Front Digit Health. 2024 Oct 24;6:1469860. doi: 10.3389/fdgth.2024.1469860. eCollection 2024.

ABSTRACT

BACKGROUND: Remote care usefulness and climate change co-benefits should be addressed simultaneously to incentivize political action.

OBJECTIVES: To assess the changes in healthcare consumption, lung function and greenhouse gas (GHG) emissions during the COVID-19 pandemic in Dutch cystic fibrosis (CF) care.

DESIGN: Retrospective multicentre observational study in five Dutch CF centres.

METHODS: Eighty-one participants were included. Healthcare consumption was described alongside the COVID-19 Stringency Index (2019-2022). Travel related GHG emissions were calculated for every clinic visit. Changes in percentage predicted Forced Expiratory Volume in one second (ppFEV1) were assessed using a paired-samples T-test.

RESULTS: Healthcare consumption patterns followed COVID-19 public health measure stringency but returned back to the "old normal". Emission of 5.450, 3 kg of carbon dioxide equivalents were avoided while quality of care was relatively preserved. ppFEV1 declined as expected (ΔMeans 3.69%, 95%CI 2.11-5.28).

CONCLUSION: Remote monitoring of lung function and symptoms and teleconsultations in CF can reduce GHG emissions while maintaining quality of care. As health sectors constitute a large share of national climate change footprints, digital health can partly alleviate this burden by reducing private travel.

PMID:39512858 | PMC:PMC11540799 | DOI:10.3389/fdgth.2024.1469860

Front Pharmacol. 2024 Oct 23;15:1461473. doi: 10.3389/fphar.2024.1461473. eCollection 2024.

ABSTRACT

INTRODUCTION: Respiratory diseases encompass a diverse range of conditions that significantly impact global morbidity and mortality. While common diseases like asthma and COPD exhibit moderate symptoms, less prevalent conditions such as pulmonary hypertension and cystic fibrosis profoundly affect quality of life and mortality. The prevalence of these diseases has surged by approximately 40% over the past 3 decades. Despite advancements in pharmacotherapy, challenges in drug administration, adherence, and adverse effects persist. This study aimed to develop and perform an interim validation of a Capacity-Motivation-Opportunity (CMO) model tailored for respiratory outpatients to enhance pharmaceutical care, which is the direct, responsible provision of medication-related care for the purpose of achieving definite outcomes that improve a patient's quality of life, and overall wellbeing.

METHODOLOGY: This cross-sectional, multicenter study was conducted from March 2022 to March 2023. It comprised four phases: 1) forming an expert panel of 15 hospital pharmacists, 2) selecting respiratory pathologies based on prevalence and severity, 3) developing the CMO model's pillars, and 4) integrating and conducting an interim validation of the model. The Capacity pillar focused on patient stratification and personalized care; the Motivation pillar aligned therapeutic goals through motivational interviewing; and the Opportunity pillar promoted the use of information and communication technologies (ICTs) for telemedicine.

RESULTS: The model included eight respiratory diseases based on expert assessment. For the Capacity pillar, 22 variables were defined for patient stratification, leading to three priority levels for personalized pharmaceutical care. In a preliminary test involving 201 patients across six hospitals, the stratification tool effectively classified patients according to their needs. The Motivation pillar adapted motivational interviewing techniques to support patient adherence and behavior change. The Opportunity pillar established teleconsultation protocols and ICT tools to enhance patient monitoring and care coordination.

CONCLUSION: The CMO model, tailored for respiratory patients, provides a comprehensive framework for improving pharmaceutical care. By focusing on patient-centered care, aligning therapeutic goals, and leveraging technology, this model addresses the multifaceted needs of individuals with respiratory conditions. Future studies are necessary to validate this model in other healthcare systems and ensure its broad applicability.

PMID:39512818 | PMC:PMC11540901 | DOI:10.3389/fphar.2024.1461473

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241292502. doi: 10.1177/17534666241292502.

NO ABSTRACT

PMID:39512159 | DOI:10.1177/17534666241292502

Sci Rep. 2024 Nov 7;14(1):27036. doi: 10.1038/s41598-024-77253-5.

ABSTRACT

Pseudomonas aeruginosa (Pa) and Methicillin susceptible Staphylococcus aureus (MSSA) are the predominant bacteria found in the airways of people with cystic fibrosis (pwCF), significantly contributing to lung disease progression. While various factors influencing the initial acquisition (IA) of these pathogens are known, the impact of environmental conditions remains understudied. This epidemiological study assessed the risk of MSSA and Pa initial acquisitions in relation to seasonality and climatic zones among 1,184 French pwCF under 18 years old. The age at IA for Pa (Pa-IA) and MSSA (MSSA-IA) was estimated using the Kaplan-Meier method. Seasonality and climatic zones were analysed as risk factors using time-varying Cox regression models. The median age at MSSA-IA was notably earlier (2.0 years) than that at Pa-IA (5.1 years). MSSA-IA occurred increasingly younger in more recent birth cohorts, while the age at Pa-IA remained stable over time. The risk of Pa-IA was consistently higher in all seasons compared with spring, peaking in autumn (HR = 1.53), irrespective of climatic zones. In Oceanic and Continental climates, the highest risk for MSSA-IA was in winter (HRs = 1.45 and 1.20 respectively). In the Mediterranean climate, the risk of MSSA-IA was lower in winter compared to spring (HRs = 0.68 and 0.61 respectively), and the median age at MSSA-IA later than for Pa-IA. This study demonstrates that seasonality and meteorological factors may influence acquisition of MSSA and Pa in pwCF. These findings suggest that environmental factors play a role in pathogen acquisition dynamics in CF and could inform the development of preventive strategies.

PMID:39511324 | DOI:10.1038/s41598-024-77253-5

J Cyst Fibros. 2024 Nov 6:S1569-1993(24)01807-1. doi: 10.1016/j.jcf.2024.10.014. Online ahead of print.

ABSTRACT

BACKGROUND: Children and young people with cystic fibrosis (CYPwCF) are encouraged to do an average of 60 min of moderate-to-vigorous physical activity (MVPA) daily. However, there are no agreed heart rate (HR) thresholds for defining MVPA, so it is difficult to ascertain whether these targets are actually achieved. Wearable activity trackers enable continuous monitoring of fitness-related measures such as HR and could be used to measure duration and intensity of habitual MVPA. We aimed to define personalized and responsive MVPA thresholds from HR in CYPwCF, to determine habitual time spent in MVPA during childhood and adolescence.

METHODS: Continuous daily HR data were collected from 142 CYPwCF wearing activity trackers over 16 months. Linear mixed-effects models were used to develop personalised estimates of resting heart rate (RHR), peak heart rate (PHR) and MVPA thresholds, which were defined using the American College of Sports Medicine heart rate reserve (HRR) method.

RESULTS: 309,926 days of physical activity data showed that both RHR and PHR declined with age in CYPwCF, with considerable variability within and between individuals. The HRR method produced personalised MVPA thresholds for each CYPwCF based on age, which inherently accounted for individual demographic variability and personal factors such as cardiovascular fitness or disease severity.

CONCLUSIONS: By accounting for within and between person variability in RHR and PHR, our novel method provides more accurate age-related personalised MVPA thresholds for CYPwCF than existing estimates. Our findings provide population-based estimates for RHR, PHR and MVPA thresholds at different ages in CYPwCF. This approach may help guide development of international standards for objective MVPA measurement in the era of remote HR and activity monitoring and facilitate accurate measurement of habitual physical activity in children and young people.

PMID:39510931 | DOI:10.1016/j.jcf.2024.10.014

Eur Respir J. 2024 Nov 7;64(5):2401224. doi: 10.1183/13993003.01224-2024. Print 2024 Nov.

NO ABSTRACT

PMID:39510593 | DOI:10.1183/13993003.01224-2024

Eur Respir J. 2024 Nov 7:2400691. doi: 10.1183/13993003.00691-2024. Online ahead of print.

ABSTRACT

BACKGROUND: We have previously developed Core Outcome Measures sets for Severe Asthma (COMSA) by multi-stakeholder consensus. There are no patient-centred tools to quantify response to biologics for severe asthma. We aimed to develop paediatric and adult CompOsite iNdexes For Response in asthMa (CONFiRM) incorporating clinical parameters and patient-reported quality of life (QoL).

METHODS: International expert healthcare professionals (HCPs) and patients with severe asthma were invited to: 1) develop consensus levels of clinically relevant changes for each outcome measure within COMSA; 2) use multicriteria decision analysis to develop the CONFiRM scores and 3) assess their internal validity. A separate group of HCPs evaluated CONFiRM's external validity.

RESULTS: Five levels of change for each COMSA outcome were agreed. Severe exacerbations and maintenance oral corticosteroids use were rated as most important in determining both paediatric and adult CONFiRM scores. There was strong agreement between HCPs and patients, although patients assigned greater importance to QoL. The CONFiRM score quantified response to a biological from -31 (deterioration) to 69 (best possible response). Paediatric and adult CONFiRMs had good discriminative ability for a sufficient (AUC≥0.92) and a substantial (AUC≥0.95) response to biologics. Both CONFiRMs demonstrated excellent external validity (Spearman correlation coefficients 0.9 and 0.8 for paediatric and adult respectively (p<0.0001)).

CONCLUSIONS: We have developed novel patient-centred paediatric and adult CONFiRMs which include QoL measures. CONFiRMs should allow a more holistic understanding of response for the patient and a standardised assessment of the effectiveness of biologics between studies. Further research is needed to prospectively validate CONFiRM scores.

PMID:39510551 | DOI:10.1183/13993003.00691-2024

Cell Mol Gastroenterol Hepatol. 2024 Nov 5:101424. doi: 10.1016/j.jcmgh.2024.101424. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Cystic fibrosis (CF) is an autosomal recessive genetic disorder, affecting multiple organ systems. CF intestinal disease develops early, manifesting as intestinal bacterial overgrowth/dysbiosis, neutrophilic inflammation and obstruction. As unresolvable infection and inflammation reflect host immune deficiency, we sought to determine if the CF-affected immune system plays any significant role in CF intestinal disease pathogenesis.

METHODS: CF and sibling wild-type (WT) mice underwent reciprocal bone marrow transplantation. After immune reconstitution, their mortality, intestinal transit, fecal inflammatory markers, and mucosal immune cell composition were assessed. Moreover, reciprocal neutrophil transfusion was conducted to determine if neutrophil function affects intestinal movement. Furthermore, expression of induced nitric oxide synthase (iNOS) and production of nitric oxide (NO) in CF and WT neutrophils were compared. Lastly, specific iNOS inhibitor 1400W was tested to prevent CF intestinal obstruction.

RESULTS: Immune restoration in CF mice reversed the intestinal neutrophilic inflammation, improved the intestinal dysmotility, and rescued the mice from mortality. Transfusion of WT neutrophils into CF mice ameliorated the retarded bowel movement. CF neutrophils expressed significantly more iNOS and produced significantly more NO. Pharmaceutical blocking of iNOS significantly improved intestinal transit and survival of CF mice.

CONCLUSION: CF immune defect plays a critical role in CF intestinal disease development. Activation of iNOS in inflammatory cells produces excessive NO, slows the bowel movement, and facilitates intestinal paralysis and obstruction in CF. Thus, normalization of the CF immune system may offer a novel therapy to treat CF intestinal disease.

PMID:39510500 | DOI:10.1016/j.jcmgh.2024.101424

R Soc Open Sci. 2024 Nov 6;11(11):241108. doi: 10.1098/rsos.241108. eCollection 2024 Nov.

ABSTRACT

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.

PMID:39508002 | PMC:PMC11539137 | DOI:10.1098/rsos.241108

Hepatobiliary Surg Nutr. 2024 Oct 1;13(5):894-897. doi: 10.21037/hbsn-24-467. Epub 2024 Sep 26.

NO ABSTRACT

PMID:39507743 | PMC:PMC11534791 | DOI:10.21037/hbsn-24-467

Hepatobiliary Surg Nutr. 2024 Oct 1;13(5):875-878. doi: 10.21037/hbsn-24-442. Epub 2024 Sep 26.

NO ABSTRACT

PMID:39507715 | PMC:PMC11534764 | DOI:10.21037/hbsn-24-442

Front Pediatr. 2024 Oct 23;12:1457517. doi: 10.3389/fped.2024.1457517. eCollection 2024.

ABSTRACT

This case report presents a comprehensive evaluation of the complex balance of therapeutic benefits and potential risks associated with the cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI) therapy in managing an eight-year-old male with cystic fibrosis (CF) and exocrine pancreatic insufficiency (EPI). While ETI therapy significantly enhanced exocrine pancreatic function, it led to hepatotoxicity, necessitating therapy discontinuation. Attempts to restart ETI at reduced doses were unsuccessful due to persistent hepatic dysfunction. Reduced ETI dosing frequency, implemented due to hepatic dysfunctions, did not result in substantial therapeutic benefits. Clinical markers showed a resurgence of severe EPI and sustained need for gastrostomy tube feeds, with only modest improvement in hepatic function compared to the period following ETI cessation or during prior use of CFTR modulator therapy with lumacaftor/ivacaftor. This case underscores the importance of personalized therapeutic approaches, biomarker-guided monitoring, and multidisciplinary insights to optimize CF management while also highlighting the ongoing need for research to mitigate hepatotoxicity risks and ensure long-term therapeutic efficacy.

PMID:39507496 | PMC:PMC11538068 | DOI:10.3389/fped.2024.1457517

Liver Transpl. 2024 Nov 7. doi: 10.1097/LVT.0000000000000529. Online ahead of print.

NO ABSTRACT

PMID:39504000 | DOI:10.1097/LVT.0000000000000529

Pediatr Pulmonol. 2024 Nov 6. doi: 10.1002/ppul.27382. Online ahead of print.

ABSTRACT

BACKGROUND: The benefits of Elexecaftor-Tezacaftor-Ivacaftor (ETI) therapy on the health and wellbeing of people with CF (pwCF) are well documented. Since approval, however, a growing number of potential side effects have emerged in reports from clinical practice. With current understanding of ETI tolerability limited to data from clinical trials, the prevalence of side effects and their impact on care decision making remains poorly categorized.

METHODS: A 10-question survey was developed and distributed to patients 18 years or older who were treated at the Massachusetts General Hospital CF centers. Reports of side effects were measured across 12 distinct categories, and dose adjustments and discontinuation due to side effects were collected. If a patient reported no side effects, they did not have to complete the entire survey.

RESULTS: Among 92 respondents initiated on ETI, 51 respondents (55.4%) reported potential side effects and 41 (44.5%) respondents reported no adverse events. The most commonly reported side effects were mental health, changes in appearance, and gastrointestinal complaints, which were reported by 22.8%, 30.4%, and 21.7% of patients, respectively. Eighteen (19.6%) respondents modified their dosing in response to side effects, and six discontinued treatment permanently (6.52%) due to persistent side effects.

CONCLUSIONS: Responses demonstrated marked heterogeneity, with most respondents reporting at least one side effect following initiation. Dose modification was commonly utilized to mitigate adverse effects, however few respondents had to discontinue treatment. These findings demonstrate the importance of monitoring for potential drug-related side effects of ETI in clinical settings.

PMID:39503182 | DOI:10.1002/ppul.27382

Pediatr Pulmonol. 2024 Nov 6. doi: 10.1002/ppul.27380. Online ahead of print.

NO ABSTRACT

PMID:39503159 | DOI:10.1002/ppul.27380

Med Pharm Rep. 2024 Oct;97(4):429-437. doi: 10.15386/mpr-2801. Epub 2024 Oct 30.

ABSTRACT

BACKGROUND: Hepatic disease represents a significant complication in children with cystic fibrosis (CF), yet its relationship with specific genetic factors, including CFTR (Cystic fibrosis transmembrane conductance regulator) mutations and SERPINA1 alleles, is not well understood. This study aims to clarify these associations within a Romanian pediatric CF population.

METHODS: In this cross-sectional, prospective study, we examined 71 children with CF, comparing those with hepatic disease (n=25) to those without (n=46). We collected comprehensive clinical, biochemical, and genetic data, focusing on CFTR genotypes and SERPINA1 alleles. Key outcomes included the prevalence of hepatic disease in relation to specific genotypes, fibrosis markers, and liver function tests.

RESULTS: The DF508/DF508 genotype was the most prevalent, occurring in 49% of the cohort. No significant associations were found between hepatic disease and specific CFTR genotypes or SERPINA1 alleles. However, children with hepatic disease exhibited significantly higher fibrosis scores (APRI and FIB-4), suggesting more advanced liver involvement. Additionally, a slight delay in CF diagnosis was observed in those with hepatic disease, though this difference did not reach statistical significance.

CONCLUSION: This pioneering study in Romania underscores the complexity of hepatic disease in CF. While specific CFTR genotypes and SERPINA1 alleles were not significantly associated with hepatic complications, the findings emphasize the importance of early diagnosis and monitoring using fibrosis markers to identify children at risk for liver involvement.

PMID:39502765 | PMC:PMC11534388 | DOI:10.15386/mpr-2801

Radiol Case Rep. 2024 Oct 19;20(1):187-190. doi: 10.1016/j.radcr.2024.09.098. eCollection 2025 Jan.

ABSTRACT

In about 10%-15% of instances, meconium ileus (MI) is the first sign of cystic fibrosis (CF). If a newborn exhibits signs of intestinal obstruction and does not pass meconium within a short period of time after birth, MI is suspected. The cystic fibrosis transmembrane conductance regulator gene (CFTR), which is found on chromosome 7q31, is mutated in CF patients. A premature baby, 5 days old, with clinical signs that were typical of MI. These attempts failed in spite of conservative therapies, such as rectal injection of gastrografin. An ileostomy was made and meconium was manually evacuated after an exploratory laparotomy revealed the presence of a typical MI. At ≥1300 µg/L (reference value ≤1000 µg/L), immunoreactive trypsinogen (IRT) levels were increased, which prompted the start of oral pancreatic enzyme replacement treatment. Discharge at 65 days of age included referrals to primary care and a specialized CF clinic. The baby has since shown normal growth and development. This case highlights the rapid onset of CF in a premature infant with complex MI as the initial clinical presentation.

PMID:39502278 | PMC:PMC11535884 | DOI:10.1016/j.radcr.2024.09.098

Nat Protoc. 2024 Nov 5. doi: 10.1038/s41596-024-01067-y. Online ahead of print.

ABSTRACT

Durable and functional regeneration of the airway epithelium in vivo with transplanted stem cells has the potential to reconstitute healthy tissue in diseased airways, such as in cystic fibrosis or primary ciliary dyskinesia. Here, we present detailed protocols for the preparation and culture expansion of murine primary and induced pluripotent stem cell-derived airway basal stem cells (iBCs) and methods for their intra-airway transplantation into polidocanol-conditioned murine recipients to achieve durable in vivo airway regeneration. Reconstitution of the airway tissue resident epithelial stem cell compartment of immunocompetent mice with syngeneic donor cells leverages the extensive self-renewal and multipotent differentiation properties of basal stem cells (BCs) to durably generate a broad diversity of mature airway epithelial lineages in vivo. Engrafted donor-derived cells re-establish planar cell polarity as well as functional ciliary transport. By using this same approach, human primary BCs or iBCs transplanted into NOD-SCID gamma recipient mice similarly display engraftment and multilineage airway epithelial differentiation in vivo. The time to generate mouse or human iBCs takes ~60 d, which can be reduced to ~20 d if previously differentiated cells are thawed from cryopreserved iBC archives. The tracheal conditioning regimen and cell transplantation procedure is completed in 1 d. A competent graduate student or postdoctoral trainee should be able to perform the procedures listed in this protocol.

PMID:39501108 | DOI:10.1038/s41596-024-01067-y

J Cyst Fibros. 2024 Nov 4:S1569-1993(24)01802-2. doi: 10.1016/j.jcf.2024.10.009. Online ahead of print.

ABSTRACT

We conducted a descriptive analysis of people with CF 40 years of age and older using CF Foundation Patient Registry data from 2022 to provide a current estimate of the population size and characteristics. We summarized demographic details including biological sex, race, ethnicity, insurance and employment status. Clinical data including body mass index, lung function, respiratory infections, hospitalization rates, prevalence of CF-related complications and CF therapy prescriptions were collated. A total of 5,243 individuals aged 40 years or older contributed data to the CFFPR: 2,687 (51 %) people aged 40-49 years; 1,410 (27 %) people aged 50-59 years; and 1,146 (22 %) people aged 60 years or older. The ≥60 year old group have unique characteristics compared to younger individuals, with later diagnosis of CF and greater proportion of females (58 %). These results highlight heterogeneity in the older CF adult population and the need to develop and individualize CF care practices.

PMID:39500648 | DOI:10.1016/j.jcf.2024.10.009

J Cyst Fibros. 2024 Nov 4:S1569-1993(24)01798-3. doi: 10.1016/j.jcf.2024.10.004. Online ahead of print.

ABSTRACT

BACKGROUND: Antisense Oligonucleotides (ASOs) are small synthetic nucleic acid molecules able to bind specific sequences within target Ribonucleic Acid (RNA) molecules. SPL84 is an ASO drug developed for treatment of cystic fibrosis (CF) patients carrying the 3849 + 10 kb C->T Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) splicing mutation. The 3849 + 10 kb C->T variant leads to inclusion of cryptic exon harboring stop codon leading to the production of truncated non-functional CFTR proteins. in vitro, SPL84 treatment results in splicing modulation, which leads to an increase of correctly spliced CFTR RNA and higher levels of functional CFTR proteins.

METHODS: SPL84 was tested in a blinded, placebo-controlled phase 1 study in thirty two (32) healthy volunteers (HVs), each received a single dose of either SPL84 or placebo by inhalation. A total of 8 participants were randomized to each of the 4 escalating cohorts in a 3:1 ratio (active: placebo). Safety and tolerability were evaluated by monitoring adverse events (AEs), vital signs, physical exam findings, spirometry, electrocardiograms (ECG), and analyses of safety laboratories. Blood samples were obtained periodically over 24 h for measurement of systemic exposure.

RESULTS: There were no significant changes from baseline in vital signs, clinical laboratory values, ECG, physical examination, or pulmonary function. There were no Serious Adverse Events (SAEs) in the study, and there were no significant adverse events. The systemic exposure to SPL84 was low and tended to be dose dependent. The exposure, expressed in terms of area under the curve to infinity (AUCinf), at the no observed adverse effect level (NOAEL) in 9-week toxicological mice study was 7.51 µg/ml*hrs, which is ∼20 times higher than the exposure at the 160 mg dose (444 ng/ml*hrs).

CONCLUSIONS: SPL84 was safe and well-tolerated when administered as a single inhaled dose to HVs at doses up to 160 mg, with minimal systemic exposure. There were no safety issues observed, no SAEs, no significant related AEs, and, importantly, no significant effect on pulmonary function. The successful completion of the study enabled the initiation of multi-dosing of CF patients in a phase 2 clinical study.

PMID:39500647 | DOI:10.1016/j.jcf.2024.10.004