BACKGROUND Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon- (IFN) α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. OBJECTIVES We evaluated the hypothesis that human genetic factors might underlie AVM in previously healthy children. METHODS We tested the role of TLR3-IFN immunity utilizing human-induced pluripotent stem cell-derived cardiomyocytes. We then performed whole exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral etiologies. RESULTS We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to coxsackievirus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous, but not heterozygous, rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). CONCLUSIONS Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections.

Background Accurate prostate zonal segmentation on magnetic resonance images (MRI) is a critical prerequisite for automated prostate cancer detection. We aimed to assess the variability of manual prostate zonal segmentation by radiologists on T2-weighted (T2W) images, and to study factors that may influence it. Methods Seven radiologists of varying levels of experience segmented the whole prostate gland (WG) and the transition zone (TZ) on 40 axial T2W prostate MRI images (3D T2W images for all patients, and both 3D and 2D images for a subgroup of 12 patients). Segmentation variabilities were evaluated based on: anatomical and morphological variation of the prostate (volume, retro-urethral lobe, intensity contrast between zones, presence of a PI-RADS ≥ 3 lesion), variation in image acquisition (3D vs 2D T2W images), and reader’s experience. Several metrics including Dice Score (DSC) and Hausdorff Distance were used to evaluate differences, with both a pairwise and a consensus (STAPLE reference) comparison. Results DSC was 0.92 (± 0.02) and 0.94 (± 0.03) for WG, 0.88 (± 0.05) and 0.91 (± 0.05) for TZ respectively with pairwise comparison and consensus reference. Variability was significantly (p < 0.05) lower for the mid-gland (DSC 0.95 (± 0.02)), higher for the apex (0.90 (± 0.06)) and the base (0.87 (± 0.06)), and higher for smaller prostates (p < 0.001) and when contrast between zones was low (p < 0.05). Impact of the other studied factors was non-significant. Conclusions Variability is higher in the extreme parts of the gland, is influenced by changes in prostate morphology (volume, zone intensity ratio), and is relatively unaffected by the radiologist’s level of expertise.

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Prostate volume prediction on MRI: tools, accuracy and variability.

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