ≤ 0.05) in the final logistic regression model predicting probability of lung transplant/death were: FEV1 (% predicted), BMI, age of diagnosis, age, number of pulmonary exacerbations, race, sex, CF-related diabetes (CFRD), corticosteroid use, infections with B. cepacia, P. aeruginosa, S. aureus, MRSA, pancreatic enzyme use, insurance status, and consecutive ibuprofen use for at least 4 years. The final Cox regression model predicting time to lung transplant identified these predictors as significant FEV1 (% predicted), BMI, age of diagnosis, age, number of pulmonary exacerbations, race, sex, CF-related diabetes (CFRD), corticosteroid use, infections with B. cepacia, P. aeruginosa, S. aureus, MRSA, pancreatic enzyme use, and consecutive ibuprofen use for at least 4 years. The concordance indices were 0.89 and 0.92, respectively.

CONCLUSIONS: The models are translated into nomograms to simplify investigation of how various characteristics relate to lung transplant and survival prognosis individuals with CF not receiving highly effective CFTR modulator therapy.

PMID:39636871 | DOI:10.1371/journal.pone.0292568

Cell Surf. 2024 Nov 8;12:100133. doi: 10.1016/j.tcsw.2024.100133. eCollection 2024 Dec.

ABSTRACT

Biofilm-associated infections constitute a significant challenge in managing infectious diseases due to their high resistance to antibiotics and host immune responses. Biofilms are responsible for various infections, including urinary tract infections, cystic fibrosis, dental plaque, bone infections, and chronic wounds. Quorum sensing (QS) is a process of cell-to-cell communication that bacteria use to coordinate gene expression in response to cell density, which is crucial for biofilm formation and maintenance.. Its disruption has been proposed as a potential strategy to prevent or treat biofilm-associated infections leading to improved treatment outcomes for infectious diseases. This review article aims to provide a comprehensive overview of the literature on QS-mediated disruption of biofilms for treating infectious diseases. It will discuss the mechanisms of QS disruption and the various approaches that have been developed to disrupt QS in reference to multiple clinical pathogens. In particular, numerous studies have demonstrated the efficacy of QS disruption in reducing biofilm formation in various pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus. Finally, the review will discuss the challenges and future directions for developing QS disruption as a clinical therapy for biofilm-associated infections. This includes the development of effective delivery systems and the identification of suitable targets for QS disruption. Overall, the literature suggests that QS disruption is a promising alternative to traditional antibiotic treatment for biofilm-associated infections and warrants further investigation.

PMID:39634722 | PMC:PMC11615143 | DOI:10.1016/j.tcsw.2024.100133

Med J Aust. 2024 Dec 4. doi: 10.5694/mja2.52547. Online ahead of print.

NO ABSTRACT

PMID:39632447 | DOI:10.5694/mja2.52547

Eur Respir Rev. 2024 Dec 4;33(174):240068. doi: 10.1183/16000617.0068-2024. Print 2024 Oct.

ABSTRACT

The advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, especially the triple therapy combining the drugs elexacaftor, tezacaftor, ivacaftor (ETI), has significantly changed the course of the disease in people with cystic fibrosis (pwCF). ETI, which is approved for the majority (80-90%) of pwCF, partially restores CFTR channel function, resulting in improved mucociliary clearance and, consequently, improved lung function, respiratory symptoms and pulmonary exacerbations. The bacterial burden of classical CF pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus is reduced without reaching eradication in the majority of infected patients. Limited data is available on less common or emerging bacterial pathogens. ETI has a positive effect on the lung microbiome but does not fully restore it to a healthy state. Due to the significant reduction in sputum production under ETI, respiratory samples such as deep-throat swabs are commonly taken, despite their inadequate representation of lower respiratory tract pathogens. Currently, there are still unanswered questions related to this new therapy, such as the clinical impact of infection with cystic fibrosis (CF) pathogens, the value of molecular diagnostic tests, the durability of the effects on respiratory infection and the role of fungal and viral infections. This article reviews the changes in bacterial lung infections and the microbiome in CF to provide evidence for the use of antibiotics in the era of ETI.

PMID:39631927 | DOI:10.1183/16000617.0068-2024

Chest. 2024 Dec 2:S0012-3692(24)05600-9. doi: 10.1016/j.chest.2024.11.026. Online ahead of print.

ABSTRACT

BACKGROUND: The prevalence of non-Tuberculous Mycobacteria pulmonary disease (NTM-pd) is rising globally. Previously, we described a high prevalence of M. simiae isolation in Israel.

RESEARCH QUESTIONS: What is the prevalence of NTM-pd and M. simiae-pd in Northern Israel? Which factors are associated with mortality among people with NTM?

STUDY DESIGN AND METHODS: We retrospectively recorded all samples from Clalit Health Services- Haifa district reference mycobacteria laboratory for growth of NTM, between January 2010 and March 2021. We manually reviewed a random sample of corresponding patients' electronic medical files and extracted demographic, clinical, and radiological data, as well as data on the course of the disease. Univariate and multivariate analyses were performed to assess factors associated with features of NTM-pd and mortality.

RESULTS: 2968 clinical isolates from 1501 people yielded NTM species. The relative abundance of M. simiae, MAC and other species increased over the study period. Among the 550 patients' files reviewed, clinical presentation, fulfilment of established criteria for NTM-pulmonary disease, and mortality rates were not significantly different between patients with M. simiae, MAC and M. kansassi/szulgai species, with 27.7, 35.3, and 27.8% of people fulfilling criteria for NTM-pd. Factors associated with mortality included age, male sex, and immunosuppression. Compared to MAC isolation, M. simiae was associated with elevated mortality: HR 1.84 (95% CI 1.05-3.23). The extrapolated national annual incidence rate of NTM- pd was 1.7-2.0:100,000 population.

INTERPRETATION: Infection with M.simiae is prevalent in Israel, and although considered minimally pathogenic, demonstrated similar clinical and radiologic features to MAC-pd.

PMID:39631683 | DOI:10.1016/j.chest.2024.11.026

AJR Am J Roentgenol. 2024 Dec 4. doi: 10.2214/AJR.24.32405. Online ahead of print.

NO ABSTRACT

PMID:39629774 | DOI:10.2214/AJR.24.32405

iScience. 2024 Oct 30;27(12):111286. doi: 10.1016/j.isci.2024.111286. eCollection 2024 Dec 20.

ABSTRACT

Cystic fibrosis (CF) is an autosomal recessive disease characterized by microbial infection and progressive decline in lung function, leading to significant morbidity and mortality. The bitter taste receptor T2R14 is a chemosensory receptor that is significantly expressed in airways. Using a combination of cell-based assays and T2R14 knockdown in bronchial epithelial cells from CF and non-CF individuals, we observed that T2R14 plays a crucial role in the detection of bacterial and fungal signals and enhances host innate immune responses. Expression of Gαi protein is enhanced in CF bronchial epithelial cells and T2R14-Gαi specific signaling leads to increased calcium mobilization. Knockdown of T2R14 leads to reduced innate immune activation by bacterial strains deficient in quorum sensing. The results demonstrate that T2R14 helps protect against microbial infection and thus may play an important role in the innate immune defense of the CF airway epithelium.

PMID:39628561 | PMC:PMC11613190 | DOI:10.1016/j.isci.2024.111286

Acta Pharmacol Sin. 2024 Dec 3. doi: 10.1038/s41401-024-01427-0. Online ahead of print.

ABSTRACT

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has demonstrated significant clinical benefits in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, inevitable acquired resistance to osimertinib limits its clinical utility, and there is a lack of effective countermeasures. Here, we established osimertinib-resistant cell lines and performed drug library screening. This screening identified ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, as a synergistic enhancer of osimertinib-induced anti-tumor activity both in vitro and in vivo. Mechanistically, ivacaftor facilitated the colocalization of CFTR and PTEN on the plasma membrane to promote the function of PTEN, subsequently inhibiting the PI3K/AKT signaling pathway and suppressing tumor growth. In summary, our study suggests that activating CFTR enhances osimertinib-induced anti-tumor activity by regulating the PTEN-AKT axis. Furthermore, ivacaftor and osimertinib constitute a potential combination strategy for treating osimertinib-resistant EGFR-mutated NSCLC patients.

PMID:39627385 | DOI:10.1038/s41401-024-01427-0

J Cyst Fibros. 2024 Dec 2:S1569-1993(24)01848-4. doi: 10.1016/j.jcf.2024.11.013. Online ahead of print.

ABSTRACT

Treatment-associated differences in Pseudomonas aeruginosa (Pa) density in sputum have been used as a response biomarker in clinical trials of cystic fibrosis (CF) therapies. Although most studies have included placebo-treated groups as comparators, variability of Pa density in untreated individuals has rarely been reported. We measured day-to-day differences in Pa density in 267 sputum sample pairs collected from 13 adults with CF during days in which no changes in antibiotic therapy occurred. Although the mean sputum Pa density change across all sample pairs was modest (-0.09 log10 16S rRNA gene copies/mL), variability in day-to-day changes were substantial (SD = 1.09) with one-quarter of sample pairs having >1 log10 differences in Pa density; approximately 8 % of pairs had >2 log10 differences in density. Day-to-day variability in Pa density differed substantially between study participants (p = .001). These results will support the design and interpretation of studies using sputum Pa density change as an efficacy biomarker.

PMID:39627109 | DOI:10.1016/j.jcf.2024.11.013

An Pediatr (Engl Ed). 2024 Dec 2:S2341-2879(24)00284-9. doi: 10.1016/j.anpede.2024.11.006. Online ahead of print.

NO ABSTRACT

PMID:39627094 | DOI:10.1016/j.anpede.2024.11.006

Gen Hosp Psychiatry. 2024 Nov 26;91:212-222. doi: 10.1016/j.genhosppsych.2024.11.011. Online ahead of print.

ABSTRACT

PURPOSE: Psychological distress, including anxiety and depression, is common among adults with CF, associating with poor quality of life, lung function, and healthcare utilization. This 3-year, multi-site, telehealth-delivered randomized trial sought to determine whether Acceptance and Commitment Therapy (ACT with CF) is superior to supportive psychotherapy (SP), in improving psychological functioning for adults with CF.

METHODS: One hundred twenty-four adults with CF and elevated anxiety and/or depressive symptoms were recruited coincident with the first COVID lockdown, from Thomas Jefferson University Hospitals, University of Virginia, Augusta University, Duke University Medical Center, and social media. Participants were randomized to 6 weeks of either ACT with CF or SP, delivered via Zoom. They completed measures of psychological functioning: depression (BDI-II), anxiety (BAI), cognitive fusion (CFQ-13), acceptance and committed action (AAQ-II); and barriers to adherence at baseline, post-treatment, and at 3-months follow-up. Biobehavioral outcomes, including CF severity and treatment burden, were gathered using EMR data.

RESULTS: Participants were young adults (mean age 25 years [SD = 12]), female (75 %), on CFTR modulators (67 %), psychotropic medication(s) (60 %), with previous psychotherapy engagement (72 %). Treatment effects were evaluated using analysis of covariance, controlling for baseline levels of respective outcomes, age, biological sex, and FEV1. ACT demonstrated greater improvements in psychological functioning at 6-weeks (mean score = 57.3 [51.6, 63.0]) relative to SP (mean score = 67.8 [62.2, 73.5], Cohen's d = 0.59, P = .017), with largest improvements in cognitive fusion (CFQ-13) and acceptance and committed action (AAQ-II). Treatment improvements in psychological functioning persisted at 3-months (ACT: 59.7 (53.5, 65.9) vs. SP: 69.0 [62.6, 75.4], Cohen's d = 0.40, P = .041), with ACT demonstrating continued improvements in the CFQ-13 and AAQ-II. Negative affect scores were not consistently improved on our mean-rank composite outcome variable (Cohen's d = 0.22, P = .170), despite post hoc reductions in BDI-II scores (ACT: -7.4 [-9.4, -5.4] vs. SP: -4.5 [-6.4, -2.6], P = .040). Improvements in psychological flexibility (CFQ-13 and AAQ-II) were also robustly associated with reductions in negative affect (B = -0.45, P < .001). Individuals in ACT with greater baseline barriers to medication adherence reported greater reductions in barriers after treatment (P = .026). Individuals with lower baseline FEV1/FVC ratios (e.g. ≤ 65 %) demonstrating greater improvements in ACT compared with SP (ACT: 7.3 [1.7, 12.8] vs. SP: 1.3 [-3.2, 5.8], P = .036 for interaction).

CONCLUSIONS: ACT with CF was superior to SP in improving psychological functioning among adults with CF and elevated psychological distress, with additional benefits in secondary biobehavioral outcomes in a subset of individuals with greater medical burden. Improvements in psychological flexibility strongly associated with reductions in negative affect.

CLINICALTRIALS: gov ID #NCT04114227 Supported by the Boomer Esiason Foundation.

PMID:39626332 | DOI:10.1016/j.genhosppsych.2024.11.011

J Med Internet Res. 2024 Dec 3;26:e60892. doi: 10.2196/60892.

ABSTRACT

BACKGROUND: Portable spirometers are increasingly used to measure lung function at home, but doubts about the accuracy of these devices persist. These doubts stand in the way of the digital transition of chronic respiratory disease care, hence there is a need to address the accuracy of home spirometry in routine care across multiple settings and ages.

OBJECTIVE: This study aimed to assess the accuracy, reproducibility, and responsiveness to the treatment of home spirometry in long-term pediatric and adult cystic fibrosis care.

METHODS: This retrospective observational study was carried out in 5 Dutch cystic fibrosis centers. Home spirometry outcomes (forced expiratory volume in one second [FEV1], and forced vital capacity [FVC]) for 601 anonymized users were collected during 3 years. For 81 users, data on clinic spirometry and elexacaftor/tezacaftor/ivacaftor (ETI) use were available. Accuracy was assessed using Bland-Altman plots for paired clinic-home measurements on the same day and within 7 days of each other (nearest neighbor). Intratest reproducibility was assessed using the American Thoracic Society/European Respiratory Society repeatability criteria, the coefficient of variation, and spirometry quality grades. Responsiveness was measured by the percentage change in home spirometry outcomes after the start of ETI.

RESULTS: Bland-Altman analysis was performed for 86 same-day clinic-home spirometry pairs and for 263 nearest neighbor clinic-home spirometry pairs (n=81). For both sets and for both FEV1 and FVC, no heteroscedasticity was present and hence the mean bias was expressed as an absolute value. Overall, home spirometry was significantly lower than clinic spirometry (mean ΔFEV1clinic-home 0.13 L, 95% CI 0.10 to 0.19; mean ΔFVCclinic-home 0.20 L, 95% CI 0.14 to 0.25) and remained lower than clinic spirometry independent of age and experience. One-way ANOVA with post hoc comparisons showed significantly lower differences in clinic-home spirometry in adults than in children (Δmean 0.11, 95% CI -0.20 to -0.01) and teenagers (Δmean 0.14, 95% CI -0.25 to -0.02). For reproducibility analyses, 2669 unique measurement days of 311 individuals were included. Overall, 87.3% (2331/2669) of FEV1 measurements and 74.3% (1985/2669) of FVC measurements met reproducibility criteria. Kruskal-Wallis with pairwise comparison demonstrated that for both FVC and FEV1, coefficient of variation was significantly lower in adults than in children and teenagers. A total of 5104 unique home measurements were graded. Grade E was given to 2435 tests as only one home measurement was performed. Of the remaining 2669 tests, 43.8% (1168/2669) and 43.6% (1163/2669) received grade A and B, respectively. The median percentage change in FEV1 from baseline after initiation of ETI was 19.2% after 7-14 days and remained stable thereafter (n=33).

CONCLUSIONS: Home spirometry is feasible but not equal to clinic spirometry. Home spirometry can confirm whether lung functions remain stable, but the context of measurement and personal trends are more relevant than absolute outcomes.

PMID:39626236 | DOI:10.2196/60892

PLoS One. 2024 Dec 3;19(12):e0313510. doi: 10.1371/journal.pone.0313510. eCollection 2024.

ABSTRACT

INTRODUCTION: Prolonged gaps in care of >12-months are frequent among people with cystic fibrosis (pwCF) and are associated with reduced lung function. Comprehensive analysis of patient-level predictors of visit frequency is needed to optimize protocols for stable pwCF and identify subgroups at high risk of gaps and poor outcomes, promoting equitable treatment for all pwCF.

OBJECTIVE: To determine sociodemographic and disease-related factors predictive of visit frequency in pwCF and to assess how these effects vary across the lifespan.

METHODS: We conducted an observational cohort study using data from 2004-2016 for pwCF aged 6-60 years in the US Cystic Fibrosis Foundation Patient Registry. We modeled the relationship between patient-level characteristics and between-visit interval (BVI) using multivariable longitudinal semiparametric regression. BVI was defined as the number of days from the index encounter to the previously recorded visit.

RESULTS: The study included 28,588 pwCF with 859,568 encounters. Overall, 55% of visits occurred within 90 days of the prior visit, adhering to national guidelines. On average, adults without common CF-complications attended clinic approximately every 4 months, with a BVI ≥ 110 days from age 23-56. Males attended clinic less frequently than females (9.8% longer BVI; 95% CI 9.1%, 10.5%; p<0.001), as did non-white individuals (3.6% longer BVI than whites; 95% CI 2.2%, 5.0%; p<0.001), with the greatest differences seen in young adults. Those with public and private insurance largely adhered to current guidelines (maximum average BVI of 90 and 95 days, respectively). In contrast, uninsured individuals over age 25 had a mean BVI ≥ 30 days longer than the insured.

CONCLUSIONS: Frequent visits in those with CF-complications likely reflects higher need, while less frequent visits in male, non-white, and uninsured individuals may reflect patient-preference or structural barriers to care. Risk factors for gaps in care should inform changes to CF care recommendations going forward.

PMID:39625878 | DOI:10.1371/journal.pone.0313510

Microbiol Spectr. 2024 Dec 3:e0151324. doi: 10.1128/spectrum.01513-24. Online ahead of print.

ABSTRACT

Reproducibility is a fundamental expectation in science and enables investigators to have confidence in their research findings and the ability to compare data from disparate sources, but evaluating reproducibility can be elusive. For example, generating RNA sequencing (RNA-seq) data includes multiple steps where variance can be introduced. Thus, it is unclear if RNA-seq data from different sources can be validly compared. While most studies on RNA-seq reproducibility focus on eukaryotes, we evaluate bias in bacteria using Pseudomonas aeruginosa gene expression data from five laboratory models of cystic fibrosis. We leverage a large data set that includes samples prepared in three different laboratories and paired data sets where the same sample was sequenced using at least two different sequencing pipelines. We report here that expression data are highly reproducible across laboratories. In addition, while samples sequenced with different sequencing pipelines showed significantly more variance in expression profiles than between labs, gene expression was still highly reproducible between sequencing pipelines. Further investigation of expression differences between two sequencing pipelines revealed that library preparation methods were the largest source of error, though analyses to identify the source of this variance were inconclusive. Consistent with the reproducibility of expression between sequencing pipelines, we found that different pipelines detected over 80% of the same differentially expressed genes with large expression differences between conditions. Thus, bacterial RNA-seq data from different sources can be validly compared, facilitating the ability to advance understanding of bacterial behavior and physiology using the wide array of publicly available RNA-seq data sets.IMPORTANCERNA sequencing (RNA-seq) has revolutionized biology, but many steps in RNA-seq workflows can introduce variance, potentially compromising reproducibility. While reproducibility in RNA-seq has been thoroughly investigated in eukaryotes, less is known about pipelines and workflows that introduce variance and biases in bacterial RNA-seq data. By leveraging Pseudomonas aeruginosa transcriptomes in cystic fibrosis models from different laboratories and sequenced with different sequencing pipelines, we directly assess sources of bacterial RNA-seq variance. RNA-seq data were highly reproducible, with the largest variance due to sequencing pipelines, specifically library preparation. Different sequencing pipelines detected overlapping differentially expressed genes, especially those with large expression differences between conditions. This study confirms that different approaches to preparing and sequencing bacterial RNA libraries capture comparable transcriptional profiles, supporting investigators' ability to leverage diverse RNA-seq data sets to advance their science.

PMID:39625302 | DOI:10.1128/spectrum.01513-24