Cystic Fibrosis

Discrepancy between Mexican paediatricians and ESPGHAN experts regarding cow's milk allergy

Thu, 2025-02-13 06:00

JPGN Rep. 2024 Nov 20;6(1):27-38. doi: 10.1002/jpr3.12147. eCollection 2025 Feb.

ABSTRACT

OBJECTIVES: Cow's milk allergy (CMA) is a common food allergy in infants. Guidelines and recommendations for the diagnosis and management of CMA are based on scientific review of the available evidence. However, real-world situations may oblige clinicians to adapt a different attitude.

METHODS: This paper evaluated the opinion of 42 Mexican paediatricians on the 73 statements presented in the recent position paper of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Voting on the statements and their interpretation were identical for both groups (online and anonymous). Both groups were unaware of the other's outcome at the moment of the voting.

RESULTS: While the ESPGHAN group accepted all 73 statements, the Mexican group rejected 19 statements. Two rejections were due to the mean and median being below the predefined and agreed-upon cut-off, and 17 were due to over 75% of participants disagreeing with the statements. The greatest discrepancy was observed regarding the role of vitamin D in preventing CMA.

CONCLUSION: While opinions on the prevalence, diagnosis and management of CMA were comparable between European paediatric gastroenterologists and Mexican general paediatricians for the majority of statements, significant differences were observed. It is essential to gather information from various regions and healthcare levels to enhance the impact of recommendations.

PMID:39944093 | PMC:PMC11810815 | DOI:10.1002/jpr3.12147

Categories: Literature Watch

Pancreatitis Risk Associated with GLP-1 Receptor Agonists, Considered as a Single Class, in a Comorbidity-Free Subgroup of Type 2 Diabetes Patients in the United States: A Propensity Score-Matched Analysis

Thu, 2025-02-13 06:00

J Clin Med. 2025 Feb 1;14(3):944. doi: 10.3390/jcm14030944.

ABSTRACT

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly prescribed for the management of type 2 diabetes mellitus (T2DM). However, the potential connection between GLP-1 RAs and the risk of pancreatitis presents a complex and nuanced issue. Although these drugs are effective in improving blood sugar control and cardiovascular health, their association with pancreatitis remains an area of concern. Our study aims to evaluate the association between the use of GLP-1 RAs, considered as a single class, and the risk of pancreatitis in a comorbidity-free subgroup of patients with type 2 diabetes mellitus (T2DM) in the United States. Methods: Data were retrieved from the TriNetX research database using the US Collaborative Network, which included information from 61 healthcare organizations within the U.S. Patients diagnosed with T2DM were categorized into two cohorts: one consisting of the patients prescribed with GLP-1 RAs and the other comprising patients who did not receive GLP-1 RAs. Of this class of medications, the agents analyzed were dulaglutide, lixisenatide, exenatide, liraglutide, and semaglutide. Using a 1:1 propensity score matching (PSM) model, we matched patients of both cohorts based on baseline demographics, comorbidities (hypertensive disorders, ischemic heart disease, gallstones, annular pancreas, alcohol use disorders, hypertriglyceridemia, hypercalcemia, cystic fibrosis, and cannabis use), medications known to cause drug-related pancreatitis, and laboratory values. Results: Of 969,240 patients with T2DM, 9.7% (93,608) were on GLP-1 RA, and 90.3% (875,632) were not. After PSM, the sample included 81,872 patients in each cohort. The risk of pancreatitis between the two groups was not statistically different between the two cohorts at 6 months at (0.1% vs. 0.1%, p = 0.04), and remained without significant increase with time; at 1 year (0.1% vs. 0.2%, p = 0.02), 3 years (0.2% vs. 0.3%, p = 0.001), and 5 years (0.3% vs. 0.4%, p < 0.001). The lifetime risk of developing pancreatitis in patients on GLP-1 RA was lower (0.3% vs. 0.4%, p < 0.001). Conclusions: In our comorbidity-free U.S.-based population with T2DM, the use of GLP-1 RAs did not increase their risk of pancreatitis. Their use was associated with a lower lifetime risk of pancreatitis.

PMID:39941615 | DOI:10.3390/jcm14030944

Categories: Literature Watch

A Novel Medical Device for Airway Clearance

Thu, 2025-02-13 06:00

J Clin Med. 2025 Jan 30;14(3):907. doi: 10.3390/jcm14030907.

ABSTRACT

Background: Airway clearance techniques are a key element in the daily treatment of people with bronchiectasis. There are several methods and devices to assist in effective airway clearance. We investigated LibAirty, a novel medical device, and compared it with the common practice performed today. Methods: Twenty adults enrolled, and each one had three different treatments in a randomized order: a human respiratory physiotherapist, a High-Frequency Chest Wall Oscillator, and LibAirty with BiPAP. The outcome parameters were mucus weight and a questionnaire. Further studies were performed to investigate LibAirty with hypertonic saline (HS) inhalation and using the device as a standalone. Results: No adverse events were recorded. The sputum amount expectorated in all arms using LibAirty was 14.4 ± 11.1 g with BIPAP, 16.4 ± 7 g with HS, and 11.3 ± 4.1 g for the standalone treatment. For HFCWO, 4.45 ± 3.28 g was obtained, and for CPT, 15.9 ± 11.1 g was obtained. The amount obtained by LibAirty (all arms) was significantly higher than HFCWO. Conclusions: All arms of LibAirty were superior to HFCWO and similar to the human physiotherapist. Further studies should be performed to investigate the long-term effects of LibAirty.

PMID:39941578 | DOI:10.3390/jcm14030907

Categories: Literature Watch

Advertisement for Editor-in-Chief, Journal of Cystic Fibrosis

Wed, 2025-02-12 06:00

J Cyst Fibros. 2025 Feb 11:S1569-1993(25)00056-6. doi: 10.1016/j.jcf.2025.02.006. Online ahead of print.

NO ABSTRACT

PMID:39939279 | DOI:10.1016/j.jcf.2025.02.006

Categories: Literature Watch

Histamine Promotes Pseudomonas aeruginosa Biofilm Formation and Renders Pseudomonas aeruginosa Biofilms More Resistant to Gentamicin and Azithromycin

Wed, 2025-02-12 06:00

Med Princ Pract. 2025 Feb 12:1-16. doi: 10.1159/000544111. Online ahead of print.

ABSTRACT

OBJECTIVE: Pseudomonas aeruginosa biofilms contribute to the persistent presence of this bacterium in the cystic fibrosis airways. P. aeruginosa produces histamine in vitro and expresses histamine receptors. We investigated whether histamine regulated P. aeruginosa biofilm formation in vitro and contributed to bacterial virulence in Galleria mellonella.

SUBJECT AND METHODS: P. aeruginosa biofilms were measured by staining bacteria adhered on polystyrene with crystal violet. Histamine concentrations were measured by ELISA. G. mellonella survival upon inoculation with P. aeruginosa was measured in the absence or presence of histamine.

RESULTS: The concentration of histamine in the BHI broth was 140 ng/ml (1.3 M). Addition to the broth of diamine oxidase (DAO), an enzyme that catabolizes histamine, reduced by ~ 3-fold the concentration of histamine and by 2-fold PAO1 strain biofilms. Addition of histamine (10-9 M - 10-4 M) to the LB medium augmented P. aeruginosa biofilms. Maximum effects were observed with concentrations of 10-5 M and 10-8 M for the mucoid NH57388A strain and the PAO1 strain, respectively. DAO reduced mucoid NH57388A biofilms induced by histamine (10-4 M) added to the LB medium. Addition of histamine to 48 h formed biofilms reduced anti-biofilm activities of gentamicin and azithromycin. Inoculation of G. mellonella with the PAO1 strain led to augmented histamine concentration in the haemolymph. Inoculation of histamine (10-8 M) reduced the survival rate of G. mellonella infected with the PAO1 strain.

CONCLUSION: Histamine produced during periods of infection may augment P. aeruginosa virulence by promoting the biofilm mode of life of this bacterium.

PMID:39938505 | DOI:10.1159/000544111

Categories: Literature Watch

Televisit with TytoHome™ device in medically complex child in long-term mechanical ventilation: a pilot study

Wed, 2025-02-12 06:00

Ital J Pediatr. 2025 Feb 12;51(1):45. doi: 10.1186/s13052-025-01885-0.

ABSTRACT

BACKGROUND: During the pandemic, the pneumology team at Bambino Gesù Children's Hospital highlighted that telemedicine was a valuable tool for remotely managing the medical needs of children with medical complexity (CMC). Following the telemedicine experience during the emergency phase, a telemedicine service was established, and new tools were tested to optimize televisits and the overall eHealth approach for patients. In this context, the TytoHome™ device was tested for performing objective examinations remotely. This pilot study, conducted at our hospital, explored the management of CMC patients on long-term mechanical ventilation via the telemedicine platform and the TytoHome™ device.

METHODS: This study involved the treatment of 10 pediatric patients over one year using this approach. The patients were already receiving care at our hospital and were undergoing long-term mechanical ventilation (LTV) at home-4 on invasive mechanical ventilation (IMV) and 6 on non-invasive ventilation (NIV). A database was developed to collect patient data, including personal details, vital parameters, objective examinations, audio quality, and patient satisfaction. A descriptive analysis was subsequently performed using the data collected during the earlier stages of the study.

RESULTS: The utility of the TytoCare device for medically complex children was evaluated. The families were "satisfied" with the remote follow-up visits, and healthcare personnel rated the audio quality of the visits as "good."

CONCLUSIONS: In conclusion, the remote management of these patients using the Tyto device offered several advantages. In our experience, Tyto proved to be a useful tool for the remote medical management of complex patients.

PMID:39939975 | DOI:10.1186/s13052-025-01885-0

Categories: Literature Watch

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use in Pregnancy: Is There Enough Evidence to Tip the Scale?

Wed, 2025-02-12 06:00

Chest. 2025 Feb;167(2):297-299. doi: 10.1016/j.chest.2024.10.019.

NO ABSTRACT

PMID:39939046 | DOI:10.1016/j.chest.2024.10.019

Categories: Literature Watch

Mucus Physically Restricts Influenza A Viral Particle Access to the Epithelium

Wed, 2025-02-12 06:00

Adv Biol (Weinh). 2025 Feb 12:e2400329. doi: 10.1002/adbi.202400329. Online ahead of print.

ABSTRACT

Prior work suggests influenza A virus (IAV) crosses the airway mucus barrier in a sialic acid-dependent manner through the actions of the viral envelope proteins, hemagglutinin, and neuraminidase. However, host and viral factors that influence how efficiently mucus traps IAV remain poorly defined. In this work, how the physicochemical properties of mucus influence its ability to effectively capture IAV is assessed using fluorescence video microscopy and multiple particle tracking. Our studies suggest an airway mucus gel layer must be produced with virus-sized pores to physically constrain IAV. While sialic acid binding by IAV may improve mucus trapping efficiency, sialic acid binding preference is found to have little impact on IAV mobility and the fraction of viral particles expected to penetrate the mucus barrier. Further, synthetic polymeric hydrogels engineered with mucus-like architecture are similarly protective against IAV infection despite their lack of sialic acid decoy receptors. Together, this work provides new insights on mucus barrier function toward IAV with important implications on innate host defense and transmission of respiratory viruses.

PMID:39936480 | DOI:10.1002/adbi.202400329

Categories: Literature Watch

Simulated exposures of oritavancin in in vitro pharmacodynamic models select for methicillin-resistant Staphylococcus aureus with reduced susceptibility to oritavancin but minimal cross-resistance or seesaw effect with other antimicrobials

Wed, 2025-02-12 06:00

J Antimicrob Chemother. 2025 Feb 12:dkaf042. doi: 10.1093/jac/dkaf042. Online ahead of print.

ABSTRACT

BACKGROUND: Dalbavancin exposures select for VAN and daptomycin cross-resistance in Staphylococcus aureus often by walK-related mutations. Oritavancin is another long-acting lipoglycopeptide, but its proclivity to select for cross-resistance is unknown. The objective of this study was to determine if post-distributional pharmacokinetic oritavancin exposures select for meaningful susceptibility changes in S. aureus.

METHODS: We simulated average post-distributional, free-drug exposures of oritavancin 1200 mg IV once (fCmax 11.2 µg/mL; β-elimination t1/2 13.4 h; γ-elimination t1/2 245 h) in an in vitro pharmacodynamic model for 28 days against five S. aureus including four MRSA. Samples were taken daily for colony enumeration and resistance screening. Susceptibility testing was repeated on isolates from resistance screening plates against oritavancin, vancomycin, daptomycin, dalbavancin and 6 beta-lactams with varying penicillin-binding protein affinities.

RESULTS: Tested oritavancin exposures were bactericidal against 5/5 strains for 2-17 days before regrowth of less-susceptible subpopulations occurred. Isolates with reduced susceptibility to oritavancin were detected as early as 5 days, but the MIC increased above the susceptibility breakpoint (>0.125 mg/L) in 4/5 strains eventually. Vancomycin and daptomycin MICs increased by 2- to 8-fold but did not exceed the susceptibility breakpoints in most isolates. β-lactam MICs were largely unchanged among the recovered isolates with reduced oritavancin susceptibility. Mutations were diverse but often involved purR with 13 unique variants identified among 4/5 strains.

CONCLUSIONS: Oritavancin-selected resistance was primarily associated with purR mutation and less frequently associated with cross-resistance and walK mutation than dalbavancin-selected resistance in similar strains and conditions. The reason for this is unclear but may stem from differences in the mechanism(s) and divergent mutational pathways.

PMID:39936452 | DOI:10.1093/jac/dkaf042

Categories: Literature Watch

Proteomics profiling of inflammatory responses to elexacaftor/tezacaftor/ivacaftor in cystic fibrosis

Wed, 2025-02-12 06:00

Front Immunol. 2025 Jan 28;16:1486784. doi: 10.3389/fimmu.2025.1486784. eCollection 2025.

ABSTRACT

BACKGROUND: CFTR modulator therapies have positive clinical outcomes, yet chronic inflammation and bacterial infections persist in people with CF (pwCF). How elexacaftor-tezacaftor-ivacaftor (ETI) fails to improve innate immune signaling responsible for bacterial clearance and inflammation resolution remains unknown.

METHODS: We used an unbiased proteomics approach to measure the effect of ETI on inflammatory proteins. Plasma from 20 pediatric pwCF and 20 non-CF (NCF) was collected during routine examination and 3 months after ETI initiation. Protein screening was performed with an inflammation panel (Target 96, Olink®). Bioinformatics analysis was used to determine changes in protein expression.

RESULTS: There were significantly fewer pulmonary exacerbations after ETI initiation, along with sustained improvement in lung function and reduced bacterial colonization. Unpaired analysis of CF pre-ETI and NCF resulted in 34 significantly different proteins. Of these, CCL20, MMP-10, EN-RAGE, and AXIN1 had a log2 fold change of 1.2 or more. There was a modest shift in overall CF protein profiles post-ETI toward the NCF cluster. Unpaired analysis of protein differential expression between NCF and CF post-ETI identified a total of 24 proteins significantly impacted by ETI therapy (p-value ≤ 0.05), with only CCL20 having a log2 fold change higher than 1.2. Paired analysis (CF pre- and CF post-ETI) of differential protein expression demonstrated significant expression changes of MMP-10, EN-RAGE, and IL-17A. Pathway analysis identified significantly impacted pathways such as the NF-κB pathway.

CONCLUSION: This study showed that ETI in a pediatric cohort had a modest effect on several inflammatory proteins with potential as biomarkers. Pathways significantly impacted by ETI can be further studied for future therapies to combat persistent inflammation and dysregulated immunity.

PMID:39935472 | PMC:PMC11811078 | DOI:10.3389/fimmu.2025.1486784

Categories: Literature Watch

Investigating the Potential Hearing Impairment and Ototoxicity in Children up to Six Years With Cystic Fibrosis After Aminoglycoside Exposure (PIANO-CF Extension)

Wed, 2025-02-12 06:00

Pediatr Pulmonol. 2025 Feb;60(2):e27505. doi: 10.1002/ppul.27505.

ABSTRACT

BACKGROUND: People with CF (pwCF) are often treated with prolonged courses of aminoglycosides (AGs), for which known adverse effects include ototoxicity as a subset of hearing impairment (HI).

METHODS: The PIANO-CF trial was a single-center study conducted at The Royal Children's Hospital where 28 pediatric patients aged < 7 years underwent sequential hearing tests at increased range up to 12,500 Hz in relation to receiving intravenous (IV) AGs. More than 85% of the cohort (n = 24) participated in the follow-up hearing testing up to 1 year.

RESULTS: HI was defined by degree (dB) and frequency (Hz) on the audiogram. This was further reviewed to determine if the type of HI was consistent with ototoxicity as there are frequently other causes of HI in this age group. At baseline the prevalence of HI and ototoxicity were 11% and 7%, respectively. Over a period of 1 year, HI was identified in 12.5% and that of ototoxicity in 6%. No correlation was found between degree of IV AG exposure and HI or ototoxicity.

DISCUSSION: The finding of HI in young children with CF, including in those with minimal IV AG exposure, has implications for CF services to proactively screen for HI. Undetected HI may compromise learning outcomes and given the age of children studied, this is not insignificant during the acquisition and development of language skills.

CONCLUSION: Routine audiometric testing for pwCF up to 12,500 Hz or beyond may increase sensitivity in detection of ototoxicity and should be considered for use in screening, monitoring, and future research.

PMID:39935234 | DOI:10.1002/ppul.27505

Categories: Literature Watch

A family cluster of persistent Pandoraea vervacti infection in cystic fibrosis

Wed, 2025-02-12 06:00

J Immunoassay Immunochem. 2025 Feb 11:1-6. doi: 10.1080/15321819.2025.2462807. Online ahead of print.

ABSTRACT

Bacterial colonization of the cystic fibrosis (CF) airways is polymicrobial and several emerging microorganisms with a potential pathogenic role may be present. We report a case of three siblings with CF colonized by Pandoraea over a period of 10 years. Isolates identified as various non-fermentative Gram-negative bacilli from sputum cultures were successfully re-identified as Pandoraea vervacti (P. vervacti) by a combination of matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA and gyrB sequencing. Furthermore, the transcript expression of type I and type III interferon (IFN) genes was examined in the cells of respiratory samples from these patients and compared with a Pandoraea-negative group of CF individuals. Increased respiratory levels of IFNβ, IFNε and IL28R1 mRNA were found in the three siblings. Our results demonstrate that P. vervacti can chronically colonize CF patients and alter IFN response, likely contributing to immunopathogenesis and disease progression.

PMID:39935049 | DOI:10.1080/15321819.2025.2462807

Categories: Literature Watch

Life With Cystic Fibrosis: The Socioeconomic Impact on Patients and Their Caregivers

Tue, 2025-02-11 06:00

Value Health Reg Issues. 2025 Feb 10;47:101085. doi: 10.1016/j.vhri.2025.101085. Online ahead of print.

ABSTRACT

OBJECTIVES: This study aimed to provide the first evidence of the socioeconomic burden of cystic fibrosis (CF) in Czechia.

METHODS: In a cross-sectional questionnaire-based primary data collection conducted from 2020 to 2021 among Czech patients with CF, we collected demographic, clinical, and healthcare resource use data, out-of-pocket and social transfer costs, and questionnaires: Cystic Fibrosis Questionnaire-Revised, Work Productivity and Activity Impairment, EQ-5D, and Zarit Burden Interview. Productivity loss/costs were assessed using the human capital approach with patient patient-assumed life expectancy of 45 years and caregiver retirement age of 64 years and discounted by 3%.

RESULTS: A total of 257 patients completed the questionnaires (37% of the Czech CF population). The average age was 17 years; most were females (59%), and the average forced expiratory volume in 1 second was 81.4% (SD 25.4%). A total of 107 patients had caregivers with an average age of 39 years and a significant caregiver time burden (extra 4.6 hours/day). The average Zarit Burden Interview score (25.4) was comparable with advanced cancer, dementia, or Duchenne muscular dystrophy. The proportion of unemployed caregivers was 10× higher than the general population (31% vs 3.2%). Total out-of-pocket family costs related to CF were €278/month, mainly for medicines (€105), foods (€73), and transport (€59); 25% received a disability pension and 18% other social security benefits. The work impairment of employed patients and caregivers was 25% and 15%, respectively, mostly due to presenteeism. Total lifetime productivity costs extrapolated to all Czech patients with CF (n = 687) and their caregivers were €155 181 286 (€225 883/person).

CONCLUSIONS: The societal burden imposed on Czech patients with CF and their caregivers is significant. Caregivers seem to be affected by higher disease activity more than patients.

PMID:39933437 | DOI:10.1016/j.vhri.2025.101085

Categories: Literature Watch

Ciprofloxacin Dosage Optimization in Cystic Fibrosis Through Therapeutic Drug Monitoring

Tue, 2025-02-11 06:00

Ther Drug Monit. 2024 Nov 12. doi: 10.1097/FTD.0000000000001267. Online ahead of print.

ABSTRACT

BACKGROUND: Ciprofloxacin (CIP) is effective against many Gram-negative pathogens and penetrates well into respiratory secretions and pulmonary tissues, thus making it useful for treating respiratory infections in patients with cystic fibrosis (CF).

METHODS: A 13-year-old patient with severe CF and an acute respiratory exacerbation from multidrug-resistant Pseudomonas aeruginosa was treated with 700 mg of CIP every 8 hours. Bronchial secretions confirmed that P. aeruginosa was sensitive to high doses of CIP. Pharmacokinetic monitoring using 2 blood samples estimated the AUC24 at 50 hours*mg/L. This led to an increase in CIP dosage to 850 mg three time a day (TID), then to 1000 mg TID, and finally to 1200 mg every 6 hours.

RESULTS: CIP pharmacokinetics can vary significantly, particularly in patients with CF due to increased clearance, ultimately resulting in shorter half-lives and higher risks of therapeutic failure and resistance. Therapeutic drug monitoring helps when adjusting dosages to maintain effective blood concentrations.

CONCLUSIONS: This case underscores the role of therapeutic drug monitoring in optimizing CIP dosing for patients with CF and highlights the necessity for close collaboration between clinicians and pharmacologists to ensure effective antibiotic exposure.

PMID:39933065 | DOI:10.1097/FTD.0000000000001267

Categories: Literature Watch

Aquagenic Wrinkling of the Palms in a Patient with Cystic Fibrosis

Tue, 2025-02-11 06:00

Acta Med Port. 2025 Feb 3;38(2):117-118. doi: 10.20344/amp.21948. Epub 2025 Feb 3.

NO ABSTRACT

PMID:39932840 | DOI:10.20344/amp.21948

Categories: Literature Watch

A framework for modelling whole-lung and regional transfer factor of the lung for carbon monoxide using hyperpolarised xenon-129 lung magnetic resonance imaging

Tue, 2025-02-11 06:00

ERJ Open Res. 2025 Feb 10;11(1):00442-2024. doi: 10.1183/23120541.00442-2024. eCollection 2025 Jan.

ABSTRACT

BACKGROUND: Pulmonary gas exchange is assessed by the transfer factor of the lungs (T L) for carbon monoxide (T LCO), and can also be measured with inhaled xenon-129 (129Xe) magnetic resonance imaging (MRI). A model has been proposed to estimate T L from 129Xe MRI metrics, but this approach has not been fully validated and does not utilise the spatial information provided by three-dimensional 129Xe MRI.

METHODS: Three models for predicting T L from 129Xe MRI metrics were compared: 1) a previously-published physiology-based model, 2) multivariable linear regression and 3) random forest regression. Models were trained on data from 150 patients with asthma and/or COPD. The random forest model was applied voxel-wise to 129Xe images to yield regional T L maps.

RESULTS: Coefficients of the physiological model were found to differ from previously reported values. All models had good prediction accuracy with small mean absolute error (MAE): 1) 1.24±0.15 mmol·min-1·kPa-1, 2) 1.01±0.06 mmol·min-1·kPa-1, 3) 0.995±0.129 mmol·min-1·kPa-1. The random forest model performed well when applied to a validation group of post-COVID-19 patients and healthy volunteers (MAE=0.840 mmol·min-1·kPa-1), suggesting good generalisability. The feasibility of producing regional maps of predicted T L was demonstrated and the whole-lung sum of the T L maps agreed with measured T LCO (MAE=1.18 mmol·min-1·kPa-1).

CONCLUSION: The best prediction of T LCO from 129Xe MRI metrics was with a random forest regression framework. Applying this model on a voxel-wise level to create parametric T L maps provides a useful tool for regional visualisation and clinical interpretation of 129Xe gas exchange MRI.

PMID:39931664 | PMC:PMC11808933 | DOI:10.1183/23120541.00442-2024

Categories: Literature Watch

Human-based complex <em>in vitro</em> models: their promise and potential for rare disease therapeutics

Tue, 2025-02-11 06:00

Front Cell Dev Biol. 2025 Jan 27;13:1526306. doi: 10.3389/fcell.2025.1526306. eCollection 2025.

ABSTRACT

Rare diseases affect a small percentage of an individual country's population; however, with over 7,000 in total, rare diseases represent a significant disease burden impacting up to 10% of the world's population. Despite this, there are no approved treatments for almost 95% of rare diseases, and the existing treatments are cost-intensive for the patients. More than 70% of rare diseases are genetic in nature, with patient-specific mutations. This calls for the need to have personalised and patient-specific preclinical models that can lead to effective, speedy, and affordable therapeutic options. Complex in vitro models (CIVMs), including those using induced pluripotent stem cells (iPSCs), organoids, and organs-on-chips are emerging as powerful human-based pre-clinical systems with the capacity to provide efficacy data enabling drugs to move into clinical trials. In this narrative review, we discuss how CIVMs are providing insights into biomedical research on rare diseases. We also discuss how these systems are being used in clinical trials to develop efficacy models for rare diseases. Finally, we propose recommendations on how human relevant CIVMs could be leveraged to increase translatability of basic, applied and nonclinical research outcomes in the field of rare disease therapeutics in developed as well as middle-and low-income countries.

PMID:39931243 | PMC:PMC11807990 | DOI:10.3389/fcell.2025.1526306

Categories: Literature Watch

Elexacaftor/tezacaftor/ivacaftor and inflammation in children and adolescents with cystic fibrosis: a retrospective dual-center cohort study

Tue, 2025-02-11 06:00

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251314706. doi: 10.1177/17534666251314706.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic neutrophilic inflammation in the airways. Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has demonstrably improved clinical outcomes and quality of life in people with CF (pwCF), but its effects on systemic inflammatory parameters remain unclear.

OBJECTIVE: To evaluate the impact of ETI on systemic inflammation in children and adolescents with CF.

DESIGN: Retrospective, dual-center observational, propensity score-matching study of pediatric pwCF on ETI.

METHODS: PwCF aged ⩽ 18 years treated with ETI at two Italian reference centers were included in this study. Data on immunoglobulins (Ig) (A, G, and M), γ-globulin, leukocyte levels, percent predicted forced expiratory volume in the first second (ppFEV1), sweat chloride (SC) concentration, and sputum cultures were collected at baseline, 12, and 24 months of treatment. Laboratory data of a control group (pwCF, not in ETI therapy, same demographic characteristics as the study group) were also collected.

RESULTS: Sixty-six patients (30 males, median age: 12 years, F508del homozygous: 23) were included. Mean IgG levels (SD) significantly decreased (p = 0.001) from 1168.20 mg/dl (344.41) at baseline to 1093.05 mg/dl (258.73; 12 months) and 1092.87 mg/dl (232.42; 24 months). Similar reductions were observed for IgA and γ-globulin; IgM reduction was not statistically significant. Leukocyte levels also decreased significantly from 8.04 × 103/µl (3.23 × 103) at baseline to 6.61 × 103/µl (1.74 × 103) (12 months) and 6.45 × 103/µl (1.70 × 103; 24 months). As for the control group, no significant changes in the levels of Ig, leukocytes, and γ-globulin were detected throughout the study period (p > 0.05).The mean (SD) ppFEV1 and the overall mean (SD) SC concentration significantly decreased during the follow-up. Regarding cultures, 18 (27%) of the 27 patients positive (41%) for Staphylococcus aureus at baseline became negative during treatment. Three patients (4%) with persistently positive cultures for Pseudomonas aeruginosa during the first 12 months, became negative after 24 months. One patient (1.5%), with a baseline positive culture for Pseudomonas Aeruginosa, showed negative cultures after 12 months.

CONCLUSION: ETI treatment improved respiratory outcomes and significantly reduced values of IgG, IgA, γ-globulin, and leukocytes, suggesting an effect on the systemic inflammatory response. Further research is warranted to elucidate the role of inflammatory parameters in monitoring response to therapy.

PMID:39930791 | DOI:10.1177/17534666251314706

Categories: Literature Watch

Feeding hope: A quality improvement initiative to improve identification of food insecurity

Tue, 2025-02-11 06:00

J Pediatr Gastroenterol Nutr. 2025 Feb 10. doi: 10.1002/jpn3.70010. Online ahead of print.

ABSTRACT

OBJECTIVES: Food insecurity (FI), limited or uncertain access to adequate food, impacts every state, county, and community in the United States. The goals of this quality improvement (QI) initiative were to first achieve greater than 90% compliance with FI screening for patients seen at pediatric GI clinics within 1 year and second increase the proportion of families identified as FI connected with resources to 50% at follow-up visits.

METHODS: Using plan-do-study-act cycles, interventions were implemented to (1) educate, (2) create a screening process, (3) optimize communication with EMR utilization, and (4) connect families to resources. Descriptive statistics on all variables collected were performed. Differences between the FI and food secure groups were assessed using the Mann-Whitney test for continuous variables and the Chi-squared test for categorical variables. QIMacros® Quality Improvement/SPC Software for Excel was used to create process control charts to show improvement.

RESULTS: During the timeframe from August 29, 2022, to February 29, 2024, 2946 visits were completed in the GI clinic, and 58% (1731 patients) were screened for FI. Of the patients that were screened for FI, 13% screened positive. Compliance with FI screening improved to 90%, and connection to resources improved to 75%. Race, ethnicity, preferred language, and insurance were all significantly associated with FI, p < 0.001 CONCLUSIONS: This QI initiative demonstrates standardized FI screening improves FI identification and connection to resources.

PMID:39930736 | DOI:10.1002/jpn3.70010

Categories: Literature Watch

The Prognostic Significance of MELD-XI in Patients Admitted to the Intensive Care Unit for Respiratory Failure

Tue, 2025-02-11 06:00

Thorac Res Pract. 2025 Jan 20. doi: 10.4274/ThoracResPract.2024.24047. Online ahead of print.

ABSTRACT

OBJECTIVE: Composite Model for End-Stage Liver Disease (MELD), an adapted version of the model score excluding international normalised ratio (MELD-XI), was reported to predict outcomes in patients with organ failure. Aim of study was to evaluate the prognostic significance of the MELD-XI score and compare it with the Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation 2 (APACHE 2) scores in patients admitted to the intensive care unit (ICU) for respiratory failure.

MATERIAL AND METHODS: Out of 822 patients with respiratory failure between September 2020 and June 2023, a total of 727 patients with etiologies of chronic obstructive pulmonary disease exacerbation, cardiogenic pulmonary edema, pulmonary thromboembolism, pneumonia, bronchiectasis, kyphoscoliosis, neuromuscular diseases, obesity hypoventilation syndrome, and diffuse parenchymal lung disease were included.

RESULTS: A statistically significant correlation was found between MELD-XI, SOFA, and APACHE 2 scores. The cutoff value of the MELD-XI score was 11 on receiver operating characteristic analysis, indicating a higher risk of mortality in patients with a score of 11 or above. The APACHE 2 and SOFA scores of the MELD-XI ≥11 group were found to be higher and the Glasgow Coma Scale were lower than the MELD-XI <11 group. MELD-XI ≥11 was associated with an increased risk of mortality in overall [Hazard ratio (HR): 4.1, 95% confidence interval (CI): 2-6.4, P < 0.001] and subgroups with different etiologies in Cox regression analysis. In the multivariate analysis, MELD-XI was the most important independent variable indicating an increased risk of mortality, regardless of etiology (HR: 2.4, 95% CI: 2.0-2.5, P < 0.001).

CONCLUSION: MELD-XI is an important marker of ICU mortality in patients with respiratory failure due to different etiologies and is as effective as the SOFA and APACHE 2 in predicting mortality.

PMID:39930732 | DOI:10.4274/ThoracResPract.2024.24047

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