Proc Natl Acad Sci U S A. 2023 Jul 25;120(30):e2301538120. doi: 10.1073/pnas.2301538120. Epub 2023 Jul 17.

ABSTRACT

Pseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.

PMID:37459522 | DOI:10.1073/pnas.2301538120

Allergy. 2023 Jul 17. doi: 10.1111/all.15820. Online ahead of print.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) develops in the presence or absence of asthma, either atopic or nonatopic. We have tried to explore the essential components in the pathogenesis of the disease, which are either consistent and variable according to the presence and type of asthma.

METHODS: Non-cystic fibrosis ABPA cases satisfying Asano's criteria were extracted from a prospective registry of ABPA and related diseases in Japan between 2013 and 2023. According to the type of preceding asthma, ABPA was classified into three groups: ABPA sans asthma (no preceding asthma), ABPA with atopic asthma, and ABPA with nonatopic asthma. Exploratory and confirmatory factor analyses were performed to identify the components that determined the clinical characteristics of ABPA.

RESULTS: Among 106 cases of ABPA, 25 patients (24%) had ABPA sans asthma, whereas 57 (54%) and 24 (23%) had ABPA with atopic and nonatopic asthma, respectively. Factor analysis identified three components: allergic, eosinophilic, and fungal. Patients with atopic asthma showed the highest scores for the allergic component (p < .001), defined by total and allergen-specific IgE titers and lung opacities, and the lowest scores for the fungal component defined by the presence of specific precipitin/IgG or positive culture for A. fumigatus. Eosinophilic components, including peripheral blood eosinophil counts and presence of mucus plugs/high attenuation mucus in the bronchi, were consistent among the three groups.

CONCLUSION: The eosinophilic component of ABPA is considered as the cardinal feature of ABPA regardless of the presence of preceding asthma or atopic predisposition.

PMID:37458287 | DOI:10.1111/all.15820

Front Immunol. 2023 Jun 29;14:1180282. doi: 10.3389/fimmu.2023.1180282. eCollection 2023.

ABSTRACT

Cystic fibrosis (CF) is a monogenetic disease caused by an impairment of the cystic fibrosis transmembrane conductance regulator (CFTR). CF affects multiple organs and is associated with acute and chronic inflammation. In 2020, Elexacaftor-Tezacaftor-Ivacaftor (ETI) was approved to enhance and restore the remaining CFTR functionality. This study investigates cellular innate immunity, with a focus on neutrophil activation and phenotype, comparing healthy volunteers with patients with CF before (T1, n = 13) and after six months (T2, n = 11) of ETI treatment. ETI treatment reduced sweat chloride (T1: 95 mmol/l (83|108) vs. T2: 32 mmol/l (25|62), p < 0.01, median, first|third quartile) and significantly improved pulmonal function (FEV1 T1: 2.66 l (1.92|3.04) vs. T2: 3.69 l (3.00|4.03), p < 0.01). Moreover, there was a significant decrease in the biomarker human epididymis protein 4 (T1: 6.2 ng/ml (4.6|6.3) vs. T2: 3.0 ng/ml (2.2|3.7), p < 0.01) and a small but significant decrease in matrix metallopeptidase 9 (T1: 45.5 ng/ml (32.5|140.1) vs. T2: 28.2 ng/ml (18.2|33.6), p < 0.05). Neutrophil phenotype (CD10, CD11b, CD62L, and CD66b) and function (radical oxygen species generation, chemotactic and phagocytic activity) remained largely unaffected by ETI treatment. Likewise, monocyte phenotype and markers of platelet activation were similar at T1 and T2. In summary, the present study confirmed a positive impact on patients with CF after ETI treatment. However, neither beneficial nor harmful effects of ETI treatment on cellular innate immunity could be detected, possibly due to the study population consisting of patients with well-controlled CF.

PMID:37457734 | PMC:PMC10347380 | DOI:10.3389/fimmu.2023.1180282

Front Immunol. 2023 Jun 29;14:1202009. doi: 10.3389/fimmu.2023.1202009. eCollection 2023.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) airway disease is characterized by chronic inflammation, featuring neutrophil influx to the lumen. Airway macrophages (AMs) can promote both inflammation and resolution, and are thus critical to maintaining and restoring homeostasis. CF AM functions, specifically scavenging activity and resolution of inflammation, have been shown to be impaired, yet underlying processes remain unknown. We hypothesized that impaired CF AM function results from an altered expression of receptors that mediate or regulate scavenging, and set out to investigate changes in expression of these markers during the early stages of CF lung disease.

METHODS: Bronchoalveolar lavage fluid (BALF) was collected from 50 children with CF aged 1, 3 or 5 years. BALF cells were analyzed using flow cytometry. Expression levels of surface markers on AMs were expressed as median fluorescence intensities (MFI) or percentage of AMs positive for these markers. The effect of age and neutrophilic inflammation, among other variables, on marker expression was assessed with a multivariate linear regression model.

RESULTS: AM expression of scavenger receptor CD163 decreased with age (p = 0.016) and was negatively correlated with BALF %neutrophils (r = -0.34, p = 0.016). AM expression of immune checkpoint molecule SIRPα also decreased with age (p = 0.0006), but did not correlate with BALF %neutrophils. Percentage of AMs expressing lipid scavenger CD36 was low overall (mean 20.1% ± 16.5) and did not correlate with other factors. Conversely, expression of immune checkpoint PD-1 was observed on the majority of AMs (mean PD-1pos 72.9% ± 11.8), but it, too, was not affected by age or BALF %neutrophils. Compared to matched blood monocytes, AMs had a higher expression of CD16, CD91, and PD-1, and a lower expression of CD163, SIRPα and CD36.

CONCLUSION: In BALF of preschool children with CF, higher age and/or increased neutrophilic inflammation coincided with decreased expression of scavenger receptors on AMs. Expression of scavenging receptors and regulators showed a distinctly different pattern in AMs compared to blood monocytes. These findings suggest AM capacity to counter inflammation and promote homeostasis reduces during initiation of CF airway disease and highlight new avenues of investigation into impaired CF AM function.

PMID:37457715 | PMC:PMC10338875 | DOI:10.3389/fimmu.2023.1202009

J Cyst Fibros. 2023 Jul 14:S1569-1993(23)00821-4. doi: 10.1016/j.jcf.2023.06.008. Online ahead of print.

ABSTRACT

BACKGROUND: Antibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF.

METHODS: ALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above -20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs).

RESULTS: In total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3-17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), -8.0% (-24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed.

CONCLUSIONS: Non-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF.

CLINICALTRIALS: GOV: NCT03219164.

PMID:37455237 | DOI:10.1016/j.jcf.2023.06.008

J Cyst Fibros. 2023 Jul 13:S1569-1993(23)00831-7. doi: 10.1016/j.jcf.2023.07.001. Online ahead of print.

ABSTRACT

BACKGROUND: Association of a high-fat diet with increased risks of cardiovascular disease (CVD) and type 2 diabetes, has prompted evaluation of lipids in people with CF (pwCF). However, most evidence on dyslipidemia was published before CF transmembrane conductance regulator (CFTR) modulators became a standard of care. The main goal of this study was to investigate the effect of CFTR modulator therapies on lipid and lipoprotein profiles in children and adolescents with CF.

METHODS: Blood samples were collected from 153 pwCF (10.1 ± 4.7 years of age) and 60 age-matched controls. Most pwCF were pancreatic insufficient on pancreatic enzyme replacement therapy. By the end of the study, 65% of CF participants were on CFTR modulator therapy for >1 month. The results of traditional and advanced lipid testing in pwCF were correlated with clinical and dietary information.

RESULTS: Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly lower in pwCF compared to non-CF participants. Those not receiving CFTR modulators also had significantly lower high-density lipoprotein (HDL) cholesterol and HDL particle number than controls. Individuals with CF on modulator therapy had significantly higher concentrations of anti-atherogenic HDL cholesterol and HDL particles along with lower levels of atherogenic large very-low density lipoprotein (VLDL) particles, total and small LDL particles, and triglycerides compared to those without CFTR modulator therapy.

CONCLUSION: CFTR modulator therapy has a beneficial effect on dyslipidemia in CF. It remains to be seen if these positive changes translate into decreased CVD risk later in life given the increasing life expectancy in CF.

PMID:37453889 | DOI:10.1016/j.jcf.2023.07.001

Thorax. 2023 Jul 14:thorax-2023-220031. doi: 10.1136/thorax-2023-220031. Online ahead of print.

ABSTRACT

INTRODUCTION: People with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach for people already on DNase is to add hypertonic saline (HS). The effects of DNase and HS used alone have been studied in randomised trials, but their effects in combination have not. This study investigates whether, for people already prescribed DNase, adding HS has additional benefit for lung function or use of intravenous antibiotics.

METHODS: Using UK CF Registry data from 2007 to 2018, we emulated a target trial. We included people aged 6 years and over who were prescribed DNase without HS for 2 years. We investigated the effects of combinations of DNase and HS over 5 years of follow-up. Inverse-probability-of-treatment weighting was used to control confounding. The period predated triple combination CF transmembrane conductance regulator modulators in routine care.

RESULTS: 4498 individuals were included. At baseline, average age and forced expiratory volume in 1 s (FEV1%) predicted were 21.1 years and 69.7 respectively. During first year of follow-up, 3799 individuals were prescribed DNase alone; 426 added HS; 57 switched to HS alone and 216 were prescribed neither. We found no evidence that adding HS improved FEV1% at 1-5 years, or use of intravenous antibiotics at 1-4 years, compared with DNase alone.

CONCLUSION: For individuals with CF prescribed DNase, we found no evidence that adding HS had an effect on FEV1% or prescription of intravenous antibiotics. Our study illustrates the emulated target trial approach using CF Registry data.

PMID:37451864 | DOI:10.1136/thorax-2023-220031

PDA J Pharm Sci Technol. 2023 Jul 14:pdajpst.2021.012720. doi: 10.5731/pdajpst.2021.012720. Online ahead of print.

ABSTRACT

USP General Chapter <60> for the detection of Burkholderia cepacia complex (Bcc) members in non-sterile products became official in December 2019. This isolation method requires to confirm the identity of any growth found on Burkholderia cepacia Selective Agar (BCSA) by additional identification tests (refer to the Interpretation section). This article presents a singleplex PCR method to rapidly confirm the membership of any microbial grown on BCSA (& other nutrient medium) in the Bcc group. This method is cost effective as it does not require expensive equipment nor reagents; therefore, it can be easily adopted in the industry. We validated this singleplex PCR Bcc identification method with previously published PCR primers with an expanded panel of 37 clinical and environmental Bcc isolates. The sources and repositories of these Bcc isolates include contaminated health products and medical devices, patients infected with cystic fibrosis, the National Microbiology Laboratory (NML) internal bank and the American type culture collection (ATCC). All 37 isolates that belong to the Bcc have been tested positive using our confirmatory identification method. Twenty-two negative controls including 4 isolates belonging to the genus Burkholderia have been tested negative as expected. Our work indicates this singleplex PCR is an efficient confirmatory method for a Bcc identification, and it can successfully supplement USP chapter <60> in Bcc isolate identification found in pharmaceutical products.

PMID:37451835 | DOI:10.5731/pdajpst.2021.012720

Arch Dis Child. 2023 Jul 14:archdischild-2023-325629. doi: 10.1136/archdischild-2023-325629. Online ahead of print.

ABSTRACT

OBJECTIVE: We conducted a systematic review and meta-analysis of diagnostic test accuracy studies to summarise the properties of sweat conductivity (SC) to rule in/out cystic fibrosis (CF).

DATA SOURCE: We searched PubMed, Embase, Web of Science, Google Scholar, SciELO and LILACS up to 13 March 2023.

STUDY SELECTION: We selected prospective and retrospective diagnostic test accuracy studies which compared SC, measured through two well-established and commercially available devices, that is, Nanoduct or Sweat-Chek Analyser, to quantitative measurement of sweat chloride.

MAIN OUTCOME MEASURES: Pooled sensitivity, specificity, positive likelihood ratio (+LR) and negative likelihood ratio (-LR), and their corresponding 95% CIs.

DATA EXTRACTION AND SYNTHESIS: The Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies guidelines were followed. Data were extracted by one reviewer and checked by another. The hierarchical summary receiver operating characteristics model was used to estimate diagnostic test accuracy.

RESULTS: Ten studies involving 8286 participants were included. The pooled estimates of sensitivity, specificity, +LR and -LR were 0.97 (95% CI 0.94 to 0.98), 0.99 (95% CI 0.98 to 0.99), 171 (95% CI 58 to 500) and 0.02 (95% CI 0.01 to 0.05), respectively. Sensitivity analyses did not reveal a substantial impact of study-level factors on the results, such as study quality, cut-off values for a positive test, study sample size and participant age group. The quality of evidence was considered moderate.

CONCLUSION: SC demonstrated excellent diagnostic performance. In addition, its accuracy parameters suggest its role as an alternative to the sweat test for CF diagnosis.

PROSPERO REGISTRATION NUMBER: CRD42022284504.

PMID:37451832 | DOI:10.1136/archdischild-2023-325629

PLoS One. 2023 Jul 14;18(7):e0288704. doi: 10.1371/journal.pone.0288704. eCollection 2023.

ABSTRACT

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease resulting in chronic cough, thick sputum, and lower airway microbial colonization, akin to patients with cystic fibrosis (CF). NCFB is a common, yet under recognized entity which inflicts significant morbidity and mortality particularly to older individuals, with a rising prevalence in the developed world. Given that sputum cultures are a non-invasive method to characterize the lower airway microbiota in NCFB patients, for which pathogenic organisms are associated with worsened outcomes, we sought to characterize the microbiological pattern and clinical outcomes associated with sputum culture in a cohort of NCFB patients from Western Canada. A total of 20 subjects were prospectively recruited from various bronchiectasis clinics across the Greater Edmonton area. A retrospective chart review and a symptoms questionnaire was performed, gathering information not limited to symptoms, comorbidities, exacerbations, hospitalizations, sputum production, and sputum culture results over the prior 5 years. Subjects reported frequent hospitalization alongside a significant burden of symptoms. A large majority of sputum cultures grew pathogenic organisms such as Haemophilus influenzae and Pseudomonas aeruginosa. We also note the considerable waste and inefficiency associated with sputum cultures, outlining areas for which this important diagnostic modality can be improved. Accurate characterization of the airway microbiota alongside efficient delivery of health services are key to ensuring the proper treatment of individuals with NCFB, given their high disease burden and frequent hospitalization.

PMID:37450508 | DOI:10.1371/journal.pone.0288704

Heliyon. 2023 Jun 29;9(7):e17553. doi: 10.1016/j.heliyon.2023.e17553. eCollection 2023 Jul.

ABSTRACT

Pathophysiological manifestations of cystic fibrosis (CF) result from a functional defect in the cystic fibrosis transmembrane conductance regulator (CFTR) paving way for mucus obstruction and pathogen colonization. The role of CFTR in modulating immune cell function and vascular integrity, irrespective of mucus thickening, in determining the host cell response to pathogens/allergens and causing systemic inflammation is least appreciated. Since CFTR plays a key role in the conductance of anions like Cl-, loss of CFTR function could affect various basic cellular processes, such as cellular homeostasis, lysosome acidification, and redox balance. CFTR aids in endotoxin tolerance by regulating Toll-like receptor-mediated signaling resulting in uncontrolled activation of innate immune cells. Although leukocytes of CF patients are hyperactivated, they exhibit compromised phagosome activity thus favouring the orchestration of sepsis from defective pathogen clearance. This review will emphasize the importance of innate immunity and systemic inflammatory response in the development of CF and other CFTR-associated pathologies.

PMID:37449112 | PMC:PMC10336457 | DOI:10.1016/j.heliyon.2023.e17553

Mediators Inflamm. 2023 Jul 5;2023:3406399. doi: 10.1155/2023/3406399. eCollection 2023.

ABSTRACT

INTRODUCTION: Bronchiolitis obliterans (BO) is a chronic lung disease, which occurs after an insult to the lower airways, in particular after airway infections or after stem cell transplantation, and which results in persistent inflammation. N-3 and n-6 polyunsaturated fatty acids (PUFA) have been shown to influence the inflammatory processes in chronic inflammatory conditions. Since BO is maintained by persistent pulmonary inflammation, a disbalanced n-6/n-3 fatty acid profile could support the inflammatory process in patients with BO and therefore, could become an approach to new therapeutic options.

METHODS: Twenty-five patients with BO (age: 13; 7-39) and 26 healthy controls (age: 19; 7-31) participated in the study. Lung function (forced viral capacity (FVC), forced expiratory volume 1 (FEV1), residual volume (RV)), and lung clearance index (LCI) were measured. Induced sputum was analyzed for cytology and cytokine levels (IL-1ß, IL-6, IL-8, TNF-α) using cytometric bead array (CBA). The PUFA profile was determined in the serum and induced sputum by gas chromatography.

RESULTS: Patients presented with significantly lower FVC and FEV1 as well as higher RV and LCI measurements compared to the control group. Apart from a massive airway inflammation indicated by elevated numbers of total cells and neutrophils, the CBA analysis showed significantly increased levels of IL-1β, IL-6, and IL-8. The analysis of PUFA in sputum and serum revealed a significant difference in the ratio between the n-6 PUFA arachidonic acid (AA) and the n-3 PUFA docosahexaenoic acid (DHA) (AA : DHA). Furthermore, the AA : DHA ratio significantly correlated with the inflammatory cytokines in induced sputum.

CONCLUSION: Lung function in BO is significantly impaired and associated with uncontrolled neutrophil-dominated airway inflammation. Furthermore, the imbalance in the AA/DHA ratio in favor of n-6 PUFA demonstrates a pro-inflammatory microenvironment in the cell membrane, which correlates with the inflammatory cytokines in induced sputum and might be an option for an anti-inflammatory therapy in BO.

PMID:37448886 | PMC:PMC10338129 | DOI:10.1155/2023/3406399

Front Med (Lausanne). 2023 Jun 28;10:1198173. doi: 10.3389/fmed.2023.1198173. eCollection 2023.

ABSTRACT

CONTEXT: While oral immunotherapy (OIT) has been shown to promote the remission of mild peanut allergy in young children, there is still an unmet need for a disease-modifying intervention for older patients and those with severe diseases. In mice models, abatacept, a cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) immunoglobulin fusion protein, has been shown to promote immune tolerance to food when used as an adjuvant to allergen immunotherapy. The goal of this study is to explore the potential efficacy of abatacept in promoting immune tolerance to food allergens during OIT in humans.

METHODS: In this phase 2a proof-of-concept study (NCT04872218), 14 peanut-allergic participants aged from 14 to 55 years will be randomized at a 1:1 ratio to abatacept vs. placebo for the first 24 weeks of a peanut OIT treatment (target maintenance dose of 300 mg peanut protein). The primary outcome will be the suppression of the OIT-induced surge in peanut-specific IgE/total IgE at 24 weeks, relative to the baseline. Sustained unresponsiveness will be assessed as a secondary outcome starting at 36 weeks by observing incremental periods of peanut avoidance followed by oral food challenges.

DISCUSSION: This is the first study assessing the use of abatacept as an adjuvant to allergen immunotherapy in humans. As observed in preclinical studies, the ability of abatacept to modulate the peanut-specific immune response during OIT will serve as a proxy outcome for the development of clinical tolerance, given the small sample size. The study will also test a new patient-oriented approach to sustained tolerance testing in randomized controlled trials.

PMID:37448803 | PMC:PMC10336224 | DOI:10.3389/fmed.2023.1198173

J Clin Transl Endocrinol. 2023 Jun 24;33:100320. doi: 10.1016/j.jcte.2023.100320. eCollection 2023 Sep.

ABSTRACT

AIMS: Combined CFTR modulator therapies have dramatically altered pulmonary outcomes in patients with cystic fibrosis (CF). Their impact on glucose metabolism requires further investigations. This study aims to evaluate insulin requirements after initiation of combined CFTR modulator therapy in patients with CF-related diabetes (CFRD) and HOMA indices changes in CF patients without diabetes.

METHODS: We retrospectively analyzed: 1) the effects of tezacaftor + ivacaftor and elexacaftor + tezacaftor + ivacaftor on FEV1, weight, BMI, HbA1c, and daily insulin dose, in 17 CFRD patients and 2) the impact of tezacaftor + ivacaftor on HOMA indices in 15 CF patients without diabetes.

RESULTS: Age was 37±12y in the CFRD group (70% men), 88% of whom were homozygous for F508del mutation. Diabetes duration was 15±10y. Median duration of combined CFTR modulator therapy was 16 months (IQR: 4) Thirteen patients received tezacaftor + ivacaftor, of whom 9 were switched to elexacaftor + tezacaftor + ivacaftor. Four patients received elexacaftor + tezacaftor + ivacaftor up front. A decrease in insulin needs was noticed in 88% of patients (0.85±0.3 vs 0.71±0.3U/kg/day; p = 0001). Total daily insulin dose decreased from 50±16 to 44±20U/day (p = 0.017). BMI improved (20.9 (IQR: 1.90) vs 22.1 kg/m2 (IQR: 3.70); p = 0.014). HbA1c went from 7.3±1.1 to 7.7±1.6% (p = 0.072). Median age was 22y (IQR: 11) in the CF group without diabetes (67% men), 93% of whom were homozygous for F508del mutation. Duration of combined CFTR modulator therapy was 10±5 months. HOMA-B changes were not significant (129.2 (IQR: 84.8) vs 103.5% (IQR: 66.3) nor were HOMA-S changes (from 94±64 to 95±49%). HOMA-BxS decreased from 112±45 to 104±29% (NS). BMI rose from 21.9±3 to 23.1±3.5 kg/m2 (p = 0.047). HbA1c was unchanged (5.0±0.5%). FEV1 improved in both groups (+11% and + 7% of predicted value; p < 0.001; p = 0.013).

CONCLUSION: Combined CFTR modulator therapies are correlated with a decrease in insulin doses and positive effects on BMI and FEV1. HOMA indices did not change on tezacaftor + ivacaftor among CF patients without diabetes.

PMID:37448650 | PMC:PMC10336243 | DOI:10.1016/j.jcte.2023.100320

Learn Health Syst. 2022 Dec 19;7(3):e10354. doi: 10.1002/lrh2.10354. eCollection 2023 Jul.

ABSTRACT

INTRODUCTION: A learning health network is a type of learning health system in which stakeholders use network organization to improve health and health care. Building on existing resources in the cystic fibrosis (CF) community, the Cystic Fibrosis Learning Network (CFLN) was designed to improve medical outcomes and quality of life through an intentional focus on achieving reliable evidence-based chronic care delivery and creating a system for data-driven collaborative learning.

METHODS: We describe the development and growth of the CFLN considering six domains of a Network Maturity Grid: system leadership; governance and policy management; quality improvement (QI); engagement and community building; data and analytics; and research. We illustrate the impact of the CFLN experience on chronic care processes and indicators of collaborative infrastructure.

RESULTS: The CFLN represents 36 accredited care centers in the CF Foundation Care Center Network caring for over 6300 patients. Of 6779 patient clinical care visits/quarter, 77% are entered into the CF Foundation Patient Registry within 30 days, providing timely means to track outcomes. Collaborative visit planning is occurring in 93% of clinical care visits to share agenda setting with patients and families. Almost all CFLN teams (94%, n = 34) have a patient/family partner (PFP), and 74% of PFPs indicate they are actively participating, taking ownership of, or leading QI initiatives with the interdisciplinary care team. In 2022, 97% of centers reported completing 1-13 improvement cycles per month, and 82% contributed to monthly QI progress reports to share learning.

CONCLUSION: The CFLN is a maturing, collaborative infrastructure. CFLN centers practice at an advanced level of coproduction. The CFLN fosters interdisciplinary and PFP leadership and the performance of consistent data-driven improvement cycles. CFLN centers are positioned to respond to rapid changes in evidence-based care and advance the practice of QI and implementation science on a broader scale.

PMID:37448461 | PMC:PMC10336485 | DOI:10.1002/lrh2.10354

Nutrients. 2023 Jun 25;15(13):2875. doi: 10.3390/nu15132875.

ABSTRACT

Tube feeding is a life-saving treatment for children with neurological disabilities (ND), who often suffer from malnutrition and feeding disorders. Nonetheless, it is still not widely used. Our aim was to evaluate the outcomes of exclusive tube feeding in a cohort of ND children. All consecutive ND children who started tube feeding at our center within the last 5 years were included in this retrospective study. Weight-for-age, body mass index (BMI), mid-upper arm circumference (MUAC) Z-scores, and symptoms were collected at baseline (V0), 6 (V1), and 12 months (V2) after gastrostomy placement. Fifty children (62% males) were included. The ND-underlying disease was genetic (n = 29, 58%), hypoxic-ischemic encephalopathy (n = 17, 34%), or metabolic (n = 4, 8%). Indications for tube feeding were malnutrition (n = 35, 70%), recurrent respiratory infections (n = 11, 22%), or both (n = 4, 8%). Enteral formulae were polymeric (n = 29, 58%), semi-elemental (n = 17, 34%), hypercaloric (n = 3, 6%), or elemental (n = 1, 2%). Homemade blended feed was offered to three children (6%) in addition to the formula. Weight and BMI increased over the study period. Except for constipation, all symptoms (cough, vomiting, and diarrhea) improved at 6 and 12 months (p < 0.05). Non-serious complications (n = 8; track disruption, granuloma, and skin infection) were observed. Longer disease duration (p < 0.001) at the start of tube feeding was associated with the absence of normalization of nutritional status (BMI Z-score > 2 SD) at 12 months. Tube feeding with commercially available enteral formulae should be started as early as possible for better outcomes.

PMID:37447202 | DOI:10.3390/nu15132875

Int J Mol Sci. 2023 Jul 4;24(13):11069. doi: 10.3390/ijms241311069.

ABSTRACT

Renal proximal tubular epithelial cells (PTCs) are central players during renal inflammation. In response to inflammatory signals, PTCs not only self-express altered mRNAs, microRNAs (miRNAs), proteins, and lipids, but also release altered extracellular vesicles (EVs). These EVs also carry inflammation-specific cargo molecules and are key players in cell-cell-communication. Understanding the precise molecular and cellular mechanisms that lead to inflammation in the kidney is the most important way to identify early targets for the prevention or treatment of acute kidney injury. Therefore, highly purified human PTCs were used as an in vitro model to study the cellular response to an inflammatory microenvironment. A cytokine-induced inflammatory system was established to analyze different miRNA expression in cells and their EVs. In detail, we characterized the altered miR expression of PTCs and their released EVs during induced inflammation and showed that 12 miRNAs were significantly regulated in PTCs (6 upregulated and 6 downregulated) and 9 miRNAs in EVs (8 upregulated and 1 downregulated). We also showed that only three of the miRNAs were found to overlap between cells and EVs. As shown by the KEGG pathway analysis, these three miRNAs (miR-146a-5p, miR-147b, and miR-155-5p) are functionally involved in the regulation of the Toll-like receptor signaling pathway and significantly correlated with the inflammatory mediators IL6 and ICAM1 released by stimulated PTCs. Especially with regard to a possible clinical use of miRs as new biomarkers, an accurate characterization of the miR expression altered during inflammatory processes is of enormous importance.

PMID:37446246 | DOI:10.3390/ijms241311069

Int J Mol Sci. 2023 Jul 4;24(13):11062. doi: 10.3390/ijms241311062.

ABSTRACT

Mycobacterium abscessus, a species of nontuberculous mycobacteria (NTM), is an opportunistic pathogen that is readily cleared by healthy lungs but can cause pulmonary infections in people with chronic airway diseases. Although knowledge pertaining to molecular mechanisms of host defense against NTM is increasing, macrophage receptors that recognize M. abscessus remain poorly defined. Dectin-1, a C-type lectin receptor identified as a fungal receptor, has been shown to be a pathogen recognition receptor (PRR) for both M. tuberculosis and NTM. To better understand the role of Dectin-1 in host defense against M. abscessus, we tested whether blocking Dectin-1 impaired the uptake of M. abscessus by human macrophages, and we compared M. abscessus pulmonary infection in Dectin-1-deficient and wild-type mice. Blocking antibody for Dectin-1 did not reduce macrophage phagocytosis of M. abscessus, but did reduce the ingestion of the fungal antigen zymosan. Laminarin, a glucan that blocks Dectin-1 and other PRRs, caused decreased phagocytosis of both M. abscessus and zymosan. Dectin-1-/- mice exhibited no defects in the control of M. abscessus infection, and no differences were detected in immune cell populations between wild type and Dectin-1-/- mice. These data demonstrate that murine defense against M. abscessus pulmonary infection, as well as ingestion of M. abscessus by human macrophages, can occur independent of Dectin-1. Thus, additional PRR(s) recognized by laminarin participate in macrophage phagocytosis of M. abscessus.

PMID:37446240 | DOI:10.3390/ijms241311062

Int J Mol Sci. 2023 Jun 30;24(13):10940. doi: 10.3390/ijms241310940.

ABSTRACT

It is reported that about 10% of cystic fibrosis (CF) patients worldwide have nonsense (stop) mutations in the CFTR gene, which cause the premature termination of CFTR protein synthesis, leading to a truncated and non-functional protein. To address this issue, we investigated the possibility of rescuing the CFTR nonsense mutation (UGA) by sequence-specific RNA editing in CFTR mutant CFF-16HBEge, W1282X, and G542X human bronchial cells. We used two different base editor tools that take advantage of ADAR enzymes (adenosine deaminase acting on RNA) to edit adenosine to inosine (A-to-I) within the mRNA: the REPAIRv2 (RNA Editing for Programmable A to I Replacement, version 2) and the minixABE (A to I Base Editor). Immunofluorescence experiments show that both approaches were able to recover the CFTR protein in the CFTR mutant cells. In addition, RT-qPCR confirmed the rescue of the CFTR full transcript. These findings suggest that site-specific RNA editing may efficiently correct the UGA premature stop codon in the CFTR transcript in CFF-16HBEge, W1282X, and G542X cells. Thus, this approach, which is safer than acting directly on the mutated DNA, opens up new therapeutic possibilities for CF patients with nonsense mutations.

PMID:37446121 | DOI:10.3390/ijms241310940

Int J Mol Sci. 2023 Jun 26;24(13):10678. doi: 10.3390/ijms241310678.

ABSTRACT

More than 2000 variations are described within the CFTR (Cystic Fibrosis Transmembrane Regulator) gene and related to large clinical issues from cystic fibrosis to mono-organ diseases. Although these CFTR-associated diseases have been well documented, a large phenotype spectrum is observed and correlations between phenotypes and genotypes are still not well established. To address this issue, we present several regulatory elements that can modulate CFTR gene expression in a tissue-specific manner. Among them, cis-regulatory elements act through chromatin loopings and take part in three-dimensional structured organization. With tissue-specific transcription factors, they form chromatin modules and can regulate gene expression. Alterations of specific regulations can impact and modulate disease expressions. Understanding all those mechanisms highlights the need to expand research outside the gene to enhance our knowledge.

PMID:37445855 | DOI:10.3390/ijms241310678