Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Sudden Cardiac Arrest in a Youth with Multiple Arrhythmic Substrates.

Background: Mitral valve prolapse (MVP) is a common condition with an estimated prevalence of 1-3%, in which there is systolic displacement of a morphologically redundant mitral valve towards the left atrium. Mitral annular disjunction (MAD) is a separation of the MV attachment with the left ventricle, with hypermobility of the leaflets, and with systolic "curling" of the basal LV (left ventricle) myocardium. It is frequently associated with MVP and may confer an increased arrhythmic risk. Case Description. A 28-year-old male had ventricular fibrillation leading to out-of-hospital cardiac arrest, which was successfully resuscitated. His coronary arteries were unobstructed on invasive coronary angiography. Transthoracic echocardiogram (TTE) demonstrated MAD, confirmed by cardiac magnetic resonance (CMR) imaging and transoesophageal echocardiogram (TOE). The LV was severely dilated with reduced EF (ejection fraction), and the QTc interval was also prolonged. His father had died suddenly aged 50 years. Conclusions: This report describes the clinical dilemma of identifying and treating a patient with multiple potential causes of cardiac arrest. Despite being relatively common, the clinical significance of MAD is still uncertain and the extent to which it may be linked with complications such as ventricular arrhythmias and sudden cardiac death. MAD appears to confer an increased risk of ventricular arrhythmias, particularly when associated with MVP, particularly nonsustained VT.

pH Quantification in Human Dermal Interstitial Fluid Using Ultra-Thin SOI Silicon Nanowire ISFETs and a High-Sensitivity Constant-Current Approach.

In this paper, we propose a novel approach to utilize silicon nanowires as high-sensitivity pH sensors. Our approach works based on fixing the current bias of silicon nanowires Ion Sensitive Field Effect Transistors (ISFETs) and monitor the resulting drain voltage as the sensing signal. By fine tuning the injected current levels, we can optimize the sensing conditions according to different sensor requirements. This method proves to be highly suitable for real-time and continuous measurements of biomarkers in human biofluids. To validate our approach, we conducted experiments, with real human sera samples to simulate the composition of human interstitial fluid (ISF), using both the conventional top-gate approach and the optimized constant current method. We successfully demonstrated pH sensing within the physiopathological range of 6.5 to 8, achieving an exceptional level of accuracy in this complex matrix. Specifically, we obtained a maximum error as low as 0.92% (equivalent to 0.07 pH unit) using the constant-current method at the optimal current levels (1.71% for top-gate). Moreover, by utilizing different pools of human sera with varying total protein content, we demonstrated that the protein content among patients does not impact the sensors' performance in pH sensing. Furthermore, we tested real-human ISF samples collected from volunteers. The obtained accuracy in this scenario was also outstanding, with an error as low as 0.015 pH unit using the constant-current method and 0.178 pH unit in traditional top-gate configuration.

Measurement of the Induced Magnetic Polarisation of Rotated-Domain Graphene Grown on Co Film with Polarised Neutron Reflectivity.

In this paper, we determine the magnetic moment induced in graphene when grown on a cobalt film using polarised neutron reflectivity (PNR). A magnetic signal in the graphene was detected by X-ray magnetic circular dichroism (XMCD) spectra at the C K-edge. From the XMCD sum rules an estimated magnetic moment of 0.3 µB/C atom, while a more accurate estimation of 0.49 µB/C atom was obtained by carrying out a PNR measurement at 300 K. The results indicate that the higher magnetic moment in Co is counterbalanced by the larger lattice mismatch between the Co-C (1.6%) and the slightly longer bond length, inducing a magnetic moment in graphene that is similar to that reported in Ni/graphene heterostructures.

Predictors of 1- and 12-month mortality in bifurcation coronary intervention: a contemporary perspective.

Aim: Bifurcation-PCI is performed frequently, although without extensive evidence to back up a definitive solution for its complexity. We set out to identify factors associated with 1- and 12-month mortality after bifurcation-PCI between 2017 and 2021 in our tertiary center in Wales, UK. Results: Of 732 bifurcation PCI cases (mean age 69; 25% female), 67% were in ACS, 42% were left main PCI and 25.3% involved two-stent strategy. 30-day and 12-month mortality were 1.9 and 8.2%, respectively. Age, diabetes, smoking and renal failure are associated with mortality after bifurcation-PCI, while the choice between provisional and 2-stent strategies did not impact mortality/TLR. Conclusion: Awareness of 'real-world' outcomes of bifurcation-PCI should be used for appropriate patient selection, technique planning and procedural consent.

Determining the Proximity Effect-Induced Magnetic Moment in Graphene by Polarized Neutron Reflectivity and X-ray Magnetic Circular Dichroism.

We report the magnitude of the induced magnetic moment in CVD-grown epitaxial and rotated-domain graphene in proximity with a ferromagnetic Ni film, using polarized neutron reflectivity (PNR) and X-ray magnetic circular dichroism (XMCD). The XMCD spectra at the C K-edge confirm the presence of a magnetic signal in the graphene layer, and the sum rules give a magnetic moment of up to ∼0.47 µB/C atom induced in the graphene layer. For a more precise estimation, we conducted PNR measurements. The PNR results indicate an induced magnetic moment of ∼0.41 µB/C atom at 10 K for epitaxial and rotated-domain graphene. Additional PNR measurements on graphene grown on a nonmagnetic Ni9Mo1 substrate, where no magnetic moment in graphene is measured, suggest that the origin of the induced magnetic moment is due to the opening of the graphene's Dirac cone as a result of the strong C pz-Ni 3d hybridization.

Interchangeability in Left Ventricular Ejection Fraction Measured by Echocardiography and cardiovascular Magnetic Resonance: Not a Perfect Match in the Real World.

Comparisons of transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR) derived left ventricular ejection fraction (LVEF) have been reported in core-lab settings but are limited in the real-world setting. We retrospectively identified outpatients from 4 hospital sites who had clinically indicated quantitative assessment of LVEFTTE and LVEFCMR and evaluated their concordance. In 767 patients (mean age 47.6 years; 67.9% males) the median inter-modality interval was 35 days. There was significant positive correlation between the 2 modalities (r = 0.75; P < 0.001). Median LVEF was 54% (IQR 47%, 60%) for TTE and 59% (IQR 51%, 64%) for CMR, (P < 0.001). Normal LVEFTTE was confirmed by CMR in 90.6% of cases. Of patients with severely impaired LVEFTTE, 42.3% were upwardly reclassified by CMR as less severely impaired. The overall proportion of patients that had their LVEF category confirmed by both imaging modalities was 64.4%; Cohen's Kappa 0.41, indicating fair-to-moderate agreement. Overall, CMR upwardly reclassified 28% of patients using the British Society of Echocardiography LVEF grading, 18.6% using the European Society of Cardiology heart failure classification, and 29.6% using specific reference ranges for each modality. In a multi-site "real-worldˮ clinical setting, there was significant discrepancy between LVEFTTE and LVEFCMR measurement. Only 64.4% had their LVEF category confirmed by both imaging modalities. LVEFTTE was generally lower than LVEFCMR. LVEFCMR upwardly reclassified almost half of patients with severe LV dysfunction by LVEFTTE. Clinicians should consider the inter-modality variation before making therapeutic recommendations, particularly as clinical trial LVEF thresholds have historically been guided by echocardiography.

Prognostic Value of Late Gadolinium Enhancement Detected on Cardiac Magnetic Resonance in Cardiac Sarcoidosis.

BACKGROUND: Sarcoidosis is a complex multisystem inflammatory disorder, with approximately 5% of patients having overt cardiac involvement. Patients with cardiac sarcoidosis are at an increased risk of both ventricular arrhythmias and sudden cardiac death. Previous studies have shown that the presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is associated with an increased risk of mortality and ventricular arrhythmias and may be useful in predicting prognosis. OBJECTIVES: This systematic review and meta-analysis assessed the value of LGE on CMR imaging in predicting prognosis for patients with known or suspected cardiac sarcoidosis. METHODS: The authors searched the Embase and MEDLINE databases from inception to March 2022 for studies reporting individuals with known or suspected cardiac sarcoidosis referred for CMR with LGE. Outcomes were defined as all-cause mortality, ventricular arrhythmia, or a composite outcome of either death or ventricular arrhythmias. The primary analysis evaluated these outcomes according to the presence of LGE. A secondary analysis evaluated outcomes specifically according to the presence of biventricular LGE. RESULTS: Thirteen studies were included (1,318 participants) in the analysis, with an average participant age of 52.0 years and LGE prevalence of 13% to 70% over a follow-up of 3.1 years. Patients with LGE on CMR vs those without had higher odds of ventricular arrhythmias (odds ratio [OR]: 20.3; 95% CI: 8.1-51.0), all-cause mortality (OR: 3.45; 95% CI: 1.6-7.3), and the composite of both (OR: 9.2; 95% CI: 5.1-16.7). Right ventricular LGE is invariably accompanied by left ventricular LGE. Biventricular LGE is also associated with markedly increased odds of ventricular arrhythmias (OR: 43.6; 95% CI: 16.2-117.2). CONCLUSIONS: Patients with known or suspected cardiac sarcoidosis with LGE on CMR have significantly increased odds of both ventricular arrhythmias and all-cause mortality. The presence of biventricular LGE may confer additional prognostic information regarding arrhythmogenic risk.

Millimeter-wave to near-terahertz sensors based on reversible insulator-to-metal transition in VO2.

In the quest for low power bio-inspired spiking sensors, functional oxides like vanadium dioxide are expected to enable future energy efficient sensing. Here, we report uncooled millimeter-wave spiking detectors based on the sensitivity of insulator-to-metal transition threshold voltage to the incident wave. The detection concept is demonstrated through actuation of biased VO2 switches encapsulated in a pair of coupled antennas by interrupting coplanar waveguides for broadband measurements, on silicon substrates. Ultimately, we propose an electromagnetic-wave-sensitive voltage-controlled spike generator based on VO2 switches in an astable spiking circuit. The fabricated sensors show responsivities of around 66.3 MHz.W-1 at 1 µW, with a low noise equivalent power of 5 nW.Hz-0.5 at room temperature, for a footprint of 2.5 × 10-5 mm2. The responsivity in static characterizations is 76 kV.W-1. Based on experimental statistical data measured on robust fabricated devices, we discuss stochastic behavior and noise limits of VO2 -based spiking sensors applicable for wave power sensing in mm-wave and sub-terahertz range.

Giant switchable non thermally-activated conduction in 180° domain walls in tetragonal Pb(Zr,Ti)O3.

Conductive domain walls in ferroelectrics offer a promising concept of nanoelectronic circuits with 2D domain-wall channels playing roles of memristors or synoptic interconnections. However, domain wall conduction remains challenging to control and pA-range currents typically measured on individual walls are too low for single-channel devices. Charged domain walls show higher conductivity, but are generally unstable and difficult to create. Here, we show highly conductive and stable channels on ubiquitous 180° domain walls in the archetypical ferroelectric, tetragonal Pb(Zr,Ti)O3. These electrically erasable/rewritable channels show currents of tens of nanoamperes (200 to 400 nA/µm) at voltages ≤2 V and metallic-like non thermally-activated transport properties down to 4 K, as confirmed by nanoscopic mapping. The domain structure analysis and phase-field simulations reveal complex switching dynamics, in which the extraordinary conductivity in strained Pb(Zr,Ti)O3 films is explained by an interplay between ferroelastic a- and c-domains. This work demonstrates the potential of accessible and stable arrangements of nominally uncharged and electrically switchable domain walls for nanoelectronics.

Predictors of 30-day and 12-month mortality in left main stem percutaneous coronary intervention 2016-2020: A study from two UK centers.

INTRODUCTION: Left main stem percutaneous coronary intervention (LMS-PCI) is a complex high-risk procedure which can be performed as an alternative to coronary artery bypass graft (CABG) procedure in surgical turn-down patients or where there is equipoise in percutaneous versus surgical strategies. Current guidelines suggest that PCI is an appropriate alternative to CABG in patients with unprotected LMS disease and low SYNTAX score. However, "real world" data on outcomes of LMS-PCI remain limited. This study aims to quantify and determine predictors of mortality following LMS-PCI. METHODS: Using local coronary angioplasty registries from two UK centers, all LMS-PCI cases were identified from 2016 to 2020. Descriptive statistics and multivariate logistic regressions were used to examine the association between baseline and procedural characteristics with 30-day and 12-month mortality. RESULTS: We identified 484 cases of LMS-PCI between 2016 and 2020. There was a year-on-year increase in the number of LMS-PCI, the highest being in 2020. Covariates associated with higher 30-day mortality were age (OR 1.07, 95% CI: 1.02-1.12) and shock preprocedure (OR 23.88, 95% CI: 7.90-72.20). Covariates associated with higher 12-month mortality were age (OR 1.04, 95% CI: 1.01-1.08), acute coronary syndrome (ACS) (OR 2.50, 95% CI: 1.08-5.80), renal disease (OR 5.24, 95% CI: 1.47-18.68), and shock preprocedure (OR 7.93, 95% CI: 3.30-19.05). Overall, 30-day and 12-month mortality in this contemporary data set were 9.5% and 16.7%, respectively, with significantly lower rates in elective cases (p < 0.01). CONCLUSIONS: Older age and cardiogenic shock preprocedure were associated with increased 30-day mortality after LMS-PCI. Twelve-month mortality was associated with older age, ACS presentation, preexisting renal disease, and cardiogenic shock preprocedure.

An Unusual Cause of Cerebral Embolism: PFO-Straddling, Spontaneously Fractured Pacemaker Lead.

We report an exceptionally rare complication of cardiac pacing: a case of spontaneous fracture of a modern bipolar pacing lead that led to migration across a patent foramen ovale into the left atrium and embolic stroke. (Level of Difficulty: Advanced.).

Kissing Balloon "Valvuloplasty" of Obstructed Mechanical Aortic Valve: When You Are Running Out of Options.

We report an unusual case where "stuck" bileaflet aortic prosthetic valve occluders were partly released by performing emergency balloon dilatation with 2 noncompliant balloons by a percutaneous femoral approach. (Level of Difficulty: Advanced.).

Aortic regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Guidelines for the diagnosis and management of aortic regurgitation (AR) contain recommendations that do not always match. We systematically reviewed clinical practice guidelines and summarized similarities and differences in the recommendations as well as gaps in evidence on the management of AR. We searched MEDLINE and Embase (1 January 2011 to 1 September 2021), Google Scholar, and websites of relevant organizations for contemporary guidelines that were rigorously developed as assessed by the Appraisal of Guidelines for Research and Evaluation II tool. Three guidelines met our inclusion criteria. There was consensus on the definition of severe AR and use of echocardiography and of multimodality imaging for diagnosis, with emphasis on comprehensive assessment by the heart valve team to assess suitability and choice of intervention. Surgery is indicated in all symptomatic patients and aortic valve replacement is the cornerstone of treatment. There is consistency in the frequency of follow-up of patients, and safety of non-cardiac surgery in patients without indications for surgery. Discrepancies exist in recommendations for 3D imaging and the use of global longitudinal strain and biomarkers. Cut-offs for left ventricular ejection fraction and size for recommending surgery in severe asymptomatic AR also vary. There are no specific AR cut-offs for high-risk surgery and the role of percutaneous intervention is yet undefined. Recommendations on the treatment of mixed valvular disease are sparse and lack robust prospective data.

Tricuspid regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Tricuspid regurgitation (TR) is a highly prevalent condition and an independent risk factor for adverse outcomes. Multiple clinical guidelines exist for the diagnosis and management of TR, but the recommendations may sometimes vary. We systematically reviewed high-quality guidelines with a specific focus on areas of agreement, disagreement, and gaps in evidence. We searched MEDLINE and EMBASE (1 January 2011 to 30 August 2021), the Guidelines International Network International, Guideline Library, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, Google Scholar, and websites of relevant organizations for contemporary guidelines that were rigorously developed (as assessed by the Appraisal of Guidelines for Research and Evaluation II tool). Three guidelines were finally retained. There was consensus on a TR grading system, recognition of isolated functional TR associated with atrial fibrillation, and indications for valve surgery in symptomatic vs. asymptomatic patients, primary vs. secondary TR, and isolated TR forms. Discrepancies exist in the role of biomarkers, complementary multimodality imaging, exercise echocardiography, and cardiopulmonary exercise testing for risk stratification and clinical decision-making of progressive TR and asymptomatic severe TR, management of atrial functional TR, and choice of transcatheter tricuspid valve intervention (TTVI). Risk-based thresholds for quantitative TR grading, robust risk score models for TR surgery, surveillance intervals, population-based screening programmes, TTVI indications, and consensus on endpoint definitions are lacking.

Mitral regurgitation management: a systematic review of clinical practice guidelines and recommendations.

Multiple guidelines exist for the diagnosis and management of mitral regurgitation (MR), the second most common valvular heart disease in high-income countries, with recommendations that do not always match. We systematically reviewed guidelines on diagnosis and management of MR, highlighting similarities and differences to guide clinical decision-making. We searched national and international guidelines in MEDLINE and EMBASE (1 June 2010 to 1 September 2021), the Guidelines International Network, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, and websites of relevant organizations. Two reviewers independently screened the abstracts and identified articles of interest. Guidelines that were rigorously developed (as assessed with the Appraisal of Guidelines for Research and Evaluation II instrument) were retained for analysis. Five guidelines were retained. There was consensus on a multidisciplinary approach from the heart team and for the definition and grading of severe primary MR. There was general agreement on the thresholds for intervention in symptomatic and asymptomatic primary MR; however, discrepancies were present. There was agreement on optimization of medical therapy in severe secondary MR and intervention in patients symptomatic despite optimal medical therapy, but no consensus on the choice of intervention (surgical repair/replacement vs. transcatheter approach). Cut-offs for high-risk intervention in MR, risk stratification of progressive MR, and guidance on mixed valvular disease were sparse.

Management of mitral stenosis: a systematic review of clinical practice guidelines and recommendations.

A number of guidelines exist with recommendations for diagnosis and management of mitral stenosis (MS). We systematically reviewed existing guidelines for diagnosis and management of MS, highlighting their similarities and differences, in order to guide clinical decision-making. We searched national and international guidelines in MEDLINE and EMBASE (5/4/2011-5/9/2021), the Guidelines International Network, Guideline Library, National Guideline Clearinghouse, National Library for Health Guidelines Finder, Canadian Medical Association Clinical Practice Guidelines Infobase, and websites of relevant organizations. Two independent reviewers screened titles and abstracts, and the full text of potentially relevant articles where needed. Selected guidelines were assessed for rigor of development; only guidelines with Appraisal of Guidelines for Research and Evaluation II instrument score >50% were included in the final analysis. Four guidelines were retained for analysis. There was consensus for percutaneous mitral balloon commissurotomy as first-line treatment of symptomatic severe rheumatic MS with suitable anatomy. In patients with unfavourable anatomy, surgical intervention should be considered. Exercise testing is indicated if discrepancy exists between symptoms and echocardiographic measurements. There was no clear divide between rheumatic MS and degenerative MS for their respective diagnoses and management. Pregnancy in severe MS is discouraged and the stenosis should be treated before conception. Long-term antibiotic prophylaxis is recommended for patients with rheumatic MS. Recommendations for the management of patients with mixed valvular diseases are lacking.

Aliased Flow Signal Planimetry by Cardiovascular Magnetic Resonance Imaging for Grading Aortic Stenosis Severity: A Prospective Pilot Study.

Objectives: Transthoracic echocardiography (TTE) is the standard technique for assessing aortic stenosis (AS), with effective orifice area (EOA) recommended for grading severity. EOA is operator-dependent, influenced by a number of pitfalls and requires multiple measurements introducing independent and random sources of error. We tested the diagnostic accuracy and precision of aliased orifice area planimetry (AOAcmr), a new, simple, non-invasive technique for grading of AS severity by low-VENC phase-contrast cardiovascular magnetic resonance (CMR) imaging. Methods: Twenty-two consecutive patients with mild, moderate, or severe AS and six age- and sex-matched healthy controls had TTE and CMR examinations on the same day. We performed analysis of agreement and correlation among (i) AOAcmr; (ii) geometric orifice area (GOAcmr) by direct CMR planimetry; (iii) EOAecho by TTE-continuity equation; and (iv) the "gold standard" multimodality EOA (EOAhybrid) obtained by substituting CMR LVOT area into Doppler continuity equation. Results: There was excellent pairwise positive linear correlation among AOAcmr, EOAhybrid, GOAcmr, and EOAecho (p < 0.001); AOAcmr had the highest correlation with EOAhybrid (R 2 = 0.985, p < 0.001). There was good agreement between methods, with the lowest bias (0.019) for the comparison between AOAcmr and EOAhybrid. AOAcmr yielded excellent intra- and inter-rater reliability (intraclass correlation coefficient: 0.997 and 0.998, respectively). Conclusions: Aliased orifice area planimetry by 2D phase contrast imaging is a simple, reproducible, accurate "one-stop shop" CMR method for grading AS, potentially useful when echocardiographic severity assessment is inconclusive or discordant. Larger studies are warranted to confirm and validate these promising preliminary results.

Repeated echocardiographic imaging of aortic stenosis: Real-life lessons.

BACKGROUND: Timing of aortic valve intervention is dependent on the accuracy and reproducibility of echocardiographic (ECHO) parameters. We aimed to assess haemodynamic subsets of aortic stenosis (AS), their change over time, and variability of ECHO parameters. METHOD: This retrospective, longitudinal study compared sequential ECHO over 15 months to identify concordant or discordant aortic valve area (AVA) and mean pressure gradient (MPG) in order to determine the real world variability of echocardiographic indices. RESULTS: We included 143 patients with a mean age of 76.0 years. The median length of time between studies was 112 days (IQR 38-208). Initially, participants were classified as 9 (6.4%) mild, 47 (33.6%) moderate, and 84 (60.0%%) severe AS. In 80 (55.9%) AVA and MPG were concordant; stroke volume index (SVi) was < 35 mL/m2 in 53 (74.6%). AS severity was downgraded in 29 (20.7%) patients. MPG was most consistent and AVA was the least consistent between successive investigations (intraclass correlation coefficients R = .86 and R = .76, respectively). Even small variations in left ventricular outflow tract (LVOT) measurement of 1 standard deviation reclassified up to 67% of participants from severe to non-severe. CONCLUSION: Almost half of patients with AS have valve area/gradient discordance. Variations in LVOT diameter measurement commensurate with clinical practice reclassified AS severity in up to two-third of cases. Change in AS severity should only be accepted following careful scrutiny of all available ECHO data.