Cardiff University

The benzopyrone molecule coumarin is a popular fluorescent scaffold, but how chemical modifications affect its properties is not well understood. We investigated this using halogenated 7‐hydroxycoumarin, unsubstituted 4‐methylumbiliferone, and ortho‐chloro and bromo substitutions on the phenolic ring. Charge density data from X‐Ray diffraction and computational methods revealed that halogenation at the ortho position significantly reduced quantum yield (QY). Specifically, 7‐hydroxycoumarin (1) had a QY of 70 %, while ortho‐chloro (2) and ortho‐bromo (3) had QYs of 61 % and 30 %, respectively. Experimental data showed that these molecules excited similarly, but the electrostatic potential and dipole moments indicated that 2 and 3 dissipated excitation energy more easily due to charge separation. The heavy‐atom effect of Cl and Br did not fully explain the QY reductions, suggesting other radiative decay processes were involved. By incorporating spin‐orbit coupling (SOC) effects, we estimated intersystem crossing (ISC) and phosphorescence rates, providing theoretical QYs of 78 % for 1, 59 % for 2, and 15 % for 3. The large deviation for 3 was attributed to its higher SOC potential derived in computational calculations. Our overall findings indicate that 3’s reduced QY results from a mix of SOC‐induced ISC and charge dissipation due to the electronegativity of Br atom, while 2’s reduction is primarily due to charge separation caused by Cl alone. Further studies are needed to validate this approach with other scaffolds.

The ability to understand relational concepts, such as ‘same’ and ‘different’, is a critical feature of human cognition. To what extent non-human animals can acquire such concepts and which factors influence their learning are still unclear. We examined the acquisition and the breadth of understanding the ‘same–different’ concept in budgerigars (Melopsittacus undulatus). Budgerigars trained to discriminate stimulus pairs in which two identical figures were either the same or different size (Experiment 1) successfully generalized the discrimination to novel stimuli belonging to various categories (size, colour, shape, geometric type and number of dots). The results of Experiment 1 thus demonstrate that budgerigars can perceive and generalize the same–different concept across dimensions after training with a limited set of stimuli differing along a single dimension. In contrast, while most budgerigars trained to discriminate two pairs of discs that were either the same or different in colour (Experiment 2) could generalize the discrimination to novel stimuli within the training category (colour), only few generalized the discrimination to another category suggesting a generalization based on perceptual similarity. The results thus show that whether budgerigars generalize a relationship by conceptual or perceptual similarity depends on the nature of the training stimuli.

The item-based directed-forgetting effect is explained as a difference in how strongly people encode remember-cued over forget-cued targets. In contrast, the production effect is typically explained as a difference in the distinctiveness of the memory of produced over unproduced targets. The procedural alignment of the two effects – directing participants to remember or forget, produce or not – coupled with their different theoretical explanations (i.e., strength vs. distinctiveness) presents an opportunity to investigate common versus differential effects of elaborative encoding. This study aims to bridge the gap between these two well-established phenomena by comparing the differences in directed forgetting and the production effect in the context of recognition. Mixed- and pure-list designs were utilized to provide an index of each of these mechanisms in both procedures. Along with a standard production effect and directed forgetting effect in the mixed-list conditions, we found evidence for strength primarily driving results in both procedures. Results are explained using a global matching model of recognition memory, MINERVA 2, by assuming varying levels of encoding strength in relation to task demands. Critically, we obtain the best fit using a strength mechanism over a combined strength and distinctiveness mechanism for our data.

Colorectal cancer (CRC) is the second leading cause of cancer‐related deaths worldwide. Despite extensive research, the mechanistic underpinnings driving CRC progression remain largely unknown. As a fundamental component of the brush border cytoskeleton, villin‐1 (VIL1) acts as a marker for intestinal cell differentiation and maturation. Through a comprehensive transcriptomics analysis of eight studies (total sample: n = 1952), we consistently observed significant upregulation of VIL1 expression in CRC tumors compared with adjacent normal tissue. In our independent cohort, this notable upregulation has been further validated at both mRNA and protein levels in colon tumor tissues, relative not only to adjacent normal tissue but also to normal controls. Our data show that VIL1 promotes proliferation and migration while inhibiting apoptosis. Conversely, knockout of VIL1 suppresses proliferation and migration while inducing apoptosis. Mechanistically, we reveal that knocking out VIL1 activates ferroptosis and inhibits the migration of CRC cells, while overexpressing VIL1 yields the opposite effects, and vice versa. Additionally, VIL1 binds to Nuclear factor NF‐kappa‐B p105 subunit (NF‐κB) and controls NF‐κB expression. In vivo, overexpressing VIL1 inhibits ferroptosis, and induces the expression of NF‐κB and lipocalin 2 (LCN2), thereby promoting CRC tumor growth. Thus, we have identified the VIL1/NF‐κB axis as a pivotal regulator of CRC progression through ferroptosis modulation, unveiling VIL1 as a promising therapeutic target for CRC treatment via ferroptosis. Our study offers novel avenues for exploring the therapeutic potential of ferroptosis in CRC management, emphasizing the high potential of VIL1 in regulating colorectal tumorigenesis.

Background Markers of inflammation and cannabis exposure are associated with an increased risk of mental disorders. In the current study, we investigated associations between cannabis use and biomarkers of inflammation. Methods Utilizing a sample of 914 participants from the Avon Longitudinal Study of Parents and Children, we investigated whether interleukin-6 (IL-6), tumor necrosis factor α (TNF α ), C-reactive protein (CRP), and soluble urokinase plasminogen activator receptor (suPAR) measured at age 24 were associated with past year daily cannabis use, less frequent cannabis use, and no past year cannabis use. We adjusted for a number of covariates including sociodemographic measures, body mass index, childhood trauma, and tobacco smoking. We found evidence of a strong association between daily or near daily cannabis use and suPAR. Results We did not find any associations between less frequent cannabis use and suPAR. We did not find evidence of an association between IL-6, TNF α or CRP, and cannabis use. Conclusions Our finding that frequent cannabis use is strongly associated with suPAR, a biomarker of systemic chronic inflammation implicated in neurodevelopmental and neurodegenerative processes is novel. These findings may provide valuable insights into biological mechanisms by which cannabis affects the brain and impacts the risk of serious mental disorders.

The paper determines and classifies the spectrum of a non-self-adjoint operator pencil generated by the time-harmonic Maxwell problem with a nonlinear dependence on the frequency for the case of two homogeneous materials joined at a planar interface. We study spatially one-dimensional and two-dimensional reductions in the whole space ${\mathbb {R}}$ and ${\mathbb {R}}^2$. The dependence on the spectral parameter, i.e. the frequency, is in the dielectric function and we make no assumptions on its form. These function values determine the spectral sets. In order to allow also for non-conservative media, the dielectric function is allowed to be complex, yielding a non-self-adjoint problem. The whole spectrum consists of eigenvalues and the essential spectrum, but the various standard types of essential spectra do not coincide in all cases. The main tool for determining the essential spectra are Weyl sequences.

Background Overcrowding is common within Emergency departments (EDs). Consequently, a Rapid Assessment and Treatment Zone (RATZ) was implemented within an ED in South Wales. RATZ is a scheme where a senior clinician assesses patients presenting to the ED as soon as possible with the aim of timely senior assessment along with redirecting unsuitable patients to other services. Methods This was a mixed methods service evaluation utilising observation, interviews, and an online survey to create a visual model of ‘work as done’ using the Functional Resonance Analysis Method (FRAM). Qualitative data was analysed using thematic analysis. Longitudinal administrative data was used to quantify the time taken to complete key FRAM functions. Data on time to triage, first clinician assessment, discharge and admission was collected using Lightfoot Software. Results RATZ has not improved time from arrival to triage. It has improved time to first clinician when compared to the mean, one year earlier. Interviews highlighted that the main benefits of RATZ include timely investigations and access to consultants. The online survey showcased that most staff thought RATZ ‘somewhat’ improved staff satisfaction and patient safety. However, when RATZ is implemented in isolation it inadvertently created safety risks due to having an unobserved waiting room. Other negatives included poor staffing and inconsistency in RATZ operation by senior clinicians. Suggested improvements explored improving patient safety via electronic patient-reported triage and better monitoring of the waiting room. Conclusions The implementation of RATZ has faced several challenges, with patient safety being an important area requiring improvement. As a result of this study the waiting room has several inputs to try to improve patient safety. Additionally electronic triage is to be implemented. More data is needed to assess the long-term implications of RATZ and its benefits within this ED.

Background The Welsh Ambulance Services University NHS Trust handles over 1,800 calls daily, with nearly a quarter of the 470,653 incidents in 2021 being non-urgent. To address this, the Trust educates the next generation about appropriate 999 use. During the Covid-19 pandemic, the Trust developed the Blue Light Hub gaming app for 7–11 years old to teach them to distinguish between emergency and non-emergency scenarios, understand services like NHS 111 Wales, and use 999 appropriately. Methods An evaluation in partnership with Cardiff University evaluated whether the app enhanced children’s knowledge, awareness, and confidence in using emergency services. Three primary schools in South Wales participated in a two-week classroom evaluation. Children used the app and completed quizzes, with parental consent obtained for data use. The evaluation focused on 393 children who completed both pre and post-test quizzes, averaging 8–9 years (47.8% male, 50.9% female). Sociodemographic information was sourced from school inspection reports. Results Post app usage, children’s knowledge of appropriate actions in non-emergency scenarios increased significantly from 19.4% to 33.7%. The proportion who could identify a question a 999-call handler would ask rose from 91.6% to 96.9%. Awareness of NHS services for that could help them if they were unwell increased from 59.8% to 74.8%, understanding of NHS roles from 58.3% to 68.7%, and knowledge of how dialling 111 could help from 25.8% to 57.5%. Conclusion Using the Blue Light Hub app for just two hours over two weeks significantly improved children’s knowledge and awareness of emergency services. They better understood when not to call an ambulance, were more likely to identify NHS services for non-emergencies and demonstrated increased awareness of the NHS 111 Wales service.These findings support ongoing app development, support children’s rights, and encourage informed decision-making and resilience within the community.

Background Busy periods, such as ‘winter pressures’ months, can create challenges for Emergency Departments (EDs) managing patient flow. This may increase risks throughout the healthcare system. ED patients may receive suboptimal care, some patients may remain in ambulances, sometimes for hours, whilst queued ambulances cannot attend other patients.In some EDs, ambulance queueing is relatively rare; in others, it is more common. As part of the STALLED study, we investigated any association between mean ambulance handover time and the number of monthly handovers. Methods We analysed publicly available ambulance collection data for English NHS Trusts between October 2023 and March 2024 from NHS England. We included all Type 1 Acute Trusts, excluding children’s hospitals, those with fewer than 100 handovers per month, and clear outliers. Results 105 Trusts were included (10 to 18 per English region). The number of handovers recorded per month varied between 716 and 8,404 with a mean of 3,090. Monthly mean handover time varied between 8 minutes, 45 seconds and 129 minutes, 6 seconds. Figure 1 shows a weak relation between mean handover time and mean monthly handovers. • Download figure • Open in new tab • Download powerpoint Abstract PP35 Figure 1 Conclusion Mean ambulance handover time is not obviously correlated with mean monthly number of handovers. Therefore, we propose the existence of deeper-rooted obstacles/challenges which warrant further exploration. It also remains to assess temporal patterns in more detail.While queueing is a problem everywhere to some extent, there is variation in how EDs manage it. Understanding these variations may lead to improvements in patient safety, health outcomes, experience, and costs.

Background Multi-agency case management across the UK addresses the needs of those who call 999 ambulance services frequently (≥5 times in a month, or ≥12 times in a three-month period). However, there is little evidence about what works and how. STRETCHED (Strategies to Manage Emergency Ambulance Telephone Callers with Sustained High needs – an Evaluation using Linked Data) evaluated case management using mixed methods. One objective was to develop and refine a logic model to describe cross-sectoral case management and its expected impacts, as a basis for evaluation. Methods Stage 1: We conducted a stakeholder event with 37 people from Wales, England and Northern Ireland including public partners (with lived experience) and relevant staff to develop an initial logic model.Stage 2: Following the main data collection and analysis phases of the study, we reviewed and refined the logic model in the light of findings. Results The logic model summarises in graphic form: • Inputs resources and activities • Mechanisms of change at organisational and individual level • Impacts on service users, ambulance services, individual staff, and wider service networks. Study findings showed that: case management initiatives varied considerably between sites; patients had a high level of need with high mortality and rates of hospital admission; the conditions of many patients are not amenable to individual behaviour change. We then revised the logic model to show: • the range of contextual/mediating factors shaping local initiatives • variation in case management activities between sites • a reduced emphasis on individual behaviour change. Conclusion In this challenging and complex area of health care, a logic model can be an essential tool to support evaluation, and refined on the basis of study insights.

Downregulated in Metastasis Protein (DRIM) was discovered in malignant epithelial cells and was thought to be mainly a nucleus protein affecting cancer cells. Recent single‐cell sequencing analysis suggests that DRIM is abundantly expressed in vascular endothelial cells. There has been no knowledge of the role of DRIM in the endothelium. In the present study, using protein fraction method and cell imaging, we identified that the DRIM protein was abundantly present in both nucleus and the cytoskeletal fractions of human vascular endothelial cells. Knockdown of DRIM in the endothelial cells significantly affected growth, migration, and angiogenic tubule formation. Proteomics analyses revealed that Src was an important direct target protein of DRIM, a finding further confirmed by protein interaction assay. Silencing DRIM activated the tyrosine 419 site phosphorylation of Src kinase in endothelial cells, thereby affecting the downstream proteins of Src including p‐FAK and p‐STAT3, and exerting biological effects. To conclude, our results provide evidence of DRIM being a nuclear and cytoskeletal‐associated protein, having a novel key role of the protein in vascular endothelial cells.

This paper introduces an extended multivariate EGARCH model that overcomes the zero‐return problem and allows for negative news and volatility spillover effects, making it an attractive tool for multivariate volatility modeling. Despite limitations, such as noninvertibility and unclear asymptotic properties of the QML estimator, our Monte Carlo simulations indicate that the standard QML estimator is consistent and asymptotically normal for larger sample sizes (i.e., ). Two empirical examples demonstrate the model's superior performance compared to multivariate GJR‐GARCH and Log‐GARCH models in volatility modeling. The first example analyzes the daily returns of three stocks from the DJ30 index, while the second example investigates volatility spillover effects among the bond, stock, crude oil, and gold markets. Overall, this extended multivariate EGARCH model offers a flexible and comprehensive framework for analyzing multivariate volatility and spillover effects in empirical finance research.

Introduction There are many recognised benefits of public involvement, including more relevant research. The COVID‐19 pandemic highlighted the existing health inequalities and disparities in access to care and treatment for under‐served groups, necessitating meaningful and sustainable approaches to engaging them in health research. However, there is limited guidance to suggest what groundwork and processes are necessary for initiating such projects. This paper outlines the practical approaches taken to initiate a community involvement project scheme and offers key recommendations from this work. Methods The National Institute for Health and Care Research (NIHR) Health Protection Research Unit established a community involvement scheme in 2021, funding four community involvement projects enabling researchers to engage with under‐served communities. Reflections were captured through regular quarterly meeting group discussions, meeting notes and email correspondence. Results The paper presents the steps taken to initiate a scheme that provided funding for a diverse range of projects working with under‐served communities. The projects demonstrated the value of allocating time to build relationships and trust, maintaining flexibility, and providing short‐term benefits such as remuneration and training to the community. Discussion This paper has highlighted the need for research organisations to allocate funding and resources within their infrastructures for building trusting relationships with community leaders and communities. Conclusion This paper has outlined the steps undertaken to engage with under‐served communities to bridge the gap between public health research and those communities. We present key recommendations to guide future initiatives aspiring to engage under‐served communities in health research. Patient or Public Contribution Public contributors have been involved in all of the four community involvement projects mentioned in this paper. Two public contributors are also co‐authors and have provided input to the writing and review of this manuscript.