A broader view on deriving a reference dose for THC traces in foods

An Acute Reference Dose (ARfD) of 1 µg of delta-9-tetrahydrocannabinol (THC) per kilogram (kg) of body weight (bw) per day was recommended by the European Food Safety Authority (EFSA) for its assessment of possible acute health risks from the intake of industrial hemp food products. The scientific basis for this opinion, such as their choice of a Point of Departure for identification of the Lowest Observed Adverse Effect Level (LOAEL) for THC on the central nervous system, and the seeming absence of an experimental No Observed Adverse Effect Level (NOAEL), is critically reviewed. Moreover, the risk assessment for an ARfD derivation for THC is then reconsidered. In contrast to the EFSA Scientific Opinion of 2015, a higher LOAEL is presently identified from pharmacokinetic and pharmacodynamic studies, and forensic data, in representative cohorts of healthy humans after oral administrations of low THC doses. A NOAEL for THC is derived through this combination of results, demonstrating a threshold for impairment of psychomotor function only after intake of an oral THC bolus beyond 2.5 mg for the average healthy adult. This 2.5 mg dose produces mean THC blood serum levels of <2 ng/mL, as well as do two doses when taken daily within a time interval of ≥6 h. The forensic threshold of THC that is correlated with the impairment of psychomotor function is known to be between 2 and 5 ng/mL in blood serum for adults. For an appropriately spaced intake of 2 x 2.5 mg THC per day, an adult can therefore be regarded as being at the NOAEL. Applying a default uncertainty factor of 10 for intraspecies variability to a NOAEL of 2 x 2.5 mg (over ≥6 hours) for THC, yields a “daily dose of no concern” or a “tolerable upper intake level” of 0.50 mg, corresponding to 7 µg/kg bw. Starting with a NOAEL of only 2.5 mg, consumed as a single bolus, the lowest possible daily ARfD of THC would therefore be 0.25 mg, or 3.5 µg/kg bw for healthy adults, as the absolutely most conservative estimate. Other justifiable estimates have ranged up to 14 µg/kg bw per day

Company ‘Emigration’ and EC Freedom of Establishment: Daily Mail Revisited

Following the ECJ’s recent case law on EC freedom of establishment (the Centros, Überseering and Inspire Art cases), regulatory competition for corporate law within the European Union takes place at an early stage of the incorporation of new companies. In contrast, as regards the ‘moving out’ of companies from the country of incorporation, the ECJ once considered a tax law restriction against the transfer abroad of a company’s administrative seat as compatible with EC freedom of establishment (the Daily Mail case). For years, this decision has been regarded as applicable to all restrictions imposed by countries of incorporation, even the forced liquidation of the ‘emigrating’ company. This paper addresses the question whether EC freedom of establishment really allows Member States to place any limit on the ‘emigration’ of nationally registered companies. It argues that EC freedom of establishment covers the transfer of the administrative seat as well as the transfer of the registered office and, therefore, that the country of incorporation cannot liquidate ‘emigrating’ companies. In addition, it addresses the question whether a new Directive is needed to allow the transfer of a com- pany’s registered office and the identity-preserving company law changes. It argues that such a Directive is necessary to avoid legal uncertainty and to protect the interests of employees, creditors and minority shareholders, among others, who could be detrimentally affected by the ‘emigration’ of national companies

Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

The influence of left ventricular assist device inflow cannula position on thrombosis risk

\ua9 2020 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.The use of left ventricular assist devices (LVADs) as a treatment method for heart failure patients has been steadily increasing; however, pathological studies showed presence of thrombi around the HeartWare ventricular assist device inflow cannula (IC) in more than 95% of patients after device explantation. Flow fields around the IC might trigger thrombus formation and require further investigation. In this study flow dynamics parameters were evaluated for different patient geometries using computational fluid dynamics (CFD) simulations. Left ventricular (LV) models of two LVAD patients were obtained from CT scans. The LV volumes of Patient 1 (P1) and Patient 2 (P2) were 264 and 114 cm3 with an IC angle of 20\ub0 and 9\ub0 from the mitral-IC tip axis at the coronal plane. The IC insertion site at the apex was central for P1, whereas it was lateral for P2. Transient CFD simulations were performed over 9 cardiac cycles. The wedge area was defined from the cannula tip to the wall of the LV apex. Mean velocity magnitude and blood stagnation region (volume with mean velocity &lt;5 mm/s) as well as the wall shear stress (WSS) at the IC surface were calculated. Cardiac support resulted in a flow mainly crossing the ventricle from the mitral valve to the LVAD cannula for P2, while the main inflow jet deviated toward the septal wall in P1. Lower WSS at the IC surface and consequently larger stagnation volumes were observed for P2 (P1: 0.17, P2: 0.77 cm3). Flow fields around an LVAD cannula can be influenced by many parameters such as LV size, IC angle, and implantation site. Careful consideration of influencing parameters is essential to get reliable evaluations of the apical flow field and its connection to apical thrombus formation. Higher blood washout and lower stagnation were observed for a central implantation of the IC at the apex

Left atrial appendage occlusion in ventricular assist device patients to decrease thromboembolic events: A computer simulation study

Copyright \ua9 2022 Ghodrati-Misek, Schl\uf6glhofer, Gross, Maurer, Zimpfer, Beitzke, Zonta, Moscato, Schima and Aigner. Atrial fibrillation (AF) is a common comorbidity in left ventricular assist device (LVAD) patients and has been identified as a risk factor for thromboembolic stroke. Blood stagnation within the left atrial appendage (LAA) is considered a possible major source of thrombosis and clinical studies have shown reduced thromboembolic risk after LAA occlusion (LAAO). Therefore, this study aims to investigate the effect of LAAO on thrombosis-related parameters using patient-specific simulations. Left ventricular and left atrial geometries of an LVAD patient were obtained from computed tomography and combined with hemodynamic data with either sinus rhythm (SR) or AF generated by a lumped parameter model. In four simulations applying contractile walls, stagnation volume and blood residence times were evaluated with or without AF and with or without LAAO. Reduced atrial contraction in AF resulted in unfavorable flow dynamics within the left atrium. The average atrial velocity was lower for the AF simulation when compared to SR, resulting in a 55% increase in the atrial stagnation volume (from 4.2 to 6.5 cm3). Moreover, blood remained in the LAA for more than 8 cardiac cycles. After LAAO the atrial stagnation decreased from 4.2 to 1.4 cm3 for SR and from 6.5 to 2.3 cm3 for the AF simulation. A significant stagnation volume was found in the LAA for both SR and AF, with larger values occurring with AF. These regions are known as potential sources for thrombus formation and can be diminished by LAAO. This significantly improved the thrombus-related flow parameters and may also lower the risk of thromboembolic events from the appendage

Effects of the atrium on intraventricular flow patterns during mechanical circulatory support

\ua9 The Author(s) 2021. Simulations of the ventricular flow patterns during left ventricular assist device (LVAD) support are mainly performed with idealized cylindrical inflow, neglecting the influence of the atrial vortex. In this study, the influence of the left atrium (LA) on the intra-ventricular flow was investigated via Computational Fluid Dynamics (CFD) simulations. Ventricular flow was simulated by a combined Eulerian (carrier flow)/Lagrangian (particles) approach taking into account either the LA or a cylindrical inflow section to mimic a fully support condition. The flow deviation at the mitral valve, the blood low-velocity volume as well as the residence time and shear stress history of the particles were calculated. Inclusion of the LA deflects the flow at the mitral valve by 25\ub0, resulting in an asymmetric flow jet entering the left ventricle. This reduced the ventricular low-velocity volume by 40% (from 6.4 to 3.9 cm3), increased (40%) the shear stress experienced by particles and correspondingly increased (27%) their residence time. Under the studied conditions, the atrial geometry plays a major role in the development of intraventricular flow patterns. A reliable prediction of blood flow dynamics and consequently thrombosis risk analysis within the ventricle requires the consideration of the LA in computational simulations

Cardiac imaging procedures and the COVID-19 pandemic:recommendations of the European Society of Cardiovascular Radiology (ESCR)

The severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) pandemic currently constitutes a significant burden on worldwide health care systems, with important implications on many levels, including radiology departments. Given the established fundamental role of cardiovascular imaging in modern healthcare, and the specific value of cardiopulmonary radiology in COVID-19 patients, departmental organisation and imaging programs need to be restructured during the pandemic in order to provide access to modern cardiovascular services to both infected and non-infected patients while ensuring safety for healthcare professionals. The uninterrupted availability of cardiovascular radiology services remains, particularly during the current pandemic outbreak, crucial for the initial evaluation and further follow-up of patients with suspected or known cardiovascular diseases in order to avoid unnecessary complications. Suspected or established COVID-19 patients may also have concomitant cardiovascular symptoms and require further imaging investigations. This statement by the European Society of Cardiovascular Radiology (ESCR) provides information on measures for safety of healthcare professionals and recommendations for cardiovascular imaging during the pandemic in both non-infected and COVID-19 patients

Long-Term Monitoring of Cardiac Involvement under Migalastat Treatment Using Magnetic Resonance Tomography in Fabry Disease

Background: Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat. Methods: A total of 11 females and four males with pathogenic amenable GLA mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR. Results: After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level (p = 0.005). Conclusion: Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient

Increased [18^{18}F]FDG uptake in the infarcted myocardial area displayed by combined PET/CMR correlates with snRNA-seq-detected inflammatory cell invasion

Combined [$^{18}$F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [$^{18}$F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI