Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles

The 3Rs principles—reduction, refinement, replacement—are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character in vivo imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments. The repetitive monitoring of pathology progression and the effects of therapy becomes feasible by assessment of quantitative biomarkers. Moreover, imaging has translational prospects by facilitating the comparison of studies performed in small rodents and humans. Also, learnings from the clinic may be potentially back-translated to preclinical settings and therefore contribute to refining animal investigations. By concentrating on activities around the application of magnetic resonance imaging (MRI) and ultrasound elastography to small rodent models of disease, we aim to illustrate how in vivo imaging contributes primarily to reduction and refinement in the context of pharmacological research

Evolving and Sustaining Ocean Best Practices to Enable Interoperability in the UN Decade of Ocean Science for Sustainable Development

The UN Decade of Ocean Science for Sustainable Development (Ocean Decade) challenges marine science to better inform and stimulate social and economic development while conserving marine ecosystems. To achieve these objectives, we must make our diverse methodologies more comparable and interoperable, expanding global participation and foster capacity development in ocean science through a new and coherent approach to best practice development. We present perspectives on this issue gleaned from the ongoing development of the UNESCO Intergovernmental Oceanographic Commission (IOC) Ocean Best Practices System (OBPS). The OBPS is collaborating with individuals and programs around the world to transform the way ocean methodologies are managed, in strong alignment with the outcomes envisioned for the Ocean Decade. However, significant challenges remain, including: (1) the haphazard management of methodologies across their lifecycle, (2) the ambiguous endorsement of what is "best" and when and where one method may be applicable vs. another, and (3) the inconsistent access to methodological knowledge across disciplines and cultures. To help address these challenges, we recommend that sponsors and leaders in ocean science and education promote consistent documentation and convergence of methodologies to: create and improve context-dependent best practices; incorporate contextualized best practices into Ocean Decade Actions; clarify who endorses which method and why; create a global network of complementary ocean practices systems; and ensure broader consistency and flexibility in international capacity development

Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naive individuals

Peer reviewe

TROPOMI/S5P total ozone column data: global ground-based validation and consistency with other satellite missions

In this work, the TROPOMI near real time (NRTI) and offline (OFFL) total ozone column (TOC) products are presented and compared to daily ground-based quality-assured Brewer and Dobson TOC measurements deposited in the World Ozone and Ultraviolet Radiation Data Centre (WOUDC). Additional comparisons to individual Brewer measurements from the Canadian Brewer Network and the European Brewer Network (Eubrewnet) are performed. Furthermore, twilight zenith-sky measurements obtained with ZSL-DOAS (Zenith Scattered Light Differential Optical Absorption Spectroscopy) instruments, which form part of the SAOZ network (Système d'Analyse par Observation Zénitale), are used for the validation. The quality of the TROPOMI TOC data is evaluated in terms of the influence of location, solar zenith angle, viewing angle, season, effective temperature, surface albedo and clouds. For this purpose, globally distributed ground-based measurements have been utilized as the background truth. The overall statistical analysis of the global comparison shows that the mean bias and the mean standard deviation of the percentage difference between TROPOMI and ground-based TOC is within 0 –1.5 % and 2.5 %–4.5 %, respectively. The mean bias that results from the comparisons is well within the S5P product requirements, while the mean standard deviation is very close to those limits, especially considering that the statistics shown here originate both from the satellite and the ground-based measurements.This research has been supported by the European Space Agency “Preparation and Operations of the Mission Performance Centre (MPC) for the Copernicus Sentinel-5 Precursor Satellite” (contract no. 4000117151/16/1-LG)

Motivation and treatment engagement intervention trial (MotivaTe-IT): The effects of motivation feedback to clinicians on treatment engagement in patients with severe mental illness

Background: Treatment disengagement and non-completion poses a major problem for the successful treatment of patients with severe mental illness. Motivation for treatment has long been proposed as a major determinant of treatment engagement, but exact mechanisms remain unclear. This current study serves three purposes: 1) to determine whether a feedback intervention based on the patients' motivation for treatment is effective at improving treatment engagement (TE) of severe mentally ill patients in outpatient psychiatric treatment, 2) to gather insight into motivational processes and pos

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation