Antimicrob Agents Chemother. 2024 Dec 10:e0153924. doi: 10.1128/aac.01539-24. Online ahead of print.

ABSTRACT

Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h-1. Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC (fT >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC24h of 1,191 (781-1,496) mg/L*h. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% fT >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC24h of 1,279 (1,054-1,590) mg/L*h. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal fT >MIC exposure for pathogens up to MICs of 8 mg/L and AUC24h estimates similar to previously reported estimates in non-CF patients.

PMID:39655913 | DOI:10.1128/aac.01539-24

Eurasian J Med. 2024 May 9;56(3):189-198. doi: 10.5152/eurasianjmed.2024.23302.

ABSTRACT

This study aimed to conduct a retrospective Middle East systematic review and meta-analysis on the prevalence and antibiotic susceptibility pattern for this microorganism isolated from cystic fibrosis patients. We searched MEDLINE, the Cochrane Library, SCOPUS, and Web of Science (ISI) to identify studies that reported the prevalence of Pseudomonas aeruginosa isolated from cystic fibrosis (CF) patients, and antibiotic resistance patterns. To assess the quality of publications was used of a checklist provided by the Joanna Briggs Institute. Finally, the data was analyzed by comprehensive meta-analysis software. The studied populations comprised children and young, and adult CF patients. Patients were aged between 3 months-65 years. A higher percentage of CF patients were males. Pseudomonas aeruginosa frequency varied between 5.9 and 76.2% in the studies included. The combined prevalence of P. aeruginosa was reported 34.3%. The lowest level resistance of P. aeruginosa was toward colistin (0%-13.3%) and ticarcillin (3.9%-24%). Our study showed the prevalence of P. aeruginosa and antibiotic resistance are almost high, while colistin and ticarcillin are the best antibiotics to decrease postantibiotic efects (PAEs) in CF patients from the Middle East. Therefore, physicians should pay more attention to therapeutic protocols to prevent further resistance.

PMID:39655837 | DOI:10.5152/eurasianjmed.2024.23302

ERJ Open Res. 2024 Dec 9;10(6):00547-2024. doi: 10.1183/23120541.00547-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: The aim of this study was to quantify mediators of neutrophilic inflammation within airway extracellular vesicles (EVs) of children treated for a cystic fibrosis (CF) pulmonary exacerbation (PEx).

METHODS: EVs were isolated from stored sputum samples collected before and after antibiotic therapy for PEx between 2011 and 2013, and characterised by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Western blot analysis of EV protein extracts was used for EV canonical protein markers CD63, CD9 and flotillin-1 (FLOT1), as well as neutrophil elastase (NE), myeloperoxidase (MPO) and interleukin-8. The EV content of NE and MPO were expressed as ratios of NE/FLOT1 and MPO/FLOT1 protein band densities.

RESULTS: Sputum samples from 21 children aged 13.3 (range 8.0-17.0) years were analysed. NTA showed high concentrations of particles at the size of small EVs (50-200 nm), and typical EV morphology was confirmed by TEM. CD63, CD9 and FLOT1 were detectable in all samples. Median (interquartile range (IQR)) NE/FLOT1 increased from 2.46 (1.68-5.25) before to 6.83 (3.89-8.89, p<0.001) after PEx therapy, and median (IQR) MPO/FLOT1 increased from 2.30 (1.38-4.44) before to 5.76 (3.45-6.94, p<0.01) after, while EV size remained unchanged. Improvement in lung function (percent predicted forced expiratory volume in 1 s (ppFEV1)) with PEx therapy correlated with NE EV content (r=0.657, p=0.001).

CONCLUSIONS: Airways of children with CF contain EVs that carry NE and MPO as cargo. The lower NE and MPO content at the time of PEx, compared with after therapy, and the correlation with pulmonary function suggest both a functional role of EVs in CF airway inflammation and the potential of EVs as a biomarker to monitor CF lung disease.

PMID:39655173 | PMC:PMC11626615 | DOI:10.1183/23120541.00547-2024

ERJ Open Res. 2024 Dec 9;10(6):00339-2024. doi: 10.1183/23120541.00339-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: People living with cystic fibrosis in Denmark had early, universal access to triple modulator treatment with elexacaftor/tezacaftor/ivacaftor. Close monitoring allowed us to assess the impact of treatment on lung function and progression of lung disease in an unselected nationwide cystic fibrosis population from 6 years of age.

METHODS: Data were analysed using linear mixed-effect models to assess changes in levels and annual rates of change (slopes) in percent predicted (pp) forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC (ppFEF25-75%) between the 12 months pre-treatment and treatment periods. Subgroup analyses assessed the impact of elexacaftor/tezacaftor/ivacaftor among those with/without previous modulator treatment, normal/mild/moderate/severe lung disease at treatment initiation, children/adults and birth cohorts.

RESULTS: We included 392 people living with cystic fibrosis with a median (interquartile range) 12 (nine to 15) spirometry measurements per person. The mean (95% CI) improvement in ppFEV1 was 13.0 (11.3-14.6) 12 months after initiation of elexacaftor/tezacaftor/ivacaftor treatment. The annual rate of change improved from -1.4 (-2.1 - -0.6) ppFEV1 in the pre-treatment year to 2.7 (1.8-3.5) ppFEV1 per year during treatment. Similarly, ppFVC increased by 8.0 (7.1-8.9) and FEF25--75% by 19.5 (17.0-21.9).

CONCLUSIONS: Using high-resolution data from a nationwide real-world setting, our study documents the impact of elexacaftor/tezacaftor/ivacaftor on lung function across subgroups based on age, disease severity and treatment history. These findings point towards a new period of consistent lung function improvement among people living with cystic fibrosis on elexacaftor/tezacaftor/ivacaftor.

PMID:39655171 | PMC:PMC11626609 | DOI:10.1183/23120541.00339-2024

Front Microbiol. 2024 Nov 25;15:1484510. doi: 10.3389/fmicb.2024.1484510. eCollection 2024.

ABSTRACT

The lungs of patients with cystic fibrosis (CF) are vulnerable to persistent polymicrobial colonization by bacterial pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, and the non-tuberculous mycobacterium (NTM) Mycobacterium abscessus. The polymicrobial milieu within the CF lung impacts individual species fitness, influences biofilm-forming capabilities, pathogenicity, production of virulence factors and even antimicrobial responses, all potentially compromising therapeutic success. Interaction studies among these CF pathogens are very limited, especially studies on the influences of P. aeruginosa and S. aureus on M. abscessus co-existence and virulence. Based on the little known thus far about coinfection of these pathogens, we hypothesize that the co-existence of P. aeruginosa and S. aureus alters M. abscessus virulence and phenotypic characteristics. We evaluated the direct (co-culture) and indirect (using supernatant) effects of P. aeruginosa and S. aureus on M. abscessus growth rate, biofilm formation, macrophage internalization and glycopeptidolipids (GPL) expression. Our observations indicate that P. aeruginosa and S. aureus exert a competitive behavior toward M. abscessus during direct contact or indirect interaction in-vitro, probably as is the case of polymicrobial infections in the lungs of patients with CF. This is the first report that demonstrates S. aureus inhibitory effects on M. abscessus growth and biofilm forming capabilities. Collectively, co-culture studies enhance our understanding of polymicrobial interactions during coinfection and can guide to establish better management of coinfections and treatment strategies for M. abscessus.

PMID:39654682 | PMC:PMC11627178 | DOI:10.3389/fmicb.2024.1484510

Diabetes Metab. 2024 Dec 7:101599. doi: 10.1016/j.diabet.2024.101599. Online ahead of print.

ABSTRACT

OBJECTIVE: We investigated strategies to mitigate hypoglycemic risk during and after different aerobic exercises in people with type 1 diabetes (pwT1D) using continuous subcutaneous insulin infusion.

RESEARCH DESIGN AND METHODS: Thirty-seven pwT1D (21 adults, 16 adolescents; HbA1c = 7.5 ± 1.0%) participated in two post-absorptive (4-h post-meal) exercise sessions (60-min continuous moderate intensity [CONT] vs. intermittent [INT]). Pre-exercise basal rate reduction (BRR) was either 40% or 80%, 90 min before exercise. Post-exercise, participants undertook either a 20% BRR for 10 hours with 20% reduced dinner bolus (INS) or a 45g post-exercise carbohydrate (CHO) snack with a 50% insulin bolus, and a 30g bedtime CHO snack without bolus (snack).

RESULTS: While a similar number of hypoglycemic events (31 vs. 28) were observed between exercise modalities, CONT led to a greater decrease in blood glucose during exercise compared to INT (-3.1 ± 2.3, CONT vs. -2.7 ± 2.2 mmol/l, INT, P = 0.005). Changes in blood glucose during exercise (-3.0 ± 2.4, 40%BRR vs. -2.8 ± 2.1 mmol/l, 80%BRR, P = 0.076) and the number of hypoglycemic events (35 vs. 24) were similar between 40% and 80%BRR. Time in hyperglycemia was lower with INS compared to snack in the first 30min after exercise, but no differences were observed for late recovery period or nighttime.

CONCLUSION: Compared to INT, CONT led to greater blood glucose decline without increasing hypoglycemia risk. A larger pre-exercise BRR did not further reduce hypoglycemia risk during exercise. Post-exercise INS and snack strategies led to comparable glucose profiles in pwT1D.

PMID:39653075 | DOI:10.1016/j.diabet.2024.101599

Ther Adv Pulm Crit Care Med. 2024 Dec 5;19:29768675241302903. doi: 10.1177/29768675241302903. eCollection 2024 Jan-Dec.

ABSTRACT

Cystic fibrosis patients may be considered for lung transplantation. Although these patients may experience more successful outcomes and survival rates compared to others, various complications can arise. In particular, infectious complications and septic deaths may be more prevalent in cystic fibrosis patients compared to other lung transplant indications. Considering all these factors, recognizing and managing complications that may arise during the postoperative period in this patient group are of critical importance. In this article, multiple life-threatening complications occurring in the post-transplant period in a patient who underwent lung transplantation due to cystic fibrosis are chronologically presented, and their management is discussed.

PMID:39651041 | PMC:PMC11622289 | DOI:10.1177/29768675241302903

Ann Med Surg (Lond). 2024 Nov 7;86(12):7398-7401. doi: 10.1097/MS9.0000000000002700. eCollection 2024 Dec.

ABSTRACT

INTRODUCTION AND IMPORTANCE: Cystic fibrosis (CF) is a widespread life-shortening recessive genetic disease and can present with sinus mucocele. Sinus mucocele is a rare condition, with limited prevalence data on unilateral proptosis.

CASE PRESENTATION: The authors present a case of a 19-month-old boy with CF who experienced worsening proptosis and exotropia in his right eye. A brain and orbit MRI revealed diffuse polypoid mucosal thickening, possible dense fungal deposit, deformity of the mid face, especially on the right side, with more prominent bulging of medical and inferior walls of the right lobe, a right ethmoidal mucocele causing ocular globe displacement, medial rectus compression, and optic nerve. An examination of the eye fundus showed disc edema and vascular congestion. Endoscopic sinus surgery successfully drained the mucocele, and treatment with antibiotics and corticosteroids led to symptom improvement and resolution of proptosis within 3 weeks.

CLINICAL DISCUSSION: Mucoceles represent an uncommon complication associated with CF in pediatric patients. Consequently, any child presenting with this issue should undergo evaluation for CF. Investigating this infrequent condition's underlying mechanisms and consequences may improve treatment approaches and outcomes for those impacted.

CONCLUSION: Sinus mucocele with unilateral proptosis in CF patients is uncommon, and endoscopic sinus surgery appears to be an effective cure for this complication, even in the pediatric population at high risk, like CF patients.

PMID:39649888 | PMC:PMC11623836 | DOI:10.1097/MS9.0000000000002700

Glob Pediatr Health. 2024 Dec 6;11:2333794X241304580. doi: 10.1177/2333794X241304580. eCollection 2024.

ABSTRACT

A 7-month-old girl had been suffering from progressively deteriorating pneumonia despite getting multiple courses of broad-spectrum antibiotics as well as anti-fungal drugs for adequate duration. To find out the cause behind this deterioration, the patient underwent thorough clinical and relevant laboratory evaluation including chest radiology & imaging, screening for primary immune deficiency disorders (PID), cystic fibrosis, tuberculosis, invasive fungal pneumonia, congenital heart disease, covid pneumonia, TORCH etc. but failed to solve the mystery. Upon further detailed re-evaluation, it was discovered that the child had a history of being forcefully fed lentil-based khichuri (a rice-lentil mixed dish) during her weaning process and diagnosis was finally confirmed as hypersensitive pneumonia due to lentil aspiration by a high level of IgG, specific to lentil antigen. Treatment was commenced with prednisolone resulting in significant improvement in her clinical and radiological condition within 72 hours.

PMID:39649774 | PMC:PMC11622295 | DOI:10.1177/2333794X241304580

Andrology. 2024 Dec 8. doi: 10.1111/andr.13815. Online ahead of print.

ABSTRACT

Congenital absence of the vas deferens (CAVD) is a syndrome with a heterogeneous presentation: bilateral (CBAVD) or unilateral (CUAVD), complete or partial and associated or not with other anomalies of the male urogenital system. A turning point came in 1968 when CBAVD was associated with cystic fibrosis and its CFTR gene mutations. Genetic studies then revealed that a minority of CBAVD but a majority of CUAVD are CFTR-independent. In the literature, reference is classically made to two sources from the 18th and 19th century: Hunter and Reverdin. This scarcity prompted us to look for additional observations of CAVD. By a meticulous bibliographical search, we identified a corpus of 10 European observations (8 CUAVD and 2 CBAVD) some of them richly illustrated. They were collected between 1755 and 1876 throughout adult men autopsies. We also provided their primary and unambiguous sources. Analysis of the reported data revealed some interesting facts: both CBAVD cases were unlikely linked to cystic fibrosis and half of CUAVD cases were associated with an ipsilateral kidney absence, suggesting a CFTR-independent pathophysiology. Moreover, the anatomical details of the anomalies raise interesting embryological questions we have tried to address in the light of current data. This work made it possible to identify new historical sources dealing with male genital tract pathologies. It sheds light on the origins of andrology and opens up interesting prospects for research and education in the field.

PMID:39648616 | DOI:10.1111/andr.13815

Rev Iberoam Micol. 2024 Dec 6:S1130-1406(24)00016-0. doi: 10.1016/j.riam.2024.09.001. Online ahead of print.

ABSTRACT

BACKGROUND: Candida species are frequently isolated from the oral cavity of patients with cystic fibrosis. However, the information on the role of Candida in cystic fibrosis is scarce.

AIMS: This study aimed to evaluate the prevalence, virulence profile and antifungal susceptibility of oral isolates of Candida albicans recovered from patients with cystic fibrosis.

METHODS: Oropharyngeal swab samples were collected from sixty-five cystic fibrosis patients and sixty-five healthy individuals. Candida isolates were identified by MALDI-TOF VITEK-MS. Proteinase, phospholipase and esterase activity, biofilm production and level expression of ALS, SAP and PLB genes in C. albicans were evaluated. Minimal inhibitory concentration values were determined by means of an antifungal susceptibility test.

RESULTS: Oral Candida colonization in cystic fibrosis patients was 66.15%, while in healthy individuals was 36.92%. C. albicans was the most frequently isolated species. C. albicans strains from cystic fibrosis patients were high producers of protease and biofilm, and had higher expression levels of adhesin and protease-associated genes in comparison with healthy subjects. Among the C. albicans strains isolated from cystic fibrosis patients, 18.91% were resistant to itraconazole, while 16.21% exhibited resistance to ketoconazole and fluconazole, and only one strain was resistant to voriconazole.

CONCLUSIONS: This work represents a surveillance study on virulence patterns and antifungal susceptibility of Candida from the oropharyngeal tract in cystic fibrosis.

PMID:39645528 | DOI:10.1016/j.riam.2024.09.001

J Cyst Fibros. 2024 Dec 6:S1569-1993(24)01844-7. doi: 10.1016/j.jcf.2024.11.009. Online ahead of print.

ABSTRACT

The introduction of elexacaftor/tezacaftor/ivacaftor (ETI) therapy has further extended life expectancy of adults with cystic fibrosis (awCF), highlighting the need for increased attention to potential long-term health issues. Given the increasing prevalence of cardiovascular diseases in the ageing population and the presence of cardiovascular risk factors associated with CF, understanding the impact of ETI on cardiometabolic risk factors is a crucial clinical concern. The aim of our prospective observational study was to explore early changes in cardiac and metabolic biomarkers after 6 months of ETI therapy. A total of 58 consecutive awCF were enrolled during clinical stability at the Adult CF Center of the Policlinico Hospital in Milan, Italy between January 2021 and June 2022. Blood samples were obtained before ETI initiation and after 6 months, and underwent central processing for an extended panel of cardiometabolic biomarkers. We observed a rise in cholesterol, triglycerides, apolipoprotein-B and adipokine levels, while inflammatory markers decreased. The direct relationship between leptin and adiponectin suggest a disruption in the normal regulatory mechanisms that control these hormones, potentially leading to metabolic imbalances, such as increased risk of obesity and cardiovascular events. The impact of ETI on cardiovascular risk in awCF is heterogeneous and while it improves some risk factors, such as chronic inflammation, it has a worsening effect on lipoproteins. Our findings suggest that the dysregulation of adipokines could be a potential cause of the metabolic disturbances observed in awCF.

PMID:39645478 | DOI:10.1016/j.jcf.2024.11.009

J Cyst Fibros. 2024 Dec 6:S1569-1993(24)01843-5. doi: 10.1016/j.jcf.2024.11.011. Online ahead of print.

ABSTRACT

As cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies including elexacaftor/tezacaftor/ivacaftor (ETI) have become widely used in eligible patients with cystic fibrosis (CF), the use of these medications in pregnant people has become a critical area of investigation. Since these medications appear generally safe to both mother and fetus when taken by pregnant people with CF, interest has pivoted to the use of ETI in CF carrier mothers to decrease morbidity and mortality from meconium ileus (MI) in fetuses with cystic fibrosis. Here we discuss three infants at our institution with ultrasound findings of MI who were exposed to prenatal ETI through CF carrier mothers for the purposes of treating MI and lowering risk of intestinal complications from this severe manifestation of CF. These cases differ in the timing of ETI initiation, severity of outcome, and accessibility of this off-label medication use to families depending on their insurance. All infants and mothers tolerated the medication well without significant side effects. One infant had complete MI resolution, one had persistent MI at birth with easy clearance with minimally invasive therapies, and one had persistent MI requiring jejunostomy. The infant with the most severe outcome had the shortest duration of ETI exposure and may have been able to receive this medication sooner had a referral to a CF center been made. These cases highlight the potentially life-altering effects of prenatal ETI use and the need for awareness of this clinical situation among fetal care providers.

PMID:39645477 | DOI:10.1016/j.jcf.2024.11.011

J Cyst Fibros. 2024 Dec 6:S1569-1993(24)01847-2. doi: 10.1016/j.jcf.2024.11.012. Online ahead of print.

ABSTRACT

Even as many outcomes for people living with cystic fibrosis (PLwCF) improve, individuals still experience extensive symptom burdens. From birth, many PLwCF experience both pain as a symptom of their CF disease and procedural pain, posing detriments to health, functioning, and quality of life. Despite its prevalence and impact, there is no CF-specific guidance for the assessment and management of pain. Similarly, no guidance exists regarding communication with PLwCF about their pain experiences or its impact on their lives. Therefore, the Cystic Fibrosis Foundation (CFF) assembled an expert panel of clinicians, researchers, PLwCF, and caregivers to develop consensus recommendations for pain management in CF. We utilized literature review and expert opinion to develop 13 recommendations addressing pain assessment, management, and communication. Recommendations are centered on guiding principles of utilizing a multimodal approach to pain management, offering age and developmentally appropriate assessment and interventions, concurrently treating underlying conditions causing, contributing to, and/or exacerbated by pain, considering societal stigma of the pain experience, particularly for minoritized and marginalized people, and sensitivity to issues of access and cost. These recommendations are intended to guide clinicians in managing pain and improving quality of life for PLwCF with pain at all stages of illness and development.

PMID:39645476 | DOI:10.1016/j.jcf.2024.11.012

J Cyst Fibros. 2024 Dec 5:S1569-1993(24)01845-9. doi: 10.1016/j.jcf.2024.11.010. Online ahead of print.

ABSTRACT

BACKGROUND: The splice variant 3849+10kbC->T (c.3717+12191C>T) (3849 variant) is a residual function CFTR variant, characterized by insertion of an in-frame stop codon into most CFTR transcripts. Both ivacaftor (Iva) and tezacaftor/ivacaftor (Tez/Iva) have been approved for people with CF (pwCF) carrying the 3849 variant. In-vitro studies for elexacaftor/tezacaftor/ivacaftor (ETI) did not include the 3849 variant as responsive to ETI. We present the clinical effectiveness of ETI in pwCF homozygous for the 3849 variant or heterozygous for 3849 and class I variants previously treated with Iva or Tez/Iva.

METHODS: We conducted a multi-center observational study of pwCF homozygous for the 3849 variant or heterozygous for 3849 and class I variants who were transitioned from Iva or Tez/Iva to ETI. We collected clinical data, including sweat chloride concentrations, pulmonary function tests, BMI and intravenous antibiotic treatments.

RESULTS: We identified nine pwCF heterozygous for 3849 and class I variants and one pwCF homozygous for the 3849 variant. Prior to transitioning to ETI, nine pwCF were treated with Tez/Iva and one with Iva. Compared to baseline, median sweat chloride concentration declined from 48 to 35 mEq/L (p = 0.009). Median FEV1 increased from 53 % to 65 % (p = 0.006). Pulmonary exacerbations requiring intravenous antibiotics declined from mean 1.4 to 0.6 in the twelve months before and after ETI.

CONCLUSIONS: We demonstrate the clinical effectiveness of ETI in pwCF carrying the 3849 variant, in excess of the response to Iva or Iva/Tez. Our results provide preliminary support for clinical use of ETI in pwCF carrying the 3849+10kbC->T variant.

PMID:39643544 | DOI:10.1016/j.jcf.2024.11.010

J Cyst Fibros. 2024 Dec 5:S1569-1993(24)01851-4. doi: 10.1016/j.jcf.2024.11.014. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Elexacaftor-tezacaftor-ivacaftor (ETI) is a drug treatment for cystic fibrosis that is debatable for use in pregnant women. Fetal ocular changes following prenatal exposure and while breastfeeding to ETI have been reported. The aim of this study was to assess eye development in rat fetuses following in-utero exposure to ETI.

DESIGN AND METHODS: Eyes from Sprague Dawley rats born to dams given clinically relevant ETI or sham treatment from embryonic day 12-19 (E12-E19) were investigated using histology and optical coherence tomography (OCT).

RESULTS: Lens thickness was higher in the ETI-exposure group, as measured by OCT (p = 0.0003). Lens cavities were observed in both groups, but the median individual lens cavities area was higher in the ETI-exposed eyes (p < 0.0001), as measured by histology.

CONCLUSION: In-utero exposure to ETI during E12-E19 was associated with subtle changes to lens anatomy, however the mechanism and clinical significance of this observation requires further investigation.

PMID:39643543 | DOI:10.1016/j.jcf.2024.11.014

Sleep Med. 2024 Nov 29;126:67-72. doi: 10.1016/j.sleep.2024.11.039. Online ahead of print.

ABSTRACT

PURPOSE: The aim of the study was to analyze the characteristics of otherwise healthy children with obstructive sleep apnea (OSA; OSA-I) and children with OSA and non-syndromic obesity (OSA-II) treated with long term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in 2019 in France.

METHODS: Data were collected from a national survey on paediatric home noninvasive ventilatory support. CPAP/NIV initiation criteria and duration, age at CPAP/NIV initiation, equipment used and CPAP/NIV settings, and objective compliance were analyzed.

RESULTS: Patients with OSA-I and OSA-II represented 6 % (n = 84, 71 % males) and 10 % (n = 144, 72 % males) of the national cohort, respectively. The apnea-hypopnea index (63 % vs 76 %), alone or combined with nocturnal gas exchange (25 % vs 21 %, for OSA-II and OSA-I patients respectively) were used as initiation criteria of CPAP/NIV. OSA-II patients were older at CPAP/NIV initiation (mean age 11.0 ± 4.0 vs 6.8 ± 4.5 years, p < 0.001) and were treated for a longer time (2.3 ± 2.6 vs 1.3 ± 1.5 years, p = 0.008) than OSA-I patients. NIV was used in 6 % of OSA-I patients and 13 % of OSA-II patients (p = 0.142). Both groups used preferentially a nasal mask. Mean CPAP level was higher in OSA-II patients as compared to OSA-I patients (8.7 ± 2.0 vs 7.7 ± 2.4 cmH2O, p = 0.02). Objective compliance was comparable (mean use 6.8 ± 2.6 vs 5.9 ± 3.0 h/night in OSA-I and OSA-II, respectively, p = 0.054).

CONCLUSION: Six and 10 % of children treated with long term CPAP/NIV in France in 2019 had OSA-I and OSA-II, respectively. Both groups were preferentially treated with CPAP and were comparable except for age, with OSA-II patients being older at CPAP/NIV initiation.

PMID:39642650 | DOI:10.1016/j.sleep.2024.11.039

Eur Arch Otorhinolaryngol. 2024 Dec 7. doi: 10.1007/s00405-024-09125-7. Online ahead of print.

ABSTRACT

PURPOSE: Chronic rhinosinusitis (CRS) has been distinguished in primary CRS, a primary inflammatory disorder limited to airways and secondary CRS, in which the sinonasal pathology is caused by a systemic disease or a local pathologic condition. Primary CRS is in turn classified in Type 2 and Non-type 2 on the basis of the endotype and of the pattern of the immune response. Advance in the knowledge of CRS has led to new therapeutic options, among which Dupilumab (anti-IL4R). We report the clinical response to Dupilumab in two patients with cystic fibrosis and nasal polyposis, in which the coexistence of a primary and secondary CRS could not be excluded.

METHODS: Nasal endoscopy, smell and quality of life of the patients were evaluated at each follow-up.

RESULTS: In the first case, increased blood eosinophils, allergy to inhalants and NSAIDs intolerance supported the suspect of primary CRS with type 2 inflammatory pattern, in addition to cystic fibrosis and the therapy was effective. In the second case the patient did not show atopy or peculiar blood test and even if the phenotype could suggest a primary CRS combined with a secondary one, the treatment was ineffective and it was suspended.

CONCLUSION: Even though classifications can be helpful, they can be reductive in cases where different aetiologies overlap. The presence of a concomitant primary CRS must not be excluded a priori in patients affected by secondary CRS. Each patient must be investigated to identify endotype characteristics and select the most appropriate therapeutic option.

PMID:39643811 | DOI:10.1007/s00405-024-09125-7

Eur J Med Chem. 2024 Dec 3;283:117133. doi: 10.1016/j.ejmech.2024.117133. Online ahead of print.

ABSTRACT

Pendrin (SLC26A4) is an anion exchanger expressed in epithelial cells of kidney and lung. Pendrin inhibition is a potential treatment approach for edema, hypertension and inflammatory lung diseases. We have previously identified first-in-class pendrin inhibitors by high-throughput screening, albeit with low potency for pendrin inhibition (IC50 ∼10 μM). Here, we performed a de novo small molecule screen with follow-on structure-activity studies to identify more potent pendrin inhibitors. Screening of 50,000 synthetic small molecules identified four novel classes of pendrin inhibitors with diverse scaffolds, including 5-benzyloxy-2-methylbenzofurans, N-aryl urea substituted 5-methyltryptamines, N-aryl urea substituted anthranilic acids, and substituted N-benzyl 3-carboxyindoles. The most potent inhibitor from the initial screen, a 3-carboxy-2-methylbenzofuran (1a), had IC50 of 4.1 μM. Structure-activity studies using 732 benzofuran analogs identified 1d with IC50 ∼ 0.5 μM for pendrin inhibition. Selectivity studies showed that 1d has minimal or no activity against related ion channels/transporters including SLC26A3, SLC26A6 and CFTR at high concentrations. 1d administration to mice at 10 mg/kg had no effect on urine volume when used alone, but potentiated the diuretic effect of furosemide by 45 %. In conclusion, we have identified novel pendrin inhibitors with greatly improved potency and good in vivo efficacy. These compounds can be used as pharmacological tools to study the roles of pendrin, and potentially developed as drug candidates for edema, hypertension and lung diseases.

PMID:39642691 | DOI:10.1016/j.ejmech.2024.117133

Islets. 2024 Dec 31;16(1):2436696. doi: 10.1080/19382014.2024.2436696. Epub 2024 Dec 6.

ABSTRACT

BACKGROUND: Knockout (KO) ferrets with the cystic fibrosis transmembrane conductance regulator (CFTR) exhibit distinct phases of dysglycemia and pancreatic remodeling prior to cystic fibrosis-related diabetes (CFRD) development. Following normoglycemia during the first month of life (Phase l), hyperglycemia occurs during the subsequent 2 months (Phase Il) with decreased islet mass, followed by a period of near normoglycemia (Phase Ill) in which the islets regenerate. We aimed to characterize islet hormone expression patterns across these Phases.

METHODS: Immunofluorescence staining per islet area was performed to characterize islet hormone expression patterns in age matched CFTR KO and wild type (WT) ferrets, focusing on the first three phases.

RESULTS: In Phase I, insulin staining intensity was higher in CF (p < 0.01) than WT but decreased in Phase III (p < 0.0001). Glucagon was lower in CF during Phases I and increased in Phase III, while proinsulin decreased (p < 0.0001) Phases II and III. CF sections showed lower proinsulin-to-insulin ratio in Phase I (p < 0.01) and in Phase III (p < 0.05) compared to WT. Conversely, glucagon-to-insulin ratio was lower in CF in Phase I (p < 0.0001) but increased in Phase III (p < 0.0001). Mender's coefficient overlap showed higher overlap of insulin over proinsulin in CF sections in Phase II (p < 0.001) and Phase III (p < 0.0001) compared to WT. Mender's coefficient rate was higher in CF sections during Phase II (p < 0.001).

CONCLUSION: CF ferret islets revealed significant immunofluorescent staining changes compared to WT during various phases of disease, providing insights into CRFD pathophysiology.

PMID:39641365 | DOI:10.1080/19382014.2024.2436696