Comparison of MRI and VQ-SPECT as a screening test for patients with suspected CTEPH: CHANGE-MRI study design and rationale

The diagnostic strategy for chronic thromboembolic pulmonary hypertension (CTEPH) is composed of two components required for a diagnosis of CTEPH: the presence of chronic pulmonary embolism and an elevated pulmonary artery pressure. The current guidelines require that ventilation–perfusion single-photon emission computed tomography (VQ-SPECT) is used for the first step diagnosis of chronic pulmonary embolism. However, VQ-SPECT exposes patients to ionizing radiation in a radiation sensitive population. The prospective, multicenter, comparative phase III diagnostic trial CTEPH diagnosis Europe - MRI (CHANGE-MRI, ClinicalTrials.gov identifier NCT02791282) aims to demonstrate whether functional lung MRI can serve as an equal rights alternative to VQ-SPECT in a diagnostic strategy for patients with suspected CTEPH. Positive findings are verified with catheter pulmonary angiography or computed tomography pulmonary angiography (gold standard). For comparing the imaging methods, a co-primary endpoint is used. (i) the proportion of patients with positive MRI in the group of patients who have a positive SPECT and gold standard diagnosis for chronic pulmonary embolism and (ii) the proportion of patients with positive MRI in the group of patients with negative SPECT and gold standard. The CHANGE-MRI trial will also investigate the performance of functional lung MRI without i.v. contrast agent as an index test and identify cardiac, hemodynamic, and pulmonary MRI-derived parameters to estimate pulmonary artery pressures and predict 6–12 month survival. Ultimately, this study will provide the necessary evidence for the discussion about changes in the recommendations on the diagnostic approach to CTEPH

Role of structural dynamics at the receptor G protein interface for signal transduction

GPCRs catalyze GDP/GTP exchange in the α-subunit of heterotrimeric G proteins (Gαßγ) through displacement of the Gα C-terminal α5 helix, which directly connects the interface of the active receptor (R*) to the nucleotide binding pocket of G. Hydrogen-deuterium exchange mass spectrometry and kinetic analysis of R* catalysed G protein activation have suggested that displacement of α5 starts from an intermediate GDP bound complex (R*•GGDP). To elucidate the structural basis of receptor-catalysed displacement of α5, we modelled the structure of R*•GGDP. A flexible docking protocol yielded an intermediate R*•GGDP complex, with a similar overall arrangement as in the X-ray structure of the nucleotide free complex (R*•Gempty), however with the α5 C-terminus (GαCT) forming different polar contacts with R*. Starting molecular dynamics simulations of GαCT bound to R* in the intermediate position, we observe a screw-like motion, which restores the specific interactions of α5 with R* in R*•Gempty. The observed rotation of α5 by 60° is in line with experimental data. Reformation of hydrogen bonds, water expulsion and formation of hydrophobic interactions are driving forces of the α5 displacement. We conclude that the identified interactions between R* and G protein define a structural framework in which the α5 displacement promotes direct transmission of the signal from R* to the GDP binding pocket

Multicenter standardization of phase-resolved functional lung MRI in patients with suspected chronic thromboembolic pulmonary hypertension

Background Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. Purpose To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. Study Type This is a prospective cohort sub-study. Population Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. Field Strength/Sequence 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). Assessment Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDPPREFUL) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDPDCE). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. Statistical Tests t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. Results Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion −4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). Data Conclusion PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. Level of Evidence 3 Technical Efficacy Stage

Mismatch negativity: a tool for studying morphosyntactic processing?

International audienceOBJECTIVE: Mismatch negativity (MMN) was originally shown in a passive auditory oddball paradigm to be generated by any acoustical change. More recently, it has been applied to the study of higher order linguistic levels including the morphosyntactic level in spoken language comprehension. In this study, we present two MMN experiments to determine whether morphosyntactic features are involved in the representations underlying the morphosyntactic processing. METHODS: We reported two MMN experiments in passive auditory oddball paradigm with pairs of French words, a pronoun and a verb, differing in agreement grammaticality. These two experiments differed in the number of morphosyntactic features producing agreement violations, i.e. either of person and number features or of person feature. RESULTS: We observed no effect of grammaticality on the MMN response for these two experiments. CONCLUSIONS: Our studies highlight the difficulties encountered in studying morphosyntactic level with the passive auditory oddball paradigm. SIGNIFICANCE: The reasons for our inability to replicate previous studies are presented, and methodological changes in the passive auditory oddball paradigm are proposed to better tap into the morphosyntactic level

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the effects of L2 perception and of individual difference

The interplay of syntax and form in sentence production: A cross-linguistic study of form effects on agreement

We report four cross-linguistic experiments (in Spanish, Italian and French) testing the influence of morphophonological gender marking in the subject noun phrase on the production of gender agreement. Agreement errors are elicited using a methodology in which participants are required to complete, with a predicative adjective, a sentence preamble. Results confirm a role for morphophonological gender marking in agreement. More precisely, we show that this role varies with two factors of different nature. The first factor is structural and has to do with the position of the marker in the noun phrase (article vs. noun). The second factor is distributional and has to do with the validity of the marker in the language. A model of agreement production is proposed in which two functionally distinct processes are identified: Feature selection, the locus of the morphophonological influences, and Feature copy, operating under strict syntactic guidance

On the resolution of phonological constraints in spoken production: Acoustic and response time evidence

This study examines the production of words the pronuncia- tion of which depends on the phonological context. Participants pro- duced adjective-noun phrases starting with the French determiner un. The pronunciation of this determiner requires a liaison consonant before vowels. Naming latencies and determiner acoustic durations were shorter when the adjective and the noun both started with vowels or both with consonants, than when they had different onsets. These results suggest that the liaison process is not governed by the application of a local contextual phonological rule; they rather favor the hypothesis that pronunciation variants with and without the liaison consonant are stored in memory