Drugs. 2023 Jul 6. doi: 10.1007/s40265-023-01913-5. Online ahead of print.

ABSTRACT

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.

PMID:37410209 | DOI:10.1007/s40265-023-01913-5

Health (London). 2023 Jul 6:13634593231185265. doi: 10.1177/13634593231185265. Online ahead of print.

ABSTRACT

Using the theoretical perspective of "social participation" as considered in the Human Development-Disability Creation Process, this article examines certain obstacles and facilitators to sustainable access to work among young French adults with cystic fibrosis. Drawing from the analyses of 29 qualitative interviews, the results show how such obstacles do not depend solely on their health status or on the medical management of the illness, but also on the work environments that these young professionals have recently entered or are trying to access. In these contexts, managing information about the illness can represent a means of obtaining cooperation from colleagues and superiors to reduce material or organizational obstacles (e.g. adapted work schedules), as well as a means of preventing socially uncomfortable or disabling situations. In this light, the social participation model can complement Corbin and Strauss' illness trajectory model, by setting the multi-factorial disabling or participatory situations along illness or medical trajectories. This enables dynamic consideration of how workplaces contribute to producing or reducing disability, in interaction with the actions taken by young people with cystic fibrosis to manage their career paths but also the evolution of illness, symptoms, or medical requirements.

PMID:37409611 | DOI:10.1177/13634593231185265

J Sep Sci. 2023 Jul 6:e2300228. doi: 10.1002/jssc.202300228. Online ahead of print.

ABSTRACT

Lumacaftor is a transmembrane conductance regulator potentiator drug, prescribed for the treatment of cystic fibrosis in patients who are homozygous for the F508del mutation. Quantitation of lumacaftor besides its degradation products and ivacaftor was achieved on a fused-core silica particle column packed with pentafluorophenylpropyl stationary phase (Ascentis Express F5, 2.7 μm particle size 100 mm × 4.6 mm; Supelco) using gradient elution (A: 0.1% [v/v] formic acid in water, B: 0.1% [v/v] formic acid in acetonitrile [the mobile phase pH 2.5]). A constant flow rate at 1 mL/min was applied, and the detection was realized using a photodiode array detector set at 216 nm. The pseudo tablet formulation of the lumacaftor/ivacaftor fixed-dose combination preparation, namely, Orkambi®, was prepared in vitro and used for the analytical performance validation and method application studies. In addition, five novel degradation products, four of which even have no Chemical Abstracts Services registry number, were identified using high-resolution mass spectrometry instrument, and their possible mechanisms of formation were proposed. According to current literature, this paper can be regarded as the most comprehensive liquid chromatographic study on lumacaftor determination, among its counterparts.

PMID:37409384 | DOI:10.1002/jssc.202300228

Front Pharmacol. 2023 Jun 20;14:1180826. doi: 10.3389/fphar.2023.1180826. eCollection 2023.

ABSTRACT

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

PMID:37408761 | PMC:PMC10318131 | DOI:10.3389/fphar.2023.1180826

Psychol Health. 2023 Jul 5:1-23. doi: 10.1080/08870446.2023.2231489. Online ahead of print.

ABSTRACT

OBJECTIVE: Caring for a child with cystic fibrosis (CF) is a rigorous daily commitment for caregivers and treatment burden is a major concern. We aimed to develop and validate a short form version of a 46-item tool assessing the Challenge of Living with Cystic Fibrosis (CLCF) for clinical or research use.

DESIGN: A novel genetic algorithm based on 'evolving' a subset of items from a pre-specified set of criteria, was applied to optimise the tool, using data from 135 families.

MAIN OUTCOME MEASURES: Internal reliability and validity were assessed; the latter compared scores to validated tests of parental well-being, markers of treatment burden, and disease severity.

RESULTS: The 15-item CLCF-SF demonstrated very good internal consistency [Cronbach's alpha 0.82 (95%CI 0.78-0.87)]. Scores for convergent validity correlated with the Beck Depression Inventory (Rho = 0.48), State Trait Anxiety Inventory (STAI-State, Rho = 0.41; STAI-Trait, Rho = 0.43), Cystic Fibrosis Questionnaire-Revised, lung function (Rho = -0.37), caregiver treatment management (r = 0.48) and child treatment management (r = 0.45), and discriminated between unwell and well children with CF (Mean Difference 5.5, 95%CI 2.5-8.5, p < 0.001), and recent or no hospital admission (MD 3.6, 95%CI 0.25-6.95, p = 0.039).

CONCLUSION: The CLCF-SF provides a robust 15-item tool for assessing the challenge of living with a child with CF.

PMID:37408463 | DOI:10.1080/08870446.2023.2231489

Int J Pharm. 2023 Jul 3:123198. doi: 10.1016/j.ijpharm.2023.123198. Online ahead of print.

ABSTRACT

Since gene therapy can regulate gene and protein expression directly, it has a great potential to prevent or treat a variety of genetic or acquired diseases through vaccines such as viral infections, cystic fibrosis, and cancer. Owing to their high efficacy, in vivo gene therapy trials are usually conducted intravenously, which is usually costly and invasive. There are several advantages to oral drug administration over intravenous injections, such as better patient compliance, ease of use, and lower cost. However, gene therapy is successful if the oligonucleotides can cross the cell membrane easily and reach the nucleus after the endosomal escape. In order to accomplish this task and deliver the cargo to the intended location, appropriate delivery systems should be introduced. This review summarizes oral delivery systems developed for effective gene delivery, vaccination, and treatment of various diseases. Studies have also shown that oral delivery approaches are potentially applicable to treat various diseases, especially inflammatory bowel disease, stomach, and colorectal cancers. Also, the current review provides an update overview on the development of non-viral and oral gene delivery techniques for gene therapy and vaccination purposes.

PMID:37406949 | DOI:10.1016/j.ijpharm.2023.123198

J Pediatr. 2023 Jul 3:113595. doi: 10.1016/j.jpeds.2023.113595. Online ahead of print.

ABSTRACT

Newborn screening (NBS) for cystic fibrosis (CF) was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive NBS tests persist. Through evaluation of national patient registry data, we determined that late initiation of CF care is associated with poorer long-term nutritional outcomes.

PMID:37406853 | DOI:10.1016/j.jpeds.2023.113595

J Cyst Fibros. 2023 Jul 3:S1569-1993(23)00826-3. doi: 10.1016/j.jcf.2023.06.012. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary exacerbations (PEx) remain a major cause of morbidity and mortality in people with cystic fibrosis (PWCF). Although the combination cystic fibrosis transmembrane conductance regulator (CFTR) modulators lumacaftor/ivacaftor and tezacaftor/ivacaftor have been shown to reduce PEx frequency, their influence on clinical and biochemical responses to acute PEx treatment is unknown.

METHODS: We performed a secondary analysis of STOP2, a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx. Propensity score matching was used to compare outcomes in antibiotic-treated F508del/F508del PWCF receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor with those observed in antibiotic-treated F508del/F508del controls not receiving CFTR modulator therapy. The primary outcome measure was the change in percent predicted FEV1 (ppFEV1) following completion of intravenous (IV) antibiotics, with post-antibiotic changes in symptoms, serum C-reactive protein (CRP) concentrations and weight included as secondary endpoints.

RESULTS: Among 982 PEx events in randomized PWCF, 480 were homozygous for F508del, of whom 289 were receiving lumacaftor/ivacaftor or tezacaftor/ivacaftor at initiation of antibiotic therapy. Modulator-treated F508del/F508del PWCF did not demonstrate greater improvements in ppFEV1, symptoms, serum CRP or weight following antibiotic treatment compared to modulator-naïve controls matched for age, sex, baseline ppFEV1, genotype, body mass index, initial CRP, initial symptoms, exacerbation history, diabetic status, randomization arm and concomitant medical therapy.

CONCLUSION: In the acute setting, CFTR modulator therapy with lumacaftor/ivacaftor or tezacaftor/ivacaftor does not convey additional clinical or biochemical advantage above standardized PEx treatment in F508del/F508del PWCF.

PMID:37407341 | DOI:10.1016/j.jcf.2023.06.012

Oncoimmunology. 2023 Jun 29;12(1):2224672. doi: 10.1080/2162402X.2023.2224672. eCollection 2023.

ABSTRACT

In a recent paper in Science, Fidelle et al. unravel a gut immune checkpoint that is subverted by antibiotic treatment. Post-antibiotic dysbiosis of the ileum causes an increase in bile acids that downregulate MAdCAM-1, thereby triggering the exodus of immunosuppressive T cells from gut-associated lymphoid tissues toward tumors.

PMID:37405191 | PMC:PMC10316723 | DOI:10.1080/2162402X.2023.2224672

ERJ Open Res. 2023 Jul 3;9(4):00021-2023. doi: 10.1183/23120541.00021-2023. eCollection 2023 Jul.

ABSTRACT

BACKGROUND: Patients with bronchiectasis experience persistent symptoms and frequent pulmonary exacerbations; this study investigated the frequency of exacerbations and all-cause hospitalisation.

METHODS: This longitudinal, retrospective, claims database study (IBM® MarketScan®) identified patients aged ≥18 years from 1 July 2015 through 30 September 2018. Exacerbations were identified by bronchiectasis inpatient claim or a healthcare interaction, followed by antibiotic prescription within 7 days. Patients with ≥36 months of continuous health plan enrolment (12 months preceding the first bronchiectasis claim, i.e., baseline period and ≥24 months of follow-up) were included. Patients with cystic fibrosis at baseline were excluded. A multivariable logistic regression model identified baseline factors associated with having ≥2 exacerbations over the 2-year follow-up period.

RESULTS: In total, 14 798 patients with bronchiectasis were identified; 64.5% were female, 82.7% were aged ≥55 years and 42.7% had ≥2 exacerbations at baseline. Having ≥2 exacerbations after 2 years was positively associated with chronic macrolide use, long-acting β2 agonist use, gastro-oesophageal reflux disease, heart failure and Pseudomonas aeruginosa. Frequent exacerbations (≥2) at baseline were significantly associated with greater likelihood of experiencing ≥2 exacerbations during the first and second year's follow-up (unadjusted odds ratios 3.35 (95% CI 3.1-3.6) and 2.96 (95% CI 2.8-3.2), respectively). The proportion of patients experiencing ≥1 all-cause hospitalisation cumulatively increased from 41.0% in the first year of follow-up to 51.1% over 2 years' follow-up.

CONCLUSION: Frequent exacerbations in patients with bronchiectasis may increase the likelihood of future exacerbations over 2 years of follow-up, with increased hospitalisation rates over time.

PMID:37404848 | PMC:PMC10316032 | DOI:10.1183/23120541.00021-2023

Transpl Int. 2023 Jun 12;36:11180. doi: 10.3389/ti.2023.11180. eCollection 2023.

ABSTRACT

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

PMID:37404718 | PMC:PMC10316425 | DOI:10.3389/ti.2023.11180

Infect Immun. 2023 Jul 5:e0006523. doi: 10.1128/iai.00065-23. Online ahead of print.

ABSTRACT

The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated class-dependent interactions between ΦJB10 and antibiotics in both biofilm clearance and P. aeruginosa killing. Despite identifying antagonism between some antibiotic classes and ΦJB10 at early time points, all classes showed neutral to favorable interactions with the phage at later time points. In one notable example where the antibiotic alone had poor activity against both biofilm and high-density planktonic cells, we found that addition of ΦJB10 demonstrated synergy and resulted in effective treatment of both. Further, ΦJB10 seemed to act as an adjuvant to several antibiotics, reducing the concentration of antibiotics required to ablate the biofilm. This report shows that phages such as ΦJB10 may be valuable additions to the armamentarium against difficult-to-treat biofilm-based infections.

PMID:37404162 | DOI:10.1128/iai.00065-23

Radiology. 2023 Jul;308(1):e230084. doi: 10.1148/radiol.230084.

ABSTRACT

Background The triple combination of the cystic fibrosis transmembrane regulator (CFTR) modulators elexacaftor, tezacaftor, and ivacaftor (hereafter, elexacaftor/tezacaftor/ivacaftor) has a positive effect on lung function in patients with cystic fibrosis (CF). Purpose To compare three-dimensional (3D) ultrashort echo time (UTE) MRI functional lung data to common functional lung parameters in assessing lung function in patients with CF undergoing elexacaftor/tezacaftor/ivacaftor therapy. Materials and Methods In this prospective feasibility study, 16 participants with CF consented to undergo pulmonary MRI with a breath-hold 3D UTE sequence at baseline (April 2018-June 2019) and follow-up (April-July 2021). Eight participants received elexacaftor/tezacaftor/ivacaftor after baseline, and eight participants with unchanged treatment served as the control group. Lung function was assessed with body plethysmography and lung clearance index (LCI). Image-based functional lung parameters, such as ventilation inhomogeneity and ventilation defect percentage (VDP), were calculated from signal intensity change between MRI scans at inspiration and expiration. Metrics at baseline and follow-up were compared within groups (permutation test), correlation was tested (Spearman rank correlation), and 95% CIs were calculated (bootstrapping technique). Results MRI ventilation inhomogeneity correlated with LCI at baseline (r = 0.92, P < .001) and follow-up (r = 0.81, P = .002). Mean MRI ventilation inhomogeneity (baseline, 0.74 ± 0.15 [SD]; follow-up, 0.64 ± 0.11; P = .02) and mean VDP (baseline, 14.1% ± 7.4; follow-up, 8.5% ± 3.3; P = .02) decreased from baseline to follow-up in the treatment group. Lung function was stable over time (mean LCI: 9.3 turnovers ± 4.1 at baseline vs 11.5 turnovers ± 7.4 at follow-up; P = .34) in the control group. In all participants, correlation of forced expiratory volume in 1 second with MRI ventilation inhomogeneity was good at baseline (r = -0.61, P = .01) but poor during follow-up (r = -0.06, P = .82). Conclusion Noncontrast 3D UTE lung MRI functional parameters of ventilation inhomogeneity and VDP can be used to assess lung function over time in patients with CF and can add regional information to established global parameters, such as LCI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Iwasawa in this issue.

PMID:37404154 | DOI:10.1148/radiol.230084

Radiology. 2023 Jul;308(1):e230052. doi: 10.1148/radiol.230052.

ABSTRACT

Background Lung MRI with ultrashort echo times (UTEs) enables high-resolution and radiation-free morphologic imaging; however, its image quality is still lower than that of CT. Purpose To assess the image quality and clinical applicability of synthetic CT images generated from UTE MRI by a generative adversarial network (GAN). Materials and Methods This retrospective study included patients with cystic fibrosis (CF) who underwent both UTE MRI and CT on the same day at one of six institutions between January 2018 and December 2022. The two-dimensional GAN algorithm was trained using paired MRI and CT sections and tested, along with an external data set. Image quality was assessed quantitatively by measuring apparent contrast-to-noise ratio, apparent signal-to-noise ratio, and overall noise and qualitatively by using visual scores for features including artifacts. Two readers evaluated CF-related structural abnormalities and used them to determine clinical Bhalla scores. Results The training, test, and external data sets comprised 82 patients with CF (mean age, 21 years ± 11 [SD]; 42 male), 28 patients (mean age, 18 years ± 11; 16 male), and 46 patients (mean age, 20 years ± 11; 24 male), respectively. In the test data set, the contrast-to-noise ratio of synthetic CT images (median, 303 [IQR, 221-382]) was higher than that of UTE MRI scans (median, 9.3 [IQR, 6.6-35]; P < .001). The median signal-to-noise ratio was similar between synthetic and real CT (88 [IQR, 84-92] vs 88 [IQR, 86-91]; P = .96). Synthetic CT had a lower noise level than real CT (median score, 26 [IQR, 22-30] vs 42 [IQR, 32-50]; P < .001) and the lowest level of artifacts (median score, 0 [IQR, 0-0]; P < .001). The concordance between Bhalla scores for synthetic and real CT images was almost perfect (intraclass correlation coefficient, ≥0.92). Conclusion Synthetic CT images showed almost perfect concordance with real CT images for the depiction of CF-related pulmonary alterations and had better image quality than UTE MRI. Clinical trial registration no. NCT03357562 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Schiebler and Glide-Hurst in this issue.

PMID:37404152 | DOI:10.1148/radiol.230052

Radiology. 2023 Jul;308(1):e231367. doi: 10.1148/radiol.231367.

NO ABSTRACT

PMID:37404145 | DOI:10.1148/radiol.231367

mSphere. 2023 Jul 5:e0004623. doi: 10.1128/msphere.00046-23. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a heritable disease that causes altered physiology at mucosal sites; these changes result in chronic infections in the lung, significant gastrointestinal complications as well as dysbiosis of the gut microbiome, although the latter has been less well explored. Here, we describe the longitudinal development of the gut microbiome in a cohort of children with CF (cwCF) from birth through early childhood (0-4 years of age) using 16S rRNA gene amplicon sequencing of stool samples as a surrogate for the gut microbiota. Similar to healthy populations, alpha diversity of the gut microbiome increases significantly with age, but diversity plateaus at ~2 years of age for this CF cohort. Several taxa that have been associated with dysbiosis in CF change with age toward a more healthy-like composition; notable exceptions include Akkermansia, which decreases with age, and Blautia, which increases with age. We also examined the relative abundance and prevalence of nine taxa associated with CF lung disease, several of which persist across early life, highlighting the possibility of the lung being seeded directly from the gut early in life. Finally, we applied the Crohn's Dysbiosis Index to each sample, and found that high Crohn's-associated dysbiosis early in life (<2 years) was associated with significantly lower Bacteroides in samples collected from 2 to 4 years of age. Together, these data comprise an observational study that describes the longitudinal development of the CF-associated gut microbiota and suggest that early markers associated with inflammatory bowel disease may shape the later gut microbiota of cwCF. IMPORTANCE Cystic fibrosis is a heritable disease that disrupts ion transport at mucosal surfaces, causing a buildup of mucus and dysregulation of microbial communities in both the lungs and the intestines. Persons with CF are known to have dysbiotic gut microbial communities, but the development of these communities over time beginning at birth has not been thoroughly studied. Here, we describe an observation study following the development of the gut microbiome of cwCF throughout the first 4 years of life, during the critical window of both gut microbiome and immune development. Our findings indicate the possibility of the gut microbiota as a reservoir of airway pathogens and a surprisingly early indication of a microbiota associated with inflammatory bowel disease.

PMID:37404016 | DOI:10.1128/msphere.00046-23

Pharmacotherapy. 2023 Jul 3. doi: 10.1002/phar.2845. Online ahead of print.

ABSTRACT

BACKGROUND: Vancomycin is commonly used to treat acute pulmonary exacerbations in pediatric patients with cystic fibrosis (CF) and a history of methicillin-resistant Staphylococcus aureus. Optimizing vancomycin exposure during therapy is essential and area under the curve (AUC)-guided dosing is now recommended. Model-informed precision dosing (MIPD) utilizing Bayesian forecasting is a powerful approach that can support AUC-guided dose individualization. The objective of the current study was to examine the impact of implementing an AUC-guided dose individualization approach supported via a MIPD clinical decision support (CDS) tool on vancomycin exposure, target attainment rate, and safety in pediatric patients with CF treated with vancomycin during clinical care.

METHODS: Retrospective chart review was performed in patients with CF at a single children's hospital comparing pre- and post-implementation of a MIPD approach for vancomycin supported by a cloud-based, CDS tool integrated into the electronic health record (EHR). In the pre-MIPD period, vancomycin starting doses of 60 mg/kg/day (<13 years) or 45 mg/kg/day (≥13 years) were used. Dose adjustment was guided by therapeutic drug monitoring (TDM) with a target trough 10-20 mg/L. In the post-MIPD period, starting dose and dose-adjustment were based on the MIPD CDS tool predictions with a target 24 hour AUC (AUC24 ) 400-600 mg*hr/L. Exposure and target achievement rates were retrospectively calculated and compared. Rates of acute kidney injury (AKI) were also compared.

RESULTS: Overall, 23 patient courses were included in the pre-MIPD period and 21 patient courses in the post-MIPD period. In the post-MIPD period, an individualized MIPD starting dose resulted in 71% of patients achieving target AUC24 compared to 39% in the pre-MIPD period (p<0.05). After the first TDM and dose adjustment, target AUC24 achievement was also higher post-MIPD versus pre-MIPD (86% vs 57%; p<0.05). AKI rates were low and similar between periods (pre-MIPD 8.7% vs post-MIPD 9.5%; p=0.9).

CONCLUSION: An MIPD approach implemented within a cloud-based, EHR integrated CDS tool safely supported vancomycin AUC-guided dosing and resulted in high rates of target achievement.

PMID:37401162 | DOI:10.1002/phar.2845

Sci Rep. 2023 Jul 3;13(1):10707. doi: 10.1038/s41598-023-37792-9.

NO ABSTRACT

PMID:37400506 | DOI:10.1038/s41598-023-37792-9

Arch Bronconeumol. 2023 Jun 9:S0300-2896(23)00176-X. doi: 10.1016/j.arbres.2023.05.017. Online ahead of print.

ABSTRACT

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease.

METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations.

RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia.

CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

PMID:37400317 | DOI:10.1016/j.arbres.2023.05.017

J Cyst Fibros. 2023 Jul 1:S1569-1993(23)00820-2. doi: 10.1016/j.jcf.2023.06.006. Online ahead of print.

ABSTRACT

BACKGROUND: Medical radiation exposure is of increasing concern in patients with cystic fibrosis (PWCF) due to improving life expectancy. We aimed to assess and quantify the cumulative effective dose (CED) in PWCF in the context of CFTR-modulator therapy and the advancement of dose reduction techniques.

METHODS: We performed a retrospective observational study in a single University CF centre over a 11-year period. We included PWCF, aged over 18 years who exclusively attended our institution. Relevant clinical data (demographics, transplantation history and modulator status) and radiological data (modality, quantity, and radiation exposure measured as CED) were collected. For those on modulator therapy the quantified imaging and radiation data was dichotomised into pre-and-post therapy periods.

RESULTS: The study included 181 patients: 139 on CFTR modulator therapy, 15 transplant recipients and 27 with neither exposure. 82% of patients received <25 mSv over the study period. Mean study duration was 6.9 ± 2.6 years pre-modulation and 4.2 ± 2.6 years post-modulation. Pre-modulation CT contributed 9.6% of total chest imaging (n = 139/1453) and 70.9% of the total CED. Post-modulation CT use increased contributing 42.7% of chest imaging (n = 444/1039) and comprised 75.8% of CED. Annual CED was 1.55 mSv pre and 1.36 mSv post modulation (p = 0.41). Transplant recipients had an annual CED of 64 ± 36.1mSv.

CONCLUSION: Chest CT utilisation for PWCF is rising in our institution, replacing chest radiography amidst CFTR-modulation. Despite the increasing use of CT, no significant radiation dose penalty was observed with a reduction in mean annual CED, primarily due to the influence of CT dose reduction strategies.

PMID:37400300 | DOI:10.1016/j.jcf.2023.06.006