(9R,9aS,12aR,13S)-9,13-Diphenyl-9,9a,12a,13-tetrahydro-9,13-methanotriphenyleno[2,3-c]furan-10,12,14-trione

X-ray crystallography was used to characterise the title compound for the first time, and the 1H NMR, 13C NMR and IR spectroscopic data from earlier reports were also updated.Publisher PDFPeer reviewe

The NCI Imaging Data Commons as a platform for reproducible research in computational pathology

Background and Objectives: Reproducibility is a major challenge in developing machine learning (ML)-based solutions in computational pathology (CompPath). The NCI Imaging Data Commons (IDC) provides >120 cancer image collections according to the FAIR principles and is designed to be used with cloud ML services. Here, we explore its potential to facilitate reproducibility in CompPath research. Methods: Using the IDC, we implemented two experiments in which a representative ML-based method for classifying lung tumor tissue was trained and/or evaluated on different datasets. To assess reproducibility, the experiments were run multiple times with separate but identically configured instances of common ML services. Results: The AUC values of different runs of the same experiment were generally consistent. However, we observed small variations in AUC values of up to 0.045, indicating a practical limit to reproducibility. Conclusions: We conclude that the IDC facilitates approaching the reproducibility limit of CompPath research (i) by enabling researchers to reuse exactly the same datasets and (ii) by integrating with cloud ML services so that experiments can be run in identically configured computing environments.Comment: 13 pages, 5 figures; improved manuscript, new experiments with P100 GP

Highdicom: A Python library for standardized encoding of image annotations and machine learning model outputs in pathology and radiology

Machine learning is revolutionizing image-based diagnostics in pathology and radiology. ML models have shown promising results in research settings, but their lack of interoperability has been a major barrier for clinical integration and evaluation. The DICOM a standard specifies Information Object Definitions and Services for the representation and communication of digital images and related information, including image-derived annotations and analysis results. However, the complexity of the standard represents an obstacle for its adoption in the ML community and creates a need for software libraries and tools that simplify working with data sets in DICOM format. Here we present the highdicom library, which provides a high-level application programming interface for the Python programming language that abstracts low-level details of the standard and enables encoding and decoding of image-derived information in DICOM format in a few lines of Python code. The highdicom library ties into the extensive Python ecosystem for image processing and machine learning. Simultaneously, by simplifying creation and parsing of DICOM-compliant files, highdicom achieves interoperability with the medical imaging systems that hold the data used to train and run ML models, and ultimately communicate and store model outputs for clinical use. We demonstrate through experiments with slide microscopy and computed tomography imaging, that, by bridging these two ecosystems, highdicom enables developers to train and evaluate state-of-the-art ML models in pathology and radiology while remaining compliant with the DICOM standard and interoperable with clinical systems at all stages. To promote standardization of ML research and streamline the ML model development and deployment process, we made the library available free and open-source

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

Background Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology

Qualitative Impact Assessment of Land Management Interventions on Ecosystem Services (“QEIA”). Report-1: Executive Summary: QEIA Evidence Review & Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten teams involving 45 experts drawn from the independent research community in a consistent series of Evidence Reviews covering the broad topics of: • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services). It should be noted that this piece of work is just one element of the wider underpinning work Defra has commissioned to support the development of the ELM schemes

Qualitative impact assessment of land management interventions on Ecosystem Services (‘QEIA’). Report-2: Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten expert teams drawn from the independent research community in a consistent series of ten Evidence Reviews covering the broad topics of; • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services) These reviews were undertaken rapidly at Defra’s request by ten teams involving 45 experts who together captured more than 2,400 individual sources of evidence. This was followed by the Integrated Assessment (IA) reported here to provide a more accessible summary of these evidence reviews with a focus on capturing the actions with the greatest potential magnitude of change for the intended ES, and their potential co-benefits and trade-offs for the other ES

DICOM Structured Reporting and Cancer Clinical Trials Results

The use of biomarkers derived from radiological images as surrogate end-points in therapeutic cancer clinical trials is well established. DICOM is the ubiquitous standard for the interchange of images for both clinical use as well as research. It also has capabilities for the exchange of image-related information, including categorical and quantitative information derived from images. The use of DICOM Structured Reporting for the encoding and interchange of clinical trial results in a standard manner is reviewed