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

Results From the Austrian Stroke Unit Registry

Evaluation of: Gattringer T, Ferrari J, Knoflach M et al. Sex-related differences of acute stroke unit care results from an Austrian stroke unit registry. Stroke 45, 1632–1638 (2014). The authors analyzed data from 47,209 patients diagnosed with ischemic stroke or transient ischemic attack from January 2005 to December 2012. In this study, epidemiological data, stroke type, diagnostics and clinical scores were analyzed for age-adjusted preclinical and clinical characteristics as well as quality of acute stroke care. Moreover, outcome at 3 months was included in a multivariate model corrected for demographic and clinical confounders. While there were no reported sex differences in stroke care and thrombolysis rates, males more often received magnetic resonance imaging (MRI) brain scans. From follow-up data, a worse functional outcome was observed for females in univariate and multivariate analysis. In fact, females were less likely to be prescribed statins and more likely to receive antiplatelet therapy. A..

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

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

Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function - A multicentre, double-blind, randomized, placebo-controlled trial - SERVE

AIMS In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function. METHODS AND RESULTS This was a double-blind, randomized, placebo-controlled, multicentre superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 ± 10.7 years), comparing tadalafil 20 mg once daily versus placebo (1:1 ratio). The primary endpoint was the change in right ventricular end-systolic volume after 3 years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and N-terminal pro-B-type natriuretic peptide concentration. Primary endpoint assessment by intention to treat analysis at 3 years of follow-up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular end-systolic volumes were observed in the tadalafil and the placebo group, and no significant differences between treatment groups (3.4 ml, 95% confidence interval -4.3 to 11.0, p = 0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo group. CONCLUSIONS In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a 3-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles

Delayed intracardial shunting and hypoxemia after massive pulmonary embolism in a patient with a biventricular assist device

We describe the interdisciplinary management of a 34-year-old woman with dilated cardiomyopathy three months postpartum on a cardiac biventricular assist device (BVAD) as bridge to heart transplantation with delayed onset of intracardial shunting and subsequent hypoxemia due to massive pulmonary embolism. After emergency surgical embolectomy pulmonary function was highly compromised (PaO2/FiO2 54) requiring bifemoral veno-venous extracorporeal membrane oxygenation. Transesophageal echocardiography detected atrial level hypoxemic right-to-left shunting through a patent foramen ovale (PFO). Percutaneous closure of the PFO was achieved with a PFO occluder device. After placing the PFO occluder device oxygenation increased significantly (Δ paO2 119 Torr). The patient received heart transplantation 20 weeks after BVAD implantation and was discharged from ICU 3 weeks after transplantation

Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function - a multi-center, double-blind, randomized, placebo-controlled trial - SERVE.

BACKGROUND AND AIMS In adults with congenital heart disease and systemic right ventricles, progressive right ventricular systolic dysfunction is common and is associated with adverse outcomes. Our aim was to assess the impact of the phosphodiesterase-5-inhibitor tadalafil on right ventricular systolic function. METHODS AND RESULTS This was a double-blind, randomized, placebo-controlled, multi-center superiority trial (NCT03049540) involving 100 adults with systemic right ventricles (33 women, mean age: 40.7 years, SD 10.7), comparing tadalafil 20mg once daily versus placebo (1:1-ratio). Primary endpoint was the change in right ventricular endsystolic volume after three years of therapy. Secondary endpoints were changes in right ventricular ejection fraction, exercise capacity and NT-proBNP-concentration. Primary endpoint assessment by intention to treat analysis at three years of follow up was possible in 83 patients (42 patients in the tadalafil group and 41 patients in the placebo group). No significant changes over time in right ventricular endsystolic volumes were observed in the tadalafil and the placebo-group, and no significant differences between treatment groups (3.4ml, 95% CI, -4.3 to 11.0, p=0.39). No significant changes over time were observed for the pre-specified secondary endpoints for the entire study population, without differences between the tadalafil and the placebo-group. CONLCUSIONS In this trial in adults with systemic right ventricles, right ventricular systolic function, exercise capacity and neuro-hormonal activation remained stable over a three-year follow-up period. No significant treatment effect of tadalafil was observed. Further research is needed to find effective treatment for improvement of ventricular function in adults with systemic right ventricles. This article is protected by copyright. All rights reserved

Dysautonomia, A Heuristic Approach to a Revised Model for Etiology of Disease

Dysautonomia refers to a disease where the autonomic nervous system is dysfunctional. This may be a central control mechanism, as in genetically determined familial dysautonomia (Riley-Day Syndrome), or peripherally in the distribution of the sympathetic and parasympathetic systems. There are multiple reports of a number of different diseases associated with dysautonomia. The etiology of this association has never been explained. There are also multiple publications on dysautonomia associated with specific non-caloric nutritional deficiencies. Beriberi is the prototype of autonomic dysfunction. It is the best known nutritional deficiency disease caused by an imbalance between ingested calories and the vitamins required for their oxidation, particularly thiamin. Long thought to be abolished in modern medical thinking, there are occasional isolated reports of the full-blown disease in developed Western cultures

Multicenter Standardization of Phase-Resolved Functional Lung MRI in Patients With Suspected Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase-resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. PURPOSE To assess the feasibility and image quality of PREFUL-MRI in a multicenter setting in suspected CTEPH. STUDY TYPE This is a prospective cohort sub-study. POPULATION Forty-five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. FIELD STRENGTH/SEQUENCE 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). ASSESSMENT Lung signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL-MRI (QDP$_{PREFUL}$ ) was compared to QDP from the established dynamic contrast-enhanced MRI technique (QDP$_{DCE}$ ). Furthermore, QDP$_{PREFUL}$ was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. STATISTICAL TESTS t-Test, one-way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. RESULTS Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion -4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDP$_{PREFUL}$ was significantly correlated with QDP$_{DCE}$ (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDP$_{PREFUL}$  = 33.9 ± 17.2%). DATA CONCLUSION PREFUL-MRI could be considered as a non-invasive method for imaging regional lung perfusion in multicenter studies. LEVEL OF EVIDENCE 3 TECHNICAL EFFICACY: Stage 1