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improving Pain mAnagement for childreN and young people attendeD by Ambulance (PANDA): protocol for a realist review [version 3; peer review: 3 approved]
Get PDFBackgroundEach year in England, 450,000 children and young people (CYP) under 18 years of age are transported by ambulance to emergency departments. Approximately 20% of these suffer acute pain caused by illness or injury. Pain is a highly complex sensory and emotional experience. The intersection between acute pain, unwell CYP and the unpredictable pre-hospital environment is convoluted. Studies have shown that prehospital pain management in CYP is poor, with 61% of those suffering acute pain not achieving effective pain relief (abolition or reduction of pain score by 2 or more out of 10) when attended by ambulance. Consequences of poor acute pain management include altered pain perception, post-traumatic stress disorder and the development of chronic pain. This realist review will aim to understand how ambulance clinicians can provide improved prehospital acute pain management for CYP.MethodsA realist review will be conducted in accordance with the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) guidance. A five-stage approach will be adopted; 1) Developing an Initial Programme Theory (IPT): develop an IPT with key stakeholder input and evidence from informal searching; 2) Searching and screening: conduct a thorough search of relevant research databases and other literature sources and perform screening in duplicate; 3) Relevance and rigour assessment: assess documents for relevance and rigour in duplicate; 4) Extracting and organising data: code relevant data into conceptual “buckets” using qualitative data analysis software; and 5) Synthesis and Programme Theory (PT) refinement: utilise a realist logic of analysis to generate context-mechanism-outcome configurations (CMOCs) within and across conceptual “buckets”, test and refine the IPT into a realist PT.ConclusionThe realist PT will enhance our understanding of what works best to improve acute prehospital pain management in CYP, which will then be tested and refined within a realist evaluation
improving Pain mAnagement for childreN and young people attendeD by Ambulance (PANDA): protocol for a realist review
Get PDFBackgroundEach year in England, 450,000 children and young people (CYP) under 18 years of age are transported by ambulance to emergency departments. Approximately 20% of these suffer acute pain caused by illness or injury. Pain is a highly complex sensory and emotional experience. The intersection between acute pain, unwell CYP and the unpredictable pre-hospital environment is convoluted. Studies have shown that prehospital pain management in CYP is poor, with 61% of those suffering acute pain not achieving effective pain relief (abolition or reduction of pain score by 2 or more out of 10) when attended by ambulance. Consequences of poor acute pain management include altered pain perception, post-traumatic stress disorder and the development of chronic pain. This realist review will aim to understand how ambulance clinicians can provide improved prehospital acute pain management for CYP.MethodsA realist review will be conducted in accordance with the Realist And Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) guidance. A five-stage approach will be adopted; 1) Developing an Initial Programme Theory (IPT): develop an IPT with key stakeholder input and evidence from informal searching; 2) Searching and screening: conduct a thorough search of relevant research databases and other literature sources and perform screening in duplicate; 3) Relevance and rigour assessment: assess documents for relevance and rigour in duplicate; 4) Extracting and organising data: code relevant data into conceptual “buckets” using qualitative data analysis software; and 5) Synthesis and Programme Theory (PT) refinement: utilise a realist logic of analysis to generate context-mechanism-outcome configurations (CMOCs) within and across conceptual “buckets”, test and refine the IPT into a realist PT.ConclusionThe realist PT will enhance our understanding of what works best to improve acute prehospital pain management in CYP, which will then be tested and refined within a realist evaluation
Therapeutic Advances in Targeting the Amyloid-β Pathway for Alzheimer’s Disease
Get PDFAlzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD
Mapping use of high dose or long-term oral glucocorticoids and steroid-sparing strategies in adults with chronic conditions: a rapid scoping review of reviews
Get PDFPURPOSE: Oral glucocorticoids (OGCs) have a broad range of uses and are effective in treating numerous conditions. However, it is commonly acknowledged that OGCs at high doses or over long periods have a burden of toxicity. Despite the use of steroid-sparing therapies, OGCs continue to be prescribed to treat a wide range of immune and inflammatory conditions. We aimed to address the following research questions: (1) what are the contemporary indications for high dose and/or long-term OGCs? (2) what patterns of use are described in the literature for high dose and/or long-term OGCs? (3) which evidence do we have for chronic conditions related to well-established steroid-sparing strategies and tapering regimes for OGCs? (4) what adverse effects have been reported with high dose and/or long-term OGCs? METHODS: A rapid scoping review was conducted using the Joanna Briggs Institute guidelines. The Protocol has been published on the Open Science Framework. A systematic search of MEDLINE (Sep 2014 to Sep 2024) identified systematic reviews and scoping reviews involving adults (≥ 18 years) treated with high doses and/or long-term OGCs for chronic inflammatory conditions. Studies involving pregnant women were excluded. RESULTS: In total, 137 reviews were included. OGCs were indicated in 47 different conditions in dermatology, respiratory, gastrointestinal, hematology, immunology, rheumatology, and other miscellaneous categories. Across all specialties, OGCs were used either at high doses (at least 20 mg prednisone equivalent per day) or for long durations (for at least 3 months). For types of adverse effects reported in the included reviews, 20 were labeled as endocrine, 13 as immunological, 21 as musculoskeletal, 30 as gastrointestinal, and 16 as cardiovascular. Sixty-four reviews looked for/reported unspecified adverse events. One hundred and fifteen reviews had evidence of steroid-sparing/tapering regimes, indicating the wide use of these strategies to mitigate the harmful effects of OGCs. CONCLUSION: OGCs are used for a broad range of inflammatory conditions across multiple specialties. There is evidence related to a broad range of potential adverse effects across multiple body systems regardless of the indication of use. Further research is needed using a combined cross-condition approach to their measurement and reduction, alongside gaining more insight into the impact of OGCs on patients' quality of life
Phase-Retrieved High-Throughput Multi-Channel Simultaneous Surface Plasmon Resonance Detection
Get PDFSurface plasmon resonance (SPR) enables real-time, label-free detection of biomolecular interactions, but traditional intensity-based methods suffer from limited sensitivity due to noise and environmental fluctuations. Phase-sensitive SPR methods provide significant sensitivity and signal-to-noise ratio improvements by measuring phase variations in reflected light, however, current systems rely on relatively complex interferometry, making them prone to misalignment and environmental drift. Neural networks have been explored for phase retrieval and have shown some potential. However, they often require large datasets or lack generalization and precision. This work presents a framework for robust, alignment-tolerant phase retrieved high-sensitivity high-throughput SPR sensing. By integrating an objective lens-based coupling system with a rotation-based ePIE (r-ePIE) phase retrieval on the back focal planes, the method reduces beam distortion and significantly enhances spatial resolution over prism-based setups. System aberration is accurately reconstructed and calibrated with the algorithm. Experiments demonstrate accurate recovery of complex phase patterns, including high-order optical vortices, and thus enabling high-precision multi-point SPR sensing with minimal crosstalk. Reconstructed resonance shifts and sample thicknesses agree well with measured data. The state-of-the-art throughput spacing of 14.23 × 9.50 í µí½m has been experimentally demonstrated, showing strong promise for sensitive, high-throughput SPR sensing in biochemical and biomedical applications
Genome-centric investigation of bile acid-metabolizing microbiota in chickens and their association with Eimeria tenella and Salmonella typhimurium infections
Get PDFIntroduction: Bile acid (BA) metabolism by gut microbiota plays a crucial role in host health by influencing nutrient absorption, immune responses, and resistance to pathogens. Elucidating how enteric infections disrupt the BA-microbiota axis is crucial for advancing microbiota-based therapeutics, precision nutrition, and post-antibiotic disease control strategies. Methods: We reconstructed 9,990 high-quality microbial genomes from the gut microbiota of chicken and performed genome-resolved metabolic profiling. Comparative analyses were conducted across host species, including humans and pigs. Also, 135 intestinal samples collected from different regions of the chicken gut were analyzed. Additional samples from chickens infected with Salmonella typhimurium and Eimeria tenella were included to assess infection-associated alterations. Results: Our results reveal that the phylum Bacillota_A is predominant, with key BA-transforming enzymes, including bile salt hydrolase (BSH) and 7α-hydroxysteroid dehydrogenase (7α-HSDH), present in a substantial proportion of the genomes. Chickens harbored a higher proportion of BSH genes compared to humans and pigs, with Ligilactobacillus and Alistipes identified as major contributors. Region-specific analysis showed that BA-metabolizing microbes are unevenly distributed along the intestinal tract, with the highest diversity observed in the cecum and colon. Experimental pathogen challenges revealed that S. typhimurium infection altered BSH gene abundance and overall microbial community structure, whereas E. tenella infection increased taxonomic richness but reduced community evenness. Discussion: Together, these findings advance our understanding of microbial contributions to BA dynamics in poultry and offer insights into the role of BA metabolism in gut health and pathogen resistance
Developing pangenomes for large and complex plant genomes and their representation formats
Get PDFBackgroundThe development of pangenomes has revolutionized genomic studies by capturing the complete genetic diversity within a species. Pangenome assembly integrates data from multiple individuals to construct a comprehensive genomic landscape, revealing both core and accessory genomic elements. This approach enables the identification of novel genes, structural variations, and gene presence-absence variations, providing insights into species evolution, adaptation, and trait variation. Representing pangenomes requires innovative visualization formats that effectively convey the complex genomic structures and variations.AimThis review delves into contemporary methodologies and recent advancements in constructing pangenomes, particularly in plant genomes. It examines the structure of pangenome representation, including format comparison, conversion, visualization techniques, and their implications for enhancing crop improvement strategies.Key scientific concepts of reviewEarlier comparative studies have illuminated novel gene sequences, copy number variations, and presence-absence variations across diverse crop species. The concept of a pan-genome, which captures multiple genetic variations from a broad spectrum of genotypes, offers a holistic perspective of a species’ genetic makeup. However, constructing a pan-genome for plants with larger genomes poses challenges, including managing vast genome sequence data and comprehending the genetic variations within the germplasm. To address these challenges, researchers have explored cost-effective alternatives to encapsulate species diversity in a single assembly known as a pangenome. This involves reducing the volume of genome sequences while focusing on genetic variations. With the growing prominence of the pan-genome concept in plant genomics, several software tools have emerged to facilitate pangenome construction.This review sheds light on developing and utilizing software tools tailored for constructing pan-genomes in plants. It also discusses representation formats suitable for downstream analyses, offering valuable insights into the genetic landscape and evolutionary dynamics of plant species. In summary, this review underscores the significance of pan-genome construction and representation formats in resolving the genetic architecture of plants, particularly those with complex genomes. It provides a comprehensive overview of recent advancements, aiding in exploring and understanding plant genetic diversity
Digital twin-based self-learning decision-making framework for industrial robots in manufacturing
Get PDFIndustry 4.0 demands intelligent and autonomous manufacturing systems that can adapt to dynamic environments. A key enabler of such systems is self-learning, which supports effective decision-making under uncertainty. However, traditional approaches typically depend on large volumes of physical production data, limiting their utility during early deployment phases. To address this, we propose a digital twin-based self-learning decision-making framework that enables virtual training of decision models before physical deployment. The framework consists of four modular components: a digital twin for simulating the production environment, a learning module for generating and evaluating decisions, a real controller for executing validated actions, and the physical production system. A time-delayed deployment mechanism is introduced to ensure the safe application of learned behaviors. We also define the concept of self-learning in manufacturing and classify relevant learning paradigms—model-driven, data-driven, and hybrid. The framework is validated through two industrial use cases involving FANUC robots. In the first use case, Bayesian optimization is applied to a pick-and-place task, reducing energy consumption by 74.79%. In the second, a Genetic Algorithm is used for welding optimization, achieving a 36.06% reduction in energy usage. These results confirm the framework’s generalizability and effectiveness in enabling autonomous learning during the commissioning phase
Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings
Get PDFDuring drug development, candidate compounds are extensively tested for proarrhythmic risk and in particular risk of Torsade de Pointes (TdP), as indicated by prolongation of the QT interval. Drugs that inhibit the rapid delayed rectifier K+ current (IKr) can prolong the action potential duration (APD) and thereby the QT interval, and so are routinely rejected. However, simultaneous inhibition of the L-type Ca2+ current (ICaL) can mitigate the effect of Ikr inhibition, so that including both effects can improve test specificity. Mathematical models of the action potential (AP) can be used to predict the APD prolongation resulting from a given level of IKr and ICaL inhibition, but for use in safety-testing their predictive capabilities should first be carefully verified. We present the first systematic comparison between experimental drug-induced APD and predictions by AP models. New experimental data were obtained ex vivo for APD response to IKr and/or ICaL inhibition by applying 9 compounds at different concentrations to adult human ventricular trabeculae at physiological temperature. Compounds with similar effects on IKr and ICaL exhibited less APD prolongation compared to selective IKr inhibitors. We then integrated in vitro IC50 patch-clamp data for IKr and ICaL inhibition by the tested compounds into simulations with AP models. Models were assessed against the ex vivo data on their ability to recapitulate drug-induced APD changes observed experimentally. None of the tested AP models reproduced the APD changes observed experimentally across all combinations and degrees of IKr and/or ICaL inhibition: they matched the data either for selective IKr inhibitors or for compounds with comparable effects on IKr and ICaL. This work introduces a new benchmarking framework to assess the predictivity of current and future AP models for APD response to IKr and/or ICaL inhibition. This is an essential primary step towards an in silico framework that integrates in vitro data for translational clinical cardiac safety
Habitus transformation of students from low socioeconomic backgrounds at medical school: the five core narratives
Get PDFBackground: Widening Participation initiatives aim to attract students from non-traditional backgrounds to study medicine; students from diverse backgrounds will be better equipped to cater to the needs of a diverse population. But medical students are moulded by our expectations of how a doctor should think, feel, and act, and this may fundamentally alter their behaviours, attitudes, and tendencies (habitus). Methods: Semi-structured interviews were conducted with 16 students and 5 family members who came from low socioeconomic backgrounds. Bourdieu’s habitus was used as a theoretical framework. Interviews were analysed using narrative analysis. Results: Five core narratives were identified. ‘Outsiders’ have poor social integration prior to and at medical school. Those with ‘Enduring Identity’ narratives have strong social networks outside of medical school. ‘Pre-socialised’ students have experiences which prepare them for the middle-class culture of medical school, and ‘Encouraged Upward Mobility’ describes those who are strongly guided by their parents’ desire for middle-class status. Finally, those with ‘Personal Growth’ narrative describe a transformational experience, adopting new behaviours, values and tastes. Conclusions: The extent of habitus transformation in students from low socioeconomic backgrounds varied. Financial constraints, not drinking alcohol, and being on the gateway course all discouraged habitus transformation. Further research could explore whether this affects their interactions and abilities to empathise with patients from similar backgrounds
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