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A note on indefinite matrix splitting and preconditioning
Get PDFThe solution of systems of linear(ized) equations lies at the heart of many problems in Scientific Computing. In particular for systems of large dimension, iterative methods are a primary approach. Stationary iterative methods are generally based on a matrix splitting, whereas for polyno8 mial iterative methods such as Krylov subspace iteration, the splitting matrix is the preconditioner. The smoother in a multigrid method is generally a stationary or polynomial iteration.
Here we consider real symmetric indefinite and complex Hermitian indefinite coefficient matrices and prove that no splitting matrix can lead to a contractive stationary iteration unless the inertia is exactly preserved. This has consequences for preconditioning for indefinite systems and smoothing for multigrid as we further describe
Exploring rearrangements towards oxocarbenium ions
No full textThe work described in this thesis focuses on understanding the mechanism and scope of a novel reaction, termed a Friedel-Crafts Pinacol Rearrangement (FCPR).
Chapter 1 contains a brief introduction to trialkyloxonium ions and to oxocarbenium ions, focusing on previous methods to generate and characterise oxocarbenium ions via NMR.
Chapter 2 focuses on the silver-mediated FCPR generation of ฮฑ, ฮฒ-unsaturated oxocarbenium ions and their characterisation via NMR studies.
Chapter 3 describes the development of an acid-mediated FCPR methodology towards ฮฑ, ฮฒ-unsaturated ketones. Using TFA, the FCPR process could be used to access synthetically useful building blocks. This chapter also includes investigations into the mechanism of the FCPR transformation.
Chapter 4 focuses on harnessing the reactivity of ฮฑ, ฮฒ-unsaturated oxocarbenium ions in a tandem FCPR - conjugate addition process towards complex scaffolds.
Chapter 5 details preliminary work on developing an intermolecular Lewis acid-mediated FCPR method.
Chapter 6 contains all experimental procedures and compounds data
Global Initiative on AI for Health (GI-AI4H): strategic priorities advancing governance across the United Nations
Get PDFThe Global Initiative on Artificial Intelligence for Health (GI-AI4H), established by the World Health Organization, serves to harmonize governance standards for artificial intelligence (AI). The GI-AI4H spearheads novel on-the-ground efforts, especially in low- and middle-income countries, to advance ethical, regulatory, implementation, and operational dimensions of global governance for health AI. The GI-AI4Hโs efforts across the United Nations drives safe, ethical, equitable, and sustainable health AI use for the global community
Multiple endocrine neoplasia type 1 (MEN1): recommendations and guidelines for best practice
Get PDFMultiple endocrine neoplasia type 1 (MEN1) is characterised by combined occurrence of parathyroid tumours, duodenopancreatic neuroendocrine tumours, and anterior pituitary adenomas. Some patients might also develop thymic and bronchopulmonary neuroendocrine tumours, and adrenal tumours. MEN1 is an autosomal dominant disorder caused by mutations in the tumour-suppressor geneย MEN1, which encodes a scaffold protein, menin. Without treatment, patients with MEN1 have high morbidity and premature mortality, which can be mitigated by early tumour detection and intervention. Identification of individuals at high risk for MEN1 can be facilitated by genetic testing of patients and their first-degree relatives, and undertaking periodic clinical, biochemical, and radiological screening in patients andย MEN1ย mutation carriers. However, no consensus exists regarding the optimal assessment and management of MEN1. To provide such recommendations, a multidisciplinary group was convened to undertake systematic reviews and a meta-analysis of the literature, and to use a Delphi approach for the development of consensus statements. 55 clinical recommendations were developed to guide clinicians, patients, and stakeholders about approaches for MEN1 in adults and children
Localized tension-induced giant folding in unstructured elastic sheets
Get PDFBuckling in compression is the archetype of elastic instability: when compressed along its longest dimension, a thin structure such as a playing card will buckle outof-plane accommodating the imposed compression without a significant change of length. However, recent studies have demonstrated that tension applied to sheets with microscopic structure leads to out-of-plane deformation in applications from โgroovy metasheetsโ for multistable morphing to kirigami grippers. Here, we demonstrate that this counterintuitive behaviorโa large transverse folding induced by a relatively small imposed longitudinal tensionโoccurs also in unstructured sheets of isotropic material. The key to this behavior is that a localized uniaxial tension induces giant folding; we refer to this as โlocalized tension-induced giant (TUG) foldingโ to reflect the importance of localized tension, and its mode of actuation and the similarity of the loading condition to โtuggingโ the sheet. We show that localized TUG folding occurs because of an efficient transfer of applied tensile load into compressionโa geometric consequence of a localized applied tension. We determine scaling results for the folding angle as a function of applied strain in agreement with both experiments and simulations. The generic nature of localized TUG folding suggests that it might be utilized in a broader range of materials and structures than previously realized
Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia
Get PDFINTRODUCTION: Higher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females. METHODS: We included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex. RESULTS: Females with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe. DISCUSSION: Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation. Highlights: Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases
Reply to: What evidence is required to justify the NHS Health Check programme?
Get PDFMedications that reduce blood pressure and cholesterol are among the most cost-effective healthcare interventions available, but their delivery remains suboptimal. In 2009, the National Health Service (NHS) Health Check was introduced to increase the detection and treatment of major cardiovascular risk factors in people aged 40โ74 years. In a prospective observational study using the UK Biobank, we compared health outcomes between NHS Health Check attenders and matched non-attenders. Attenders exhibited higher early rates of new hypertension, hyperlipidaemia, and chronic kidney disease, followed by significantly lower long-term multi-system disease and mortality. A recent critique of our work raises questions regarding observational design limitations, self-selection bias, and discrepancies with randomised controlled trials (RCTs). However, RCTs face ethical and feasibility challenges in large-scale public health interventions and are not immune to self-selection. Furthermore, the argument that self-selection explains our findings is inconsistent with our results. If healthier individuals were disproportionately attending NHS Health Checks, we would expect lower risk across all outcomes. However, we observed an initial increase in new diagnoses suggesting that NHS Health Checks are detecting pre-existing conditions earlier rather than merely attracting healthier individuals. Additionally, the cited RCTs predate modern antihypertensive and statin treatments, and considered heterogenous non-validated interventions. In summary, this critique relies on selective citation of outdated and inappropriate RCTs, an overstatement of selection bias, and an underappreciation of the role of observational research in shaping public health improvements. Our findings indicate that NHS Health Checks contribute to the prevention of multi-system morbidity and mortality, warranting continued investment
Subgroups of word hyperbolic groups in dimension 2 over arbitrary rings
Get PDFIn 1996, Gersten proved that finitely presented subgroups of a word hyperbolic group of integral cohomological dimension 2 are hyperbolic. We use isoperimetric functions over arbitrary rings to extend this result to any ring. In particular, we study the discrete isoperimetric function and show that its linearity is equivalent to hyperbolicity, which is also equivalent to it being subquadratic. We further use these ideas to obtain conditions for subgroups of higher rank hyperbolic groups to be again higher rank hyperbolic of the same rank. The appendix discusses the equivalence between isoperimetric functions and coning inequalities in the simplicial setting and the general setting, leading to combinatorial definitions of higher rank hyperbolicity in the setting of simplicial complexes and allowing us to give elementary definitions of higher rank hyperbolic groups
Stories written in stone: Langdale axes in early Neolithic Cumbria and beyond
No full textThe study explores the characteristics of Group VI Langdale axes and the Cumbrian landscapes where they were found. A range of research approaches has been used, including direct examination, digital analyses and experiential methods, with results integrated to build a well-rounded picture of the axes and their landscapes. These findings have been compared with the characteristics and depositions of Group VI examples found in Yorkshire and eastern England.
Firstly, the dataset of known Group VI artefacts in Cumbria has been increased by recording axes hidden away in museum storerooms and by a local publicity campaign to bring out axes in private ownership. All examples, catalogued or not, have been photographed and examined, to build a detailed dataset of visual, metrical and descriptive information. Then the shapes and sizes of Group VI artefacts have been analysed using hands-on and digital techniques, to refresh and update typological classifications. Group VI chaรฎnes opรฉratoires have been unpicked by close observation of the artefacts, following a complex and variable set of pathways from quarrying to final deposition. Lastly, landscapes of deposition have been explored experientially and by digital modelling, with distributions of Group VI artefacts contextualised within natural features and Early Neolithic archaeology.
Clear distinctions have emerged between Group VI artefacts of differing manufacturing stages or classes, in how they were made, used, deposited and perceived by Early Neolithic people. Roughouts are shown to have been tools, as well as the first stages of shaping in making polished axes. A new class of very large and finely flaked axes has been recognised, crafted like the well-known polished โprestigeโ examples but with an exquisite, flaked finish. Most other polished axes are shown to have been used as tools, although to greatly varying degrees and with distinct differences between typological classes. Post-use modifications have been identified, including a final resharpening of tool blades, deliberate breaking, taking flakes from polished axes and transforming surface colours and textures. Some axes are shown to have multiple modifications, interspersed with periods of deposition in the landscape.
Similar transformations are seen in Group VI axes, flakes and fragments left on the Yorkshire Wolds or in the ditches of causewayed enclosures in eastern England. An updated timeline has been pieced together, suggesting that Group VI artefacts may have travelled surprisingly quickly from north-west England to the eastern side of the country. This finding has implications for how these enigmatic objects may have been moved from their source area
Characterising the transcriptomic response of peripheral blood mononuclear cells to very low pH at single-cell resolution
No full textThe tumour microenvironment (TME) is characterised by being acidic with pH as low as 6, which is accompanied by hypoxia, lactic acid accumulation and increased glycolysis levels. While previous studies have focused on the association between TME acidity and tumour development, our understanding of the transcriptomic response to environmental acidosis among immune cells is incomplete. Here, we have performed the first single-cell transcriptomic profiling of cultured peripheral blood mononuclear cells (PBMCs) in acidic environments, investigating molecular mechanisms underlying immune response to extracellular acidification. I have found that low pH is associated with distinct gene expression features, describing a conserved low pH-specific signature of 34 genes that was identified with differential expression (DE) analysis and high-dimensional weighted gene co-expression network analysis (hdWGCNA). Further, I described the cell types most transcriptomically affected by low pH, peforming UMAP visualization to identify pH-sensitive cell types, including normal and low pH-specific clusters. Subsequent transcription factor (TF) analysis using the package SCENIC, identified TF regulons in response to low pH, including CREM and FOXO3. Finally I explored the effect of single nucleotide variation at the gene GPR65 that encodes a pH-sensitive G protein coupled receptor (GPCR) implicated in autoimmunity, describing genetically determined heterogeneity in acidity response. In summary, this project provides a novel transcriptomic reference to study the impact of acidity on transcriptomic response to low pH, which might be helpful for discovering novel targets associated with acidic TME