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Exploring the literature on the award gap between international and UK medical graduates in general practice training: a scoping review protocol
Get PDFBACKGROUND: International medical graduates (IMGs) currently account for 41% of the UK medical workforce. IMGs in training posts face challenges in progression including a significant 'award gap' (previously differential attainment) in postgraduate training compared to UK medical graduates. General practice (GP) is disproportionately impacted by these issues as over 50% of GP trainees are IMGs. Previous studies focusing on educational interventions to reduce the award gap have failed to improve training outcomes. AIM: To identify literature addressing the factors underlying the award gap. DESIGN & SETTING: The scoping review will follow the process outlined in the Joanna Briggs Institute (JBI) guidance. Input was sought from a specialist librarian, patient and public contributors, stakeholders with lived experience of working as an IMG and experts in the research field. Studies eligible for inclusion will be those reporting educational outcomes (concept) for IMGs (participants) undertaking UK GP training (context). METHOD: Searches will be conducted in Medline, EMBASE, SCOPUS and PsycINFO for articles reporting educational outcomes for IMGs in UK GP training. A two-step screening process will be employed to identify eligible articles. Analysis will involve basic descriptive statistics reporting the number and type of evidence sources. Reporting of the data will be in line with the PRISMA-ScR checklist and will include visual representations of findings including graphs and figures developed with stakeholders and PPI group members. CONCLUSION: By exploring the literature which reports the factors underlying the award gap in GP training we will identify areas for further research
A factor integrating transcription and repression of surface antigen genes in African trypanosomes
Get PDFAntigenic variation in Trypanosoma brucei (T. brucei) requires monoallelic expression of one variant surface glycoprotein (VSG) from one of the subtelomeric bloodstream form (BSF) expression sites (BESs). This transcription is unusually mediated by RNA polymerase I (RNA Pol I) and occurs in a specialized nuclear body, the expression site body (ESB). While factors promoting active BES transcription and silencing inactive BESs are known, how these opposing activities are integrated remains unknown. Here, we identify ESBX (Tb927.3.1660) as a BSF-specific ESB protein necessary for this coordination. We show that ESBX RNAi knockdown prevents RNA Pol I localizing to the ESB and reduces active BES transcription, while also derepressing inactive BESs with low processivity transcription. Conversely, ESBX overexpression weakly activates inactive BESs in a distinct manner from ESBX knockdown, leading to processive transcription, without disrupting the active BES or forming supernumerary ESBs. ESBX knockdown causes a similar transcriptomic defect to ESB1 and VEX2 knockdown combined, establishing ESBX as a key factor linking transcriptional activation of the active BES with inactive BES silencing through the VSG exclusion (VEX) phenomenon. This allows us to suggest models for understanding the establishment and maintenance of monoallelic expression critical for parasite immune evasion
Remodeling of the cell membrane-associated protein pool affects adhesive membrane properties in filaggrin insufficient keratinocytes and impacts distinct cellular and organellar functions
Get PDFBackground: Atopic dermatitis (AD) is a highly prevalent inflammatory skin disease, affecting up to 30% of children at some point in their life and frequently persisting into adulthood. Insufficiency in the late epidermal protein filaggrin is frequently observed in the lesional skin of patients, with direct and indirect impact on the skin barrier quality and function. We hypothesized that filaggrin reduction influences intracellular, surface, and derived extracellular membranes of keratinocytes with multiple impacts on the cell function. Results: Using filaggrin knockdown keratinocytes generated by shRNA interference (shFLG), we determined that the physical characteristics of the cellular membranes (reported by refractive index) are changed on a filaggrin insufficiency background. Using proteomics, protein binding modeling, and functional assays, we established that filaggrin insufficiency in keratinocytes results in changes in both organelles comprised of internal cellular membranes (i.e., small extracellular vesicles, sEVs) and the plasma membrane. We detected increased association of anti-adhesive proteins (tenascin-C and matrilin-2) with sEVs, resulting in a reduction of the fibronectin-1-mediated sEV uptake by dendritic cell subsets. At the same time, dysregulation of the tight junction and cell adhesion molecules at the level of the cell increased keratinocyte adhesiveness to reconstituted basement membrane substratum as well as faster gap closure in the wound healing assay. We also independently confirmed the findings on sEV uptake and wound healing in filaggrin knockout N/TERT-2G keratinocytes, which more closely resemble primary cells. Conclusions: We conclude that the alterations in different membrane compartments in filaggrin insufficiency are reflected in changes in keratinocyte functions of relevance to AD pathology, and strategies to target those could open up new therapeutic approaches
Characterisation of bacteria‐induced colitis and its modulation by probiotics in naked mole rats: a new mammalian model for acute inflammatory disease
Get PDFEnteropathogenic bacteria are a major cause of morbidity and mortality globally. While mouse models have been indispensable in advancing our understanding of infectious enteric diseases, key differences in intestinal microbiota and immunobiology between mice and humans underscore the need for alternative mammalian models that better recapitulate human disease states. The naked mole rat (NMR), the longest‐lived rodent and a model of healthy ageing, presents a unique opportunity. It possesses an exceptionally robust intestinal barrier, an abundance of goblet cells, a thicker mucin layer, and reduced gut permeability compared to mice. Additionally, the NMR gut microbiome exhibits compositional and functional features shared with human centenarians and traditional‐lifestyle populations (e.g. Hadza hunter‐gatherers), including an enrichment of health‐associated taxa and metabolic pathways. Here, we leverage this model to show that systemic Citrobacter braakii infection is associated with colonic inflammation and epithelial injury that closely mimics human haemorrhagic colitis. Infected NMRs develop mucosal erosions, ulcerations, depletion of goblet cells, expansion of proliferative compartments, and active inflammation in the lamina propria. Without intervention, systemic inflammation associated with sepsis ensues and results in high mortality. Furthermore, we demonstrate the utility of this model for therapeutic testing by showing a strong effect of a probiotic cocktail comprising lactobacilli, bifidobacteria, streptococci, and enterococci. Treatment with this cocktail promoted mucosal healing, restored intestinal homeostasis, and exerted an anti‐inflammatory effect. Taken together, we establish the NMR as a translatable model for investigating disease mechanisms in infectious colitis, including disruptions in mucosal barrier permeability, gut microbial ecology, and local and systemic immune regulation, as well as for testing functional probiotic strains as potential therapeutics. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland
TomoRay cranial: synthesis of cranial CT imaging from biplanar radiographs using a generative adversarial network
Get PDFObjectivesBesides clinical examination, cranial CT plays a critical role in diagnostics in neurosurgery. In trauma cases or perioperatively, having low-barrier access to CT-like imaging would be highly beneficial. Therefore, this feasibility study examines at an early stage if and how well synthetic cranial CT imaging can be generated from biplanar radiographs of adult neurosurgical patients using deep learning.Materials and methodsTwo 2D to 3D generative adversarial networks (GANs) were trained for the generation of synthetic cranial CTs using radiographs taken in two planes as input. Model 1 uses digitally reconstructed radiographs (DRRs) as input, while model 2 was trained using real X-rays. In total, model 1 was trained and validated using 235 images from three separate centers. Model 2 was trained and tested using 1323 images from a single center.ResultsThe performance of the model using DDRs as input reached a peak-signal-to-noise ratio (PSNR) of 15.61 and a structural similarity index measure (SSIM) of 0.782 during external validation. The second model, using real X-rays as input, attained a PSNR of 14.69 and an SSIM of 0.717 upon internal validation.ConclusionsAt the present stage, the synthetic cranial tomography scans generated as part of this study show promise but do not seamlessly correspond to ground-truth CTs. However, this proof-of-concept study is the first to derive such artificial cranial images using deep learning and can serve as a starting point for further investigation.Key PointsQuestionCranial computed tomography involves radiation, logistical challenges, and access is limited in rural areas. Generating synthetic CT images with deep learning could address these challenges.FindingsTwo deep-learning models were trained to produce CT images from radiographs. Reconstruction from DRRs is promising, but using real X-rays remains more challenging.Clinical relevanceAs a proof-of-concept, the models’ exact clinical relevance remains to be defined. The proposed approach may broaden access to tomographic neuroimaging, reduce radiation, and enhance intraoperative and maybe even diagnostic support, potentially improving outcomes in neurosurgery and neuro-critical care.Graphical Abstrac
Electrochemical Insight into the Copper Redox Chemistry and H 2 O 2 and O 2 Reducing Capability of Two AA10 Lytic Polysaccharide Monooxygenases
Get PDFLytic polysaccharide monooxygenases ([L]PMOs) are copper-containing enzymes that catalyse cleavage of the glycosidic bond, a process central to microbial biomass degradation. Here, we describe electrochemical methods used to investigate the Cu2+/1+ redox chemistry and the polysaccharide-free catalytic activity of two AA10 LPMOs: CjAA10B from Cellvibrio japonicus and CfAA10 from Cellulomonas fimi. Immobilisation of these enzymes on the surface of a graphite electrode allows for direct electrochemical measurements of Cu2+/1+ redox cycling as well as the ability of both LPMOs to reduce H2O2 vs O2. These measurements can be advantageous when compared to biological dye assays as they provide direct kinetic measurements and allow for investigation over a wider range of environmental conditions. Values of k cat and K M- are reported for H2O2 and O2 reduction by CjAA10B and CfAA10 from pH 5–7, with CfAA10 consistently outperforming CjAA10B. Both enzymes perform faster catalysis with H2O2 but when comparing the affinity-coupled specificity constant (k cat/K M), the LPMOs perform similarly with both H2O2 and O2, suggesting both substrates are viable. We also note an increase in redox signals as pH is decreased that correlates with EPR data suggesting a second species is forme
Accelerated Chronic Lymphocytic Leukaemia Complicated by Bilateral Pathological Humeral Fractures
Get PDFRickettsial seropositivity in Lao PDR smallholder livestock farms: Implications for animal and human health
Get PDFRickettsioses are emerging zoonotic diseases in Southeast Asia caused by vector-borne, intracellular Rickettsia bacteria that threaten public health, animal welfare, and food security. Despite their importance to rural livelihoods, the epidemiology of rickettsial exposure in livestock remains poorly understood. This study used abattoir-based serology to evaluate livestock as sentinels of environmental exposure to Rickettsia in Lao PDR and to identify spatial hotspots and risk factors for seropositivity. Abattoir-based serological data were generated from cattle, pigs, and water buffalo samples collected in 18 provinces between January 2022 and April 2023. The immunofluorescence assay was used to detect antibodies against three rickettsial antigens: Scrub Typhus Group (Orientia tsutsugamushi), Typhus Group (R. typhi), and Spotted Fever Group (R. conorii, R. honei). Samples with IgG titres ≥1:100 were considered positive. Of 821 samples tested, 32 were seropositive: 25 cattle (9.9%), seven pigs (2.4%), and none of the buffalo. Breed and age were significant predictors, with non-native breeds and animals under one year old more likely to be positive (p < 0.05). Spatial-temporal analysis revealed one significant cluster in cattle (p = 0.0056) in southern Laos. These results represent the first nationwide serological assessment of Rickettsia exposure in Lao livestock
Homogenised optoelectronic properties in perovskites: achieving high-efficiency solar cells with common chloride additives
Get PDFImproving the bulk quality of perovskite films is critical for achieving higher-performance photovoltaic devices. Chloride-containing additives, including lead chloride (PbCl₂) and methylammonium chloride (MACl)—standard additives widely adopted in perovskite photovoltaics—are effective for controlling crystallisation kinetics and grain morphology. However, the distinct impacts of different forms of chloride additives on nanoscale phase uniformity and luminescence homogeneity remains underexplored. Here, we provide new insights into how the choice and combination of chloride additives influence phase transitions and spatially uniform carrier dynamics within perovskite films. We demonstrate that strategically combining MACl and PbCl2 improves crystallinity and optoelectronic uniformity across dimensions spanning micrometres to millimetres. Leveraging these findings, we fabricated inverted (p-i-n) perovskite solar cells achieving certified quasi-steady-state efficiencies of 26.4% and 24.5% at device areas of 0.05 and 1 cm², respectively. Furthermore, these devices exhibit robust operational stability, retaining 88% of their initial performance after 1200 hours of continuous maximum power point tracking at elevated temperatures (65 °C) under simulated AM1.5G illumination. Our results elucidate the mechanistic differences between chloride additive forms, providing a viable strategy for advancing large-area, high-efficiency, and thermally stable perovskite photovoltaics