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Unlocking the potential of electronic blood transfusion systems: Implementation insights from NHS hospitals in England.
Electronic blood transfusion (EBT) systems have the potential to significantly enhance patient safety and healthcare efficiency. Although national guidelines recommend their implementation, widespread adoption requires addressing gaps in evidence regarding cost-effectiveness and clinical impact. This study assessed EBT implementation in English hospitals via a 2023 survey focusing on three key components: (i) electronic blood fridges (EBFs) for traceability and stock management, (ii) electronic blood ordering systems with clinical decision support (CDSS) and (iii) bedside patient identification (PID) systems. The survey also examined EBT integration with electronic health records (EHRs) and inter-hospital record linkages. Among 206 surveyed hospitals, 114 responded, resulting in a 55.6% response rate. Of the responding sites, 76 (67.3%) had implemented at least one EBT component. EBFs were the most adopted technology (65 sites; 57.5%), followed by bedside identification systems (37 sites; 32.7%). Advanced systems like CDSS were implemented in only 16 sites (14.2%). Barriers to adoption included financial constraints, limited senior management engagement and technical challenges. Our results show variability in EBT system adoption across NHS England hospitals. There is a pressing need for cost-effectiveness analyses to support investment decisions, while evidence of clinical effectiveness is needed to justify advanced EBT systems and overcome organisational barriers.
Learning to utilize internal protein 3D nanoenvironment descriptors in predicting CRISPR-Cas9 off-target activity.
Despite advances in determining the factors influencing cleavage activity of a CRISPR-Cas9 single guide RNA (sgRNA) at an (off-)target DNA sequence, a comprehensive assessment of pertinent physico-chemical/structural descriptors is missing. In particular, studies have not yet directly exploited the information-rich internal protein 3D nanoenvironment of the sgRNA-(off-)target strand DNA pair, which we obtain by harvesting 634 980 residue-level features for CRISPR-Cas9 complexes. As a proof-of-concept study, we simulated the internal protein 3D nanoenvironment for all experimentally available single-base protospacer-adjacent motif-distal mutations for a given sgRNA-target strand pair. By determining the most relevant residue-level features for CRISPR-Cas9 off-target cleavage activity, we developed STING_CRISPR, a machine learning model delivering accurate predictive performance of off-target cleavage activity for the type of single-base mutations considered in this study. By interpreting STING_CRISPR, we identified four important Cas9 residue spatial hotspots and associated structural/physico-chemical descriptor classes influencing CRISPR-Cas9 (off-)target cleavage activity for the sgRNA-target strand pairs covered in this study.
Platforms for studying cell-cell recognition by immune cells.
Immune cells interact directly with other cells and make decisions by integrating information from many different receptor-ligand interactions at these cell-cell interfaces. Since they encounter a huge variety of normal and abnormal cells, they experience many different combinations and concentrations of ligands. Understanding immune responses therefore requires platforms that enable ligands to be easily manipulated. We review and compare the available platforms, focusing on T-cell recognition. Although genetically modified antigen-presenting cells (APCs) offer the most physiological system, manipulating their ligands is difficult and slow. In contrast, solid surfaces or supported lipid bilayers allow easy manipulation of ligands but lack the biophysical properties of cells, such as softness, a glycocalyx, and/or ligand mobility. A recently developed CombiCell system enables easy manipulation of ligands while conserving key biophysical properties. By comparing the advantages and limitations of each platform, we provide a framework to choose the most suitable system to study signal integration in both basic and translational contexts.
RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.
Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.
Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.
Neurodegenerative Disease and Association Football (NDAF): Systematic Review and Meta-Analysis.
There is increasing concern that head injuries in Association Football (or soccer) may lead to adverse health outcomes. The aim of this study was to determine whether head impacts or injuries are associated with an increased risk of neurodegenerative disease. We performed a systematic search using PubMed, Embase, and Ovid (up to April 2025). Studies included investigated neurodegenerative diseases in football in comparison to control athletic and general populations. Data were extracted according to PRISMA guidelines. Studies with an odds ratio (OR) were included in the meta-analysis. A total of ten studies were included in this review, of which nine were suitable for meta-analysis from eight cohorts. The risk for developing any neurodegeneration was 1.69 OR (95%CI 1.11 to 2.59; p = 0.01); for Dementia, it was 2.16 OR (95%CI 1.60 to 2.93; p < 0.01; for Motor Neurone Disease (MND), it was 1.39 OR (95%CI 0.67 to 2.53; p = 0.21); for Parkinson's Disease (PD), it was 1.14 OR (95%CI 0.55 to 2.89; p = 0.79). Heterogeneity was reduced following the removal of two studies and the revised risk scores for any neurodegenerative disease; Dementia increased, with that for MND reaching significance, 1.81 OR (95%CI 1.22 to 2.30; p = 0.01), but there remained no association with PD. Evidence suggests that professional football significantly increases the odds of neurodegenerative disease.
Teaching humanities in UK medical schools: towards community-building and coherence
Medical humanities teaching in UK medical schools has lacked cohesion, having developed opportunistically in different locations. Cohesion is necessary to develop an identifiable community of practice, but within that community there can be multiple readings of what ‘medical humanities’ are and how they may develop. This article details discussions held by medical humanities scholars teaching in UK medical schools at a workshop in January 2025 at the University of Oxford covering five key areas: the role of humanities scholars in medical schools, patients as partners in medical education, core curriculum teaching, intercalated teaching, and assessment. Our discussion highlights opportunities and challenges facing humanities teaching in UK medical schools today and calls for the creation of a community of medical humanities scholars working in UK medical education embracing diversity of opinion and practices. The article is specifically written as a synopsis of a brainstorming symposium.
User requirements for quantitative radiological reports in multiple sclerosis
Objectives: Quantitative radiological reports (QReports) can enhance clinical management of multiple sclerosis (MS) by including quantitative data from MRI scans. However, the lack of consensus on the specific information to include, on and clinicians’ preferences, hinders the adoption of these imaging analysis tools. This study aims to facilitate the clinical implementation of QReports by determining clinicians’ requirements regarding their use in MS management. Materials and methods: A four-phase Delphi panel approach was employed, involving neurologists and (neuro)radiologists across Europe. Initial interviews with experts helped develop a questionnaire addressing various QReport aspects. This questionnaire underwent refinement based on feedback and was distributed through the MAGNIMS network. A second questionnaire, incorporating additional questions, was circulated following a plenary discussion at the MAGNIMS workshop in Milan in November 2023. Responses from both questionnaire iterations were collected and analyzed, with adjustments made based on participant feedback. Results: The study achieved a 49.6% response rate, involving 78 respondents. Key preferences and barriers to QReport adoption were identified, highlighting the importance of integration into clinical workflows, cost-effectiveness, educational support for interpretation, and validation standards. Strong consensus emerged on including detailed lesion information and specific brain and spinal cord volume measurements. Concerns regarding report generation time, data protection, and reliability were also raised. Conclusion: While QReports show potential for improving MS management, incorporation of the key metrics and addressing the identified barriers related to cost, validation, integration, and clinician education is crucial for practical implementation. These recommendations for developers to refine QReports could enhance their utility and adoption in clinical practice. Key Points: Question A lack of consensus on essential features for quantitative magnetic resonance imaging reports limits their integration into multiple sclerosis management. Findings This study identified key preferences, including detailed lesion information, specific brain and spinal cord measurements, and rigorous validation for effective quantitative reports. Clinical relevance This study identified essential features and barriers for implementing quantitative radiological reports in multiple sclerosis management, aiming to enhance clinical workflows, improve disease monitoring, and ultimately provide better, data-driven care for patients through tailored imaging solutions.
Reemergence of Cosmopolitan Genotype Dengue Virus Serotype 2, Southern Vietnam.
We performed phylogenetic analysis on dengue virus serotype 2 Cosmopolitan genotype in Ho Chi Minh City, Vietnam. We document virus emergence, probable routes of introduction, and timeline of events. Our findings highlight the need for continuous, systematic genomic surveillance to manage outbreaks and forecast future epidemics.
Characterisation of a pathogenic non-migratory fibroblast population in systemic sclerosis skin.
Fibroblasts are central to pathogenesis of systemic sclerosis (SSc). However, studies of conventional explant fibroblast cultures incompletely reflect disease biology and treatment response. We isolated a second non-migratory "resident" population of fibroblasts from skin biopsies after outgrowth of explant "migratory" cells. These non-motile resident fibroblasts were compared with migratory cells from the same biopsy, using functional studies, bulk and scRNAseq, and localised in situ by multichannel immunofluorescence. Migratory and resident fibroblast populations in SSc showed distinct pro-fibrotic characteristics and gene expression for pathogenic pathways differing by stage and autoantibody subgroup. TGFβ signalling was highly active in migratory fibroblasts in early stage dcSSc. Conversely, resident fibroblasts had less upregulated TGFβ signalling, especially in late dcSSc. Increased chemokine expression was a hallmark of resident fibroblasts at all stages. In vitro studies confirmed differential response to TGFβ1 and CCL2 between migratory and resident cells. We suggest that migratory fibroblasts are especially important in early skin disease whereas non-migratory fibroblasts may have a regulatory role and contribute more to fibrosis in later stage disease. Thus, we have identified a pathogenic fibroblast population in SSc, not isolated by conventional explant culture, that could play an important role in fibrosis and be targeted therapeutically.
Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.
BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.
Why does understanding the biology of fibroblasts in immunity really matter?
Fibroblasts are known for their ability to make and modify the extracellular matrix. However, there is more to them than meets the eye. It is now clear that they help define tissue microenvironments and support immune responses in organs. As technology advances, we have started to uncover the secrets of fibroblasts. In this Essay, we present fibroblasts as not only the builders and renovators of tissue environments but also the rheostat cells for immune circuits. Although they perform location-specific functions, they do not have badges of fixed identity. Instead, they display a spectrum of functional states and can swing between these states depending on the needs of the organ. As fibroblasts participate in a range of activities both in health and disease, finding the key factors that alter their development and functional states will be an important goal to restore homeostasis in maladapted tissues.
In vivo human keyhole limpet haemocyanin challenge in early phase drug development: A systematic review
Experimental exposure of healthy volunteers to the T-cell dependent neoantigen Keyhole 30 Limpet Haemocyanin (KLH) permits the evaluation of immunomodulatory investigational 31 medicinal product (IMP) pharmacology prior to the recruitment of patient populations. 32 Despite widespread use, no standardized approach to the design and conduct of such 33 studies has been agreed. The objective of this systematic review was to review the 34 published literature where KLH was employed as a challenge agent, describing 35 methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. 36 We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies 37 employing KLH challenge in humans between 1 January 1994 and 1 April 2022. We 38 described key study features, including KLH formulation, dose, use of adjuvants, route of 39 administration, co-administered IMPs and endpoints. Of 2421 titles and abstracts screened, 40 46 met the inclusion criteria including 14 (31%) early phase trials of IMP, of which 10 (71%) 41 targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of 42 the humoral response to KLH, suggesting limited specificity of this endpoint. Two early 43 phase IMP studies (14%) described the response to intradermal re-challenge (delayed type 44 hypersensitivity). Challenge regimens for IMP assessment were often incompletely 45 described, and exhibited marked heterogeneity, including primary KLH dose (25-fold 46 variation: 100-2500mcg), KLH formulation, and co-administration with adjuvants. 47 Methodological heterogeneity and failure to exploit the access to tissue-level mechanism 48 relevant endpoints afforded by KLH challenge has impaired the translational utility of this 49 paradigm to-date. Future standardisation, characterisation and methodological 50 development is required to permit tailored, appropriately powered, mechanism-dependent 51 study design to optimise drug development decisions
In vivo human keyhole limpet haemocyanin challenge in early phase drug development: A systematic review
Experimental exposure of healthy volunteers to the T-cell dependent neoantigen Keyhole Limpet Haemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to review the published literature where KLH was employed as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies employing KLH challenge in humans between 1 January 1994 and 1 April 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co-administered IMPs and endpoints. Of 2421 titles and abstracts screened, 46 met the inclusion criteria including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this endpoint. Two early phase IMP studies (14%) described the response to intradermal re-challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25-fold variation: 100-2500mcg), KLH formulation, and co-administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue-level mechanism-relevant endpoints afforded by KLH challenge has impaired the translational utility of this paradigm to-date. Future standardisation, characterisation and methodological development is required to permit tailored, appropriately powered, mechanism-dependent study design to optimise drug development decisions.
Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming.
OBJECTIVES: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. METHODS: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. RESULTS: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). CONCLUSIONS: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.
Analysis of cellular kinetic models suggest that physiologically based model parameters may be inherently, practically unidentifiable.
Physiologically-based pharmacokinetic and cellular kinetic models are used extensively to predict concentration profiles of drugs or adoptively transferred cells in patients and laboratory animals. Models are fit to data by the numerical optimisation of appropriate parameter values. When quantities such as the area under the curve are all that is desired, only a close qualitative fit to data is required. When the biological interpretation of the model that produced the fit is important, an assessment of uncertainties is often also warranted. Often, a goal of fitting PBPK models to data is to estimate parameter values, which can then be used to assess characteristics of the fit system or applied to inform new modelling efforts and extrapolation, to inform a prediction under new conditions. However, the parameters that yield a particular model output may not necessarily be unique, in which case the parameters are said to be unidentifiable. We show that the parameters in three published physiologically-based pharmacokinetic models are practically (deterministically) unidentifiable and that it is challenging to assess the associated parameter uncertainty with simple curve fitting techniques. This result could affect many physiologically-based pharmacokinetic models, and we advocate more widespread use of thorough techniques and analyses to address these issues, such as established Markov Chain Monte Carlo and Bayesian methodologies. Greater handling and reporting of uncertainty and identifiability of fit parameters would directly and positively impact interpretation and translation for physiologically-based model applications, enhancing their capacity to inform new model development efforts and extrapolation in support of future clinical decision-making.
Simulating CXCR5 Dynamics in Complex Tissue Microenvironments.
To effectively navigate complex tissue microenvironments, immune cells sense molecular concentration gradients using G-protein coupled receptors. However, due to the complexity of receptor activity, and the multimodal nature of chemokine gradients in vivo, chemokine receptor activity in situ is poorly understood. To address this issue, we apply a modelling and simulation approach that permits analysis of the spatiotemporal dynamics of CXCR5 expression within an in silico B-follicle with single-cell resolution. Using this approach, we show that that in silico B-cell scanning is robust to changes in receptor numbers and changes in individual kinetic rates of receptor activity, but sensitive to global perturbations where multiple parameters are altered simultaneously. Through multi-objective optimization analysis we find that the rapid modulation of CXCR5 activity through receptor binding, desensitization and recycling is required for optimal antigen scanning rates. From these analyses we predict that chemokine receptor signaling dynamics regulate migration in complex tissue microenvironments to a greater extent than the total numbers of receptors on the cell surface.