Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

3D Dixon water-fat LGE imaging with image navigator and compressed sensing in cardiac MRI

Objectives!#!To evaluate an image-navigated isotropic high-resolution 3D late gadolinium enhancement (LGE) prototype sequence with compressed sensing and Dixon water-fat separation in a clinical routine setting.!##!Material and methods!#!Forty consecutive patients scheduled for cardiac MRI were enrolled prospectively and examined with 1.5 T MRI. Overall subjective image quality, LGE pattern and extent, diagnostic confidence for detection of LGE, and scan time were evaluated and compared to standard 2D LGE imaging. Robustness of Dixon fat suppression was evaluated for 3D Dixon LGE imaging. For statistical analysis, the non-parametric Wilcoxon rank sum test was performed.!##!Results!#!LGE was rated as ischemic in 9 patients and non-ischemic in 11 patients while it was absent in 20 patients. Image quality and diagnostic confidence were comparable between both techniques (p = 0.67 and p = 0.66, respectively). LGE extent with respect to segmental or transmural myocardial enhancement was identical between 2D and 3D (water-only and in-phase). LGE size was comparable (3D 8.4 ± 7.2 g, 2D 8.7 ± 7.3 g, p = 0.19). Good or excellent fat suppression was achieved in 93% of the 3D LGE datasets. In 6 patients with pericarditis, the 3D sequence with Dixon fat suppression allowed for a better detection of pericardial LGE. Scan duration was significantly longer for 3D imaging (2D median 9:32 min vs. 3D median 10:46 min, p = 0.001).!##!Conclusion!#!The 3D LGE sequence provides comparable LGE detection compared to 2D imaging and seems to be superior in evaluating the extent of pericardial involvement in patients suspected with pericarditis due to the robust Dixon fat suppression.!##!Key points!#!• Three-dimensional LGE imaging provides high-resolution detection of myocardial scarring. • Robust Dixon water-fat separation aids in the assessment of pericardial disease. • The 2D image navigator technique enables 100% respiratory scan efficacy and permits predictable scan times

Non-rigid motion-corrected free-breathing 3D myocardial Dixon LGE imaging in a clinical setting

OBJECTIVES: To investigate the efficacy of an in-line non-rigid motion-compensated reconstruction (NRC) in an image-navigated high-resolution three-dimensional late gadolinium enhancement (LGE) sequence with Dixon water–fat separation, in a clinical setting. METHODS: Forty-seven consecutive patients were enrolled prospectively and examined with 1.5 T MRI. NRC reconstructions were compared to translational motion-compensated reconstructions (TC) of the same datasets in overall and different sub-category image quality scores, diagnostic confidence, contrast ratios, LGE pattern, and semiautomatic LGE quantification. RESULTS: NRC outperformed TC in all image quality scores (p < 0.001 to 0.016; e.g., overall image quality 5/5 points vs. 4/5). Overall image quality was downgraded in only 23% of NRC datasets vs. 53% of TC datasets due to residual respiratory motion. In both reconstructions, LGE was rated as ischemic in 11 patients and non-ischemic in 10 patients, while it was absent in 26 patients. NRC delivered significantly higher LGE-to-myocardium and blood-to-myocardium contrast ratios (median 6.33 vs. 5.96, p < 0.001 and 4.88 vs. 4.66, p < 0.001, respectively). Automatically detected LGE mass was significantly lower in the NRC reconstruction (p < 0.001). Diagnostic confidence was identical in all cases, with high confidence in 89% and probable in 11% datasets for both reconstructions. No case was rated as inconclusive. CONCLUSIONS: The in-line implementation of a non-rigid motion-compensated reconstruction framework improved image quality in image-navigated free-breathing, isotropic high-resolution 3D LGE imaging with undersampled spiral-like Cartesian sampling and Dixon water–fat separation compared to translational motion correction of the same datasets. The sharper depictions of LGE may lead to more accurate measures of LGE mass. KEY POINTS: • 3D LGE imaging provides high-resolution detection of myocardial scarring. • Non-rigid motion correction provides better image quality in cardiac MRI. • Non-rigid motion correction may lead to more accurate measures of LGE mass

Myocardial scar detection in free-breathing Dixon-based fat- and water-separated 3D inversion recovery late-gadolinium enhancement whole heart MRI

The aim of this study was to investigate the diagnostic accuracy and reader confidence for late-gadolinium enhancement (LGE) detection of a novel free-breathing, image-based navigated 3D whole-heart LGE sequence with fat–water separation, compared to a free-breathing motion-corrected 2D LGE sequence in patients with ischemic and non-ischemic cardiomyopathy. Cardiac MRI patients including the respective sequences were retrospectively included. Two independent, blinded readers rated image quality, depiction of segmental LGE and documented acquisition time, SNR, CNR and amount of LGE. Results were compared using the Friedman or the Kruskal–Wallis test. For LGE rating, a jackknife free-response receiver operating characteristic analysis was performed with a figure of merit (FOM) calculation. Forty-two patients were included, thirty-two were examined with a 1.5 T-scanner and ten patients with a 3 T-scanner. The mean acquisition time of the 2D sequence was significantly shorter compared to the 3D sequence (07:12 min vs. 09:24 min; p < 0.001). The 3D scan time was significantly shorter when performed at 3 T compared to 1.5 T (07:47 min vs. 09:50 min; p < 0.001). There were no differences regarding SNR, CNR or amount of LGE. 3D imaging had a significantly higher FOM (0.89 vs. 0.78; p < 0.001). Overall image quality ratings were similar, but 3D sequence ratings were higher for fine anatomical structures. Free-breathing motion-corrected 3D LGE with high isotropic resolution results in enhanced LGE-detection with higher confidence and better delineation of fine structures. The acquisition time for 3D imaging was longer, but may be reduced by performing on a 3 T-scanner

Myocardial scar detection in free-breathing Dixon-based fat- and water-separated 3D Inversion Recovery Late-Gadolinium Enhancement whole heart MRI

The aim of this study was to investigate the diagnostic accuracy and reader confidence for late-gadolinium enhancement (LGE) detection of a novel free-breathing, image-based navigated 3D whole-heart LGE sequence with fat–water separation, compared to a free-breathing motion-corrected 2D LGE sequence in patients with ischemic and non-ischemic cardiomyopathy. Cardiac MRI patients including the respective sequences were retrospectively included. Two independent, blinded readers rated image quality, depiction of segmental LGE and documented acquisition time, SNR, CNR and amount of LGE. Results were compared using the Friedman or the Kruskal–Wallis test. For LGE rating, a jackknife free-response receiver operating characteristic analysis was performed with a figure of merit (FOM) calculation. Forty-two patients were included, thirty-two were examined with a 1.5 T-scanner and ten patients with a 3 T-scanner. The mean acquisition time of the 2D sequence was significantly shorter compared to the 3D sequence (07:12 min vs. 09:24 min; p < 0.001). The 3D scan time was significantly shorter when performed at 3 T compared to 1.5 T (07:47 min vs. 09:50 min; p < 0.001). There were no differences regarding SNR, CNR or amount of LGE. 3D imaging had a significantly higher FOM (0.89 vs. 0.78; p < 0.001). Overall image quality ratings were similar, but 3D sequence ratings were higher for fine anatomical structures. Free-breathing motion-corrected 3D LGE with high isotropic resolution results in enhanced LGE-detection with higher confidence and better delineation of fine structures. The acquisition time for 3D imaging was longer, but may be reduced by performing on a 3 T-scanner