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A humanised thrombus-on-a-chip model utilising tissue-engineered arterial constructs: A method to reduce and replace mice used in thrombosis and haemostasis research [version 1; peer review: awaiting peer review]
No full textThe study of in vivo thrombus formation has principally been performed using intravital microscopy in mice and other species. These have allowed us to visualise the molecular and cellular processes that regulate thrombus formation inside the body. However current in vivo arterial thrombosis models are difficult to standardise between labs and frequently produce results that do not reliably translate successfully in human clinical trials. Here we provide a step-by-step description with accompanying video tutorials to demonstrate how to produce a 3D humanised thrombus-on-a-chip model, which uses perfusion of fluorescently-labelled human blood over a mechanically-injured human tissue engineered arterial construct (TEAC) within a 3D printed microfluidic flow chamber to replicate thrombus formation within a healthy artery. We also provide a written methodology on how to use 3D printing to produce a mechanical injury press that can reproducibly damage the TEAC as a stimulus for thrombus formation as part of a mechanical injury model. Perfusion of the uninjured TEAC with whole human blood containing DiOC6-labelled platelets without initiating notable thrombus formation. The mechanical injury press was shown to induce a reproducible puncture wound in the TEAC. Fluorescence microscopy was used to demonstrate that thrombus formation could be observed reproducibly around sites of injury. This humanised thrombosis-on-a-chip model can replace the use of animals in in vivo thrombosis models for preclinical assessment of anti-thrombotic therapies. This method also offers multiple scientific advantages: allowing new drugs to be directly tested on human blood from a diverse array of donors, facilitating use of a realistic and reproducible injury modality as well as removing the potential confounding effects of general anaesthetics in animal studies. The use of human thrombus-on-a-chip models combining TEACs offers a new methodology to reduce animal use whilst improving the predictive capabilities of preclinical trials of anti-thrombotic therapies
Monitoring for 5-aminosalicylate nephrotoxicity in adults with inflammatory bowel disease: prognostic model development and validation using data from the Clinical Practice Research Datalink
No full textObjective: To develop and validate a prognostic model for risk-stratified monitoring of 5-aminosalicylate nephrotoxicity. Methods: This UK retrospective cohort study used data from the Clinical Practice Research Datalink Aurum and Gold for model development and validation respectively. It included adults newly diagnosed with inflammatory bowel disease and established on 5-aminosalicylic acid (5-ASA) treatment between 1 January 2007 and 31 December 2019. Drug discontinuation associated with 5-ASA nephrotoxicity defined as a prescription gap of ≥90 days with decline in kidney function was the outcome. Patients prescribed 5-ASAs for ≥6 months were followed-up for up to 5 years. Penalised Cox regression was used to develop the risk equation with bootstrapping for internal validation and optimism adjustment. Model performance was assessed in terms of calibration and discrimination. Results: 13 728 and 7318 participants who contributed 40 378 and 20 679 person-years follow-up formed the development and validation cohorts with 170 (1.2%) and 98 (1.3%) outcome events respectively. Nine predictors were included in the final model, including chronic kidney disease stage 3 and hazardous alcohol use as strong predictors. Age and Body Mass Index were weak predictors. The optimism-adjusted calibration slope, C and D statistics in the development and validation data were 0.90, 0.64 and 0.98, and 1.01, 0.66 and 0.94 respectively. Conclusion: This prognostic model used information from routine clinical care and performed well in an independent validation cohort. It can be used to risk-stratify blood test monitoring during established 5-ASA treatment. A key limitation is that the decline in kidney function could have been due to factors other than 5-ASA nephrotoxicity
The VMC Survey – LI. Classifying extragalactic sources using a probabilistic random forest supervised machine learning algorithm
No full textWe used a supervised machine learning algorithm (probabilistic random forest) to classify ∼130 million sources in the VISTA Survey of the Magellanic Clouds (VMC). We used multi-wavelength photometry from optical to far-infrared as features to be trained on, and spectra of Active Galactic Nuclei (AGN), galaxies and a range of stellar classes including from new observations with the Southern African Large Telescope (SALT) and SAAO 1.9m telescope. We also retain a label for sources that remain unknown. This yielded average classifier accuracies of ∼79% (SMC) and ∼87% (LMC). Restricting to the 56,696,719 sources with class probabilities (Pclass) > 80% yields accuracies of ∼90% (SMC) and ∼98% (LMC). After removing sources classed as ‘Unknown’, we classify a total of 707,939 (SMC) and 397,899 (LMC) sources, including >77,600 extragalactic sources behind the Magellanic Clouds. The extragalactic sources are distributed evenly across the field, whereas the Magellanic sources concentrate at the centres of the Clouds, and both concentrate in optical/IR colour–colour/magnitude diagrams as expected. We also test these classifications using independent datasets, finding that, as expected, the majority of X-ray sources are classified as AGN (554/883) and the majority of radio sources are classed as AGN (1756/2694) or galaxies (659/2694), where the relative AGN–galaxy proportions vary substantially with radio flux density. We have found: >49,500 hitherto unknown AGN candidates, likely including more AGN dust dominated sources which are in a critical phase of their evolution; >26,500 new galaxy candidates and >2800 new Young Stellar Object (YSO) candidates
Exploring purchase intention in metaverse retailing: Insights from an automotive platform
No full textAs an integration of cutting-edge digital technologies, the metaverse is set to revolutionize online retailing. This study employed a well-established metaverse automotive retailing platform in China to explore the paths influencing consumers' purchase intention when shopping in the metaverse. We adopted structural equation modeling to analyze the data obtained from 348 respondents who were planning to shop for a new car in the metaverse in China. The findings showed that the perceived social presence of others positively influences consumers’ purchase intention, as mediated by their metaverse identification. Moreover, consumer stickiness and the accompaniment of friends were found to positively moderate the effect of perceived social presence on metaverse identification in metaverse retailing. Likewise, product type positively moderated the effect of metaverse identification on purchase intention. Specifically, when consumers intended to purchase environmentally-friendly (vs. unfriendly) vehicles, a stronger positive impact of metaverse identification on purchase intention was observed. The results provide valuable insight for metaverse retailers
Optimized punching shear design in steel fiber-reinforced slabs: Machine learning vs. evolutionary prediction models
No full textThis research paper focuses on utilizing Artificial Neural Networks (ANN), Multi-Objective Genetic Algorithm Evolutionary Polynomial Regression (MOGA-EPR), and Gene Expression Programming (GEP) to predict the punching shear strength of Steel Fibre-Reinforced Concrete (SFRC) slabs.In order to formulate predictions, research and analysis were carried out making use of a dataset, this dataset included several parameters that impact on punching shear strength, including SFRC slabs longitudinally and transversely, using ANN, GEP, and MOGA-EPR methods. The developed models exhibited very good performance, as the soft computing techniques (GEP and MOGA-EPR) achieved R² values of 0.91 to 0.93, while the ANN technique was higher at 0.95. Furthermore, two case studies were incorporated to carry out cost analyses of the models in real-world applications. It was shown that the efficiency of the Machine Learning (ML) models in reducing the costs of materials is relatively high, as they were capable of better predictions than the standard methods employed by the codes
Ocean crustal veins record dynamic interplay between plate-cooling-induced cracking and ocean chemistry
No full textAs ocean crust traverses away from spreading ridges, low-temperature hydrothermal minerals fill cracks to form veins, transforming the physical and chemical properties of ocean crust whilst also modifying the composition of seawater. Vein width and frequency observations compiled from the International Ocean Discovery Program (IODP) South Atlantic Transect (∼31°S) and previous scientific ocean drilling holes show that vein width distributions progressively broaden and observed strain increases with crustal age, whereas vein densities remain approximately constant. Elemental mapping and textural observations illuminate multiple precipitation and fracturing episodes that continue as the ocean crust ages. This challenges the existing notion that ocean crustal veins are passively filled; rather, they are dynamic features of ocean crust aging. These data, combined with thermal strain modelling, indicate a positive feedback mechanism where cooling of the ocean plate induces cracking and the reactivation of pre-existing veins, ultimately resulting in further cooling. Waning of this feedback provides a mechanism for the termination of the global average heat flow anomaly. Sites with total vein dilation greater than expected for their age correspond with crustal formation during periods of high atmospheric CO2. The amount of vein material thus reflects the changing balance between ocean plate cooling, ocean chemistry, and the age of the ocean crust. Our results demonstrate that ocean crust endures as an active geochemical reservoir for tens of millions of years after formation
Using rapid reviews to support software engineering practice: a systematic review and a replication study
No full textContextA few years ago, rapid reviews (RR) were introduced in software engineering (SE) to address the problem that standard systematic reviews take too long and too much effort to be of value to practitioners. Prior to our study, few practice-driven RRs had been reported, and none involved collaboration with practitioners lacking SE research experience.ObjectiveTo investigate practitioners’ perspectives on the use of RRs in supporting SE practices, we aimed to validate and build upon the findings of the seminal RR in SE study, specifically considering practitioners without explicit SE research experience.MethodFirst, we studied previously conducted RRs in SE through a systematic review. Second, we carried out an external replication of the first study that proposed the use of RRs in SE. Specifically, we conducted an RR for an agile software development team looking to improve its knowledge management practices.ResultsMost of the software development team’s perceptions about RR results were positive and strongly consistent with previous research. In particular, RR results were considered more reliable than other sources of information and adequate to address the problems detected. Some months later they confirmed using some of the recommendations.ConclusionsThe results show that practitioners without explicit SE research experience appreciate the value of evidence and can make use of the results of RRs. However, SE research may need to be translated from broad recommendations to specific process change options. Our research also reveals that SE RRs reporting needs to be substantially improved
Nursing the English from Plague to Peterloo, 1660-1820
No full textNursing the English analyses the reputations and experiences of women and men who nursed the sick before any calls for nursing reform. The book begins in the late seventeenth century with the last epidemic of plague. It concludes in 1820, the year of Florence Nightingale's birth, which also saw the first European publication calling for the founding of a Protestant nursing sisterhood - a movement that eventually propelled the drive for nurse training. Chapters cover domestic nursing by women, the long history of nursing at St Bartholomew's Hospital in London, the careers of women recruited to nurse in provincial infirmaries, and the lives of 'matrons' who nursed old soldiers at the Royal Hospital Chelsea. The final two chapters gather evidence for male nursing, chiefly in asylums and during wartime
Study protocol for the PICASSO trial: A randomized placebo-controlled trial to investigate the efficacy and safety of intraarticular steroid injections and an occupational therapy intervention in painful inflammatory carpometacarpal-1 osteoarthritis.
Get PDFOur primary objectives are to assess whether intraarticular corticosteroid injections are superior to saline injections with regards to thumb base pain after 4 weeks, and to compare the efficacy of steroid injections, saline injections, and an occupational therapy intervention on thumb base pain after 12 weeks in people with painful inflammatory osteoarthritis (OA) of the first carpometacarpal (CMC-1) joint. In this three-armed, double-blind, randomized multicenter trial, 354 participants with painful inflammatory CMC-1 OA from six Norwegian hospitals are recruited. Participants are randomized 1:1:1 to intraarticular steroid or saline injections in the CMC-1 joint or a multimodal occupational therapy intervention. The primary outcomes are thumb base pain measured on a numeric rating scale (NRS, range: 0-10) after 4 weeks and 12 weeks. Key secondary outcomes include synovitis by Magnetic Resonance Imaging (MRI) after 4 weeks and hand function by the Measure of Activity Performance of the Hand (MAP-Hand) questionnaire after 12 and 24 weeks. Other secondary outcomes are synovitis by clinical examination and ultrasound, measures of pain, function, stiffness, and health-related quality of life, and direct and indirect costs. Adverse events are recorded at each visit. The duration of the randomized controlled trial is 24 weeks, followed by an 80-week open-label observational phase to investigate the long-term efficacy and safety of repeated steroid injections and the occupational therapy intervention. The results from this trial will have important clinical implications and influence future guidelines on OA management of the CMC-1 joint. EU-CT 2023-505254-17-00, NCT06084364. [Abstract copyright: © 2024 The Authors.
Spatial profiling of ovarian clear cell carcinoma reveals immune-hot features
No full textOvarian clear cell carcinoma (OCCC) has a high incidence in Asia, with frequent occurrence at an early stage, but without sufficient data on molecular stratification for high-risk patients. Recently, immune-hot features have been proposed as indicators of poor prognosis in early stage OCCC. Specific patterns of intratumoral heterogeneity associated with immune-hot features must be defined. NanoString Digital Spatial Profiling technology was used to decipher the spatial distribution of the 18-plex protein panel. ROIs were collected based on the reference hematoxylin and eosin (H&E)-stained morphology. Areas of illumination (AOIs) were defined according to the ROI segmentation using the fluorescence signals of the visualization markers pan-cytokeratin (PanCK), CD45, or DNA. Unsupervised hierarchical clustering of 595 AOIs from 407 ROIs showed that the PanCK segments expressed different combinations of immune markers, suggestive of immune mimicry. Three immune-hot clusters were identified: granzyme B high (GZMB), immune signal high (IH), and immune-like cells (IL); two immune-cold clusters were identified: fibronectin high (FN) and immune checkpoint high cells (IC). In tumor samples at FIGO stage IC1/2 experiencing recurrence, there was an increased occurrence of PanCK+ AOIs with IH and IL groups in the papillary morphology surrounded by macrophage lineage tumor-infiltrating immune cells (TIIs). In contrast, for tumor samples at FIGO stage IC3/II with recurrence, PanCK + AOIs were prevalent in the FN group, particularly those with tubulocystic morphology surrounded by lymphoid lineage non-TIIs. Our work on the spatial profiling of early stage OCCC tumors revealed that the immune mimicry of tumor cells, presence of TIIs, and morphological patterns were associated with recurrence, which switched during tumor progression