Non-Contrast-Enhanced Functional Lung MRI to Evaluate Treatment Response of Allergic Bronchopulmonary Aspergillosis in Patients With Cystic Fibrosis: A Pilot Study.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is associated with severe lung damage and requires specific therapeutic management. Repeated imaging is recommended to both diagnose and follow-up response to treatment of ABPA in CF. However, high risk of cumulative radiation exposure requires evaluation of free-radiation techniques in the follow-up of CF patients with ABPA. PURPOSE: To evaluate whether Fourier decomposition (FD) functional lung MRI can detect response to treatment of ABPA in CF patients. STUDY TYPE: Retrospective longitudinal. POPULATION: Twelve patients (7M, median-age:14 years) with CF and ABPA with pre- and post-treatment MRI. FIELD STRENGTH/SEQUENCE: 2D-balanced-steady-state free-precession (bSSFP) sequence with FD at 1.5T. ASSESSMENT: Ventilation-weighted (V) and perfusion-weighted (Q) maps were obtained after FD processing of 2D-coronal bSSFP time-resolved images acquired before and 3-9 months after treatment. Defects extent was assessed on the functional maps using a qualitative semi-quantitative score (0 = absence/negligible, 1 = <50%, 2 = >50%). Mean and coefficient of variation (CV) of the ventilation signal-intensity (VSI) and the perfusion signal-intensity (QSI) were calculated. Measurements were performed independently by three readers and averaged. Inter-reader reproducibility of the measurements was assessed. Pulmonary function tests (PFTs) were performed within 1 week of both MRI studies as markers of the airflow-limitation severity. STATISTICAL TESTS: Comparisons of medians were performed using the paired Wilcoxon-test. Reproducibility was assessed using intraclass correlation coefficient (ICC). Correlations between MRI and PFT parameters were assessed using the Spearman-test (rho correlation-coefficient). A P-value <0.05 was considered as significant. RESULTS: Defects extent on both V and Q maps showed a significant reduction after ABPA treatment (4.25 vs. 1.92 for V-defect-score and 5 vs. 2.75 for Q-defect-score). VSI_mean was significantly increased after treatment (280 vs. 167). Qualitative analyses reproducibility showed an ICC > 0.90, while the ICCs of the quantitative measurements was almost perfect (>0.99). Changes in VSI_cv and QSI_cv before and after treatment correlated inversely with changes of FEV1%p (rho = -0.68 for both). DATA CONCLUSION: Non-contrast-enhanced FD lung MRI has potential to reproducibly assess response to treatment of ABPA in CF patients and correlates with PFT obstructive parameters. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Generating High-Resolution Synthetic CT from Lung MRI with Ultrashort Echo Times: Initial Evaluation in Cystic Fibrosis.

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.

Longitudinal Evaluation of Bronchial Changes in Cystic Fibrosis Patients Undergoing Elexacaftor/Tezacaftor/Ivacaftor Therapy Using Lung MRI With Ultrashort Echo-Times.

BACKGROUND: Lung magnetic resonance imaging (MRI) with ultrashort echo-times (UTE-MRI) allows high-resolution and radiation-free imaging of the lung structure in cystic fibrosis (CF). In addition, the combination of elexacaftor/tezacaftor/ivacaftor (ETI) has improved CF clinical outcomes such as need for hospitalization. However, the effect on structural disease still needs longitudinal evaluation at high resolution. PURPOSE: To analyze the effects of ETI on lung structural alterations using UTE-MRI, with a focus on bronchiectasis reversibility. STUDY TYPE: Retrospective. POPULATION: Fifty CF patients (mean age 24.3 ± 9.2; 23 males). FIELD STRENGTH/SEQUENCE: 1.5 T, UTE-MRI. ASSESSMENT: All subjects completed both UTE-MRI and pulmonary function tests (PFTs) during two annual visits (M0 and M12), and 30 of them completed a CT scan. They initiated ETI treatment after M0 within a maximum of 3 months from the annual examinations. Three observers scored a clinical MRI Bhalla score on UTE-MRI. Bronchiectasis reversibility was defined as a reduction in both outer and inner bronchial dimensions. Correlations were searched between the Bhalla score and PFT such as the forced expiratory volume in 1 second percentage predicted (FEV1%p). STATISTICAL TESTS: Comparison was assessed using the paired t-test, correlation using the Spearman correlation test with a significance level of 0.05. Concordance and reproducibility were assessed using intraclass correlation coefficient (ICC). RESULTS: There was a significant improvement in MRI Bhalla score after ETI treatment. UTE-MRI demonstrated bronchiectasis reversibility in a subgroup of 18 out of 50 CF patients (36%). These patients with bronchiectasis reversibility were significantly younger, with lower severity of wall thickening but no difference in mucus plugging extent (P = 0.39) was found. The reproducibility of UTE-MRI evaluations was excellent (ICC ≥ 0.95), was concordant with CT scan (N = 30; ICC ≥ 0.90) and significantly correlated to FEV1% at PFT at M0 (N = 50; r = 0.71) and M12 (N = 50; r = 0.72). DATA CONCLUSION: UTE-MRI is a reproducible tool for the longitudinal follow-up of CF patients, allowing to quantify the response to ETI and demonstrating the reversibility of some structural alterations such as bronchiectasis in a substantial fraction of this study population. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 2.

Artificial intelligence in computed tomography for quantifying lung changes in the era of CFTR modulators.

BACKGROUND: Chest computed tomography (CT) remains the imaging standard for demonstrating cystic fibrosis (CF) airway structural disease in vivo. However, visual scoring systems as an outcome measure are time consuming, require training and lack high reproducibility. Our objective was to validate a fully automated artificial intelligence (AI)-driven scoring system of CF lung disease severity. METHODS: Data were retrospectively collected in three CF reference centres, between 2008 and 2020, in 184 patients aged 4-54 years. An algorithm using three 2D convolutional neural networks was trained with 78 patients' CT scans (23 530 CT slices) for the semantic labelling of bronchiectasis, peribronchial thickening, bronchial mucus, bronchiolar mucus and collapse/consolidation. 36 patients' CT scans (11 435 CT slices) were used for testing versus ground-truth labels. The method's clinical validity was assessed in an independent group of 70 patients with or without lumacaftor/ivacaftor treatment (n=10 and n=60, respectively) with repeat examinations. Similarity and reproducibility were assessed using the Dice coefficient, correlations using the Spearman test, and paired comparisons using the Wilcoxon rank test. RESULTS: The overall pixelwise similarity of AI-driven versus ground-truth labels was good (Dice 0.71). All AI-driven volumetric quantifications had moderate to very good correlations to a visual imaging scoring (p<0.001) and fair to good correlations to forced expiratory volume in 1 s % predicted at pulmonary function tests (p<0.001). Significant decreases in peribronchial thickening (p=0.005), bronchial mucus (p=0.005) and bronchiolar mucus (p=0.007) volumes were measured in patients with lumacaftor/ivacaftor. Conversely, bronchiectasis (p=0.002) and peribronchial thickening (p=0.008) volumes increased in patients without lumacaftor/ivacaftor. The reproducibility was almost perfect (Dice >0.99). CONCLUSION: AI allows fully automated volumetric quantification of CF-related modifications over an entire lung. The novel scoring system could provide a robust disease outcome in the era of effective CF transmembrane conductance regulator modulator therapy.

Cystic fibrosis and noninvasive liver fibrosis assessment methods in children.

BACKGROUND: Noninvasive assessments of liver fibrosis are currently used to evaluate cystic fibrosis (CF)-related liver disease. However, there is scarce data regarding their repeatability and reproducibility, especially in children with CF. The present study aimed to evaluate the repeatability and reproducibility of transient elastography (TE) (FibroScan®) and point shear-wave elastography using virtual touch quantification (pSWE VTQ) in children with CF. METHODS: TE and pSWE VTQ were performed in 56 children with CF by two different operators. Analysis of repeatability and reproducibility was available in 33 patients for TE and 46 patients for pSWE VTQ. Intra- and interobserver agreement were assessed using the intraclass correlation coefficient (ICC) and their 95% confidence interval (CI), and Bland and Altman graphs. RESULTS: For TE, ICC was 0.91 (0.83-0.95) for intraobserver agreement and 0.92 (95% CI: 0.86-0.96) for interobserver agreement. For pSWE VTQ, ICC was 0.83 (0.72-0.90) for intraobserver agreement and 0.67 (0.48-0.80) for interobserver agreement. CONCLUSIONS: Both technics can be proposed in the follow-up of patients, according to their availability in CF centers. IMPACT: This study shows that TE and pSWE VTQ are reliable methods to evaluate liver fibrosis in children with CF. This study shows for the first time that TE and pSWE VTQ are both repeatable and reproducible in children with CF. These data indicate that both TE and pSWE VTQ can be proposed for the follow-up of patients with CF, according to their availability in each CF center.

Using chest CT scan and unsupervised machine learning for predicting and evaluating response to lumacaftor-ivacaftor in people with cystic fibrosis.

OBJECTIVES: Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor. METHODS: Adolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans. RESULTS: A total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (-1.40±1.53 points compared with pretherapeutic CT; p<0.001). This finding was related to a significant decrease in mucus plugging (-0.35±0.62 points; p<0.001), bronchial wall thickening (-0.24±0.52 points; p<0.001) and parenchymal consolidations (-0.23±0.51 points; p<0.001). Cluster analysis identified 3 morphological clusters. Patients from cluster C were more likely to experience an increase in percent predicted forced expiratory volume in 1 sec (ppFEV1) ≥5 under lumacaftor-ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01). CONCLUSION: One year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.

A Population Pharmacokinetic Modeling Approach to Determine the Efficacy of Intravenous Amikacin in Children with Cystic Fibrosis.

BACKGROUND: In children with cystic fibrosis (CF), the currently recommended amikacin dose ranges between 30 and 35 mg/kg/d; however, data supporting this dosing efficacy are lacking. In this article, the objectives were to develop a nonparametric pharmacokinetic population model for amikacin in children with CF and investigate the efficacy and toxicity at different dose rates for distinct minimum inhibitory concentration (MIC) clinical breakpoints using Monte Carlo simulations. METHODS: Data from 94 children with CF (613 serum concentrations) from the Bordeaux University Hospital's CF-centre were analyzed. After determination of nonparametric pharmacokinetic population model parameters and associated influent covariates in Pmetrics, 1000 Monte Carlo simulations were performed for 7 different dose rates between 30 and 60 mg/kg/d, to predict the probability of obtaining peak serum amikacin ≥10 × MIC and trough level ≤2.5 mg/L, for MIC values between 1 and 16 mg/L. RESULTS: The median (min-max) age and weight were 10 (0.3-17) years and 29 (6-71) kg, respectively, with only 2 children younger than 1 year of age. Body weight and creatinine clearance significantly impacted the amikacin volume of distribution and clearance. The mean relative bias/root mean squared error between observed and individual predicted concentrations was -0.68%/8.1%. Monte Carlo simulations showed that for sensitive bacteria with MICs ≤ 4, 30 mg/kg/d was most appropriate for a 100% success rate; for bacteria with MICs ≥ 8 [eg, Pseudomonas aeruginosa (MICamikacin = 8)], a dose of at least 40 mg/kg/d allowed a high success probability (90%), with a trough level below 2.5 mg/L. CONCLUSIONS: For intermediate pathogens, a dose of at least 40 mg/kg/d can improve efficacy, with an acceptable calculated residual trough level in cases of normal or hyperfiltration. Because amikacin undergoes renal clearance, which is immature until 1 year of age, dosing recommendations for this age group may be markedly high, warranting cautious interpretation.

Real-Life Safety and Effectiveness of Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis.

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Quantification of MRI T2-weighted High Signal Volume in Cystic Fibrosis: A Pilot Study.

Background In patients with cystic fibrosis (CF), pulmonary structures with high MRI T2 signal intensity relate to inflammatory changes in the lung and bronchi. These areas of pathologic abnormalities can serve as imaging biomarkers. The feasibility of automated quantification is unknown. Purpose To quantify the MRI T2 high-signal-intensity lung volume and T2-weighted volume-intensity product (VIP) by using a black-blood T2-weighted radial fast spin-echo sequence in participants with CF. Materials and Methods Healthy individuals and study participants with CF were prospectively enrolled between January 2017 and November 2017. All participants underwent a lung MRI protocol including T2-weighted radial fast spin-echo sequence. Participants with CF also underwent pulmonary function tests the same day. Participants with CF exacerbation underwent repeat MRI after their treatment with antibiotics. Two observers supervised automated quantification of T2-weighted high-signal-intensity volume (HSV) and T2-weighted VIP independently, and the average score was chosen as consensus. Statistical analysis used the Mann-Whitney test for comparison of medians, correlations used the Spearman test, comparison of paired medians used the Wilcoxon signed rank test, and reproducibility was evaluated by using intraclass correlation coefficient. Results In 10 healthy study participants (median age, 21 years [age range, 18-27 years]; six men) and 12 participants with CF (median age, 18 years [age range, 9-40 years]; eight men), T2-weighted HSV was equal to 0% and 4.1% (range, 0.1%-17%), respectively, and T2-weighted VIP was equal to 0 msec and 303 msec (range, 39-1012 msec), respectively (P < .001). In participants with CF, T2-weighted HSV or T2-weighted VIP were associated with forced expiratory volume in 1 second percentage predicted (ρ = -0.88 and ρ = -0.94, respectively; P < .001). In six participants with CF exacerbation and follow-up after treatment, a decrease in both T2-weighted HSV and T2-weighted VIP was observed (P = .03). The intra- and interobserver reproducibility of MRI were good (intraclass correlation coefficients, >0.99 and >0.99, respectively). Conclusion In patients with cystic fibrosis (CF), automated quantification of lung MRI high-signal-intensity volume was reproducible and correlated with pulmonary function testing severity, and it improved after treatment for CF exacerbation. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Revel and Chassagnon in this issue.

Reduced Intestinal Inflammation With Lumacaftor/Ivacaftor in Adolescents With Cystic Fibrosis.

A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. Although Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. We, therefore, investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days [IQR: 278;435]). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 µg/g [IQR: 69-210]) compared with the baseline (713 µg/g (IQR:148-852), P = 0.001). To our knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

Management of initial colonisations with Burkholderia species in France, with retrospective analysis in five cystic fibrosis Centres: a pilot study.

BACKGROUND: Whereas Burkholderia infections are recognized to impair prognosis in cystic fibrosis (CF) patients, there is no recommendation to date for early eradication therapy. The aim of our study was to analyse the current management of initial colonisations with Burkholderia cepacia complex (BCC) or B. gladioli in French CF Centres and its impact on bacterial clearance and clinical outcome. METHODS: We performed a retrospective review of the primary colonisations (PC), defined as newly positive sputum cultures, observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected. RESULTS: Seventeen patients (14 with BCC, and 3 with B. gladioli) were included. Eradication therapy, using heterogeneous combinations of intravenous, oral or nebulised antibiotics, was attempted in 11 patients. Six out of the 11 treated patients, and 4 out of the 6 untreated patients cleared the bacterium. Though not statistically significant, higher forced expiratory volume in 1 second and forced vital capacity at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. The management of PC was shown to be heterogeneous, thus impairing the statistical power of our study. Large prospective studies are needed to define whom to treat, when, and how. CONCLUSIONS: Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia 1 month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of intravenous beta-lactam + oral or intravenous fluoroquinolone + inhaled aminoglycoside.

Ontogeny of hallucal metatarsal rigidity and shape in the rhesus monkey (Macaca mulatta) and chimpanzee (Pan troglodytes).

Life history variables including the timing of locomotor independence, along with changes in preferred locomotor behaviors and substrate use during development, influence how primates use their feet throughout ontogeny. Changes in foot function during development, in particular the nature of how the hallux is used in grasping, can lead to different structural changes in foot bones. To test this hypothesis, metatarsal midshaft rigidity [estimated from the polar second moment of area (J) scaled to bone length] and cross-sectional shape (calculated from the ratio of maximum and minimum second moments of area, Imax /Imin ) were examined in a cross-sectional ontogenetic sample of rhesus macaques (Macaca mulatta; n = 73) and common chimpanzees (Pan troglodytes; n = 79). Results show the hallucal metatarsal (Mt1) is relatively more rigid (with higher scaled J-values) in younger chimpanzees and macaques, with significant decreases in relative rigidity in both taxa until the age of achieving locomotor independence. Within each age group, Mt1 rigidity is always significantly higher in chimpanzees than macaques. When compared with the lateral metatarsals (Mt2-5), the Mt1 is relatively more rigid in both taxa and across all ages; however, this difference is significantly greater in chimpanzees. Length and J scale with negative allometry in all metatarsals and in both species (except the Mt2 of chimpanzees, which scales with positive allometry). Only in macaques does Mt1 midshaft shape significantly change across ontogeny, with older individuals having more elliptical cross-sections. Different patterns of development in metatarsal diaphyseal rigidity and shape likely reflect the different ways in which the foot, and in particular the hallux, functions across ontogeny in apes and monkeys.

Inter-ray variation in metatarsal strength properties in humans and African apes: Implications for inferring bipedal biomechanics in the Olduvai Hominid 8 foot.

When measured as a ratio of mean midshaft diameter to bone length, the OH 8 fossil hominin foot exhibits a metatarsal (Mt) robusticity pattern of 1 > 5 > 3 > 4 > 2, which differs from the widely perceived "common" modern human pattern (1 > 5 > 4 > 3 > 2); African apes generally exhibit a third pattern (1 > 2 > 3 > 4 > 5). Largely because of the relative ranking of Mt2 and Mt5, OH 8 metatarsals structurally resemble the pattern exhibited by bipedal humans more than the pattern of quadrupedal and climbing African apes. Considering only these three phenotypes, however, discounts the potentially important functional implications of variation in modern human (and African ape) metatarsal robusticity patterns, suggesting that they are not useful for interpreting the specific biomechanics of a bipedal gait in fossils (i.e., whether it was modern human-like or not). Using computed tomography scans to quantify metatarsal midshaft cross-sectional geometry in a large sample of Homo (n=130), Gorilla (n=44) and Pan (n=80), we documented greater variation in metatarsal robusticity patterns than previously recognized in all three groups. While apes consistently show a 1 > 2 > 3 > 4 > 5 pattern in our larger sample, there does not appear to be a similarly precise single "common" human pattern. Rather, human metatarsals converge towards a 1 > 4/5 > 2/3 pattern, where metatarsals 4 and 5, and metatarsals 2 and 3, often "flip" positions relative to each other depending on the variable examined. After reassessing what a "common" human pattern could be based on a larger sample, the previously described OH 8 pattern of 1 > 5 > 3 > 4 > 2 is only observed in some humans (<6%) and almost never in apes (<0.5%). Although this suggests an overall greater similarity to (some) humans than to any ape in loading of the foot, the relatively rare frequency of these humans in our sample underscores potential differences in loading experienced by the medial and lateral columns of the OH 8 foot compared to modern humans.

Assessment of Liver Disease Progression in Cystic Fibrosis Using Transient Elastography.

OBJECTIVES: Cystic fibrosis-related liver disease (CFLD) can develop silently in early life and approximately 10% of children with cystic fibrosis (CF) become cirrhotic before adulthood. Clinical, biological, and ultrasound criteria used to define CFLD often reveal liver involvement at an advanced stage. The aim of this retrospective study was to assess the progression of liver stiffness measurement (LSM) in pediatric patients with CF. METHODS: The change of LSM, expressed as kPa/year and %/year, was measured using transient elastography (Fibroscan) in 82 children with CF (median age: 6.8 years, interquartile range [IQR]: 5.8). Mean time interval between the 2 LSM was 3.5 years. RESULTS: Median initial liver stiffness was 3.7 kPa (IQR: 1.3), and then progressed by 0.23 kPa/year, that is, 6%/year. The 7 patients who developed CFLD had a higher initial level of alanine aminotransferase (50 [IQR: 15] vs 30 [IQR: 18], P = 0.0001) and presented a more rapid progression of LSM (0.94 vs 0.23 kPa/year, P = 0.02). CONCLUSIONS: The present study shows that the slope of worsening of liver stiffness is greater in patients who will develop CFLD, suggesting that annual transient elastography may be useful to detect risk of severe liver disease at an earlier stage.

Toward the Standardization of Mycological Examination of Sputum Samples in Cystic Fibrosis: Results from a French Multicenter Prospective Study.

Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.

Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis: MR Imaging of Airway Mucus Contrasts as a Tool for Diagnosis.

Purpose To assess the diagnostic accuracy of mucus contrast characterization by using magnetic resonance (MR) imaging to discriminate allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Materials and Methods The study was approved by the local Ethics Committee, and all patients or their parents gave written informed consent. One hundred ten consecutive patients with CF were screened between January 2014 and July 2015. All patients underwent a non-contrast material-enhanced MR protocol that included routine T1-weighted and T2-weighted sequences. The presence of mucus with both high T1 and low T2 signal intensities and the so-called inverted mucoid impaction signal (IMIS) sign was qualitatively and quantitatively assessed by two physicians who were blinded to all other data. The reference standard for a diagnosis of ABPA was the criteria of the Cystic Fibrosis Foundation Consensus Conference. ABPA status was followed up for 1 year. Reproducibility was assessed by using the κ test, correlation was assessed by using the Spearman coefficient, and diagnostic accuracy was assessed by calculating the sensitivity and specificity of IMIS. Results One hundred eight patients with CF were included (mean age, 20 years ± 11 [standard deviation]; range, 6-53 years): 18 patients with ABPA and 90 patients without ABPA. At the lobar level, inter- and intrareader reproducibility were very good (κ > 0.90). IMIS had 94% sensitivity (95% confidence interval [CI]: 73%, 99%) and 100% specificity (95% CI: 96%, 100%) for the diagnosis of ABPA. A complete resolution of IMIS was observed in patients with ABPA after 3 months of specific treatment that was significantly correlated with decrease in total immunoglobulin E level (ρ = 0.47; P = .04). Conclusion The IMIS sign was both specific and sensitive for the diagnosis of ABPA in CF. Allergic fungal inflammation appears to induce characteristic modifications of mucus contrasts that are assessable by using a noninvasive, contrast material-free, and radiation-free method. © RSNA, 2017 Online supplemental material is available for this article.

A Quality Analysis of Systematic Reviews in Dentistry, Part 1: Meta-Analyses of Randomized Controlled Trials.

OBJECTIVES: As the volume of publications in dentistry continues to increase, clinicians are becoming increasingly reliant on systematic reviews and meta-analyses as their primary source of evidence. With an increase in the dependence on dental metaanalyses, it is important to ensure that they are being conducted with as little bias as possible. The objective of this systematic review is to assess the quality of therapeutic meta-analyses of randomized controlled trials (RCTs) on dental-related topics and to analyze how quality has changed over time. METHODS: All relevant studies were searched for through MEDLINE, Embase, PsycINFO, and the Cochrane Library. Title, abstract, and full-text review, as well as data extraction and quality assessment, were all conducted in duplicate. All reviewers used a pilot-tested extraction form that included the AMSTAR checklist to assess quality of systematic reviews. A logit link function ordinal regression was conducted to evaluate quality improvement trends over time. RESULTS: Of the 3832 studies identified, 208 studies were selected for review. Of these, 13% provided an a priori design, 53% screened and extracted data in duplicate, 29% included gray literature, 63% assessed the quality of included studies, and 39% assessed publication bias. As was indicated by the ordinal regression, the quality of meta-analyses, as per the AMSTAR criteria, has increased significantly with time (P < .001). CONCLUSIONS: This investigation illustrates that although the quality of meta-analyses of RCTs has been increasing since the start of the millennium, there remains substantial room for improvement within all aspects of systematic review reporting and methodology. Therefore, it is critical for clinicians to take caution when reading systematic reviews and meta-analyses, ensuring that the principals of critical appraisal are applied when interpreting meta-analyses of RCTs.

Clinimetric properties of bronchoalveolar lavage inflammatory markers in cystic fibrosis.

The Standardisation Committee of the European Cystic Fibrosis Society Clinical Trial Network has undertaken the evaluation of clinical end-points for therapeutic interventions regarding their use in multicentre clinical trials in cystic fibrosis (CF). This review of biomarkers in bronchoalveolar lavage (BAL) is part of the group's work. The aims of this project were: 1) to review the literature on reliability, validity and responsiveness of BAL in patients with CF; 2) to gain consensus of the group on the feasibility of BAL; and 3) to gain consensus on answers to key questions regarding the promotion of BAL to surrogate end-point status. Assessment of BAL inflammatory markers in the literature indicates that their reliability, validity and responsiveness are adequate for clinical trials. After discussion of the practical characteristics it was concluded that BAL has an attractive validity profile, albeit with limited feasibility. It is particularly applicable to multicentre trials in preschool children with CF and early or mild lung disease. This is the first article to collate the literature in this manner. This provides a rationale to support the use of BAL in early clinical trials in preschool children with CF.

Selection of Pseudomonas aeruginosa reference genes for RT-qPCR analysis from sputum of cystic fibrosis patients.

The prerequisite to monitor gene expression is the selection of reference genes for normalization of RT-qPCR results. Using 13 sputum samples collected from 9 CF patients, we demonstrated that PA2875 and PA3340 are better reference genes than the previously used clpX and oprL genes.