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Aspiration to admission: widening access to medical education: AMEE Guide No. 181
Get PDFOpening doors is only the beginning. This AMEE guide focuses on the first step in creating a more equitable medical profession: ensuring that under-represented and disadvantaged students have access to medical education. In an increasingly diverse society, addressing the structural inequalities in admissions is essential for fostering a healthcare workforce that reflects the populations it serves. This guide explores evidence-based strategies to widen access to medical education, emphasising the need for outreach, tailored support, and innovative admission processes. We delve into the initiatives that have worked, highlighting successful models in a global context and offering practical recommendations for educators who are committed to making real, lasting change. Key suggestions emphasise the need for cultural shifts within medical institutions, the importance of clear metrics for evaluating widening access programs, and the value of ongoing mentorship and support for students from disadvantaged backgrounds. By integrating these strategies, medical educators can foster a more equitable and diverse healthcare workforce, ensuring that access is not just granted but sustained and meaningful
The diachrony of Welsh subject pronouns
Get PDFIn many languages, independent pronouns become reduced to inflectional affixes which are ultimately lost, resulting in the creation of new independent pronouns. The loss of null subjects therefore often goes hand in hand with a loss of agreement morphology on the verb. Inflectional morphology has remained virtually unchanged from the Middle Welsh period up to the present day, but whereas null subjects were frequently found in the earliest period, in Present-day spoken Welsh overt pronouns are generally preferred. In this article we present a pilot study of the history of subject pronouns in Welsh based on six annotated texts from the Parsed Historical Corpus of the Welsh Language (PARSHCWL) from three different time periods (fourteenth, sixteenth and eighteenth centuries), as well as in translated and non-translated texts. We show that null subjects are favoured in all periods and use a mixed-effects logistic regression model to test which factors have an effect on whether the subject pronoun is overt or null and if this distribution changes over time
Investigating 5’ untranslated regions and translational regulation across human genes
Get PDFUntranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but the reasons remain poorly understood in humans. Here, I investigated whether this variation, specifically in 5’UTRs, correlates with gene dosage sensitivity and whether it differs between different categories of disease genes.
I investigated 5’UTR length, the number of alternative transcription start sites (TSS), the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5’UTRs to form secondary structures. I explored how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. I found that LOEUF correlates with 5’UTR length and complexity. Genes that are most intolerant to LoF have longer 5’UTRs (P<1x10-15), greater TSS diversity (P<1x10-15), and more upstream regulatory elements compared to LoF tolerant genes. These differences are evident in disease gene sets but not in recessive developmental disorder genes where LoF of a single allele is tolerated.
Finally, I focused on a single category of 5’UTR regulatory elements, start-stops, which have only recently been described. I analysed variants within them using ClinVar and the Genomics England 100,000 Genomes Project (GEL). I identified candidate variants for future functional studies and highlight the complexity of interpreting UTR variants.
These results underscore the importance of 5’UTRs in post-transcriptional regulation through tightly regulating mRNA and protein levels, particularly in genes susceptible to changes in dosage. Including UTR analysis in diagnostic pipelines should enhance diagnoses, though challenges in interpreting UTR variants remain. This work enhances our understanding of 5’UTR features and their role in disease
Targeting protein–ligand neosurfaces with a generalizable deep learning tool
Get PDFMolecular recognition events between proteins drive biological processes in living systems1. However, higher levels of mechanistic regulation have emerged, in which protein–protein interactions are conditioned to small molecules2, 3, 4–5. Despite recent advances, computational tools for the design of new chemically induced protein interactions have remained a challenging task for the field6, 7. Here we present a computational strategy for the design of proteins that target neosurfaces, that is, surfaces arising from protein–ligand complexes. To develop this strategy, we leveraged a geometric deep learning approach based on learned molecular surface representations8, 9 and experimentally validated binders against three drug-bound protein complexes: Bcl2–venetoclax, DB3–progesterone and PDF1–actinonin. All binders demonstrated high affinities and accurate specificities, as assessed by mutational and structural characterization. Remarkably, surface fingerprints previously trained only on proteins could be applied to neosurfaces induced by interactions with small molecules, providing a powerful demonstration of generalizability that is uncommon in other deep learning approaches. We anticipate that such designed chemically induced protein interactions will have the potential to expand the sensing repertoire and the assembly of new synthetic pathways in engineered cells for innovative drug-controlled cell-based therapies10
Genetic architecture in Greenland is shaped by demography, structure and selection
Get PDFGreenlandic Inuit and other indigenous populations are underrepresented in genetic research1, 2, leading to inequity in healthcare opportunities. To address this, we performed analyses of sequenced or imputed genomes of 5,996 Greenlanders with extensive phenotypes. We quantified their historical population bottleneck and how it has shaped their genetic architecture to have fewer, but more common, variable sites. Consequently, we find twice as many high-impact genome-wide associations to metabolic traits in Greenland compared with Europe. We infer that the high-impact variants arose after the population split from Native Americans and thus are Arctic-specific, and show that some of them are common due to not only genetic drift but also selection. We also find that European-derived polygenic scores for metabolic traits are only half as accurate in Greenlanders as in Europeans, and that adding Arctic-specific variants improves the overall accuracy to the same level as in Europeans. Similarly, lack of representation in public genetic databases makes genetic clinical screening harder in Greenlandic Inuit, but inclusion of Greenlandic data remedies this by reducing the number of non-causal candidate variants by sixfold. Finally, we identify pronounced genetic fine structure that explains differences in prevalence of monogenic diseases in Greenland and, together with recent changes in mobility, leads to a predicted future reduction in risk for certain recessive diseases. These results illustrate how including data from Greenlanders can greatly reduce inequity in genomic-based healthcare
Which special measure? video and leaflet': Transcripts of ISVA Focus Groups and Supplementary Material
No full textTranscription data of focus groups held with ISVAs from Rape Crisis member centres, SARCs or ISVA training organisations. ISVAs watched the draft version of the video during the focus group and gave feedback on its contents, style and accessibility. The focus groups were held online and were recorded and transcribed with participants consent. Participants also agreed for the data, suitably anonymized, to be stored in ORA
Elite persistence in Africa: historical perspectives, state of knowledge and the path forward
Get PDFIn the 1960s and 1970s elite studies formed an integral part of the research agenda on newly independent African states. Commentators sought to predict the likely political and economic paths of independent African states based on the social backgrounds and political orientations of existing elites. Historians looked back in time, and debated the social continuities across the pre-colonial, colonial and postcolonial eras. But elite studied dropped off the research agenda in the 1980s and 1990s. This paper revisits earlier literature about elite continuity and change in Africa. It provides a broad sweep of the arguments about the origins of elites and sources of elite power across different epochs, and analyses the characteristics of the African ‘top 1%’ today using census data. It concludes by charting a research agenda that would enhance knowledge of the social origins and mobility paths of Africa’s contemporary elites
Understanding how chromatin folding and enzyme competition affect rugged epigenetic landscapes
Get PDFEpigenetics plays a key role in cellular differentiation and maintaining cell identity, enabling cells to regulate their genetic activity without altering the DNA sequence. Epigenetic regulation occurs within the context of hierarchically folded chromatin, yet the interplay between the dynamics of epigenetic modifications and chromatin architecture remains poorly understood. In addition, it remains unclear what mechanisms drive the formation of rugged epigenetic patterns, characterised by alternating genomic regions enriched in activating and repressive marks. In this study, we focus on post-translational modifications of histone H3 tails, particularly H3K27me3, H3K4me3, and H3K27ac. We introduce a mesoscopic stochastic model that incorporates chromatin architecture and competition of histone-modifying enzymes into the dynamics of epigenetic modifications in small genomic loci comprising several nucleosomes. Our approach enables us to investigate the mechanisms by which epigenetic patterns form on larger scales of chromatin organisation, such as loops and domains. Through bifurcation analysis and stochastic simulations, we demonstrate that the model can reproduce uniform chromatin states (open, closed, and bivalent) and generate previously unexplored rugged profiles. Our results suggest that enzyme competition and chromatin conformations with high-frequency interactions between distant genomic loci can drive the emergence of rugged epigenetic landscapes. Additionally, we hypothesise that bivalent chromatin can act as an intermediate state, facilitating transitions between uniform and rugged landscapes. This work offers a powerful mathematical framework for understanding the dynamic interactions between chromatin architecture and epigenetic regulation, providing new insights into the formation of complex epigenetic patterns
Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis
Get PDFThe impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10−185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10−19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis
Physician associates and anaesthetic associates in UK: rapid systematic review of recent UK based research
Get PDFObjective: To summarise research on the efficacy and safety of UK physician associates and anaesthetic associates in the context of an ongoing policy review. Design: Rapid systematic review. Search strategy: Keyword and author search of three databases; citation tracking; search of previous systematic reviews. Eligible studies: Empirical research (any design) on physician associates/anaesthetic associates in UK healthcare published between 2015 and January 2025. Main outcomes: Any measure of clinical efficacy or safety. Methods: Eligible papers were grouped into categories and appraised using Critical Appraisal Skills Programme checklists. Two reviewers independently extracted data on study designs, samples, methods, and findings. Each paper was scored for trustworthiness, generalisability, and relevance; differences were resolved by discussion. Studies meeting a minimum inclusion standard were described and critiqued. Results: Of approximately 5000 titles, 52 papers were eligible (48 on physician associates, four on anaesthetic associates), of which 29 met the inclusion standard. The total number of physician associates studied was very small, especially in primary care; no studies reported direct assessment of anaesthetic associates. Only one study, of four physician associates, involved any assessment by a doctor of their clinical competence by direct observation. No studies examined safety incidents. Some studies suggested that physician associates could support the work of ward based teams and work in emergency departments when appropriately deployed and supervised in low risk clinical settings, but the number of individuals and settings studied was small, and those findings should be considered preliminary. Physician associates seemed to struggle in primary care, however, because the role was more autonomous, the case mix was more diverse, decisions were more uncertain, institutional support was more limited, and supervision arrangements were more challenging. Staff expressed concern about physician associates’ and anaesthetic associates’ competence to manage undifferentiated, clinically complex, or high dependency patients; order ionising radiation; or prescribe. Physician associates reported a range of experiences and desired a clear role within the team. No evidence was found that physician associates add value in primary care or that anaesthetic associates add value in anaesthetics; some evidence suggested that they do not. Conclusions: The UK literature on physician associates and anaesthetic associates is sparse and of variable quality, and some is outdated. In this context, the absence of evidence of safety incidents should not be misinterpreted as evidence that deployment of physician associates and anaesthetic associates is safe. Findings of apparent non-inferiority in non-randomised studies may obscure important unmeasured differences in quality of care. New research is urgently needed to explore staff concerns, examine safety incidents, and inform a national scope of practice for these relatively new and contested staff roles. The findings from this UK based study should be interpreted in the context of the wider international evidence base. Study registration: INPLASY202520039