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The Praxis Project, established at University College Cork (UCC), Ireland, in 2018, seeks to assess possible models of best practice with regard to the integration of global citizenship and development education (GCDE) into a cross-disciplinary, cross-campus, interwoven set of subject area pedagogies, policies and practices. This study--the first part of an eventual three-part framework--asserts that the themes, theories, values, skills, approaches and methodologies relevant to transformative pedagogical work are best underpinned by ongoing staff dialogue in order to build communities of support around such systemic pedagogical change. This article is based on a collaborative study with the first cohort of UCC staff (2020-1), which demonstrates many ways in which staff and students realised that smaller actions and carefully directed attention to specific issues opened doors to transformative thinking and action in surprising ways. From this viewpoint, the striking need emerged for taking a strategic approach to how GCDE is, and should be, integrated into learning across subject areas.

Most optimisation research focuses on relatively simple cases: one decision maker, one objective, and possibly a set of constraints. However, real-world optimisation problems often come with complications: they might be multi-objective, multi-agent, multi-stage or multi-level, and they might have uncertainty, partial knowledge or nonlinear objectives. Each has led to research areas with dedicated solution methods. However, when new hybrid problems are encountered, there is typically no solver available. We define a broad class of discrete optimisation problem called an influence program, and describe a lightweight algorithm based on multi-agent multi-objective reinforcement learning with sampling. We show that it can be used to solve problems from a wide range of literatures: constraint programming, Bayesian networks, stochastic programming, influence diagrams (standard, limited memory and multi-objective), and game theory (multi-level programming, Bayesian games and level-k reasoning). We expect it to be useful for the rapid prototyping of solution methods for new hybrid problems.

Background Our patient and public involvement activities were part of a project aiming to develop a master protocol and National Institute for Health and Care research application for the PROTECT trial aiming to assess the effectiveness, implementation, and efficiency of antimicrobial stewardship interventions, to safely reduce unnecessary antibiotic usage by excluding severe bacterial infection in acutely unwell patients. Methods Three public involvement sessions were held with representation from young people and parents, people from diverse backgrounds and people with experience of presenting to the emergency department with undifferentiated illness. The teleconference meetings lasted between 60-90 minutes, were recorded, notes were subsequently taken, and findings summarised. The data was collected on September 13, 2023, October 14, 2023 and February 28, 2024. Results Working with public involvement contributors and public involvement groups at the protocol development stage provided an opportunity for the public to shape and influence the trial. We were able to establish the feasibility of the trial in the proposed setting and gain insights into how it would be perceived by potential trial participants. Antibiotic resistance was viewed as an urgent problem and research evaluating new technologies was deemed timely and important. The platform design was considered appropriate, time and cost-effective. Deferred and electronic methods of consent were viewed as acceptable if a clear and inclusive explanation is provided. Conclusions Having access to public contributors with relevant lived experience was an important resource for the trial team. Identification and recruitment of public contributors via working with existing public involvement groups across the UK enabled the trial team to involve public members with varied life experiences and from diverse backgrounds. This project was a good practice example of how public involvement groups and practitioners across the UK can work together to deliver public involvement that is inclusive of relevant groups.

Short-term electricity markets are becoming more relevant due to less-predictable renewable energy sources, attracting considerable attention from the industry. The balancing market is the closest to real-time and the most volatile among them. Its price forecasting literature is limited, inconsistent and outdated, with few deep learning attempts and no public dataset. This work applies to the Irish balancing market a variety of price prediction techniques proven successful in the widely studied day-ahead market. We compare statistical, machine learning, and deep learning models using a framework that investigates the impact of different training sizes. The framework defines hyperparameters and calibration settings; the dataset and models are made public to ensure reproducibility and to be used as benchmarks for future works. An extensive numerical study shows that well-performing models in the day-ahead market do not perform well in the balancing one, highlighting that these markets are fundamentally different constructs. The best model is LEAR, a statistical approach based on LASSO, achieving a mean absolute error of 32.82 €/MWh, surpassing more complex and computationally demanding approaches with errors ranging from 33.71 €/MWh to 44.55 €/MWh.

Background: Late effects of cancer treatment, such as neurocognitive deficits and fatigue, can be debilitating. Other than head and neck–specific functional deficits such as impairments in swallowing and speech, little is known about survivorship after oropharyngeal cancer. This study examines the lived experience of fatigue and neurocognitive deficits in survivors of oropharyngeal squamous cell cancer and impact on their daily lives. Methods: This work is part of the multicentre mixed method ROC-oN study (Radiotherapy for Oropharyngeal Cancer and impact on Neurocognition), evaluating fatigue and neurocognitive function in patients following radiotherapy +/- chemotherapy for oropharyngeal cancer and impact on quality of life. Semi-structured interviews were conducted in adults treated with radiotherapy (+/-chemotherapy) for oropharyngeal squamous cell carcinoma >/=24 months from completing treatment. Reflexive thematic analysis performed. Results: 21 interviews (11 men and 10 women; median age 58 years and median time post-treatment 5 years) were conducted and analysed, yielding six themes: (1) unexpected burden of fatigue, (2) noticing changes in neurocognitive function, (3) the new normal, (4) navigating changes, (5)insufficient awareness and (6)required support. Participants described fatigue that persisted beyond the acute post-treatment period and changes in neurocognitive abilities across several domains. Paid and unpaid work, emotions and mood were impacted. Participants described navigating the new normal by adopting self-management strategies and accepting external support. They reported lack of recognition of these late effects, being poorly informed and being unprepared. Follow-up services were thought to be inadequate. Conclusions: Fatigue and neurocognitive impairment were frequently experienced by survivors of oropharyngeal cancer, at least two years after treatment. Patients felt ill-prepared for these late sequelae, highlighting opportunities for improvement of patient information and support services.

Dyadic interventions may promote physical activity (PA) amongst postpartum mothers. However, such interventions may not always be effective, and research is needed to explore the factors influencing engagement. Amongst this population, this study explores the perceived benefits, barriers to, and facilitators of a) PA participation, and b) engagement with two dyadic PA interventions. We conducted interviews with 17 postpartum mothers and 10 significant others (aged 26–61 years old). Data were analysed with reflexive thematic analysis. Barriers to PA engagement were that it was easy to set plans, but hard to carry them out due to childcare, work, studying/chores. Setting PA plans and receiving practical support from their partner were important ways to overcome barriers to being active, e.g., some participants looked after the children, so their partner could engage in PA, as a part of their plan. Feeling motivated to exercise as a family was also a facilitator of PA. Barriers to programme participation were a lack of motivation and a preference for exercise prescription. Perceived benefits of programme participation included increased PA commitment and accountability to the plans. Amongst other techniques, participants used prompts (e.g. spouse getting their children breakfast/coming home from work/their partner ‘checking in’), as a cue to start their PA plans. Findings show that tailored interventions to address the challenges of being a postpartum mother are needed; “one-size” fits all approach does not work.

Abstract Background It has been argued that ethics review committees—e.g., Research Ethics Committees, Institutional Review Boards, etc.— have weaknesses in reviewing big data and artificial intelligence research. For instance, they may, due to the novelty of the area, lack the relevant expertise for judging collective risks and benefits of such research, or they may exempt it from review in instances involving de-identified data. Main body Focusing on the example of medical research databases we highlight here ethical issues around de-identified data sharing which motivate the need for review where oversight by ethics committees is weak. Though some argue for ethics committee reform to overcome these weaknesses, it is unclear whether or when that will happen. Hence, we argue that ethical review can be done by data access committees, since they have de facto purview of big data and artificial intelligence projects, relevant technical expertise and governance knowledge, and already take on some functions of ethical review. That said, like ethics committees, they may have functional weaknesses in their review capabilities. To strengthen that function, data access committees must think clearly about the kinds of ethical expertise, both professional and lay, that they draw upon to support their work. Conclusion Data access committees can undertake ethical review of medical research databases provided they enhance that review function through professional and lay ethical expertise.

Objective To explore and model factors affecting antibiotic prescribing decision-making early in the pandemic.Design Semistructured qualitative interview study.Setting National Health Service (NHS) trusts/health boards in England and Wales.Participants Clinicians from NHS trusts/health boards in England and Wales.Method Individual semistructured interviews were conducted with clinicians in six NHS trusts/health boards in England and Wales as part of the Procalcitonin Evaluation of Antibiotic use in COVID-19 Hospitalised patients study, a wider study that included statistical analysis of procalcitonin (PCT) use in hospitals during the first wave of the pandemic. Thematic analysis was used to identify key factors influencing antibiotic prescribing decisions for patients with COVID-19 pneumonia during the first wave of the pandemic (March to May 2020), including how much influence PCT test results had on these decisions.Results During the first wave of the pandemic, recommendations to prescribe antibiotics for patients with COVID-19 pneumonia were based on concerns about secondary bacterial infections. However, as clinicians gained more experience with COVID-19, they reported increasing confidence in their ability to distinguish between symptoms and signs caused by SARS-CoV-2 viral infection alone, and secondary bacterial infections. Antibiotic prescribing decisions were influenced by factors such as clinician experience, confidence, senior support, situational factors and organisational influences. A decision-making model was developed.Conclusion This study provides insight into the decision-making process around antibiotic prescribing for patients with COVID-19 pneumonia during the first wave of the pandemic. The importance of clinician experience and of senior review of decisions as factors in optimising antibiotic stewardship is highlighted. In addition, situational and organisational factors were identified that could be optimised. The model presented in the study can be used as a tool to aid understanding of the complexity of the decision-making process around antibiotic prescribing and planning antimicrobial stewardship support in the context of a pandemic.Trial registration number ISRCTN66682918.

In a multi-objective optimization problem, a decision maker has more than one objective to optimize. In a bilevel optimization problem, there are the following two decision-makers in a hierarchy: a leader who makes the first decision and a follower who reacts, each aiming to optimize their own objective. Many real-world decision-making processes have various objectives to optimize at the same time while considering how the decision-makers affect each other. When both features are combined, we have a multi-objective bilevel optimization problem, which arises in manufacturing, logistics, environmental economics, defence applications and many other areas. Many exact and approximation-based techniques have been proposed, but because of the intrinsic nonconvexity and conflicting multiple objectives, their computational cost is high. We propose a hybrid algorithm based on batch Bayesian optimization to approximate the upper-level Pareto-optimal solution set. We also extend our approach to handle uncertainty in the leader’s objectives via a hypervolume improvement-based acquisition function. Experiments show that our algorithm is more efficient than other current methods while successfully approximating Pareto-fronts.

Luminous, compact emission-line galaxies (LCGs) are the most abundant class of confirmed Lyman continuum (LyC) emitters. An optical integral field study of the nearby LCG NGC 2366 reveals an outflow originating at the star cluster “knot B” thought to clear a channel via mechanical feedback that enables LyC escape. We observed NGC 2366 with the Chandra X-ray Observatory and detected X-ray emission from a point source coincident with the apex of the outflow at knot B. The pointlike nature and variability of the X-ray emission suggests accretion onto a compact object. The accretion could produce sufficient kinetic energy to power the outflow.

Abstract Digital pathology – the digitalisation of clinical histopathology services through the scanning and storage of pathology slides – has opened up new possibilities for health care in recent years, particularly in the opportunities it brings for artificial intelligence (AI)‐driven research. Recognising, however, that there is little scholarly debate on the ethics of digital pathology when used for AI research, this paper summarises what it sees as four key ethical issues to consider when deploying AI infrastructures in pathology, namely, privacy, choice, equity, and trust. The themes are inspired from the authors' experience grappling with the challenge of deploying an ethical digital pathology infrastructure to support AI research as part of the National Pathology Imaging Cooperative (NPIC), a collaborative of universities, hospital trusts, and industry partners largely located across the North of England. Though focusing on the UK case, internationally, few pathology departments have gone fully digital, and so the themes developed here offer a heuristic for ethical reflection for other departments currently making a similar transition or planning to do so in the future. We conclude by promoting the need for robust public governance mechanisms in AI‐driven digital pathology.

Plain English summary How might the public be authentically involved in decisions about medical data sharing for artificial intelligence (AI) research? In this paper, we highlight three ways in which public views are used to improve such decisions, namely, through lay representation on data access committees, through patient and public involvement groups, and through a variety of public engagement events we call “citizen forums.” Though each approach has common strengths and weaknesses, we argue that they are unable to support each other due to a lack of proper integration. We therefore propose combining them so that they work in a more coordinated way. The combined model, we argue, could be useful for improving the trustworthiness of big data and AI related medical research in the future.

Abstract Cellular therapies offer a promising therapeutic strategy for the highly malignant brain tumor, glioblastoma (GBM). However, their clinical translation is limited by the lack of effective target identification and stringent testing in pre-clinical models that replicate standard treatment in GBM patients. In this study, we show the detection of cell surface death receptor (DR) target on CD146-enriched circulating tumor cells (CTC) captured from the blood of mice bearing GBM and patients diagnosed with GBM. Next, we developed allogeneic “off-the-shelf” clinical-grade bifunctional mesenchymal stem cells (MSCBif) expressing DR-targeted ligand and a safety kill switch. We show that biodegradable hydrogel encapsulated MSCBif (EnMSCBif) has a profound therapeutic efficacy in mice bearing patient-derived invasive, primary and recurrent GBM tumors following surgical resection. Activation of the kill switch enhances the efficacy of MSCBif and results in their elimination post-tumor treatment which can be tracked by positron emission tomography (PET) imaging. This study establishes a foundation towards a clinical trial of EnMSCBif in primary and recurrent GBM patients.

Veena Raja,1 Ying Gu,2 Hsi-Ming Lee,1 Jie Deng,1 Glenn Prestwich,3,4 Maria Ryan5 1Department of Oral Biology and Pathology, Stony Brook School of Dental Medicine, Stony Brook, NY, USA; 2Department of General Dentistry, Stony Brook School of Dental Medicine, Stony Brook, NY, USA; 3Department of Medicinal Chemistry, The University of Utah, Salt Lake City, UT, USA; 4Health Sciences Spokane, Washington State University, Spokane, WA, USA; 5Colgate and Palmolive Company, Piscataway, NJ, USACorrespondence: Veena Raja, Department of Oral Biology and Pathology, School of Dental medicine, Stony Brook University, Stony Brook, NY, 11794-8706, USA, Tel +1 516-813-6250, Fax +1 631 632-9705, Email veenaraja18@gmail.comObjective: To determine the effect of a semi-synthetic-glycosaminoglycan Ether (SAGE) as a universal therapeutic benefit to reduce periodontal inflammation and alveolar bone loss in naturally occurring-beagle-dog model of periodontal disease as a surrogate for human non-risk associated natural periodontitis.Methods: Six adult female dogs with generalized periodontitis were distributed into two groups: control and SAGE treatment (n=3/group). After a 1-hour full-mouth scaling and root planning (SRP) at baseline, control or SAGE treatment (50mg/mL) bioadhesive gel formulation was locally applied for 12 weeks. Various clinical periodontal measurements (probing depth, CAL) were measured at different time periods (baseline, 4, 8 and 12 weeks), and gingival crevicular fluid (GCF), blood samples and gingival tissue biopsies (12 week) were analyzed for inflammatory mediators, collagenases and cell-signaling molecules. Standardized radiographs were taken at baseline and 12week period.Results: SAGE treatment significantly reduced gingival inflammation (GCF flow), pocket depth (PD), and clinical attachment loss (CAL) compared to control. SAGE also considerably reduced alveolar bone loss and reduced MMP-9, IL-6, CRP levels in gingival tissue, GCF and plasma. Cell-signaling molecules in the inflammatory cascade system TLR-2, TLR-4, p38 MAPK, ERK1/2 and NF-kB responded to SAGE in a pattern consistent with reductions at the active phase of the inflammatory process and collagenolysis.Conclusion: In the beagle dog model of periodontitis, local SAGE administration significantly attenuated clinical measures of periodontitis, pro-inflammatory cytokines, MMPs, and signal transduction molecules. All our studies, using in vitro and in vivo models, support the therapeutic potential of SAGE as an innovative adjunct to SRP in the treatment of chronic periodontal disease.Keywords: periodontitis, bone loss, matrix metalloproteinases, inflammation, semi-synthetic-sulfated polysaccharide

Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-γ, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.

Strawberry is a high-value commercial crop and a model for the economically important Rosaceae family. Strawberry is vulnerable to attack by many pathogens that can affect different parts of the plant, including the shoot, root, flowers, and berries. To restrict pathogen growth, strawberry produce a repertoire of secondary metabolites that have an important role in defense against diseases. Terpenes, allergen-like pathogenesis-related proteins, and flavonoids are three of the most important metabolites involved in strawberry defense. Genes involved in the biosynthesis of secondary metabolites are induced upon pathogen attack in strawberry, suggesting their transcriptional activation leads to a higher accumulation of the final compounds. The production of secondary metabolites is also influenced by the beneficial microbes associated with the plant and its environmental factors. Given the importance of the secondary metabolite pathways in strawberry defense, we provide a comprehensive overview of their literature and their role in the defense responses of strawberry. We focus on terpenoids, allergens, and flavonoids, and discuss their involvement in the strawberry microbiome in the context of defense responses. We discuss how the biosynthetic genes of these metabolites could be potential targets for gene editing through CRISPR-Cas9 techniques for strawberry crop improvement.

Abstract Background Chronic periodontitis is associated with an increased risk for systemic conditions such as cardiovascular disease, diabetes, and osteoporosis. During chronic periodontitis, endotoxin (lipopolysaccharide, LPS) produced by P. gingivalis provokes monocyte accumulation and differentiation into macrophages and increased secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs). While normal levels of MMPs are important in cellular function, increased levels of cytokines and MMPs can cause connective tissue destruction. Results In the current study, we investigated the therapeutic capability of a novel semi-synthetic sulfated polysaccharide (SAGE) on the production of cytokines and MMPs by cultured human mononuclear cells and macrophages stimulated with endotoxin LPS produced by P. gingivalis, a periodontally-relevant cell culture model. Our research demonstrated SAGE inhibited the LPS induced synthesis of inflammatory mediators including TNF-α, IL-1β, PGE2, and MMP-9 in this periodontal-relevant cell culture model. In addition, TLR-2 and TLR-4 levels were also reduced with the SAGE treatment. Conclusions The therapeutic potential of this novel semi-synthetic sulfated polysaccharide compound may help to prevent tissue damage and bone loss in patients with periodontal disease or other inflammatory diseases.

Objective: Job strain has been implicated in a variety of adverse health outcomes, particularly cardiometabolic and inflammatory diseases. However, the mechanisms underlying these effects remain largely unknown. One possibility is that the maladaptive coping response to stress, (perseverative cognition (PC); the cognitive representation of past stressful events (rumination) or feared future events (worry)), either in work or more generally, mediates the relationship between job strain and physical disease. The aim of this study was thus to test the potential role of both general, and work- related PC as a mediating, or potentially moderating, mechanism between job strain and ill- health outcomes. Design & Measures: Using an online cross- sectional design, 650 full- time employees completed measures of job strain, general and work- related PC (rumination & worry) and health outcomes (burnout, somatization, health behaviours & sleep quality). Results: General and work- related worry and rumination significantly mediated, often independently, the relationship between job strain and burnout, somatization, and sleep quality. No significant mediation effects were observed for health behaviours and no type of PC (general or work- related) moderated job strain- health outcome relations. Conclusion: Both general and work- related worry and rumination are likely to play important, and partly independent, roles in understanding the adverse relationships between job strain and various health outcomes. [ABSTRACT FROM AUTHOR]