A Strategy for Structuring and Reporting a Read-Across Prediction of Toxicity

Category formation, grouping and read across methods are broadly applicable in toxicological assessments and may be used to fill data gaps for chemical safety assessment and regulatory decisions. In order to facilitate a transparent and systematic approach to aid regulatory acceptance, a strategy to evaluate chemical category membership, to support the use of read-across predictions that may be used to fill data gaps for regulatory decisions is proposed. There are two major aspects of any read-across exercise, namely assessing similarity and uncertainty. While there can be an over-arching rationale for grouping organic substances based on molecular structure and chemical properties, these similarities alone are generally not sufficient to justify a read-across prediction. Further scientific justification is normally required to justify the chemical grouping, typically including considerations of bioavailability, metabolism and biological/mechanistic plausibility. Sources of uncertainty include a variety of elements which are typically divided into two main issues: the uncertainty associated firstly with the similarity justification and secondly the completeness of the read-across argument. This article focuses on chronic toxicity, whilst acknowledging the approaches are applicable to all endpoints. Templates, developed from work to prepare for the application of new toxicological data to read-across assessment, are presented. These templates act as proposals to assist in assessing similarity in the 50 context of chemistry, toxicokinetics and toxicodynamics as well as to guide the systematic characterisation of uncertainty both in the context of the similarity rationale, the read across data and overall approach and conclusion. Lastly, a workflow for reporting a read-across prediction is suggested

DES Y3 + KiDS-1000: Consistent cosmology combining cosmic shear surveys

We present a joint cosmic shear analysis of the Dark Energy Survey (DES Y3) and the Kilo-Degree Survey (KiDS-1000) in a collaborative effort between the two survey teams. We find consistent cosmological parameter constraints between DES Y3 and KiDS-1000 which, when combined in a joint-survey analysis, constrain the parameter $S_8 = \sigma_8 \sqrt{\Omega_{\rm m}/0.3}$ with a mean value of $0.790^{+0.018}_{-0.014}$. The mean marginal is lower than the maximum a posteriori estimate, $S_8=0.801$, owing to skewness in the marginal distribution and projection effects in the multi-dimensional parameter space. Our results are consistent with $S_8$ constraints from observations of the cosmic microwave background by Planck, with agreement at the $1.7\sigma$ level. We use a Hybrid analysis pipeline, defined from a mock survey study quantifying the impact of the different analysis choices originally adopted by each survey team. We review intrinsic alignment models, baryon feedback mitigation strategies, priors, samplers and models of the non-linear matter power spectrum.Comment: 38 pages, 21 figures, 15 tables, submitted to the Open Journal of Astrophysics. Watch the core team discuss this analysis at https://cosmologytalks.com/2023/05/26/des-kid

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Nucleotide sequence of the histone gene cluster in the coral Acropora formosa (Cnidaria, Scleractinia): features of histone gene structure and organization are common to diploblastic and triploblastic metazoans

We report the nucleotide sequence of the core histone gene cluster from the Cnidarian Acropora formosa. This is the first histone gene cluster to be sequenced from a diploblastic organism and the predicted amino acid sequences most resemble those of sea urchin equivalents. Each of the Cnidarian histone genes has two conserved regions 3' of the coding sequences and these closely resemble those of the metazoan α-class histone genes. In A. formosa the core histone genes are arranged as opposed (H3/H4 and H2A/H2B) pairs, a pattern common to the nondeuterostome metazoa, and tandem repetition is the predominant pattern of organization in the Cnidarian. With the recent identification of several classes of homeobox genes in Cnidarians these features clearly align the Cnidaria with triploblastic metazoans, supporting a monophyletic origin of the metazoa