The 'At-risk mental state' for psychosis in adolescents : clinical presentation, transition and remission.

Despite increased efforts over the last decade to prospectively identify individuals at ultra-high risk of developing a psychotic illness, limited attention has been specifically directed towards adolescent populations (<18 years). In order to evaluate how those under 18 fulfilling the operationalised criteria for an At-Risk Mental State (ARMS) present and fare over time, we conducted an observational study. Participants (N = 30) generally reported a high degree of functional disability and frequent and distressing perceptual disturbance, mainly in the form of auditory hallucinations. Seventy percent (21/30) were found to fulfil the criteria for a co-morbid ICD-10 listed mental health disorder, with mood (affective; 13/30) disorders being most prevalent. Overall transition rates to psychosis were low at 24 months follow-up (2/28; 7.1 %) whilst many participants demonstrated a significant reduction in psychotic-like symptoms. The generalisation of these findings may be limited due to the small sample size and require replication in a larger sample

Update of the Cancer Potency Database (CPDB) to enable derivations of Thresholds Of Toxicological Concern (TTC) for cancer potency

The purpose of this study was to update the existing Cancer Potency Database (CPDB) in order to support the development of a dataset of compounds, with associated points of departure (PoDs), to enable a review and update of currently applied values for the Threshold of Toxicological Concern (TTC) for cancer endpoints. This update of the current CPDB, last reviewed in 2012, includes the addition of new data (44 compounds and 158 studies leading to additional 359 dose-response curves). Strict inclusion criteria were established and applied to select compounds and studies with relevant cancer potency data. PoDs were calculated from dose-response modeling, including the benchmark dose (BMD) and the lower 90% confidence limits (BMDL) at a specified benchmark response (BMR) of 10%. The updated full CPDB database resulted in a total of 421 chemicals which had dose-response data that could be used to calculate PoDs. This candidate dataset for cancer TTC is provided in a transparent and adaptable format for further analysis of TTC to derive cancer potency thresholds

Toxicity Ranking and Toxic Mode of Action Evaluation of Commonly Used Agricultural Adjuvants on the Basis of Bacterial Gene Expression Profiles

The omnipresent group of pesticide adjuvants are often referred to as “inert” ingredients, a rather misleading term since consumers associate this term with “safe”. The upcoming new EU regulation concerning the introduction of plant protection products on the market (EC1107/2009) includes for the first time the demand for information on the possible negative effects of not only the active ingredients but also the used adjuvants. This new regulation requires basic toxicological information that allows decisions on the use/ban or preference of use of available adjuvants. In this study we obtained toxicological relevant information through a multiple endpoint reporter assay for a broad selection of commonly used adjuvants including several solvents (e.g. isophorone) and non-ionic surfactants (e.g. ethoxylated alcohols). The used assay allows the toxicity screening in a mechanistic way, with direct measurement of specific toxicological responses (e.g. oxidative stress, DNA damage, membrane damage and general cell lesions). The results show that the selected solvents are less toxic than the surfactants, suggesting that solvents may have a preference of use, but further research on more compounds is needed to confirm this observation. The gene expression profiles of the selected surfactants reveal that a phenol (ethoxylated tristyrylphenol) and an organosilicone surfactant (ethoxylated trisiloxane) show little or no inductions at EC20 concentrations, making them preferred surfactants for use in different applications. The organosilicone surfactant shows little or no toxicity and good adjuvant properties. However, this study also illustrates possible genotoxicity (induction of the bacterial SOS response) for several surfactants (POEA, AE, tri-EO, EO FA and EO NP) and one solvent (gamma-butyrolactone). Although the number of compounds that were evaluated is rather limited (13), the results show that the used reporter assay is a promising tool to rank commonly used agricultural adjuvants based on toxicity and toxic mode of action data

Decision making in interhospital transport of critically ill patients: national questionnaire survey among critical care physicians

Objective: This study assessed the relative importance of clinical and transport-related factors in physicians' decision-making regarding the interhospital transport of critically ill patients. Methods: The medical heads of all 95 ICUs in The Netherlands were surveyed with a questionnaire using 16 case vignettes to evaluate preferences for transportability; 78 physicians (82%) participated. The vignettes varied in eight factors with regard to severity of illness and transport conditions. Their relative weights were calculated for each level of the factors by conjoint analysis and expressed in beta. The reference value (beta = 0) was defined as the optimal conditions for critical care transport; a negative beta indicated preference against transportability. Results: The type of escorting personnel (paramedic only: beta = 3.1) and transport facilities (standard ambulance beta = 1.21) had the greatest negative effect on preference for transportability. Determinants reflecting severity of illness were of relative minor importance (dose of noradrenaline beta = 0.6, arterial oxygenation beta = 0.8, level of peep beta = 0.6). Age, cardiac arrhythmia, and the indication for transport had no significant effect. Conclusions: Escorting personnel and transport facilities in interhospital transport were considered as most important by intensive care physicians in determining transportability. When these factors are optimal, even severely critically ill patients are considered able to undergo transport. Further clinical research should tailor transport conditions to optimize the use of expensive resources in those inevitable road trip

Attitudes and Practices Among Internists Concerning Genetic Testing

Many questions remain concerning whether, when, and how physicians order genetic tests, and what factors are involved in their decisions. We surveyed 220 internists from two academic medical centers about their utilization of genetic testing. Rates of genetic utilizations varied widely by disease. Respondents were most likely to have ordered tests for Factor V Leiden (16.8 %), followed by Breast/Ovarian Cancer (15.0 %). In the past 6 months, 65 % had counseled patients on genetic issues, 44 % had ordered genetic tests, 38.5 % had referred patients to a genetic counselor or geneticist, and 27.5 % had received ads from commercial labs for genetic testing. Only 4.5 % had tried to hide or disguise genetic information, and <2 % have had patients report genetic discrimination. Only 53.4 % knew of a geneticist/genetic counselor to whom to refer patients. Most rated their knowledge as very/somewhat poor concerning genetics (73.7 %) and guidelines for genetic testing (87.1 %). Most felt needs for more training on when to order tests (79 %), and how to counsel patients (82 %), interpret results (77.3 %), and maintain privacy (80.6 %). Physicians were more likely to have ordered a genetic test if patients inquired about genetic testing (p  < .001), and if physicians had a geneticist/genetic counselor to whom to refer patients (p  < .002), had referred patients to a geneticist/genetic counselor in the past 6 months, had more comfort counseling patients about testing (p  < .019), counseled patients about genetics, larger practices (p  < .032), fewer African‐American patients (p  < .027), and patients who had reported genetic discrimination (p  < .044). In a multiple logistic regression, ordering a genetic test was associated with patients inquiring about testing, having referred patients to a geneticist/genetic counselor and knowing how to order tests. These data suggest that physicians recognize their knowledge deficits, and are interested in training. These findings have important implications for future medical practice, research, and education

Exposure considerations in human safety assessment: Report from an EPAA Partners’ Forum

Understanding and estimating the exposure to a substance is one of the fundamental requirements for safe manufacture and use. Many approaches are taken to determine exposure to substances, mainly driven by potential use and regulatory need. There are many opportunities to improve and optimise the use of exposure information for chemical safety. The European Partnership for Alternative Approaches to Animal Testing (EPAA) therefore convened a Partners’ Forum (PF) to explore exposure considerations in human safety assessment of industrial products to agree key conclusions for the regulatory acceptance of exposure assessment approaches; and priority areas for further research investment. The PF recognised the widescale use of exposure information across industrial sectors with the possibilities creating synergies between different sectors. Further, the PF acknowledged that the EPAA could make a significant contribution to promote the use of exposure data in human safety assessment, with an aim to address specific regulatory needs. To achieve this, research needs as well as synergies and areas for potential collaboration across sectors were identified

Effects of PPARs Agonists on Cardiac Metabolism in Littermate and Cardiomyocyte-Specific PPAR-γ –Knockout (CM-PGKO) Mice

Understanding the molecular regulatory mechanisms controlling for myocardial lipid metabolism is of critical importance for the development of new therapeutic strategies for heart diseases. The role of PPARγ and thiazolidinediones in regulation of myocardial lipid metabolism is controversial. The aim of our study was to assess the role of PPARγ on myocardial lipid metabolism and function and differentiate local/from systemic actions of PPARs agonists using cardiomyocyte-specific PPARγ –knockout (CM-PGKO) mice. To this aim, the effect of PPARγ, PPARγ/PPARα and PPARα agonists on cardiac function, intra-myocyte lipid accumulation and myocardial expression profile of genes and proteins, affecting lipid oxidation, uptake, synthesis, and storage (CD36, CPT1MIIA, AOX, FAS, SREBP1-c and ADPR) was evaluated in cardiomyocyte-specific PPARγ –knockout (CM-PGKO) and littermate control mice undergoing standard and high fat diet (HFD). At baseline, protein levels and mRNA expression of genes involved in lipid uptake, oxidation, synthesis, and accumulation of CM-PGKO mice were not significantly different from those of their littermate controls. At baseline, no difference in myocardial lipid content was found between CM-PGKO and littermate controls. In standard condition, pioglitazone and rosiglitazone do not affect myocardial metabolism while, fenofibrate treatment significantly increased CD36 and CPT1MIIA gene expression. In both CM-PGKO and control mice submitted to HFD, six weeks of treatment with rosiglitazone, fenofibrate and pioglitazone lowered myocardial lipid accumulation shifting myocardial substrate utilization towards greater contribution of glucose. In conclusion, at baseline, PPARγ does not play a crucial role in regulating cardiac metabolism in mice, probably due to its low myocardial expression. PPARs agonists, indirectly protect myocardium from lipotoxic damage likely reducing fatty acids delivery to the heart through the actions on adipose tissue. Nevertheless a direct non- PPARγ mediated mechanism of PPARγ agonist could not be ruled out

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate

Internationalizationof Read-Across as a Validated New Approach Method (NAM) for Regulatory Toxicology

Read-across (RAx) translates available information from well-characterized chemicals tothe substance for which there is a toxicological data gap. The OECD is working on case studies to probe general applicability of RAx, and several regulations (e.g. EU-REACH) already allow this procedure to be used to waive new in vivotests. The decision to prepare a review on the state of the art of RAx as a tool for risk assessment for regulatory purposes was taken during a workshop with international experts in Ranco, Italy in July 2018. Three major issues were identified that need optimisation to allowa higher regulatory acceptance rate of the RAx procedure: (i) the definition of similarity of source and target, (ii) the translation of biological/toxicological activity of source to target, in the RAx procedure, and (iii) how to deal with issues of ADMEthat may differ between source and target. The use of new approach methodologies (NAM) was discussed as one of the most important innovations to improve the acceptability of RAx. At present, NAM data may be used to confirm chemical and toxicological similarity. In the future, the use of NAM may be broadened to fully characterize the hazard and toxicokinetic properties of RAx compounds. Concerning available guidance, documents on Good Read-Across Practice (GRAP) and on best practices to perform and evaluatethe RAx process were identified. Here, in particular the RAx guidance, being worked out by the European Commission’s H2020 project EU-ToxRisk, together with many external partners with regulatory experience, is given

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Background: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. Objectives: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. Methods: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency &gt;5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. Results: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p &lt; 1 × 10−4 with a range of other diseases/traits. Conclusions: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk