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Ignition time and heat release rate in upward flame spread: From bench to intermediate scale
No full textThis research assesses the effect of two common assumptions in simplified flame spread models: (i) that the pyrolysis front propagates in one dimension and (ii) that ignition time ( ) and heat release rate per unit area (HRRPUA) values measured at bench scale can be utilised in simplified flame spread models. To that aim, the study introduces a methodology to measure time to ignition, time-dependent burning area, heat release rate per unit area, and ignition temperature for concurrent upward flame spread at intermediate-scale, while examining the feasibility of using these metrics to predict flame spread scenarios. The methodology employs a narrowspectrum illumination source and thermocouple arrays to precisely track the pyrolysis front progression during flame spread experiment. Measurements were obtained for Poly(methyl methacrylate), and they can serve as reference points for researchers aiming to develop or refine testing protocols or perform sensitivity analyses for assumptions relevant to time to ignition and heat release rate models. Measurements were compared with cone calorimeter data from standard and modified testing protocols in the literature. Post-ignition removal of external heating reduced HRRPUA values, aligning them more closely with intermediate-scale experiments, while spatial heat flux distribution changed the time to ignition towards the values that were measured in intermediate-scale. The impact of the solid ignition parameters on the flame spread rate was evaluated individually using a simplified flame spread model. The proposed methodology provides a means to refine extrapolation methods for solid ignition parameters
Increased ATP production and P-glycoprotein activity underlie the marked changes in blood–brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis
No full textBACKGROUND AND PURPOSE: Patients with amyotrophic lateral sclerosis (ALS) are prescribed many medications for symptomatic relief. However, how potential alterations to the blood-brain barrier (BBB) affect the brain exposure of drugs in ALS remains under-investigated. EXPERIMENTAL APPROACH: We used high-dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1G93A transgenic mice, a mouse model of familial ALS, at a late-symptomatic age (P115-120), together with a transcardiac brain perfusion technique to assess BBB function in situ. KEY RESULTS: The BBB of the SOD1G93A transgenic (TG) mice was significantly altered, including a 1.3-fold decrease in apparent brain microvascular volume, and decreased BBB transport of 3H-diazepam (1.4-fold) and 3H-2-deoxy-D-glucose (1.2-fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal/ATP-linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1G93A mouse BMECs. The BBB transport of 3H-digoxin, a specific ATP-binding cassette efflux P-glycoprotein (P-gp) substrate, was reduced by 11.0% in SOD1G93A mice. This was confirmed by a 46.7% reduction in BMEC uptake of 3H-digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1G93A BMECs. CONCLUSION AND IMPLICATIONS: These findings open possible therapeutic avenues that could be exploited to overcome P-gp-mediated CNS drug resistance in ALS
Regulating jaywalking behaviour in adaptive traffic signal control using a novel deep reinforcement learning approach
No full textThis paper presents a deep reinforcement learning based adaptive traffic signal control framework that explicitly models jaywalking at urban intersections. We integrate a behaviourally grounded Jaywalking Decision model, which endogenises red light violations through waiting time and dynamic gap acceptance, with a Branching Double Deep Q-Network and a comprehensive hybrid action space that controls both phase selection and subphase timing. A multiobjective reward balances delay and jaywalking related safety risk, enabling the controller to respond to non-compliance as it emerges. The framework is evaluated in a multimodal microsimulation of a real intersection in Melbourne across four naturalistic demand scenarios and against both actuated control and established reinforcement learning baselines. Results show that the proposed approach reduces observed pedestrian delay and jaywalking relative to actuated control while achieving a more balanced safety and efficiency profile than single objective or alternative learning architectures. The analysis highlights context-dependent trade-offs that are relevant for policy, since the controller can adapt timing to mitigate non-compliance without assuming full pedestrian obedience. The contributions are threefold: a realistic jaywalking model linked to observable states, a high-granularity action space for multimodal control, and an integrated learning framework that jointly manages delay and safety risk. The proposed framework not only facilitates a more equitable traffic operation system but also offers the first scalable approach to managing risky behaviours in urban traffic environments
Upstream history quantification and scale-decomposed energy analysis for weak-to-strong adverse-pressure-gradient turbulent boundary layers
No full textThe present study delineates the effects of pressure gradient history and local disequilibration on the small and large-scale energy in turbulent boundary layers (TBLs) imposed with a broad range of adverse-pressure-gradients (APG). This is made possible by analyzing four published high-fidelity APG TBL databases, which span weak to strong APGs and cover dynamic conditions ranging from near-equilibrium to strong disequilibrium. These databases enable the development of a methodology to understand the effects of PG history and local disequilibration, the latter defined here as the local streamwise rate of change of the pressure force contribution in the force balance. The influence of PG history on TBL statistics is quantified by the accumulated PG parameter (β¯), proposed previously by Vinuesa et al. (2017) to study integral quantities, which is compared here between cases at matched local PG strength (β), Reynolds number (Re) and dβ/dRe at nominally similar orders of magnitude. Here, β denotes a general umbrella term used for pressure gradient parameters that is estimated using different scaling parameters in this study. While the effects of local disequilibration (dβ/dRe) are investigated by considering TBL cases at matched β, Re, and fairly matched β¯. This enables analysis of accumulated PG history and local disequilibration effects separately, where applicable, to highlight qualitative differences in statistical trends. It is found that β¯ cannot unambiguously capture history effects when dβ/dRe levels are significantly high, as it does not account for the delayed response of the mean flow and turbulence, nor the attenuation of the pressure gradient effect with distance. In two comparisons of APG TBLs under strong non-equilibrium, the values of β¯ and dβ/dRe expressed using Zagarola–Smits scaling were found to be consistent with the trends in mean velocity defect and Reynolds stresses noted previously for weak APG TBLs. While an increase in β¯ is associated with energization of both the small and large scales in the outer regions of APG TBLs, it affects only the large scales in the near-wall region. This confirms the ability of near-wall small scales to rapidly adjust to changes in PG strength. By attempting to provide a structured parametric methodology to isolate effects of PG history and local disequilibration, this study reports the influence of these effects on turbulent flow statistics across the widest APG strengths documented in the literature
FGF21 analogue PF-05231023 on alcohol consumption and neuronal activity in the nucleus accumbens
No full textFibroblast growth factor 21 (FGF21) is a liver-derived hormone known to suppress alcohol consumption in mice and non-human primates. However, the role of FGF21 in modulating environmental and behavioural factors driving alcohol consumption-such as cue-driven responses and effortful actions to obtain alcohol-and its effects on neural activity related to consumption, remain unclear. Here, we evaluated the impact of PF-05231023, a long-acting FGF21 analogue, across multiple dimensions of alcohol consumption and motivation and examined consumption-related activity in the nucleus accumbens. PF-05231023 reduced alcohol intake and preference in a dose- and sex-specific manner; diminished approach behaviours following an alcohol but not sucrose cue; and decreased lever-pressing under a progressive-ratio schedule, both alone and when combined with the Glucagon-like peptide-1 (GLP-1) agonist Exendin-4; it did not reduce lever-pressing for sucrose in alcohol-naïve mice. Additionally, PF-05231023 altered the microstructure of alcohol consumption by shortening drinking bouts and increased the recruitment of nucleus accumbens (Acb) neurons associated with bout termination as determined by micro-endoscopy of GCaMP7f. These findings demonstrate that PF-05231023 broadly suppresses alcohol-motivated behaviours without impacting natural reward and that targeting FGF21 signaling in combination with GLP-1 agonists may enhance therapeutic efficacy. Mechanistically, the observed reductions in alcohol consumption following PF-05231023 may involve diminished alcohol palatability and modulation of neuronal activity from distinct subsets of Acb neurons.10.1038/s41386-025-02133-
DMAIC 4.0 - innovating the Lean Six Sigma methodology with Industry 4.0 technologies
No full textThis study employs Design Science Research to integrate I4.0 technologies into the DMAIC (Define, Measure, Analyse, Improve, Control) framework, resulting in the development and evaluation of a novel DMAIC 4.0 framework and a practical roadmap. The research journey unfolds in three phases: Problem Identification, Solution Design, and Evaluation. Initially, expert interviews revealed significant limitations in current LSS practices and highlighted opportunities to leverage modern technologies. The second phase focused on designing an innovative framework. The final phase involved rigorous evaluation through action research and a Delphi study, refining the framework into a practical implementation roadmap. The DMAIC 4.0 framework includes 42 DMAIC tasks enhanced by I4.0 technologies. As the first empirically validated DMAIC 4.0 framework in academic literature, it stands out for its novelty, comprehensiveness, and detailed approach. The validation process through action research and a Delphi study demonstrated its effectiveness and applicability across various industries. The integration of DMAIC and I4.0 provides a rich set of tools, paving the way for future research to expand and validate the framework or transform it into an audit tool for organizations to assess their degree of innovation
A First-In-Human Phase 1 Study of a Novel BCMA×CD3 Bispecific T Cell Engager EMB-06 in Relapsed or Refractory Multiple Myeloma
No full textTo the Editor,
Relapsed or refractory multiple myeloma (MM) remains a challenging disease to treat despite the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) which have substantially improved patient survival [1]. BCMA (B cell maturation antigen)—with high expression in plasmablasts (PBs) and mature plasma cells (PCs)—has emerged as a key therapeutic target in MM. In heavily pretreated patients with RRMM, BCMA-targeted CAR-T and bispecific TCEs therapies [2, 3] have demonstrated objective response rates (ORR) ranging from 61% to 97%. However, these treatments are associated with a high overall incidence of cytokine release syndrome (CRS) at 66.7%–94.8%, and immune effector cell-associated neurotoxicity syndrome (ICANS) at rates of 3%–18%
Science mapping the evolution of middle leadership research, 2002–2023
No full textThis systematic review aimed to examine the evolution of middle leadership research in a 21-year period, starting from 2002 to 2023, by employing bibliometric methods to examine the metadata of 181 documents. It summarised the key features of the middle leadership knowledge base by analysing its descriptive trends, distribution of knowledge production, key scholars, journals, and documents, and uncovered its underlying intellectual structure. The review offers insights into the development of the literature on middle leadership – a relatively new concept. The findings from this review would help scholars understand the nuances of middle leadership as well as provide insights to researchers on the current and future development of middle leadership research in schools
Communication about sexuality for adolescents with cerebral palsy and complex communication needs: A scoping review with framework synthesis
No full textAIM: To understand communication about sexuality for adolescents with cerebral palsy (CP) and complex communication needs. METHOD: We systematically searched primary research on adolescents aged 10 to 24 years with CP and/or complex communication needs. We coded the primary evidence against themes derived from a theoretical framework analysis. Consumer research partners were involved throughout. RESULTS: Most of the 16 identified papers described adolescents with CP who could speak. While these adolescents engaged in some discussions with peers about sexuality, they also reported an absence of desired communication with peers and health professionals. The evidence about adolescents with complex communication needs centred on communication with teachers and parents or carers, and on vulnerability to abuse and socially appropriate masturbatory behaviours, rather than positive aspects of sexuality. INTERPRETATION: Given the complexity of their disabilities, adolescents with CP and complex communication needs probably require support to understand and express themselves as sexual and gendered beings. Our findings reveal a sexuality evidence base that fails to address the needs of adolescents with CP during this critical life phase, emphasizing the need for more inclusive, communication-aware sexuality research
Stepped-care models for cancer symptom management: a systematic review of efficacy and cost-effectiveness.
No full textBACKGROUND: The delivery of clinical care services using personalized health approaches is an integral component of cancer care. This review synthesized evidence on the efficacy and cost-effectiveness of stepped-care interventions delivered to manage therapy-related symptoms in cancer populations compared with care as usual (CAU). METHODS: Systematic searches were conducted in MEDLINE, PsycINFO, Embase, Web of Science, Cochrane Library, National Health Service Economic Evaluation Database, and EconLit to identify studies published from January 2010 to November 2024. Peer-reviewed studies that reported outcomes of stepped interventions and CAU were included, and quality appraisal was performed using the Cochrane Risk of Bias 2 and the Risk of Bias in Non-Randomised Studies-of Interventions tools. RESULTS: The review summarizes a total of 22 studies, involving 4588 unique adult cancer survivors. Fourteen studies identified statistically significant improvements in symptom severity and clinical outcomes comparable to those of CAU. The stepped-care group showed reduced mean severity scores for distress, insomnia, and fatigue, as well as improved stress reactions and emotional reactivity, and fewer palliative care visits. The low uptake of the intervention and inadequate assessment of comorbid symptoms have hindered the ability to draw conclusive recommendations across several studies. Four studies evaulated the cost-effectiveness of stepped-care interventions compared to CAU. Two of these studies reported significant cost savings of approximately €19 991 for each point improvement on the distress scale and lower incremental costs of approximately €3950 associated with stepped-care interventions. CONCLUSIONS: This review highlights the potential clinical and economic benefits of implementing stepped-care interventions to reduce the severity of cancer-related symptoms. Further research is warranted to assess the long-term effectiveness, cost-effectiveness, and implementation feasibility of stepped-care interventions in real-world clinical care settings serving cancer populations with diverse needs