Novel role of bone morphogenetic protein 9 in innate host responses to HCMV infection.

Herpesviruses modulate immune control to secure lifelong infection. The mechanisms Human Cytomegalovirus (HCMV) employs in this regard can reveal unanticipated aspects of cellular signaling involved in antiviral immunity. Here, we describe a novel relationship between the TGF-ß family cytokine BMP9 and HCMV infection. We identify a cross-talk between BMP9-induced and IFN receptor-mediated signaling, showing that BMP9 boosts the transcriptional response to and antiviral activity of IFNß, thereby enhancing viral restriction. We also show that BMP9 is secreted by human fibroblasts upon HCMV infection. However, HCMV infection impairs BMP9-induced enhancement of the IFNß response, indicating that this signaling role of BMP9 is actively targeted by HCMV. Indeed, transmembrane proteins US18 and US20, which downregulate type I BMP receptors, are necessary and sufficient to cause inhibition of BMP9-mediated boosting of the antiviral response to IFNß. HCMV lacking US18 and US20 is more sensitive to IFNß. Thus, HCMV has a mutually antagonistic relationship with BMP9, which extends the growing body of evidence that BMP signaling is an underappreciated modulator of innate immunity in response to viral infection.

Inflammatory Type Focal Cerebral Arteriopathy of the Posterior Circulation in Children: A Comparative Cohort Study.

BACKGROUND: Inflammatory type focal cerebral arteriopathy (FCA-i) in the anterior circulation (AC) is well characterized, and the focal cerebral arteriopathy severity score (FCASS) reflects the severity of the disease. We identified cases of FCA-i in the posterior circulation (PC) and adapted the FCASS to describe these cases. METHODS: In this comparative cohort study, patients from the Swiss NeuroPaediatric Stroke Registry with ischemic stroke due to FCA-i between January 2000 and December 2018 were analyzed. A comparison between PC and AC cases regarding pediatric National Institutes of Health Stroke Scale score and pediatric stroke outcome measure and FCASS was performed. We estimated infarct size by the modified pediatric Alberta Stroke Program Early Computed Tomography Score in children with AC stroke and the adapted Bernese posterior diffusion-weighted imaging score in the PC. RESULTS: Thirty-five children with a median age of 6.3 (interquartile range, 2.7-8.2 [95% CI, 0.9-15.6]; 20 male; 57.1%) years with FCA-i were identified. The total incidence rate was 0.15/100 000/year (95% CI, 0.11-0.21). Six had PC-FCA-i. Time to final FCASS was longer in the PC compared with AC; the evolution of FCASS did not differ. Initial pediatric National Institutes of Health Stroke Scale score was higher in children with FCA-i in the PC with a median of 10.0 (interquartile range, 5.75-21.0) compared with 4.5 (interquartile range, 2.0-8.0) in those with AC-FCA-i. Different from the anterior cases, PC infarct volume did not correlate with higher discharge, maximum, or final FCASS scores (Pearson correlation coefficient [r], 0.25, 0.35, and 0.54). CONCLUSIONS: FCA-i also affects the PC. These cases should be included in future investigations into FCA-i. Although it did not correlate with clinical outcomes in our cohort, the modified FCASS may well serve as a marker for the evolution of the arteriopathy in posterior FCA-i.

Improved quantification in CEST-MRI by joint spatial total generalized variation.

PURPOSE: In this work, the use of joint Total Generalized Variation (TGV) regularization to improve Multipool-Lorentzian fitting of chemical exchange saturation transfer (CEST) Spectra in terms of stability and parameter signal-to-noise ratio (SNR) was investigated. THEORY AND METHODS: The joint TGV term was integrated into the nonlinear parameter fitting problem. To increase convergence and weight the gradients, preconditioning using a voxel-wise singular value decomposition was applied to the problem, which was then solved using the iteratively regularized Gauss-Newton method combined with a Primal-Dual splitting algorithm. The TGV method was evaluated on simulated numerical phantoms, 3T phantom data and 7T in vivo data with respect to systematic errors and robustness. Three reference methods were also implemented: The standard nonlinear fitting, a method using a nonlocal-means filter for denoising and the pyramid scheme, which uses downsampled images to acquire accurate start values. RESULTS: The proposed regularized fitting method showed significantly improved robustness (compared to the reference methods). In testing, over a range of SNR values the TGV fit outperformed the other methods and showed accurate results even for large amounts of added noise. Parameter values found were closer or comparable to the ground truth. For in vivo datasets, the added regularization increased the parameter map SNR and prevented instabilities. CONCLUSION: The proposed fitting method using TGV regularization leads to improved results over a range of different data-sets and noise levels. Furthermore, it can be applied to all Z-spectrum data, with different amounts of pools, where the improved SNR and stability can increase diagnostic confidence.

Model-based reconstructions for intravoxel incoherent motion and diffusion tensor imaging parameter map estimations.

Intravoxel incoherent motion (IVIM) imaging and diffusion tensor imaging (DTI) facilitate noninvasive quantification of tissue perfusion and diffusion. Both are promising biomarkers in various diseases and a combined acquisition is therefore desirable. This comes with challenges, including noisy parameter maps and long scan times, especially for the perfusion fraction f and pseudo-diffusion coefficient D*. A model-based reconstruction has the potential to overcome these challenges. As a first step, our goal was to develop a model-based reconstruction framework for IVIM and combined IVIM-DTI parameter estimation. The IVIM and IVIM-DTI models were implemented in the PyQMRI model-based reconstruction framework and validated with simulations and in vivo data. Commonly used voxel-wise nonlinear least-squares fitting was used as the reference. Simulations with the IVIM and IVIM-DTI models were performed with 100 noise realizations to assess accuracy and precision. Diffusion-weighted data were acquired for IVIM reconstruction in the liver (n = 5), as well as for IVIM-DTI in the kidneys (n = 5) and lower-leg muscles (n = 6) of healthy volunteers. The median and interquartile range (IQR) values of the IVIM and IVIM-DTI parameters were compared to assess bias and precision. With model-based reconstruction, the parameter maps exhibited less noise, which was most pronounced in the f and D* maps, both in the simulations and in vivo. The bias values in the simulations were comparable between model-based reconstruction and the reference method. The IQR was lower with model-based reconstruction compared with the reference for all parameters. In conclusion, model-based reconstruction is feasible for IVIM and IVIM-DTI and improves the precision of the parameter estimates, particularly for f and D* maps.

A simplified cardiac damage staging predicts the outcome of patients undergoing TAVR-A multicenter analysis.

BACKGROUND: A significant number of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) suffer from extra-aortic cardiac damage. Few studies have investigated strategies to quantify cardiac damage and stratify patients accordingly in different risk groups. The aim of this retrospective multicenter study was to provide a user-friendly simplified staging system based on the proposed classification system of Généreux et al. as a tool to evaluate the prognosis of patients undergoing TAVR more easily. Moreover, we analyzed changes in cardiac damage after TAVR. METHODS: We assessed cardiac damage in patients, who underwent TAVR at the Heart Center Bonn or Düsseldorf, using pre- and postprocedural transthoracic echocardiography. Patients were assigned to the staging system proposed by Généreux et al. according to the severity of their baseline cardiac damage. Based on the established system, we created a simplified staging system to facilitate improved applicability. Finally, we compared clinical outcomes between the groups and evaluated changes in cardiac damage after TAVR. RESULTS: A total of 933 TAVR patients were included in the study. We found a significant association between cardiac damage and 1-year all-cause mortality (stage 0: 0% vs. stage 1: 3% vs. stage 2: 6.6%; p < 0.009). In multivariate analysis, cardiac damage was an independent predictor of 1-year all-cause mortality (hazard ratio: 2.0, 95% confidence interval: 1.1-3.8; p = 0.03). CONCLUSIONS: In patients undergoing TAVR, cardiac damage is associated with enhanced mortality. A simplified staging system can help identify patients at high risk for an adverse outcome.

Joint multi-field T1 quantification for fast field-cycling MRI.

PURPOSE: Recent developments in hardware design enable the use of fast field-cycling (FFC) techniques in MRI to exploit the different relaxation rates at very low field strength, achieving novel contrast. The method opens new avenues for in vivo characterizations of pathologies but at the expense of longer acquisition times. To mitigate this, we propose a model-based reconstruction method that fully exploits the high information redundancy offered by FFC methods. METHODS: The proposed model-based approach uses joint spatial information from all fields by means of a Frobenius - total generalized variation regularization. The algorithm was tested on brain stroke images, both simulated and acquired from FFC patients scans using an FFC spin echo sequences. The results are compared to three non-linear least squares fits with progressively increasing complexity. RESULTS: The proposed method shows excellent abilities to remove noise while maintaining sharp image features with large signal-to-noise ratio gains at low-field images, clearly outperforming the reference approach. Especially patient data show huge improvements in visual appearance over all fields. CONCLUSION: The proposed reconstruction technique largely improves FFC image quality, further pushing this new technology toward clinical standards.

CG-SENSE revisited: Results from the first ISMRM reproducibility challenge.

PURPOSE: The aim of this work is to shed light on the issue of reproducibility in MR image reconstruction in the context of a challenge. Participants had to recreate the results of "Advances in sensitivity encoding with arbitrary k-space trajectories" by Pruessmann et al. METHODS: The task of the challenge was to reconstruct radially acquired multicoil k-space data (brain/heart) following the method in the original paper, reproducing its key figures. Results were compared to consolidated reference implementations created after the challenge, accounting for the two most common programming languages used in the submissions (Matlab/Python). RESULTS: Visually, differences between submissions were small. Pixel-wise differences originated from image orientation, assumed field-of-view, or resolution. The reference implementations were in good agreement, both visually and in terms of image similarity metrics. DISCUSSION AND CONCLUSION: While the description level of the published algorithm enabled participants to reproduce CG-SENSE in general, details of the implementation varied, for example, density compensation or Tikhonov regularization. Implicit assumptions about the data lead to further differences, emphasizing the importance of sufficient metadata accompanying open datasets. Defining reproducibility quantitatively turned out to be nontrivial for this image reconstruction challenge, in the absence of ground-truth results. Typical similarity measures like NMSE of SSIM were misled by image intensity scaling and outlier pixels. Thus, to facilitate reproducibility, researchers are encouraged to publish code and data alongside the original paper. Future methodological papers on MR image reconstruction might benefit from the consolidated reference implementations of CG-SENSE presented here, as a benchmark for methods comparison.

Computed tomography derived predictors of permanent pacemaker implantation after transcatheter aortic valve replacement: A meta-analysis.

OBJECTIVES: This meta-analysis sought to assess predictors of permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR) with focus on preprocedural multi-slice computed tomography (MSCT) derived data. BACKGROUND: Transcatheter aortic valve replacement (TAVR) has expanded to a well-established treatment for severe symptomatic aortic stenosis at high and intermediate surgical risk. PPI after TAVR remains one of the most frequent procedure-related complications and appears to be influenced by several factors. METHODS: The authors conducted a literature search in PubMed/MEDLINE and EMBASE databases to identify studies that investigated preprocedural MSCT data and the rate of PPI following TAVR with new-generation devices. RESULTS: Ten observational studies (n = 2707) met inclusion criteria for the final analysis. PPI was performed in 387 patients (14.3%) after TAVR. Patients requiring PPI had a larger annulus perimeter (MD: 1.66 mm; p < .001) and a shorter membranous septum length (MD: -1.1 mm; p < .05). Concerning calcification distribution, patients with requirement for new pacemaker implantation showed increased calcification of the left coronary cusp (MD: 47.6 mm3 ; p < .001), and the total left ventricular outflow tract (MD: 24.42 mm3 ; p < .01). Lower implantation depth (MD: 0.95 mm; p < .05) and oversizing (MD: 1.52%; p < .05) were procedural predictors of PPI following TAVR. CONCLUSIONS: Besides the well-known impact of electrocardiographic and procedure-related factors on conduction disturbances, MSCT derived distribution of the aortic valve and left ventricular outflow tract calcification, as well as membranous septum length, are associated with an increased risk of PPI following TAVR.

Aortic valve calcification is subject to aortic stenosis severity and the underlying flow pattern.

Sex- and flow-related aortic valve calcification (AVC) studies are still limited in number, and data on the exact calcium quantity and distribution are scarce. Therefore, we aimed to (1) re-define the best threshold of AVC load to distinguish severe from moderate aortic stenosis (AS) in common AS entities and to (2) evaluate differences in the aortic annulus and left ventricular outflow tract (LVOT) calcium load. Nine hundred and thirty-eight patients with contrast-enhanced cardiac MSCT and moderate-to-severe aortic stenosis (AS) were retrospectively enrolled. Patients with severe AS ≤ 1.0 cm2 (n = 841) were further separated into three AS entities: high gradient (HGAS, n = 370, 44.0%), paradoxical low gradient (pLGAS, n = 333, 39.6%), and classical low gradient (LGAS, n = 138, 16.4%). AVC, leaflet, and LVOT calcification were quantified. Aortic valve calcification scores were highest in severe HGAS, and lower in severe pLGAS and classical LGAS. In all severity and AS entities, the non-coronary cusp (NCC) was the most calcified one. LVOT calcification was consistently comparable between gender and AS entities. Accuracy of logistic regression was the highest in HGAS (male vs. female: AVC > 2156 Agatston units (AU), c-index 0.76; vs. AVC > 1292 AU, c-index 0.85; or AVC density > 406 AU/cm2, c-index 0.82; vs. > 259 AU/cm2, c-index 0.86; each p < 0.0001*) to diagnose severe AS. AVC could only be used in men to differentiate between severe LGAS and moderate AS. Data from this retrospective analysis indicate that the NCC is subject to pre-dominant degeneration throughout gender, AS severity, and several AS entities. AVC was consistently comparable in severe pLGAS and classical LGAS, but only AVC in severe LGAS could sufficiently distinguish from moderate AS in men. LVOT calcification failed to be a reliable indicator of accelerating AS.

Novel insights on outcome in horizontal aorta with self-expandable new-generation transcatheter aortic valve replacement devices.

BACKGROUND: The impact of a horizontal aorta (HA) on adverse events (AE) following in transcatheter aortic valve replacement (TAVR) is dealt controversially. Using new-generation self-expandable devices, we aimed to reevaluate an appropriate threshold of the aortic root angulation (ARA) in terms of HA and its impact on outcome. METHODS: The 466 consecutive patients, who underwent transfemoral TAVR with self-expandable new-generation devices, were analyzed. Patients were classified into cases with HA (ARA ≥ 51°; n = 225; 48%) and without HA (ARA <51°; n = 241; 52%). Primary endpoints were device success and 30-day mortality. Secondary endpoints were specific AE according to VARC-2 definitions. RESULTS: Contrast use (107.6 ± 50.1 vs. 94.1 ± 46.1 ml; p = .033) and radiation dose (3,176 [1,928-5,596] vs. 2,651 [1,643-4,394] Gyxcm2 ; p = .016) were higher in HA. Primary device success was comparable (97.1 vs. 97.8%; p = .773). A 30-day mortality (3.3 vs. 0.4%; p = .038, plogrank = 0.025), stroke (7.1 vs. 2.7%; p = .033), and major vascular complications (MVASC) (6.6 vs. 2.7%; p = .050) were more frequent in HA. Pronounced calcification of the noncoronary cusp and left ventricular outflow tract, the condition of HA, as well as repositioning maneuvers were independent predictors for overall specific AE. CONCLUSION: An HA above 51° is associated with an increased rate of stroke, MVASC, and 30-day mortality. Valve size and asymmetric calcification affect the incidence of repositioning maneuvers and subsequent VARC-2 AE, indicating that an HA-together with specific anatomic features-remains a crucial factor for TAVR-related outcome with self-expandable new-generation devices.

Impact of Combined "CHADS-BLED" Score to Predict Short-Term Outcomes in Transfemoral and Transapical Aortic Valve Replacement.

BACKGROUND: High CHA2DS2-VASC and HAS-BLED scores are linked to increased mortality in structural and nonstructural cardiovascular interventions irrespective of the presence of atrial fibrillation (AF) or oral anticoagulation. We aimed to use the aforementioned scores to quantify the risk of 30-day mortality, major vascular and bleeding events (MVASC/BARC), and cerebrovascular insults (CVI) in patients undergoing different access routes in transcatheter aortic valve replacement (TAVR). METHODS: Out of 1329 patients, 980 transfemoral (TF) TAVR (73.7%) and 349 transapical (TA) TAVR (26.3%) were included. CHA2DS2-VASC, HAS-BLED, and combined "CHADS-BLED" scores were calculated and compared to the predictive value of the established EuroSCORE and STS score. RESULTS: In all-comers TF TAVR patients, the applied risk models showed only poor association with 30-day mortality while, in patients with concomitant AF, a strong association was observed using the combined CHADS-BLED score (c-index: 0.83; 95% CI: 0.76-0.91; p < 0.0001). Concerning 30-day mortality, only the STS score for TF TAVR (c-index: 0.68; 95% CI: 0.59-0.76; p = 0.001) and EuroSCORE for TA TAVR (c-index: 0.66; 95% CI: 0.56-0.76; p = 0.005) could show some predictive value. High CHADS-BLED was associated with enhanced CVI (3.0% vs. 7.2%;p=0.0039 ∗ ) and more frequent MVASC/BARC (3.2% vs. 6.3%; p = 0.0362) in the all-comers TAVR cohort. All risk models failed in the prediction of CVI and MVASC/BARC for TA TAVR patients. CONCLUSION: The combined CHADS-BLED score was a strong predictor for 30-day mortality in TF TAVR patients with AF. A high CHADS-BLED score showed a good predictive value for major vascular and bleeding events as well as CVI in TF TAVR patients. This study is registered at clinical trials (NCT01805739).

Rapid T1 quantification from high resolution 3D data with model-based reconstruction.

PURPOSE: Magnetic resonance imaging protocols for the assessment of quantitative information suffer from long acquisition times since multiple measurements in a parametric dimension are required. To facilitate the clinical applicability, accelerating the acquisition is of high importance. To this end, we propose a model-based optimization framework in conjunction with undersampling 3D radial stack-of-stars data. THEORY AND METHODS: High resolution 3D T1 maps are generated from subsampled data by employing model-based reconstruction combined with a regularization functional, coupling information from the spatial and parametric dimension, to exploit redundancies in the acquired parameter encodings and across parameter maps. To cope with the resulting non-linear, non-differentiable optimization problem, we propose a solution strategy based on the iteratively regularized Gauss-Newton method. The importance of 3D-spectral regularization is demonstrated by a comparison to 2D-spectral regularized results. The algorithm is validated for the variable flip angle (VFA) and inversion recovery Look-Locker (IRLL) method on numerical simulated data, MRI phantoms, and in vivo data. RESULTS: Evaluation of the proposed method using numerical simulations and phantom scans shows excellent quantitative agreement and image quality. T1 maps from accelerated 3D in vivo measurements, e.g. 1.8 s/slice with the VFA method, are in high accordance with fully sampled reference reconstructions. CONCLUSIONS: The proposed algorithm is able to recover T1 maps with an isotropic resolution of 1 mm3 from highly undersampled radial data by exploiting structural similarities in the imaging volume and across parameter maps.

Feasibility, safety, and outcome of recanalization treatment in childhood stroke.

OBJECTIVE: Intravenous thrombolysis and endovascular therapy (IVT/EVT) are evidence-based treatments for adults with arterial ischemic stroke (AIS). However, randomized controlled trials in pediatric patients are lacking. This study aimed to describe feasibility, safety, and outcome of IVT/EVT in children with AIS. METHODS: This retrospective study (01/2000-12/2015) included a multicenter, population-based consecutive cohort of patients aged 1 month to 16 years, diagnosed with AIS and presenting with pediatric National Institutes of Health Stroke Scale (pedNIHSS) ≥ 4. Clinical and radiological data of patients receiving IVT/EVT were compared to those receiving standard care (SC) using linear regression to adjust for potential confounders. EVT included intra-arterial thrombolysis and/or mechanical thrombectomy. Outcome was assessed 6 months after stroke using the pediatric stroke outcome measure (PSOM). RESULTS: Overall, 150 patients (age 7.1 ± 4.9 years, 55 [37%] females) presented with pedNIHSS ≥ 4. Recanalization treatment was performed in 16 (11%), of whom 5 (3%) were treated with IVT and 11 (7%) with EVT. Patients receiving recanalization treatment were older (mean age = 11.0 vs 6.9 years, p = 0.01) and more severely affected (median pedNIHSS = 13.5 vs 8.0, p < 0.001). Death and bleeding complications did not differ between the 2 groups. Median (interquartile range) PSOM 6 months after AIS was 2.5 (1-4.3) and 1 (0-2) in the IVT/EVT and SC groups, respectively (p = 0.014). However, after multiple linear regression analysis, only higher baseline pedNIHSS remained associated with an unfavorable outcome (p < 0.001). INTERPRETATION: Recanalization treatment is feasible and seems to be safe in severely affected pediatric AIS patients. The assessment of efficacy of IVT/EVT in pediatric stroke patients requires larger studies. Ann Neurol 2018;83:1125-1132.

Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders.

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.

Stent fractures after common femoral artery bail-out stenting due to suture device failure in TAVR.

BACKGROUND: Vascular access site-related complications are frequent in the context of transfemoral transcatheter aortic valve replacement (TAVR). The implantation of a covered stent graft is an effective treatment option for bleeding control. However, the external iliac and common femoral arteries are exposed to flexion of the hip joint. Therefore, stent compression and stent/strut fractures may occur, facilitating stent occlusion. PATIENTS AND METHODS: In all 389 patients who received transfemoral TAVR from 2013-2015 at the Düsseldorf Heart Centre, we monitored the management of vascular access site-related complications. Our analyses focused on immediate technical success and bleeding control, primary patency, and the occurrence of stent/strut fractures after six to 12 months of follow-up. RESULTS: Vascular access site-related complications occurred in 13 % (n = 51), whereof in 10 patients, the bleeding was successfully managed by prolonged compression. In 40 out of 51 patients, a covered stent graft was implanted in the common femoral artery, leading to 100 % immediate bleeding control. After a mean follow-up of 334 ± 188 days, 28 stents out of 29 patients with completed follow-up (excluding e. g. death) were without flow-limiting stenosis (primary patency 97 %) or relevant stent compression (diameter pre/post 8.6/8.1 mm, p = 0.048, late lumen loss 1.1 ± 0.2 mm, mean flow velocity 92 ± 34 cm/s). In four asymptomatic patients, stent/strut fractures were detected (14 %) without flow-limiting stenosis. CONCLUSIONS: The implantation of a covered stent graft is highly effective and safe to control vascular access site-related complications after TAVR. Stent/strut fractures in the flexible segment of the common femoral artery may occur, as consequently verified by X-ray visualization, but show no impairment on flow or clinical parameters after six to 12 months.

A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2.

Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.

Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome.

The first described patients with pyridox(am)ine 5'-phosphate oxidase deficiency all had neonatal onset seizures that did not respond to treatment with pyridoxine but responded to treatment with pyridoxal 5'-phosphate. Our data suggest, however, that the clinical spectrum of pyridox(am)ine 5'-phosphate oxidase deficiency is much broader than has been reported in the literature. Sequencing of the PNPO gene was undertaken for a cohort of 82 individuals who had shown a reduction in frequency and severity of seizures in response to pyridoxine or pyridoxal 5'-phosphate. Novel sequence changes were studied using a new cell-free expression system and a mass spectrometry-based assay for pyridoxamine phosphate oxidase. Three groups of patients with PNPO mutations that had reduced enzyme activity were identified: (i) patients with neonatal onset seizures responding to pyridoxal 5'-phosphate (n = 6); (ii) a patient with infantile spasms (onset 5 months) responsive to pyridoxal 5'-phosphate (n = 1); and (iii) patients with seizures starting under 3 months of age responding to pyridoxine (n = 8). Data suggest that certain genotypes (R225H/C and D33V) are more likely to result in seizures that to respond to treatment with pyridoxine. Other mutations seem to be associated with infertility, miscarriage and prematurity. However, the situation is clearly complex with the same combination of mutations being seen in patients who responded and did not respond to pyridoxine. It is possible that pyridoxine responsiveness in PNPO deficiency is affected by prematurity and age at the time of the therapeutic trial. Other additional factors that are likely to influence treatment response and outcome include riboflavin status and how well the foetus has been supplied with vitamin B6 by the mother. For some patients there was a worsening of symptoms on changing from pyridoxine to pyridoxal 5'-phosphate. Many of the mutations in PNPO affected residues involved in binding flavin mononucleotide or pyridoxal 5'-phosphate and many of them showed residual enzyme activity. One sequence change (R116Q), predicted to affect flavin mononucleotide binding and binding of the two PNPO dimers, and with high residual activity was found in Groups (ii) and (iii). This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy.

Factors Influencing Implantation Depth During Transcatheter Aortic Valve Replacement.

Optimised implantation depth (OID) is crucial to obtain the best haemodynamic and clinical outcome during transcatheter heart valve (THV) deployment. OID ensures a better haemodynamic profile and is associated with a potential reduction in permanent pacemaker implantations, both of which are important during transcatheter aortic valve replacement (TAVR). Apart from patient-related anatomic conditions, many factors, such as THV and wire selection, as well as implantation strategies, can be controlled by the operator and facilitate the implantation process. However, there are only limited data dealing with predictors for OID. Therefore, the aim of this review was to outline factors and tools that might influence the final implantation depth during TAVR procedures, potentially influencing the outcome.

Temporary decrease in microvascular tissue saturation after transcatheter aortic valve implantation.

BACKGROUND: Data on the effect of transcatheter aortic valve implantation (TAVI) on peripheral microcirculation are limited. OBJECTIVE: The aim of this study is to evaluate peripheral microvascular tissue saturation (StO2) before and after TAVI in relation to central and peripheral hemodynamics, cardiac and renal function. METHODS: In this single-center prospective study, patients with severe aortic stenosis (sAS) scheduled for TAVI or cardiac catheterization (control) were assessed before and up to five days after the procedure. Cardiac function including cardiac output (CO) was assessed by echocardiography. Brachial (bBP) and central blood pressure (cBP), ankle brachial index (ABI), and parameters of arterial stiffness, including augmentation pressure (AP) and augmentation index adjusted for heart rate (AIx@HR75) were measured to assess hemodynamic changes. StO2 was measured in all extremities using a near-infrared spectroscopy (NIRS) camera. Renal function was measured by creatinine levels. RESULTS: 26 patients underwent TAVI and 11 patients served as control. Cardiac output was significantly increased, whereas hemodynamic parameters and peripheral StO2 were significantly decreased after TAVI. At follow-up, StO2 returned to baseline values. Changes in StO2 were negatively related to creatinine levels. CONCLUSION: Transcatheter aortic valve implantation causes a temporary decrease in microvascular tissue saturation that is associated with renal function.

A comparison of conventional and advanced 3D imaging techniques for percutaneous left atrial appendage closure.

Background: Understanding complex cardiac anatomy is essential for percutaneous left atrial appendage (LAA) closure. Conventional multi-slice computed tomography (MSCT) and transesophageal echocardiography (TEE) are now supported by advanced 3D printing and virtual reality (VR) techniques for three-dimensional visualization of volumetric data sets. This study aimed to investigate their added value for LAA closure procedures. Methods: Ten patients scheduled for interventional LAA closure were evaluated with MSCT and TEE. Patient-specific 3D printings and VR models were fabricated based on MSCT data. Ten cardiologists then comparatively assessed LAA anatomy and its procedure relevant surrounding structures with all four imaging modalities and rated their procedural utility on a 5-point Likert scale questionnaire (from 1 = strongly agree to 5 = strongly disagree). Results: Device sizing was rated highest in MSCT (MSCT: 1.9 ± 0.8; TEE: 2.6 ± 0.9; 3D printing: 2.5 ± 1.0; VR: 2.5 ± 1.1; p < 0.01); TEE, VR, and 3D printing were superior in the visualization of the Fossa ovalis compared to MSCT (MSCT: 3.3 ± 1.4; TEE: 2.2 ± 1.3; 3D printing: 2.2 ± 1.4; VR: 1.9 ± 1.3; all p < 0.01). The major strength of VR and 3D printing techniques was a superior depth perception (VR: 1.6 ± 0.5; 3D printing: 1.8 ± 0.4; TEE: 2.9 ± 0.7; MSCT: 2.6 ± 0.8; p < 0.01). The visualization of extracardiac structures was rated less accurate in TEE than MSCT (TEE: 2.6 ± 0.9; MSCT: 1.9 ± 0.8, p < 0.01). However, 3D printing and VR insufficiently visualized extracardiac structures in the present study. Conclusion: A true 3D visualization in VR or 3D printing provides an additional value in the evaluation of the LAA for the planning of percutaneous closure. In particular, the superior perception of depth was seen as a strength of a 3D visualization. This may contribute to a better overall understanding of the anatomy. Clinical studies are needed to evaluate whether a more comprehensive understanding through advanced multimodal imaging of patient-specific anatomy using VR may translate into improved procedural outcomes.