Respir Med Case Rep. 2024 Nov 16;52:102139. doi: 10.1016/j.rmcr.2024.102139. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF)-related central (CNS) and peripheral nervous system (PNS) disorders have not yet been fully described. We report the first case of post-infective neuromuscular hyperexcitability syndrome in a 23-year-old male patient with CF and pulmonary exacerbation. CNS radiological investigations were unremarkable and no autoantibodies were detected. The patient fully recovered after infectious state control and multidisciplinary assessment and no recurrence was observed at follow-up. In view of the rarity of this condition, an additional effort is advisable to collect data and define the optimal management strategy in patients with CF.

PMID:39764213 | PMC:PMC11703639 | DOI:10.1016/j.rmcr.2024.102139

Lung. 2025 Jan 6;203(1):24. doi: 10.1007/s00408-024-00781-4.

ABSTRACT

PURPOSE: The study evaluated the effects of elexacaftor/tezacaftor/ivacaftor (ETI) therapy in people with cystic fibrosis (pwCF) and a clinical history of Aspergillus fumigatus (AF) infection.

METHODS: This prospective cohort study included pwCF who initiated ETI therapy and had received antifungal treatment in the preceding five years due to allergic bronchopulmonary aspergillosis (ABPA group) or other AF-related clinical manifestations (AF group). A control group of pwCF with no prior respiratory cultures positive for AF was also included. Changes from baseline to 12 months in spirometry measures and lung clearance index (LCI2.5), as well as respiratory colonization by AF, were compared across groups. Annual fold changes in the geometric mean of immunological markers were estimated using generalized estimating equations with a piecewise linear spline model, fitted to data collected from three years before to one-year post-ETI.

RESULTS: The study included 16 patients in the ABPA group, 47 in the AF group, and 45 controls. Spirometry and LCI2.5 improvements were comparable across groups. Positive respiratory cultures decreased from 43.8 to 18.8% in the ABPA group (p = 0.30), and from 78.7 to 23.4% in the AF group (p < 0.001). Total IgE and IgG anti-AF decreased in both the ABPA and the AF groups, with annual reductions of 20-42%. No ABPA episodes occurred during ETI therapy.

CONCLUSION: During ETI therapy, pulmonary outcomes improved, AF colonization and sensitization decreased, and no episodes of ABPA were observed in pwCF with a clinical history of AF infection.

PMID:39762638 | DOI:10.1007/s00408-024-00781-4

Epidemiology. 2024 Dec 31. doi: 10.1097/EDE.0000000000001826. Online ahead of print.

ABSTRACT

BACKGROUND: Children with cystic fibrosis (CF) from socioeconomically deprived areas have poorer growth, worse lung function, and shorter life expectancy than their less-deprived peers. While early growth is associated with lung function around age 6, it is unclear whether improving early growth in the most deprived children reduces inequalities in lung function.

METHODS: We used data from the UK CF Registry, tracking children born 2000-2010 up to 2016. We extended the interventional disparity effects approach to the setting of a longitudinally measured mediator. Applying this approach, we estimated the association between socio-economic deprivation (children in the least versus most deprived population quintile; exposure) and lung function at first measurement (ages 6-8, outcome), and the role of early weight trajectories (ages 0-6) as mediators of this relationship. We adjusted for baseline confounding by sex, birthyear, and genotype and time-varying intermediate confounding by lung infection.

RESULTS: The study included 853 children, with 165 children from the least and 172 from the most deprived quintiles. The average lung function difference between the least and most deprived quintiles was 4.5% of predicted forced expiratory volume in 1 second (95% CI: 1.1 - 7.9). If the distribution of early weight trajectories in the most deprived children matched that in the least deprived children, this difference would reduce to 4% (95% CI: 0.57 - 7.4).

CONCLUSION: Socio-economic deprivation has a strong negative association with lung function for children with CF. We estimate that improving early weight trajectories in the most deprived children would only marginally reduce these inequalities.

PMID:39760864 | DOI:10.1097/EDE.0000000000001826

Andes Pediatr. 2024 Oct;95(5):543-552. doi: 10.32641/andespediatr.v95i5.5124.

ABSTRACT

Neonatal screening has been implemented internationally with different protocols and has become the routine method in the preclinical stage. Late diagnosis is associated with more severe symptoms with decreased survival and higher treatment costs.

OBJECTIVES: To estimate the incidence of cystic fibrosis; to evaluate the performance of the screening algorithms Immunoreactive Trypsinogen and Pancreatitis-Associated Protein (IRT/PAP) and the IRTxPAP product; to analyze the cut-off value for IRT, PAP, and IRTxPAP, and to establish a methodology for its ongoing evaluation; finally, to evaluate the quality of IRT and PAP measurements.

PATIENTS AND METHOD: a neonatal screening protocol was implemented using the IRT/PAP assays plus IRTXPAP product in a 7-year pilot study. Between 2015 and 2021, a total of 371,724 heel dried blood spot samples were collected in maternity and neonatology units from the public healthcare network in 17 hospitals in the Metropolitan Region (RM) and 15 in the Valparaíso Region (RV). 277,245 newborns met the inclusion criteria.

RESULTS: with IRT/PAP plus IRT x PAP the incidence was 1/7,109 NB. The cut-off value and percentiles were established for IRT, PAP, IRT x PAP. The best sensitivity and specificity obtained by ROC analysis gave an IRT value of 48,142 ng/mL (98.8th percentile), PAP of 1.68 ug/L and IRT x PAP of 140ug2/L. The performance of the IRT/PAP detection algorithms, the IRT x PAP product, and the quality of measurements were evaluated.

CONCLUSION: The results allow us to report that the IRT/PAP plus IRTxPAP protocol can be implemented in Chile, complying with international guidelines, with adequate government funding.

PMID:39760624 | DOI:10.32641/andespediatr.v95i5.5124

Pediatr Pulmonol. 2025 Jan 6:e27463. doi: 10.1002/ppul.27463. Online ahead of print.

ABSTRACT

OBJECTIVE: We prospectively monitored rates of change for growth, body mass and composition, muscle strength, and FEV1 in 6-11-year-olds initiating ETI therapy, comparing them to those of US reference children. We assessed factors potentially contributing to rate of change and report ranges of individual variation.

METHODS: Body composition was assessed using bioelectrical impedance analysis (BIA), and rates of change were analyzed using linear mixed effects regression models.

RESULTS: At enrollment, median BMI-Z was 0.6 (IQR: -0.2, 1.1), percent body fat (PBF) was 22.7 (14.0, 31.5), and percent predicted(pp) FEV1 was 100 (90, 106). During ETI treatment, mean Z scores for annualized change rates of BMI (0.02 ± 0.07; p = 0.74), FMI (0.02 ± 0.08; p = 0.76), and FFMI (-0.03 ± 0.07; p = 0.68) were not different from zero. The most rapid weight gain occurred in girls (p = 0.01), 10-11-year-olds (p < 0.001), and those previously treated with a modulator (p = 0.005). Individual rates of change varied widely; PBF increased for 15 children (range: 0.7 to 10.0) and decreased for 12 (range: -0.7 to -9.5). Changes in body mass and composition were not significantly associated with changes in ppFEV1; regression coefficients were positive for FFMI (0.83) and SMMI (1.07) and negative for FMI (-0.29).

CONCLUSION: Healthy, well-nourished children with CF, as a group, experienced growth and body composition changes similar to those of US children, added muscle mass, and often added more FM than FFM during ETI therapy. Individual variation underscores the need for body composition monitoring and interventions that promote healthy physical maturation for all during ETI therapy.

PMID:39760529 | DOI:10.1002/ppul.27463

J Pharm Anal. 2024 Dec;14(12):100939. doi: 10.1016/j.jpha.2024.01.007. Epub 2024 Jan 26.

ABSTRACT

In our prior research, polymer nanoparticles (NPs) containing tobramycin displayed robust antibacterial efficacy against biofilm-embedded Pseudomonas aeruginosa (P. aeruginosa) and Burkholderia cenocepacia (B. cenocepacia) cells, critical pathogens in cystic fibrosis. In the current study, we investigated the deposition of a nanoparticulate carrier composed of poly(d,l-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-block-PLGA (PEG-PLGA) that was either covalently bonded with cyanine-5-amine (Cy5) or noncovalently bound with freely embedded cationic rhodamine B (RhB), which served as a drug surrogate. After exposing these NPs to bacteria, we performed cell fractionation and fluorescence analysis, which highlighted the accumulation of Cy5 in the outer membranes (OMs) and the accumulation of RhB in the cytoplasm (CP) of cells. The results indicated that these organic NPs are effective vehicles for targeted antibiotic delivery in bacterial cells, explaining the observed increase in the efficacy of encapsulated tobramycin against biofilms. This work emphasizes the potential of PEG-PLGA-based formulations for advanced drug delivery strategies.

PMID:39759775 | PMC:PMC11697766 | DOI:10.1016/j.jpha.2024.01.007

Lancet Respir Med. 2024 Dec 20:S2213-2600(24)00407-7. doi: 10.1016/S2213-2600(24)00407-7. Online ahead of print.

ABSTRACT

BACKGROUND: In phase 2 trials in people with cystic fibrosis aged 18 years and older, vanzacaftor-tezacaftor-deutivacaftor has been shown to be a safe and effective, once-daily cystic fibrosis transmembrane conductance regulator (CFTR) modulator. Restoring normal CFTR function early in life has the potential to prevent manifestations of cystic fibrosis. We aimed to evaluate the safety, tolerability, efficacy, and pharmacokinetics of vanzacaftor-tezacaftor-deutivacaftor in children with cystic fibrosis aged 6-11 years.

METHODS: In this multicentre, single-arm, phase 3 trial (RIDGELINE Trial VX21-121-105), participants were enrolled across 33 clinical sites that care for children with cystic fibrosis in eight countries (Australia, France, Germany, Netherlands, Sweden, Switzerland, the UK, and the USA). Eligible participants were aged 6-11 years with at least one elexacaftor-tezacaftor-ivacaftor-responsive CFTR variant, FEV1 % predicted of 60% or higher, and stable cystic fibrosis as determined by investigators. Before study treatment, participants were either on stable elexacaftor-tezacaftor-ivacaftor for at least 28 days before screening or received the combination for a 4-week run-in period. Participants then received vanzacaftor-tezacaftor-deutivacaftor (<40 kg bodyweight: vanzacaftor 12 mg, tezacaftor 60 mg, and deutivacaftor 150 mg orally as three fixed-dose combination tablets once daily; ≥40 kg bodyweight: vanzacaftor 20 mg, tezacaftor 100 mg, and deutivacaftor 250 mg orally as two fixed-dose combination tablets once daily (manufactured by Patheon Pharmaceuticals, Cincinnati, OH, USA) from day 1 for 24 weeks. The primary endpoint was safety and tolerability, as measured by adverse events, vital signs, clinical laboratory values, electrocardiograms, and pulse oximetry. Endpoints were analysed in all participants who received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. This trial is registered with ClinicalTrials.gov, NCT05422222, and evaluation of the 6-11-year-old cohort is complete.

FINDINGS: Between Feb 6 and May 18, 2023, 83 children were screened, of whom five were not eligible, and 78 children aged 6-11 years received at least one dose of vanzacaftor-tezacaftor-deutivacaftor. Median age was 9·3 years (IQR 7·6-10·4), 34 (44%) of 78 participants were female, 44 (56%) were male, 71 (91%) were White, one (1%) was Black or African American, and one (1%) was of multiple races. The analysis for these data was completed on Dec 15, 2023. Median exposure of participants to vanzacaftor-tezacaftor-deutivacaftor was 168 days (IQR 166-170). 75 (96%) of 78 participants had adverse events, all of which were mild or moderate; the most common events were generally consistent with cystic fibrosis manifestations, including, cough (36 [46%]), pyrexia (16 [21%]), headache (14 [18%]), infective pulmonary exacerbation of cystic fibrosis (13 [17%]), and oropharyngeal pain (13 [17%]). Serious adverse events occurred in six (8%) participants (two had infective pulmonary exacerbation, one of whom also had failure to thrive; one participant each had adenovirus infection, constipation, pulmonary function test decreased, and cough), and one (1%) participant discontinued due to adverse events of cough and fatigue that were considered possibly related to study drug.

INTERPRETATION: Vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and maintained FEV1 % predicted from elexacaftor-tezacaftor-ivacaftor baseline with further improved CFTR function. Improvements in CFTR function compared with baseline elexacaftor-tezacaftor-ivacaftor values demonstrate the potential opportunity to restore normal physiology early and prevent development or progression of cystic fibrosis. Nearly all participants had sweat chloride below the diagnostic threshold for cytstic fibrosis (<60 mmol/L) and more than half had normal levels (<30 mmol/L). Additional long-term data in children with cystic fibrosis are being collected in an open-label extension study to demonstrate clinical benefits and safety. These findings will inform health-care providers and people with cystic fibrosis regarding the benefits of early initiation of CFTR modulators.

FUNDING: Vertex Pharmaceuticals.

PMID:39756425 | DOI:10.1016/S2213-2600(24)00407-7

Lancet Respir Med. 2024 Dec 20:S2213-2600(24)00411-9. doi: 10.1016/S2213-2600(24)00411-9. Online ahead of print.

ABSTRACT

BACKGROUND: The goal of cystic fibrosis transmembrane conductance regulator (CFTR) modulators is to reach normal CFTR function in people with cystic fibrosis. Vanzacaftor-tezacaftor-deutivacaftor restored CFTR function in vitro and in phase 2 trials in participants aged 18 years and older resulting in improvements in CFTR function, as measured by sweat chloride concentrations and lung function as measured by spirometry. We aimed to evaluate the efficacy and safety of vanzacaftor-tezacaftor-deutivacaftor compared with standard of care elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older.

METHODS: In two randomised, active-controlled, double-blind, phase 3 trials, individuals aged 12 years and older with stable cystic fibrosis with F508del-minimal function (SKYLINE Trial VX20-121-102) or with F508del-F508del, F508del-residual function, F508del-gating, or elexacaftor-tezacaftor-ivacaftor-responsive-non-F508del genotypes (SKYLINE Trial VX20-121-103) were enrolled at 126 and 159 international sites, respectively. Eligible individuals were entered into a 4-week run-in period, during which they received elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening. They were then randomly assigned (1:1) to either elexacaftor (200 mg once daily), tezacaftor (100 mg once daily), and ivacaftor (150 mg once every 12 h) as two fixed-dose combination tablets in the morning and one ivacaftor tablet in the evening, or vanzacaftor (20 mg once daily), tezacaftor (100 mg once daily), and deutivacaftor (250 mg once daily) as two fixed-dose combination tablets in the morning, for the 52-week treatment period. All participants received matching placebo tablets to maintain the treatment blinding. Randomisation was done using an interactive web-response system and stratified by age, FEV1 % predicted, sweat chloride concentration, and previous CFTR modulator use, and also by genotype for Trial VX20-121-103. The primary endpoint for both trials was absolute change in FEV1 % predicted from baseline (most recent value before treatment on day 1) through week 24 (with non-inferiority of vanzacaftor-tezacaftor-deutivacaftor shown if the lower bound of the 95% CI for the primary endpoint was -3·0 or higher). Efficacy was assessed in all participants with the intended CFTR genotype who were randomly assigned to treatment and received at least one dose of study treatment during the treatment period. Safety was assessed in all participants who received at least one dose of study drug during the treatment period. These trials are registered with ClinicalTrials.gov, NCT05033080 (Trial VX20-121-102) and NCT05076149 (Trial VX20-121-103), and are now complete.

FINDINGS: In Trial VX20-121-102 between Sept 14, 2021, and Oct 18, 2022, 488 individuals were screened, of whom 435 entered the 4-week run-in period, and subsequently 398 were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=202) or vanzacaftor-tezacaftor-deutivacaftor (n=196). Median age was 31·0 years (IQR 22·6-38·5), 163 (41%) of 398 participants were female, 235 (59%) were male, and 388 (97%) were White. In Trial VX20-121-103, between Oct 27, 2021, and Oct 26, 2022, 699 individuals were screened, of whom 597 entered the 4-week run-in period, and subsequently 573 participants were randomly assigned and received at least one dose of elexacaftor-tezacaftor-ivacaftor (n=289) or vanzacaftor-tezacaftor-deutivacaftor (n=284). Median age was 33·1 years (IQR 24·5-42·2), 280 (49%) of 573 participants were female, 293 (51%) were male, and 532 (93%) were White. The absolute change in least squares mean FEV1 % predicted from baseline through week 24 for Trial VX20-121-102 was 0·5 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·3 (0·3) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference of 0·2 percentage points [95% CI -0·7 to 1·1]; p<0·0001), and for Trial VX20-121-103, was 0·2 (SE 0·3) percentage points in the vanzacaftor-tezacaftor-deutivacaftor group versus 0·0 (0·2) percentage points in the elexacaftor-tezacaftor-ivacaftor group (least squares mean treatment difference 0·2 percentage points [95% CI -0·5 to 0·9]; p<0·0001). Most adverse events were mild or moderate, with the most common being infective pulmonary exacerbation (133 [28%] of 480 participants in the pooled vanzacaftor-tezacaftor-deutivacaftor group vs 158 [32%] of 491 in the pooled elexacaftor-tezacaftor-ivacaftor group), cough (108 [23%] vs 101 [21%]), COVID-19 (107 [22%] vs 127 [26%]), and nasopharyngitis (102 [21%] vs 95 [19%]).

INTERPRETATION: Vanzacaftor-tezacaftor-deutivacaftor is non-inferior to elexacaftor-tezacaftor-ivacaftor in terms of FEV1 % predicted, and is safe and well tolerated. Once daily dosing with vanzacaftor-tezacaftor-deutivacaftor reduces treatment burden, potentially improving adherence, compared with the twice daily regimen of the current standard of care. The restoration of CFTR function and the potential variants treated are also considerations that should be compared with currently available CFTR modulators.

FUNDING: Vertex Pharmaceuticals.

PMID:39756424 | DOI:10.1016/S2213-2600(24)00411-9

J Cyst Fibros. 2025 Jan 3:S1569-1993(24)01854-X. doi: 10.1016/j.jcf.2024.12.006. Online ahead of print.

ABSTRACT

BACKGROUND: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment.

METHODS: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time.

RESULTS: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L.

CONCLUSIONS: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators.

PMID:39755444 | DOI:10.1016/j.jcf.2024.12.006

Adv Ther. 2025 Jan 4. doi: 10.1007/s12325-024-03071-w. Online ahead of print.

ABSTRACT

INTRODUCTION: The burden of severe asthma on patients, especially on those with concomitant chronic rhinosinusitis with nasal polyps (CRSwNP), is substantial. Treatment intensification with oral corticosteroids is a common strategy for managing severe asthma exacerbations; however, prolonged exposure to systemic corticosteroids is associated with multisystem toxicity. This study aimed to quantify the association between oral corticosteroid use and annual asthma-related costs in patients with severe asthma with or without CRSwNP.

METHODS: This pharmacoeconomic analysis was based on data from the Severe Asthma Network in Italy (SANI) registry. Asthma-related costs were estimated in the context of the Italian healthcare system and included exacerbations requiring treatment intensification, unplanned visits, admissions to hospital and emergency/intensive care units, and lost workdays. For each item, the mean annual cost per patient was estimated based on national tariffs and the frequency of the event. To quantify the association between oral corticosteroid treatment and costs, the study cohort was stratified according to oral corticosteroid use in the 1-year preceding inclusion in the SANI registry.

RESULTS: A total of 669 patients from the SANI registry were included in the present analysis, 255 of whom had concomitant CRSwNP. Corticosteroid use was associated with significantly higher annual disease-related costs per patient compared with no corticosteroid use. Compared with the overall study cohort and patients without CRSwNP, patients with CRSwNP had higher disease-related costs (higher by €1307 and €1869, respectively).

CONCLUSION: Use of corticosteroids, in particular systemic corticosteroids, is associated with an increase in asthma-related costs. The concomitant presence of CRSwNP impacts negatively on costs. This study suggests that a thorough analysis of costs, expected benefits, and occurrence of adverse events is required when selecting treatment intensification strategies for managing uncontrolled severe asthma.

PMID:39754702 | DOI:10.1007/s12325-024-03071-w

JAMA Netw Open. 2025 Jan 2;8(1):e2451700. doi: 10.1001/jamanetworkopen.2024.51700.

ABSTRACT

IMPORTANCE: Administrative health data serve as promising data sources to study transgender health at a population level in the absence of self-reported gender identity.

OBJECTIVE: To develop and validate case definitions identifying transgender adults in administrative data compared with the reference standard of self-reported gender identity in a universal health care setting.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study conducted in Alberta, Canada, data from provincial administrative health data sources including inpatient hospitalizations, emergency department encounters, primary care visits, prescription drug dispensations, and the provincial health insurance registry were linked and used to develop 15 case definitions (9 for transgender women and 6 for transgender men). Participants aged 18 years or older with a provincial health care number between April 1, 1994, and March 31, 2021, were included and stratified by sex marker (eg, female or male) at study entry. Data analysis was from December 2023 to March 2024.

MAIN OUTCOMES AND MEASURES: For each case definition, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated against the reference standard of self-reported gender identity.

RESULTS: In this cohort study of 5 375 735 individuals, the reference standard consisted of 141 self-identified transgender women, 174 self-identified transgender men, 111 self-identified cisgender women, and 65 self-identified cisgender men. The final cohort representing transgender women participants who met at least 1 case definition and/or were part of the standard reference totaled 63 977. Combining a case definition employing male sex registry identification and 2 or more dispensations of estrogen or a case definition employing male sex registry identification and at least 1 gender-related diagnostic code demonstrated a sensitivity of 86.6% (95% CI, 79.9%-91.7%), specificity of 62.5% (95% CI, 51.5%-72.6%), PPV of 78.8% (95% CI, 71.6%-85.0%), and NPV of 74.3% (95% CI, 62.8%-83.8%). The final cohort representing transgender men participants who met at least 1 case definition and/or were part of the standard reference totaled 26 852. Combining a case definition employing female sex registry identification and 2 or more dispensations of testosterone or a case definition employing female sex registry identification and at least 1 gender-related diagnostic code demonstrated a sensitivity of 78.2% (95% CI, 71.3%-84.1%), specificity of 89.2% (95% CI, 82.2%-94.1%), PPV of 91.3% (95% CI, 85.5%-95.3%), and NPV of 73.8% (95% CI, 65.8%-80.7%).

CONCLUSION AND RELEVANCE: These findings suggest that case definitions using transgender-related diagnostic codes and gender-affirming hormone prescriptions can be used to study the epidemiology, disease burden, and health care utilization of transgender populations.

PMID:39752161 | PMC:PMC11699535 | DOI:10.1001/jamanetworkopen.2024.51700

J Cyst Fibros. 2025 Jan 2:S1569-1993(24)01858-7. doi: 10.1016/j.jcf.2024.12.007. Online ahead of print.

ABSTRACT

BACKGROUND: Adult people with cystic fibrosis (PwCF) have a higher risk of end-stage kidney disease than the general population. The nature and mechanism of kidney disease in CF are unknown. This study quantifies urinary kidney injury markers and examines the hypothesis that neutrophil activation and lung infection are associated with early kidney injury in CF.

METHODS: Urinary total protein, albumin, and markers of kidney injury and neutrophil activation, normalized to creatinine, as well as urinary immune cells, were quantified in adult CF and healthy cohorts. Infection burden and chronicity were defined by sputum culture and serum titers of anti-bacterial antibodies.

RESULTS: PwCF had increased urinary protein levels, consisting of low-molecular-weight tubular injury markers, independent of glomerular filtration rate (eGFR). This finding suggests subclinical renal injury processes. Urinary analysis of the CF cohort identified different associations of urinary injury markers with aminoglycoside exposure, lung function, and neutrophil activation. High urinary KIM-1 levels and increased prevalence of neutrophils among urine immune cells correlated with decreased lung function in PwCF. The relationship between tubular injury and reduced lung function was most prominent in patients harboring chronic Pseudomonas aeruginosa infection.

CONCLUSIONS: Increased urinary tubular injury markers in PwCF suggest early subclinical renal injury not readily detected by eGFR. The strong association of high urinary KIM-1 and neutrophils with diminished lung function and high Pseudomonas aeruginosa burden suggests that pulmonary disease may contribute to renal injury in CF.

PMID:39753455 | DOI:10.1016/j.jcf.2024.12.007

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 1:167652. doi: 10.1016/j.bbadis.2024.167652. Online ahead of print.

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage renal disease, contributing substantially to patient morbidity, mortality, and healthcare system strain. Emerging research highlights a pivotal role of epigenetics in ADPKD's pathophysiology, where mechanisms like DNA methylation, histone modifications, and non-coding RNA regulation significantly impact disease onset and progression. These epigenetic factors influence gene expression and regulate key processes involved in cyst formation and expansion, fibrosis, and inflammatory infiltration, thus accelerating ADPKD progression. Consequently, exploring epigenetic regulatory mechanisms presents a valuable pathway for developing novel therapeutic strategies and diagnostic biomarkers aimed at slowing or preventing ADPKD progression. This review systematically examines existing studies on epigenetic alterations-including DNA methylation, histone modification, and non-coding RNA regulation-in ADPKD patients, providing insights into gene expression changes and functions, and identifying potential drug targets for ADPKD treatment. CLINICAL SIGNIFICANCE: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage renal disease, causing significant morbidity, increasing patient mortality, and weakening the healthcare system. Further study on ADPKD has revealed that epigenetics plays an important role in the pathophysiological process of ADPKD. Epigenetics has a significant impact on the formation and progression of ADPKD through a variety of processes including DNA methylation, histone modification, and non-coding RNA. In addition to boosting cyst formation and proliferation, it induces cystic fibrosis and inflammatory cell infiltration, ultimately leading to a poor prognosis. This review summarizes the current understanding of the associated alterations in gene expression and function produced by epigenetic regulation in ADPKD, as well as potential treatment targets.

PMID:39753194 | DOI:10.1016/j.bbadis.2024.167652

Tijdschr Psychiatr. 2024;66(10):579-585.

ABSTRACT

BACKGROUND: Studies showed significant physical improvement after starting elexacaftor/tezacaftor/ivacaftor (ETI). However, some patients reported new mental health symptoms.

AIM: This study explores the impact of ETI on end-stage cystic fibrosis patients, focusing on mental health.

METHOD: A mixed-method study was conducted at the cystic fibrosis reference center, University Hospital Leuven (Belgium). Patients were eligible for ETI in a compassionate use program. Data collection included clinical records providing demographic, medical, and psychological data, and semi-structured interviews for qualitative insights.

RESULTS: Post ETI-initiation, all 27 patients demonstrated physical improvement, of which 18 reported positive or no mental health changes and 9 negative changes. Clinical records revealed specific mental health issues, including increased depressive symptoms (n=7), anxiety (n=5), suicidal tendencies (n=4), emotion-regulation difficulties (n=4), and manic episodes (n=2). Semi-structured interviews with 15 patients identified three main themes and four subthemes: revitalizing health, emotional adaption (embracing hope, confronting shadows), and personal development (second lease of life, dealing with the unknown).

CONCLUSION: Despite remarkable improvements from ETI, 9/27 patients experienced new mental health symptoms, ranging from mild anxiety to suicide attempts. Our study underscores the importance of proactive psychological support and integrated psychiatric care during ETI-initiation.

PMID:39749592

Sci Rep. 2025 Jan 2;15(1):479. doi: 10.1038/s41598-024-84191-9.

ABSTRACT

The development of targeted therapies that correct the effect of mutations in patients with cystic fibrosis (CF) and the relevant heterogeneity of the clinical expression of the disease require biomarkers correlated to the severity of the disease useful for monitoring the therapeutic effects. We applied a targeted metabolomic approach by LC-MS/MS on saliva samples from 70 adult CF patients and 63 age/sex-matched controls to investigate alterations in metabolic pathways related to pancreatic insufficiency (PI), Pseudomonas aeruginosa (PA) colonization, CF liver disease (CFLD), and CF related diabetes (CFRD). Sixty salivary metabolites were differentially expressed, with 11 being less abundant and 49 more abundant in CF patients. Among these, the most relevant alterations involved salivary ADMA, N-acetylornithine, methionine and methionine sulfoxide levels. Furthermore, methionine was significantly lower in CF patients with PI and salivary histamine levels were significantly lower in patients colonized by PA. Moreover, ADMA as well as N-acetylornithine and methionine were significantly lower in CF patients with CFRD than in patients without CFRD. Finally, the levels of DOPA resulted significantly lower in saliva from patients with liver disease. Our study revealed an imbalance in arginine methylation and tryptophan pathway related to CFRD and PI as well as alterations in dopaminergic pathway and Krebs cycle related to CFLD. This study also highlights different salivary metabolites as new potential biomarkers in a non-invasive sample that could represent a useful tool for the stratification and management of CF patients.

PMID:39747338 | DOI:10.1038/s41598-024-84191-9

Ann Am Thorac Soc. 2025 Jan 2. doi: 10.1513/AnnalsATS.202408-868OC. Online ahead of print.

ABSTRACT

RATIONALE: Chronic Pseudomonas aeruginosa (Pa) airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic Pa among PwCF include cystic fibrosis transmembrane conductance regulator genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate Pa in most adolescents and adults with cystic fibrosis.

OBJECTIVE: To identify new genetic modifiers contributing to the pathophysiology of chronic Pa infection in PwCF.

METHODS: 4,945 participants in the CF Genome Project with whole genome sequencing linked to longitudinal clinical data from the 2017 CF Foundation Patient Registry were used to conduct a time-to-event genome-wide association study using two definitions of chronic Pa infection.

MAIN RESULTS: We identified a genome-wide significant association (p=2.2E-8) between delayed onset of chronic Pa infection and rs194810, a common variant near the gene CHP2 which encodes calcineurin B homolog protein 2 (minor A allele frequency 43%). Survival curves by rs198410 allele dosage show that PwCF homozygous for the A allele are an average of 3 years older when achieving chronic Pa infection compared to G allele homozygotes.

CONCLUSION: Variants near CHP2 are associated with a significant delay in the age of chronic Pa infection in PwCF.

PMID:39746161 | DOI:10.1513/AnnalsATS.202408-868OC

Tuberk Toraks. 2024 Dec;72(4):300-306. doi: 10.5578/tt.202404964.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction observed in asthma as well as cystic fibrosis (CF) patients due to the colonization of the airways by Aspergillus fumigatus. While ABPA is most commonly observed in CF patients (2-9%), it is seen at a rate of 1-2% in patients diagnosed with asthma. ABPA is mostly seen in steroid dependent adult asthma patients and has rarely been reported in pediatric asthma patients. The aim of our study was to provide the clinical, laboratory, and radiological characteristics of two patients under our follow-up care who were also diagnosed with ABPA. In the pediatric population, ABPA is often seen in patients with cystic fibrosis and rarely as a complication of childhood asthma. However, it is not clear whether this is because ABPA is really rare or because there is low level of suspicion for this disease. Furthermore, diagnostic criteria and staging systems are created by taking adults into consideration and not having different diagnostic criteria or staging systems for pediatric patients makes the diagnosis even more difficult.

PMID:39745230 | DOI:10.5578/tt.202404964

Drug Dev Ind Pharm. 2025 Jan 1:1-15. doi: 10.1080/03639045.2024.2448271. Online ahead of print.

ABSTRACT

OBJECTIVE: Highly branched poly(β-amino ester) (HPAEs)-based gene therapy holds promise for treating lung cystic fibrosis (CF). However, the translation of HPAEs/DNA nanoparticles into clinical applications poses a significant challenge due to the requirement for high concentrations of the formulation.

METHODS: In this work, a straightforward and scalable concentration method was developed for concentrating HPAEs/DNA polyplexes. A series of different buffers with various pH values and ionic components were initially tested to develop the optimized HPAEs/DNA polyplex formulation. Subsequently, the optimized HPAEs/DNA polyplex formulation was concentrated through lyophilization and ultrafiltration.

RESULTS: The ultrafiltration outperformed the lyophilization in concentration capacity, showing a 24-fold increase in the concentrated formulation compared to the original non-concentrated formulation. The concentration does not disturb the transfection efficiency in lung CF epithelial cells, indicating its potential for lung delivery applications. Moreover, the concentrated HPAEs/DNA polyplex successfully restored the production of cystic fibrosis transmembrane conductance regulator (CFTR) protein in primary lung CF epithelial cells, surpassing the performance of the non-concentrated common gene transfection reagents such as Lipofectamine 3000 and Xfect.

CONCLUSIONS: The concentrated HPAEs/DNA formulation represents a promising step forward for preclinical testing (e.g., in vivo evaluation), with further research needed to confirm its potential for clinical use.

PMID:39743829 | DOI:10.1080/03639045.2024.2448271

J Patient Exp. 2024 Dec 27;11:23743735241302739. doi: 10.1177/23743735241302739. eCollection 2024.

ABSTRACT

People with cystic fibrosis (PwCF), families, and clinicians, partner to co-produce care, navigate access barriers, address mental health and social factors, follow specific infection prevention and control practices, and share decision-making regarding treatments and daily care. Standard patient satisfaction and experience of care surveys are not tailored to return relevant, actionable data for specific populations. To improve the care experience, the U.S. CF Foundation committed to fielding a national survey in 2015. In 2020, the onset of the COVID-19 pandemic prompted revisions to capture virtual care experiences, a mode of care delivery not previously offered to PwCF. Leveraging this opportunity, the CF Foundation also reorganized how stakeholders are engaged in survey design, implementation, and improving the care experience. These changes resulted in a focused survey instrument as well as equitable and transparent data reports available to all stakeholders.

PMID:39742073 | PMC:PMC11686623 | DOI:10.1177/23743735241302739

Infect Drug Resist. 2024 Dec 27;17:5855-5866. doi: 10.2147/IDR.S495676. eCollection 2024.

ABSTRACT

PURPOSE: Burkholderia is a conditioned pathogen in the medical setting and mainly affects patients with cystic fibrosis. We found co-infection with Burkholderia cepacia complex (Bcc) in many patients with respiratory tract infections, including H7N9 and COVID-19. However, previous studies have not focused on co-infections with BCC and respiratory viruses. Therefore, this study attempted to clarify the evolution of COVID-19-Bcc and H7N9-Bcc in terms of genetic background, antibiotic resistance, and virulence phenotypes.

METHODS: This study retrospectively collected 49 Bcc isolated from patients with H7N9 and COVID-19 in a tertiary hospital of Zhejiang Province, of which 42 isolates were isolated from patients with H7N9, seven isolates were isolated from patients with COVID-19. The collected isolates were tested for antibiotic susceptibility, Galleria mellonella infection model, and whole-genome COVID-19-Bcc Characterization.

RESULTS: The test results of 49 strains of Bcc showed that the strains isolated from COVID-19 patients accounted for 57.1% of multidrug-resistance resistant strains. Statistical analysis of the median lethal time of G. mellonella showed that the median fatal time for COVID-19-Bcc was shorter and more virulent than that of H7N9-Bcc (P<0.05). The results of phylogenetic analysis indicated that COVID-19-Bcc may have evolved from H7N9-Bcc.

CONCLUSION: In this study, co-infection with BCC in many patients with respiratory tract infections, including H7N9 and COVID-19, was first identified and clarified that COVID-19-Bcc may have evolved from H7N9-Bcc and has the characteristics of hypervirulence and multidrug resistance.

PMID:39741887 | PMC:PMC11687121 | DOI:10.2147/IDR.S495676