Assessing 129Xe multi-breath washout MRI response to elexacaftor/tezacaftor/ivacaftor intervention in pediatric CF.

BACKGROUND: Monitoring multiple-breath washout (MBW) of a xenon tracer using magnetic resonance imaging (MBW Xe-MRI) provides quantitative regional measures of gas washout (fractional ventilation, FV) and spatial ventilation heterogeneity (coefficient of variation, CoVFV) in pediatric CF lung disease, but has yet to be evaluated in an interventional setting. METHODS: 12 pediatric CF participants (median age 15.3 ± 2 years) completed MBW Xe-MRI, pulmonary function tests (PFTs) (spirometry, N2 MBW for lung clearance index (LCI)) and single-breath Xe-MRI ventilation defect percent (VDP) measurements at baseline and 1-month post-initiation of elexacaftor/tezacaftor/ivacaftor (ETI) therapy. FV maps were calculated from MBW Xe-MRI washout images, and CoVFV maps were derived from FV maps. Significant changes between visits were determined using a paired Wilcoxon signed-rank test. For correlations between absolute changes, Pearson's correlation was used. RESULTS: All measures changed significantly 1-month post-ETI therapy compared to baseline. For MRI metrics, median [IQR] VDP was significantly (P < 0.001) lower at 1 month (8.0 [3.7 12.4]) compared to baseline (17.8 [8.3 22.5]), FV was significantly (P < 0.05) higher at 1 month (0.42 [0.41 0.46]) compared to baseline (0.38 [0.33 0.44]), and CoVFV was significantly (P < 0.001) lower at 1 month (0.06 [0.05 0.07]) compared to baseline (0.09 [0.08 0.12]). Both absolute and relative differences in CoVFV and LCI were found to correlate highly (R = 0.92, P < 0.0001 and R = 0.91, P < 0.0001, respectively). CONCLUSIONS: Functional information derived from MBW Xe-MRI, particularly CoVFV, can be used to assess regional lung function in pediatric CF patients in an interventional setting and may be complementary to VDP and pulmonary function tests.

Comparison of 3D UTE free-breathing lung MRI with hyperpolarized 129Xe MRI in pediatric cystic fibrosis.

PURPOSE: To compare phase-resolved functional lung (PREFUL) regional ventilation derived from a free breathing 3D UTE radial MRI acquisition to hyperpolarized 129Xe-MRI (Xe-MRI), conventional 2D multi-slice PREFUL MRI, and pulmonary function tests in pediatric cystic fibrosis (CF) lung disease. METHODS: Free-breathing 3D UTE and 2D multi-slice 1H MRI as well as Xe-MRI were acquired in 12 stable pediatric CF patients. Using PREFUL, regional ventilation (RVent) maps were calculated from the free-breathing data. Ventilation defect percentage (VDP) was determined from 3D and 2D RVent maps (2D VDPRVent and 3D VDPRVent, respectively) and Xe-MRI ventilation (VDPXe). VDP was calculated for the whole lung and for eight regions based on left/right, anterior/posterior, and superior/inferior divisions of the lung. Global and regional VDP was compared between the three methods using Bland-Altman analysis, linear mixed model-based correlation, and one-way analysis of variance and multiple comparisons tests. RESULTS: Global 3D VDPRVent, VDPXe, and 2D VDPRVent were all strongly correlated (all R2 > 0.62, p < 0.0001) and showed minimal, non-significant bias (all <2%, p > 0.05). Three dimensional and 2D VDPRVent significantly correlated to VDPXe in most of the separate lung regions (R2 = 0.18-0.74, p < 0.04), but showed lower inter-agreement. The superior/anterior lung regions showed the least agreement between all three methods (all p > 0.12). CONCLUSION: Absolute VDP assessed by 3D UTE PREFUL MRI showed good global agreement with Xe-MRI and 2D multi-slice PREFUL MRI in pediatric CF lung disease. Therefore, 3D UTE PREFUL MRI offers a sensitive and potentially more accessible alternative to Xe-MRI for regional volumetric evaluation of ventilation.

Inter- and intravisit repeatability of free-breathing MRI in pediatric cystic fibrosis lung disease.

PURPOSE: The purpose of this study is to assess the intra- and interscan repeatability of free-breathing phase-resolved functional lung (PREFUL) MRI in stable pediatric cystic fibrosis (CF) lung disease in comparison to static breath-hold hyperpolarized 129-xenon MRI (Xe-MRI) and pulmonary function tests. METHODS: Free-breathing 1-hydrogen MRI and Xe-MRI were acquired from 15 stable pediatric CF patients and seven healthy age-matched participants on two visits, 1 month apart. Same-visit MRI scans were also performed on a subgroup of the CF patients. Following the PREFUL algorithm, regional ventilation (RVent) and regional flow volume loop cross-correlation maps were determined from the free-breathing data. Ventilation defect percentage (VDP) was determined from RVent maps (VDPRVent ), regional flow volume loop cross-correlation maps (VDPCC ), VDPRVent ∪ VDPCC , and multi-slice Xe-MRI. Repeatability was evaluated using Bland-Altman analysis, coefficient of repeatability (CR), and intraclass correlation. RESULTS: Minimal bias and no significant differences were reported for all PREFUL MRI and Xe-MRI VDP parameters between intra- and intervisits (all P > 0.05). Repeatability of VDPRVent , VDPCC , VDPRVent ∪ VDPCC , and multi-slice Xe-MRI were lower between the two-visit scans (CR = 14.81%, 15.36%, 16.19%, and 9.32%, respectively) in comparison to the same-day scans (CR = 3.38%, 2.90%, 1.90%, and 3.92%, respectively). pulmonary function tests showed high interscan repeatability relative to PREFUL MRI and Xe-MRI. CONCLUSION: PREFUL MRI, similar to Xe-MRI, showed high intravisit repeatability but moderate intervisit repeatability in CF, which may be due to inherent disease instability, even in stable patients. Thus, PREFUL MRI may be considered a suitable outcome measure for future treatment response studies.

Perspectives on the translation of in-vitro studies to precision medicine in Cystic Fibrosis.

Recent strides towards precision medicine in Cystic Fibrosis (CF) have been made possible by patient-derived in-vitro assays with the potential to predict clinical response to small molecule-based therapies. Here, we discuss the status of primary and stem-cell derived tissues used to evaluate the preclinical efficacy of CFTR modulators highlighting both their potential and limitations. Validation of these assays requires correlation of in-vitro responses to in-vivo measures of clinical biomarkers of disease outcomes. While initial efforts have shown some success, this translation requires methodologies that are sensitive enough to capture treatment responses in a CF population that now predominantly has mild lung disease. Future development of in-vitro and in-vivo biomarkers will facilitate the generation of new therapeutics particularly for those patients with rare mutations where clinical trials are not feasible so that in the future every CF patient will have access to effective targeted therapies.

Prolonged Use of Ethanol Lock Prophylaxis With Polyurethane Catheters in Children With Intestinal Failure: A Single-Center Experience.

BACKGROUND: Children with intestinal failure (IF) receiving home parenteral nutrition (HPN) require long-term central venous catheters (CVCs). Ethanol lock prophylaxis (ELP) can reduce central line-associated bloodstream infections, but there are some concerns of increased breakage rates when used with polyurethane catheters. We reviewed our experience using ethanol locks in both polyurethane and silicone CVCs. METHODS: A 10-year retrospective study of children with IF receiving HPN that used ELP was conducted. Complications per 1000 catheter days were extracted and a multivariable, mixed-effects Poisson model was used to compare catheter breakage rates and other complications between polyurethane and silicone CVCs. RESULTS: A total of 10 patients were included, comprising 85 CVCs and 13,227 catheter days. The most common cause of IF was necrotizing enterocolitis. Breakages were the most common complication: polyurethane 1.46/1000 vs silicone 3.76/1000 catheter days. Silicone catheters had a significantly higher breakage rate (adjusted rate ratio [RR], 2.86; 95% confidence interval [CI], 2.84-2.88; P < .001) whereas polyurethane catheters had higher rates of occlusion (adjusted RR, 0.14; 95% CI, 0.07-0.28; P < .001) and displacements. However, there were no differences in the overall catheter replacement rates and any other catheter-related outcomes. CONCLUSIONS: In children with IF receiving long-term HPN, the use of ELP in polyurethane catheters was associated with a lower risk of breakages when compared with silicone CVCs. These results should be regarded as preliminary data, and further studies with a higher number of participants are necessary to provide a better level of evidence.

Should you pick the PICC? Prolonged use of peripherally inserted central venous catheters in children with intestinal failure.

PURPOSE: Prolonged central vascular access is a source of significant morbidity in children with intestinal failure (IF). In an effort to decrease morbidity, our multidisciplinary IF team has primarily used peripherally inserted central catheters (PICCs) for these patients. We compared outcomes of PICCs to Broviacs®. METHODS: A review of children with IF (2006-2018) at an academic children's hospital was conducted. INCLUSION CRITERIA: total parenteral nutrition duration >42 days or small bowel length < 25% of total for gestational age. Complications/1000 catheter days were extracted, and a Poisson model was used to compare complications between PICCs and Broviacs®. RESULTS: Thirty-seven patients with IF were included, accounting for 19,452 catheter days. There were 209 PICCs (1.2-4F) and 39 Broviacs® (2.7-7F). The median duration of overall PICC access/patient was 166 days (range: 35 days-8 years). Incidences of central line associated blood stream infection and venous thrombosis were 3.95 and 0.55 per 1000 catheter days, respectively. There were no significant differences in complication rates per line per catheter day between PICCs and Broviacs® on multivariate analysis. Broviacs® showed a trend towards increased of catheter-related hospital admissions when compared to PICCs. CONCLUSIONS: PICCs in children with intestinal failure have similar complication rates to Broviacs® but may reduce catheter-related hospital admissions. Use of tunneled PICCs and increasing experience with this vascular access method may allow it to realize its potential advantages. LEVEL OF EVIDENCE: Retrospective study, level III.

Public media communications about H1N1, risk perceptions and immunization behaviours: A Quebec-France comparison.

During the H1N1 pandemic, governments tailored their communications plans in order to influence risk perception and promote public compliance with the public health plan measures. Considering the volume and the content of calls to flu information centres as indicators of the public risk perception, this mixed method study compares the relation between public communications, risk perception and immunization behaviour in Quebec and France. Results suggest that advocating for clear information and coordination between health authorities and the media promotes adherence to preventive behaviour. However, over-exaggerating the risks and minimizing the population's agency may undermine health authority credibility.