Ther Drug Monit. 2022 Oct 19. doi: 10.1097/FTD.0000000000001053. Online ahead of print.

ABSTRACT

Tobramycin is widely used to treat pulmonary exacerbations of cystic fibrosis (CF). Height has been previously found to be significantly more predictive of tobramycin pharmacokinetics (PK) than body weight. This study aimed to develop a height-based initial dosing nomogram and evaluate its performance in terms of peak concentration (Cmax) precision relative to standard and fixed dosing.Monte Carlo simulations were performed to develop a nomogram representing the doses required to reach Cmax targets at different heights. Cmax data observed at two clinical centers (McGill University Health Centre [MUHC] and Institut universitaire de cardiologie et pneumologie de Québec [IUCPQ-UL]) were compared to population-predicted Cmax using the doses derived from the nomogram alongside a fixed dose.Height-based dosing resulted in significantly less variable predicted Cmax values (coefficient of variation [CV] MUHC = 15.7% and IUCPQ-UL= 10.8%) than the Cmax values observed in clinical practice (CV MUHC= 30.0% and CV IUCPQ-UL= 26.9%) and predicted Cmax obtained from a fixed dose (CV MUHC= 21.2% and CV IUCPQ-UL= 16.3%).An initial dosing nomogram was developed to help reduce PK variability in the observed Cmax. More precise dosing would allow for better clinical outcomes in adult patients with CF.

PMID:36730982 | DOI:10.1097/FTD.0000000000001053

Curr Opin Allergy Clin Immunol. 2022 Nov 25. doi: 10.1097/ACI.0000000000000880. Online ahead of print.

ABSTRACT

PURPOSE: Severe asthma can carry significant morbidity and mortality for patients, and it places a burden on families and the healthcare system. Biologic agents have revolutionized the care of patients with severe asthma in recent years. Evidence surrounding some of these therapies is limited in the pediatric population, but recent studies show that they significantly improve asthma care when used appropriately. In this review, we discuss the biologic therapies currently approved to treat severe asthma in school-age children and adolescents.

RECENT FINDINGS: Randomized controlled trials have been published in support of biologics in children and/or adolescents. These therapies have been shown to reduce the annual rate of severe asthma exacerbations by at least 40-50%, and some up to about 70%. Improvements in asthma control, lung function, oral corticosteroid use, and quality of life have also been demonstrated, although these vary by agent. Furthermore, these therapies have reassuring safety profiles in pediatric patients.

SUMMARY: With three biologic agents approved for children ages 6-11 years and five approved for adolescents ages >12 years, it can be challenging to select one. The therapy should be chosen after careful consideration of the patient's asthma phenotype and biomarkers. Additional pediatric-specific clinical trials would be helpful in developing evidence-based guidelines on biologic therapies in this population.

PMID:36730217 | DOI:10.1097/ACI.0000000000000880

Cochrane Database Syst Rev. 2023 Feb 2;2:CD007862. doi: 10.1002/14651858.CD007862.pub5.

ABSTRACT

BACKGROUND: People with cystic fibrosis (CF) experience chronic airway infections as a result of mucus buildup within the lungs. Repeated infections often cause lung damage and disease. Airway clearance therapies aim to improve mucus clearance, increase sputum production, and improve airway function. The active cycle of breathing technique (ACBT) is an airway clearance method that uses a cycle of techniques to loosen airway secretions including breathing control, thoracic expansion exercises, and the forced expiration technique. This is an update of a previously published review.

OBJECTIVES: To compare the clinical effectiveness of ACBT with other airway clearance therapies in CF.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched clinical trials registries and the reference lists of relevant articles and reviews. Date of last search: 29 March 2021.

SELECTION CRITERIA: We included randomised or quasi-randomised controlled clinical studies, including cross-over studies, comparing ACBT with other airway clearance therapies in CF.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened each article, abstracted data and assessed the risk of bias of each study. We used GRADE to assess our confidence in the evidence assessing quality of life, participant preference, adverse events, forced expiratory volume in one second (FEV1) % predicted, forced vital capacity (FVC) % predicted, sputum weight, and number of pulmonary exacerbations.

MAIN RESULTS: Our search identified 99 studies, of which 22 (559 participants) met the inclusion criteria. Eight randomised controlled studies (259 participants) were included in the analysis; five were of cross-over design. The 14 remaining studies were cross-over studies with inadequate reports for complete assessment. The study size ranged from seven to 65 participants. The age of the participants ranged from six to 63 years (mean age 18.7 years). In 13 studies follow up lasted a single day. However, there were two long-term randomised controlled studies with follow up of one to three years. Most of the studies did not report on key quality items, and therefore, have an unclear risk of bias in terms of random sequence generation, allocation concealment, and outcome assessor blinding. Due to the nature of the intervention, none of the studies blinded participants or the personnel applying the interventions. However, most of the studies reported on all planned outcomes, had adequate follow up, assessed compliance, and used an intention-to-treat analysis. Included studies compared ACBT with autogenic drainage, airway oscillating devices (AOD), high-frequency chest compression devices, conventional chest physiotherapy (CCPT), positive expiratory pressure (PEP), and exercise. We found no difference in quality of life between ACBT and PEP mask therapy, AOD, other breathing techniques, or exercise (very low-certainty evidence). There was no difference in individual preference between ACBT and other breathing techniques (very low-certainty evidence). One study comparing ACBT with ACBT plus postural exercise reported no deaths and no adverse events (very low-certainty evidence). We found no differences in lung function (forced expiratory volume in one second (FEV1) % predicted and forced vital capacity (FVC) % predicted), oxygen saturation or expectorated sputum between ACBT and any other technique (very low-certainty evidence). There were no differences in the number of pulmonary exacerbations between people using ACBT and people using CCPT (low-certainty evidence) or ACBT with exercise (very low-certainty evidence), the only comparisons to report this outcome.

AUTHORS' CONCLUSIONS: There is little evidence to support or reject the use of the ACBT over any other airway clearance therapy and ACBT is comparable with other therapies in outcomes such as participant preference, quality of life, exercise tolerance, lung function, sputum weight, oxygen saturation, and number of pulmonary exacerbations. Longer-term studies are needed to more adequately assess the effects of ACBT on outcomes important for people with cystic fibrosis such as quality of life and preference.

PMID:36727723 | DOI:10.1002/14651858.CD007862.pub5

Pulm Med. 2023 Jan 23;2023:5082499. doi: 10.1155/2023/5082499. eCollection 2023.

ABSTRACT

BACKGROUND: Digital health technologies (DHTs) have shown potential to improve health outcomes through improved medication adherence in different disease states. Cystic fibrosis (CF) requires care coordination across pharmacies, patients, and providers. DHTs can potentially support patients, providers, and pharmacists in diseases like CF, where high medication burden can negatively impact patient quality of life and outcomes.

METHODS: In this prospective cohort study, a CF-specific mobile application (Phlo) was distributed to adults with CF who received care at the University of Utah Cystic Fibrosis Center, used an iPhone, and filled prescriptions through the University of Utah Specialty Pharmacy services. Participants were asked to use Phlo for 90 days with an optional 90-day extension period. Participants completed four surveys at baseline and after 90 days. Changes in patient-reported outcomes, adherence, clinical outcomes, and healthcare resource utilization from baseline to 90 days were tracked.

RESULTS: Phlo allowed users to track daily regimen activities, contact their care team, receive medication delivery reminders, and share progress with their healthcare team. A web-based dashboard allowed the care team to review reported performance scores from the app. Most patients (67%) said the app improved confidence in and motivation for continuing their regimen. The most important reported benefit of Phlo was having a single location to manage their whole routine.

CONCLUSIONS: Phlo is a mobile health technology designed to help patients with CF manage their treatment regimen and improve patient-provider communication.

PMID:36727045 | PMC:PMC9886457 | DOI:10.1155/2023/5082499

ERJ Open Res. 2023 Jan 30;9(1):00495-2022. doi: 10.1183/23120541.00495-2022. eCollection 2023 Jan.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a rare hereditary disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Recent therapies enable effective restoration of CFTR function of the most common F508del CFTR mutation. This shifts the unmet clinical need towards people with rare CFTR mutations such as nonsense mutations, of which G542X and W1282X are most prevalent. CFTR function measurements in patient-derived cell-based assays played a critical role in preclinical drug development for CF and may play an important role to identify new drugs for people with rare CFTR mutations.

METHODS: Here, we miniaturised the previously described forskolin-induced swelling (FIS) assay in intestinal organoids from a 96-well to a 384-well plate screening format. Using this novel assay, we tested CFTR increasing potential of a 1400-compound Food and Drug Administration (FDA)-approved drug library in organoids from donors with W1282X/W1282X CFTR nonsense mutations.

RESULTS: The 384-well FIS assay demonstrated uniformity and robustness based on coefficient of variation and Z'-factor calculations. In the primary screen, CFTR induction was limited overall, yet interestingly, the top five compound combinations that increased CFTR function all contained at least one statin. In the secondary screen, we indeed verified that four out of the five statins (mevastatin, lovastatin, simvastatin and fluvastatin) increased CFTR function when combined with CFTR modulators. Statin-induced CFTR rescue was concentration-dependent and W1282X-specific.

CONCLUSIONS: Future studies should focus on elucidating genotype specificity and mode-of-action of statins in more detail. This study exemplifies proof of principle of large-scale compound screening in a functional assay using patient-derived organoids.

PMID:36726369 | PMC:PMC9885274 | DOI:10.1183/23120541.00495-2022

J Pediatr Urol. 2023 Jan 19:S1477-5131(23)00019-0. doi: 10.1016/j.jpurol.2023.01.011. Online ahead of print.

NO ABSTRACT

PMID:36725485 | DOI:10.1016/j.jpurol.2023.01.011

Rofo. 2023 Feb 1. doi: 10.1055/a-2002-4919. Online ahead of print.

NO ABSTRACT

PMID:36724805 | DOI:10.1055/a-2002-4919

Eur J Med Chem. 2023 Jan 27;249:115149. doi: 10.1016/j.ejmech.2023.115149. Online ahead of print.

ABSTRACT

The anion exchanger protein SLC26A3 (down-regulated in adenoma, DRA) is expressed in the luminal membrane of intestinal epithelial cells in colon, where it facilitates the absorption of Cl- and oxalate. We previously identified a 4,8-dimethylcoumarin class of SLC26A3 inhibitors that act from the SLC26A3 cytoplasmic surface, and demonstrated their efficacy in mouse models of constipation and hyperoxaluria. Here, screening of 50,000 new compounds and 1740 chemical analogs of active compounds from the primary screen produced five novel classes of SLC26A3-selective inhibitors (1,3-dioxoisoindoline-amides; N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamides; thiazolo-pyrimidin-5-ones; 3-carboxy-2-phenylbenzofurans and benzoxazin-4-ones) with IC50 down to 100 nM. Kinetic washout and onset of action studies revealed an extracellular site of action for the thiazolo-pyrimidin-5-one and 3-carboxy-2-phenylbenzofuran inhibitors. Molecular docking computations revealed putative binding sites for these inhibitors. In a loperamide model of constipation in mice, orally administered 7-(2-chloro-phenoxymethyl)-3-phenyl-thiazolo [3,2-a]pyrimidin-5-one (3a) significantly increased stool weight, pellet number and water content. SLC26A3 inhibitors with an extracellular site of action offer the possibility of creating non-absorbable, luminally acting inhibitors with minimal systemic exposure following oral administration. Our findings also suggest that inhibitors of related SLC26 anion transporters with an extracellular site of action might be identified for pharmacological modulation of selected epithelial ion transport processes.

PMID:36724632 | DOI:10.1016/j.ejmech.2023.115149

J Gen Physiol. 2023 Apr 3;155(4):e202213264. doi: 10.1085/jgp.202213264. Epub 2023 Feb 1.

ABSTRACT

CFTR chloride channel mutations cause the lethal and incurable disease cystic fibrosis (CF). CFTR is activated by phosphorylation, and phosphorylated channels exhibit "bursting" behavior-"bursts" of openings separated by short "flickery" closures and flanked by long "interburst" closures-driven by ATP binding/hydrolysis at two nucleotide-binding domains. The human channel (hCFTR) and the distant zebrafish ortholog (zCFTR) display differences both in their gating properties and structures. In phosphorylated ATP-bound hCFTR, the hR117 side chain, conserved across evolution, forms an H-bond that stabilizes the open state. Lack of that bond in the hR117H mutant causes CF. In the phosphorylated ATP-bound zCFTR structure that H-bond is not observable. Here, we show that the zR118H mutation does not affect the function of zCFTR. Instead, we identify an H-bond between the zS109 and zS120 side chains of phosphorylated ATP-bound, but not of unphosphorylated apo-, zCFTR. We investigate the role of that interaction using thermodynamic mutant cycles built on gating parameters determined in inside-out patch clamp recordings. We find that zS109 indeed forms an H-bond with zN120 in the flickery closed state, but not in the open or interburst closed states. Although in hCFTR an isoleucine (hI119) replaces the asparagine, mutation hS108A produces a strong hR117H-like phenotype. Since the effects of the latter two mutations are not additive, we conclude that in hCFTR these two positions interact, and the hS108-hR117 and hR117-hE1124 H-bonds cooperate to stabilize the open state. These findings highlight an example of how the gating mechanism was optimized during CFTR molecular evolution.

PMID:36723516 | DOI:10.1085/jgp.202213264

Hosp Pract (1995). 2023 Feb 1. doi: 10.1080/21548331.2023.2176041. Online ahead of print.

ABSTRACT

OBJECTIVES: Literature regarding clinical benefits of dornase alfa (DNase) in pediatric patients without cystic fibrosis is lacking. In December 2020, the study institution implemented restrictions to limit DNase use in this patient population. The primary objective was adherence to DNase ordering restrictions. Secondary objectives included length of stay, respiratory function, and use of inhaled mucolytic agents.

METHODS: This single-center retrospective chart review included patients less than 18 years of age who received DNase one year prior to through one year after order restriction implementation. Data collected included patient demographics and respiratory clinical parameters. Dosing regimens for DNase, n-acetylcysteine and hypertonic saline were collected, as well as changes in length of stay (LOS) and adherence to ordering restrictions.

RESULTS: Of 101 orders placed after implementation of ordering restrictions, 16 (36%) met all ordering criteria. Hospital and intensive care unit (ICU) LOS after implementation of restrictions were not significantly different (p=0.767 and p=0.219 respectively). There was no significant change in patients' mean oxygenation index (p=0.252) or FiO2% (p=0.113) 24 hours after DA administration.

CONCLUSION: Respiratory function did not significantly change after DNase administration. Implementing restrictions on DNase did not impact ICU or hospital LOS. Adherence to DNase ordering restrictions could be improved.

PMID:36723457 | DOI:10.1080/21548331.2023.2176041

Am J Respir Cell Mol Biol. 2023 Feb;68(2):231-233. doi: 10.1165/rcmb.2022-0334LE.

NO ABSTRACT

PMID:36722775 | DOI:10.1165/rcmb.2022-0334LE

Pediatr Pulmonol. 2023 Feb 1. doi: 10.1002/ppul.26335. Online ahead of print.

ABSTRACT

CFTR modulators have transformed CF but are some of the most expensive medications on the market and are over-priced compared to the value given. The high price of CFTR modulators leaves people with CF dependent on Vertex's copay assistance programs. Despite record-breaking profits, Vertex is drastically decreasing its copayment assistance programs, so people with CF will have to pay thousands of dollars monthly for CFTR modulators or discontinue therapy. Vertex continues to put profits above the lives of people with CF This article is protected by copyright. All rights reserved.

PMID:36722731 | DOI:10.1002/ppul.26335

Ann Card Anaesth. 2023 Jan-Mar;26(1):36-41. doi: 10.4103/aca.aca_276_20.

ABSTRACT

BACKGROUND: Several studies have demonstrated the utility of methylene blue (MB) to treat vasoplegic syndrome (VS), but some have cautioned against its routine use in lung transplantation with only two cases described in prominent literature. Cystic fibrosis patients commonly have chronic infections which predispose them to a systemic inflammatory syndrome-like vasoplegic response during lung transplantation. We present 13 cystic fibrosis patients who underwent lung transplantation and received MB for vasoplegic syndrome while on cardiopulmonary bypass, with or without inhaled pulmonary vasodilator therapy.

METHODS: Single-center, retrospective, case series analysis of cystic fibrosis patients who underwent lung transplant and received MB for vasoplegia. We defined the primary outcome as 30-day mortality, and secondary outcomes as primary graft failure, 1-year mortality, postoperative complications, and hemodynamic response to MB.

RESULTS: MB was associated with a significant increase in mean arterial pressure (MAP) (P < 0.001) in all patients, and 84.6% (11/13) of the patients had either a decrease or no change in vasopressor requirement. No patients developed acute primary graft dysfunction and there was 100% 30-day and 1-year survival. One patient required Extracorporeal membrane oxygenation (ECMO) for hypoxemia and 69% (9/13) of the patients had evidence of postoperative right ventricular dysfunction, but no patients required a right ventricular assist device.

CONCLUSION: This case series demonstrates the effectiveness of MB in treating vasoplegia in cystic fibrosis patients during lung transplantation, without evidence of primary graft dysfunction, 30-day or 1-year mortality. The safety of MB regarding hypoxemia and increased pulmonary vascular resistance requires further investigation.

PMID:36722586 | DOI:10.4103/aca.aca_276_20

Curr Rev Clin Exp Pharmacol. 2023 Feb 1. doi: 10.2174/2772432818666230201094115. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the efficacy of the first triple CFTR protein modulators in children and adolescents with cystic fibrosis.

METHODS: Systematic review and meta-analysis were conducted, following PRISMA guidelines. The following databases were searched extensively: PubMed/Medline, Clinical trials.gov, Google Scholar, Scopus, Embase, and Europe PMC using the keywords: "Ivacaftor," "Elexacaftor," "Tezacaftor," VX_661", VX_770", "VX_445", "cystic fibrosis". A total of ten randomized clinical trials were included in our analysis. Primary outcomes included: Absolute change in predicted FEV1 from baseline, Absolute change in sweat chloride test from baseline, Absolute change in BMI from baseline, Absolute change in CF-QR from baseline, and Adverse Events.

RESULTS: Among primary findings, significant absolute change in predictive FEV1 from baseline through 4 weeks favoured the triple CFTR protein modulators. [MD=11.80,95%CI=8.47_15.12, p value=<0.00001]; as well as CF_QR score [MD=0.00,95%CI=-2.50_2.50, p value=1.00], and BMI kg/m² change [MD=16.90,95%CI=12.73_21.06, p value=<0.00001]. No significant change was noted for CFTR channels activity in the treatment group when compared to placebo or VX_770/VX_661 [MD= -12.57,95%CI=-94.46_69.32, p value=0.76].

CONCLUSION: In children aged ≥ 6 y old and adolescents with F508del_CFTR mutation, Elexacaftor-Tezacaftor-Ivacaftor tend to be more effective than first-generation therapy, demonstrating promising results by exhibiting significant improvement in lung function, body weight, and respiratory-related quality of life.

PMID:36722487 | DOI:10.2174/2772432818666230201094115

Future Microbiol. 2023 Feb 1. doi: 10.2217/fmb-2021-0278. Online ahead of print.

ABSTRACT

Aim: Meropenem-vaborbactam and delafloxacin activities were not assessed against Achromobacter spp. (Achr), Burkholderia cepacia complex (Bcc) and Stenotrophomonas maltophilia (Smal). Methodology: A total of 106 Achr, 57 Bcc and 100 Smal were tested with gradient diffusion test of meropenem-vaborbactam, delafloxacin and comparators. Results: Meropenem-vaborbactam MIC50 were 4 μg/ml for Achr, 1 μg/ml for B. cepacia, 2 μg/ml for B. cenocepacia and B. multivorans, and 32 μg/ml for Smal. Delafloxacin MIC50 were 4 μg/ml for Achr, 0.25 μg/ml for B. cepacia and B. multivorans, 2 μg/ml for B. cenocepacia, and 0.5 μg/m for Smal. meropenem-vaborbactam MICs were fourfold lower than meropenem for 28.3% Achr, 77.2% B. cepacia, 53.8% B. cenocepacia and 77.2% B. multivorans. Conclusion: Meropenem-vaborbactam and delafloxacin are in vitro active against Bcc and Achr.

PMID:36722304 | DOI:10.2217/fmb-2021-0278

Pediatr Pulmonol. 2023 Jan 31. doi: 10.1002/ppul.26339. Online ahead of print.

ABSTRACT

BACKGROUND: Children with unmet basic needs experience worse health than more advantaged counterparts. There has been limited research on screening for unmet basic needs in pediatric subspecialty care.

METHODS: Caregivers of established patients in pediatric asthma and cystic fibrosis (CF) clinics were screened for unmet basic needs with an electronic survey, which asked about concerns and stress level (5-point Likert scale) related to food, housing, transportation, health insurance, and childcare, among others. Medical record review provided patient demographic characteristics and clinical data. A follow-up survey with the clinical providers assessed the acceptability of electronic screening for unmet needs.

RESULTS: The sample included 214 pediatric patients (N=105 asthma, N=109 CF) and their caregivers. Most patients with asthma (76%) were Black, 30% in households with <$20,000 annual income. In contrast, most patients with CF (93%) were white, 12% in households with <$20,000 annual income. Reported needs included food insecurity (29% asthma, 17% CF), healthy food (75% asthma, 87% CF), financial insecurity (45% asthma, 32% CF), health insurance (15% asthma, 28% CF), smoke exposure (24% asthma, 28% CF), child's exercise (21% asthma, 28% CF), living conditions (18% asthma, 17% CF), childcare (11% asthma, 15% CF), transportation (16% asthma, 9% CF), and housing insecurity (10% asthma, 8% CF). Concerns were rated moderately to very stressful. Food insecurity, financial insecurity, and smoke exposure were significantly associated with uncontrolled asthma. In people with CF, concerns about health insurance and child exercise were significantly associated with lower lung function and increased odds of hospitalizations. Clinicians believed that screening was important and should be administered by a designated person on the clinical team.

CONCLUSIONS: Unmet basic needs and associated stress levels are linked to adverse pediatric pulmonary outcomes. Electronic screening, without face-to-face interaction or paper trail, facilitates high response rates and is easily integrated into clinic flow. Such screenings can identify vulnerable patients for targeted interventions and referral to available community resources. This article is protected by copyright. All rights reserved.

PMID:36721912 | DOI:10.1002/ppul.26339

Thorax. 2023 Jan 31:thorax-2022-219907. doi: 10.1136/thorax-2022-219907. Online ahead of print.

NO ABSTRACT

PMID:36720632 | DOI:10.1136/thorax-2022-219907

Klin Padiatr. 2023 Jan 31. doi: 10.1055/a-2004-3477. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic cough is one of the most common symptoms in childhood. Making a definite diagnosis is a challenge for all pediatricians especially in patients when cough is without an organic cause like in habit cough.

PATIENTS AND METHODS: In this retrospective analysis, all electronic outpatient charts of the Division of Allergology and Pneumology, between January 1, 2010 and December 31, 2019 were reviewed in order to study all children with potential habit cough. All children underwent the following diagnostic algorithms, skin prick test (SPT), measurement of fractional exhaled nitric oxide (FeNO), spirometry and methacholine challenge test (MCT). The value of a normal MCT and FeNO measurement for diagnosing habit cough was investigated.

RESULTS: The chart review revealed 482 patients with chronic cough>4 weeks. Of these, 99 (20.5%) with suspected habit cough were collected. 13 patients had to be excluded for other diagnosis and a complete data set was available in 55 patients. 33 (60.0%) of 55 patients were SPT negative and 22 (40.0%) had sensitization to common allergens. Five patients had elevated FeNO≥20 ppb and three showed severe bronchial hyperresponsiveness<0.1 mg methacholine, challenging the diagnosis of habit cough.

CONCLUSION: A normal FeNO and MCT can help confirm the clinical diagnosis of habit cough. However, in patients with positive MCT and/or elevated FeNO habit cough can be present. Especially in patients with elevated FeNO and severe BHR cough variant asthma and eosinophilic bronchitis have to be ruled out.

PMID:36720225 | DOI:10.1055/a-2004-3477

J Breath Res. 2023 Jan 31. doi: 10.1088/1752-7163/acb792. Online ahead of print.

ABSTRACT

BACKGROUND: Children with cystic fibrosis (CF) suffer from chronic inflammation and recurrent exacerbations of bronchopulmonary disease (PE). We aimed to test whether a specific miRNA could be associated with the occurrence of PE.

METHODS: We sequenced EV-derived miRNA in sputum (n=20), exhaled breath condensate (n=11), and serum (n=8) samples from pediatric patients during PE and the stable stage of CF. Four miRNAs: let-7c, miR-16, miR-25-3p and miR-146a, have been selected for validation in a larger group with RT-qPCR (sputum and serum) or ddPCR (exhaled breath condensate). NGS differential expression analysis was done in Base Space, and the correlation between miRNAs expression and clinical data was calculated with Statistica. Functional annotation of selected miRNAs and their potential target genes was performed with miRDip and DAVID software.

RESULTS: There were no differences in miRNA expression between stable and exacerbation in sputum and in serum. Validation of four selected miRNAs showed significant downregulation of miR-146a in serum. A panel of all four miRNAs (peripherally) was the best predictive model of exacerbation (p<0.001, AUC=0.96). Expression of airway miR-25-3p improved the diagnostic value of FEV1%pred and FVC%pred, while peripheral miR-146a improved the predictive model of CRP and neutrophilia. In silico analysis revealed a potential role for selected miRNAs in regulating processes associated with inflammation and tissue remodeling.

CONCLUSIONS: We demonstrated that extracellular vesicles contained in peripheral blood as well as local biomaterials can act as carriers for miRNAs with the diagnostic potential of predicting exacerbation in pediatric CF.

PMID:36720158 | DOI:10.1088/1752-7163/acb792

Menopause. 2023 Jan 31. doi: 10.1097/GME.0000000000002155. Online ahead of print.

ABSTRACT

OBJECTIVE: This study aimed to describe the menopause experience of people with cystic fibrosis (CF).

METHODS: We conducted a computer-based cross-sectional survey of women with CF 25 years or older at 10 US CF centers exploring a range of sexual and reproductive health concerns, including menopause. We used descriptive statistics to analyze results.

RESULTS: Of 460 participants, 5 (3%) were perimenopausal and 34 (7%) were postmenopausal. Of participants perimenopausal or menopausal (n = 39), 97% reported the following menopausal symptoms occurring at least once a week: most commonly early wake-up (83%); stiffness/soreness in joints, neck, or shoulders (65%); and night sweats (65%). Among menopausal participants, the median self-reported age at menopause was 48.5 years (interquartile range, 5.5 y). Thirty percent experienced worsened CF symptoms during menopause, and 42% experienced worsening CF symptoms after menopause. Twenty-four percent of menopausal participants were on estrogen therapy and 15% on estrogen and progesterone therapy. Three-fourths of participants using hormone therapy reported no change in their CF symptoms. One percent of the 460 survey participants reported discussing menopause with their CF provider, despite 19% wanting to discuss this topic with their CF team.

CONCLUSIONS: This is the first study to describe menopause symptoms of people with CF. People with CF experience a variety of menopausal symptoms and often report a worsening of their CF symptoms after menopause, suggesting an interplay between female sex hormones and CF. Larger studies are needed comparing the sexual and reproductive health experiences and care needs of people with CF in the menopause transition to the general population.

PMID:36720079 | DOI:10.1097/GME.0000000000002155