A new approach to mathematical and data education:A new approach to mathematical and data education that better prepares all young people for their futures, whether for jobs or to play active roles in wider society.

Mathematics, data and statistics are ever-present and increasingly influence our daily lives, whether as employees, citizens or consumers. They support decision-making by governments, guide industry and business, and feature prominently in research and innovation in all sectors. We must therefore ensure that all young people learn how to engage confidently with a data and digitally rich world

Cognitive and affective reassurance and patient outcomes in primary care:a systematic review

In the context of uncertainty about aetiology and prognosis, good clinical practice commonly recommends both affective (creating rapport, showing empathy) and cognitive reassurance (providing explanations and education) to increase self-management in groups with nonspecific pain conditions. The specific impact of each of these components in reference to patients' outcomes has not been studied. This review aimed to systematically evaluate the evidence from prospective cohorts in primary care that measured patient-practitioner interactions with reference to patient outcomes. We carried out a systematic literature search and appraisal of study methodology. We extracted measures of affective and cognitive reassurance in consultations and their associations with consultation exit and follow-up measures of patients' outcomes. We identified 16 studies from 16,059 abstracts. Eight studies were judged to be high in methodological quality. Pooling could not be achieved as a result of heterogeneity of samples and measures. Affective reassurance showed inconsistent findings with consultation exit outcomes. In 3 high-methodology studies, an association was found between affective reassurance and higher symptom burden and less improvement at follow-up. Cognitive reassurance was associated with higher satisfaction and enablement and reduced concerns directly after the consultations in 8 studies; with improvement in symptoms at follow-up in 7 studies; and with reduced health care utilization in 3 studies. Despite limitations, there is support for the notion that cognitive reassurance is more beneficial than affective reassurance. We present a tentative model based on these findings and propose priorities for future research. © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved

Can long-range PCR be used to amplify genetically divergent mitochondrial genomes for comparative phylogenetics?: a case study within spiders (Arthropoda: Araneae)

The development of second generation sequencing technology has resulted in the rapid production of large volumes of sequence data for relatively little cost, thereby substantially increasing the quantity of data available for phylogenetic studies. Despite these technological advances, assembling longer sequences, such as that of entire mitochondrial genomes, has not been straightforward. Existing studies have been limited to using only incomplete or nominally intra-specific datasets resulting in a bottleneck between mitogenome amplification and downstream high-throughput sequencing. Here we assess the effectiveness of a wide range of targeted long-range PCR strategies, encapsulating single and dual fragment primer design approaches to provide full mitogenomic coverage within the Araneae (Spiders). Despite extensive rounds of optimisation, full mitochondrial genome PCR amplifications were stochastic in most taxa, although 454 Roche sequencing confirmed the successful amplification of 10 mitochondrial genomes out of the 33 trialled species. The low success rates of amplification using long-Range PCR highlights the difficulties in consistently obtaining genomic amplifications using currently available DNA polymerases optimised for large genomic amplifications and suggests that there may be opportunities for the use of alternative amplification methods

Explaining Myanmar's Regime Transition: The Periphery is Central

In 2010, Myanmar (Burma) held its first elections after 22 years of direct military rule. Few compelling explanations for this regime transition have emerged. This article critiques popular accounts and potential explanations generated by theories of authoritarian ‘regime breakdown’ and ‘regime maintenance’. It returns instead to the classical literature on military intervention and withdrawal. Military regimes, when not terminated by internal factionalism or external unrest, typically liberalise once they feel they have sufficiently addressed the crises that prompted their seizure of power. This was the case in Myanmar. The military intervened for fear that political unrest and ethnic-minority separatist insurgencies would destroy Myanmar’s always-fragile territorial integrity and sovereignty. Far from suddenly liberalising in 2010, the regime sought to create a ‘disciplined democracy’ to safeguard its preferred social and political order twice before, but was thwarted by societal opposition. Its success in 2010 stemmed from a strategy of coercive state-building and economic incorporation via ‘ceasefire capitalism’, which weakened and co-opted much of the opposition. Having altered the balance of forces in its favour, the regime felt sufficiently confident to impose its preferred settlement. However, the transition neither reflected total ‘victory’ for the military nor secured a genuine or lasting peace

No severe genetic bottleneck in a rapidly range-expanding bumblebee pollinator

Genetic bottlenecks can limit the success of populations colonizing new ranges. However, successful colonizations can occur despite bottlenecks, a phenomenon known as the genetic paradox of invasion. Eusocial Hymenoptera such as bumblebees (Bombus spp.) should be particularly vulnerable to genetic bottlenecks, since homozygosity at the sex-determining locus leads to costly diploid male production (DMP). The Tree Bumblebee (Bombus hypnorum) has rapidly colonized the UK since 2001 and has been highlighted as exemplifying the genetic paradox of invasion. Using microsatellite genotyping, combined with the first genetic estimates of DMP in UK B. hypnorum, we tested two alternative genetic hypotheses ('bottleneck' and 'gene flow' hypotheses) for B. hypnorum's colonization of the UK. We found that the UK population has not undergone a recent severe genetic bottleneck and exhibits levels of genetic diversity falling between those of widespread and range-restricted Bombus species. Diploid males occurred in 15.4% of reared colonies, leading to an estimate of 21.5 alleles at the sex-determining locus. Overall, the findings show that this population is not bottlenecked, instead suggesting that it is experiencing continued gene flow from the continental European source population with only moderate loss of genetic diversity, and does not exemplify the genetic paradox of invasion

Connective tissue structure of the tree shrew optic nerve and associated ageing changes

purpose. To identify the structure and composition of the tree shrew optic nerve to determine its potential as a model for glaucoma. methods. Tree shrew optic nerves, aged 4 weeks to 5 years, were wax or cryoembedded for analysis of overall morphology and cellular (glial fibrillary acidic protein [GFAP]) and extracellular matrix (collagen types I, III, IV, V, VI; fibronectin; and elastin) immunolocalization studies. In addition, transmission and scanning electron microscopy were performed. In vivo optic disc imaging was performed by HRT2 and fundus camera photography. results. The optic nerve of the tree shrew comprised regions comparable to the human prelaminar and lamina cribrosa (LC) in the optic nerve head and the retrolaminar region, immediately posterior. The multilayered connective tissue plates of tree shrew LC stretched across the optic nerve canal at the level of the sclera and consisted of collagen types I, III, IV, V, and VI; elastin; and fibronectin. Significant age-related alterations in connective tissue components were indicated. Connective tissue was present in the central retinal vessel sheaths and was identified as longitudinally oriented collagen fibrils in the retrolaminar optic nerve. GFAP immunofluorescence indicated a high concentration of astrocytic processes in the LC. Myelination of axons was evident in the retrolaminar optic nerve. Ultrastructural studies supported the structural organization and spatial distribution of connective tissue. conclusions. In contrast to many rodent models of glaucoma, since the tree shrew optic nerve resembles that in humans, especially at the LC, the tree shrew offers an ideal opportunity to investigate glaucoma pathophysiology in a subprimate model

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome

Signatures of TOP1 transcription-associated mutagenesis in cancer and germline

The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but are preferentially protected by transcription-coupled repair1. In microorganisms, transcription has been demonstrated to be mutagenic2,3; however, the impact of transcription-associated mutagenesis remains to be established in higher eukaryotes4. Here we show that ID4—a cancer insertion–deletion (indel) mutation signature of unknown aetiology5 characterized by short (2 to 5 base pair) deletions —is due to a transcription-associated mutagenesis process. We demonstrate that defective ribonucleotide excision repair in mammals is associated with the ID4 signature, with mutations occurring at a TNT sequence motif, implicating topoisomerase 1 (TOP1) activity at sites of genome-embedded ribonucleotides as a mechanistic basis. Such TOP1-mediated deletions occur somatically in cancer, and the ID-TOP1 signature is also found in physiological settings, contributing to genic de novo indel mutations in the germline. Thus, although topoisomerases protect against genome instability by relieving topological stress6, their activity may also be an important source of mutations in the human genome.We thank S. Jinks-Robertson for suggesting the traffic light reporter approach; H. Klein for guidance on fluctuation assays; R. van Boxtel for sharing sequencing data for MLH1-KO organoids; A. Bretherick, O. B. Reina and G. Kudla for advice on HygroR re-coding; staff at the IGC core services (L. Murphy, C. Nicol, C. Warnock, E. Freyer, S. Brown and J. Joseph), C. Logan, A. Fluteau, A. Robertson and the staff at Edinburgh Genomics for technical assistance; staff at Liverpool CLL Biobank (funded by Blood Cancer UK) for samples used to generate GEL WGS data; A. Ewing, C.-A. Martin, N. Hastie and W. Bickmore for discussions. Funding for this work: UK Medical Research Council Human Genetics Unit core grants (MC_UU_00007/5 to A.P.J., MC_UU_00007/11 to M.S.T.); Edinburgh Clinical Academic Track PhD programme (Wellcome Trust 204802/Z/16/Z) to T.C.W.; 2021 AACR-Amgen Fellowship in Clinical/Translational Cancer Research (grant number 21-40-11-NADE) to F.N.; a CRUK Brain Tumour Centre of Excellence Award (C157/A27589) to M.D.N.; EKFS research grant (2019_A09), Wilhelm Sander-Stiftung (2019.046.1) to K.A., CRUK programme grant (C20807/A2864) to T.S.; La Caixa Foundation (CLLEvolution-LCF/PR/HR17/52150017, Health Research 2017 Program HR17-00221) to E.C.; E.C. is an Academia Researcher of the Institució Catalana de Recerca i Estudis Avançats of the Generalitat de Catalunya. Edinburgh Genomics is partly supported by NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.Peer Reviewed"Article signat per 22 autors/es: Martin A. M. Reijns, David A. Parry, Thomas C. Williams, Ferran Nadeu, Rebecca L. Hindshaw, Diana O. Rios Szwed, Michael D. Nicholson, Paula Carroll, Shelagh Boyle, Romina Royo, Alex J. Cornish, Hang Xiang, Kate Ridout, The Genomics England Research Consortium, Colorectal Cancer Domain UK 100,000 Genomes Project, Anna Schuh, Konrad Aden, Claire Palles, Elias Campo, Tatjana Stankovic, Martin S. Taylor & Andrew P. Jackson "Postprint (published version

Real World Performance of the 21st Century Cures Act Population Level Application Programming Interface

OBJECTIVE: To evaluate the real-world performance in delivering patient data on populations, of the SMART/HL7 Bulk FHIR Access API, required in Electronic Health Records (EHRs) under the 21st Century Cures Act Rule. MATERIALS AND METHODS: We used an open-source Bulk FHIR Testing Suite at five healthcare sites from April to September 2023, including four hospitals using EHRs certified for interoperability, and one Health Information Exchange (HIE) using a custom, standards-compliant API build. We measured export speeds, data sizes, and completeness across six types of FHIR resources. RESULTS: Among the certified platforms, Oracle Cerner led in speed, managing 5-16 million resources at over 8,000 resources/min. Three Epic sites exported a FHIR data subset, achieving 1-12 million resources at 1,555-2,500 resources/min. Notably, the HIE's custom API outperformed, generating over 141 million resources at 12,000 resources/min. DISCUSSION: The HIE's custom API showcased superior performance, endorsing the effectiveness of SMART/HL7 Bulk FHIR in enabling large-scale data exchange while underlining the need for optimization in existing EHR platforms. Agility and scalability are essential for diverse health, research, and public health use cases. CONCLUSION: To fully realize the interoperability goals of the 21st Century Cures Act, addressing the performance limitations of Bulk FHIR API is critical. It would be beneficial to include performance metrics in both certification and reporting processes