756 research outputs found
Essentials of business law / Ewan MacIntyre.
No full textIncludes bibliographical references and index.xxxiii, 464 pages.
Associations between birth outcomes and development of adult cardiometabolic disease: revisiting the Walker Cohort
Full text linkCardiometabolic diseases have been ranking at the top of the leading causes of
death globally for over thirty years, and their burden is only expected to continue rising
due to sedentarism, obesogenic lifestyles, and increased life expectancy. Disorders
such as coronary heart disease (CHD), type 2 diabetes (T2D) or cancer are a global
concern and have a profound impact on national economies and individual welfare.
During the latter half of the 20th century, research investigating the impact of adverse
conditions such as famines over multiple independent European populations identified
associations between low birth weight (BW) and adult cardiovascular disease (CVD)
and glucose intolerance, suggesting the existence of a mechanism for early
determination of cardiometabolic disorders, and a possible avenue for intervention
and disease prevention.
Multiple hypotheses have been proposed to explain the biological intricacies of the
mechanism of adult disease programming, but two are the most prominent. The “fetal
origins of adult disease” hypothesis by Barker and colleagues proposed that
environmental influences during fetal development, such as maternal undernutrition,
led to permanent physiological alterations which predisposed the individual for later
development of metabolic disorders. The “fetal insulin hypothesis” by Hattersley and
colleagues proposed that the observed associations were driven through insulin and
glucose metabolism alterations, primarily determined by genetics, and causing adult
metabolic disease. Both hypotheses have been revisited and refined, and current
research focuses on elucidating the mechanism of programming through novel
methodologies and finding new associations studying additional birth outcomes and
adult traits. Through familial cohorts, maternal and paternal CVD and T2D have been
associated with low offspring BW, finding intergenerational associations even for the
extended family. In addition, genome-wide association analyses have identified 243
loci associated with BW, many of which are also involved in metabolic networks. The
biologic processes behind the association between fetal growth and later development
of cardiometabolic disease remain largely unknown, a mechanism undoubtedly
complex governed by environmental, genetic, and other hereditary influences.
The goal of this PhD thesis was to investigate the associations described using a
novel dataset, the Walker Cohort, particularly focusing on the association between
parental health and offspring birth outcomes. Being a fairly unused source of data, the
original Walker datasets are described, detailing the cleaning process performed to
prepare the data for the analyses, including the merging of additional health records
and demography data. The potential of Walker resided in the number of identifiable
offspring, mothers, and fathers available, allowing for lifetime follow-up, and the
collection of additional birth outcomes such as placental weight (PW).
The first set of analyses presented investigated the association of BW and PW with
the development of T2D, CHD, and cancer as a preliminary investigation of the
correlations reported previously. Logistic regression analyses paralleled the literature,
finding negative associations between BW and both T2D and CHD. PW to BW ratio
was positively associated with T2D, and a similar but not significant association was
found for PW, providing novel associations and suggesting a link between T2D
development and placental inefficiency.
The following set of analyses aimed to identify associations between offspring BW
and PW and the post-natal development of maternal and paternal T2D, CHD, and
cancer. Offspring from fathers who developed T2D were born lighter and had lighter
placentas, associations which also were significant through Fine-Gray survival
regression analyses. The correlation of low PW and increased paternal T2D risk
suggests a genetic effect lowering PW and increasing T2D susceptibility, similar to BW.
Mothers who developed T2D gave birth to heavier babies with heavier placentas, but
these associations were not seen through survival regression, most likely due to the
independent and BW-increasing effect of maternal hyperglycaemia.
Offspring from mothers who later developed CHD were born lighter, and presented
higher PW to BW ratios, associations which also were significant through Cox survival
regression. These analyses also identified negative associations between paternal CHD
risk and offspring BW.
No significant associations were found between maternal or paternal cancer and
offspring BW, PW, or PW to BW ratio through Fine-Gray survival regression. When
analysing individual cancer types, offspring BW was negatively associated with
maternal and paternal lung cancer risk, an association most likely confounded by
parental smoking. Paternal bowel cancer risk was positively associated with offspring
BW.
The final set of analyses presented investigated the association of maternal and
paternal polygenic risk of T2D and coronary artery disease (CAD) and their offspring’s
BW and PW, aiming to identify the genetic component of the associations presented
in the previous section. The project summary and data analysis plan were sent for
consideration by the Early Growth Genetics (EGG) consortium, to identify suitable
cohorts including genotyped mothers and fathers and offspring BW and PW
measurements that could contribute data to meta-analyse. Pooling the results from 7
birth cohorts, paternal CAD polygenic score (PGS) was negatively associated with
offspring BW, with a nearly significant negative association with offspring PW. A similar
negative association trend was found between paternal T2D PGS and offspring BW.
This is the first time the association of parental cardiometabolic disease PGS and
offspring birth outcomes has been considered, and these analyses provide evidence
for direct associations between genetically common variant-determined paternal CAD
and T2D risk and offspring BW, also explaining the association between low BW and
susceptibility to these disorders when the same variants are inherited.
In conclusion, the work performed in this PhD thesis has repurposed a fairly unused
birth cohort and replicated the associations between low BW and increased T2D and
CHD incidence described in the literature. The association of parental health with
offspring outcomes was also considered, identifying novel associations with offspring
PW, and suggesting a link between genetic cardiometabolic disease predisposition
and offspring BW. Finally, novel evidence of such a link was provided through the
paternal T2D and CAD PGS association meta-analyses. This thesis has provided
additional evidence of associations between birth outcomes and adult health, and
provides new epidemiological evidence supporting the genetic determination of fetal
growth and later cardiometabolic disease development
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Applied Social Science for Early Years
No full textApplying social science subjects such as psychology, sociology, social policy and research methods to Early Years can help to raise standards and ensure good practice. These subjects inform much of the academic curriculum within many Early Years programmes and are subjects that make an important contribution to understanding children’s behaviour, growth and development. The book identifies, analyses and assesses how social science enriches Early Years as opposed to regarding Early Years and social science as distinct. Each chapter imaginatively introduces the main learning objectives and includes formative activities, which apply social science to particular themes to aid students’ cognitive skills
We carry the light, comprising : i) Writing in lockdown: exploring the impact of the Covid-19 pandemic on writers' creativity, ii) We carry the light, a family novel set in Scotland during the pandemic
No full textThis paper examines the impact of the Covid-19 pandemic on writers’ practice during the periods that social distancing restrictions were in place. The study focuses on – but is not limited to – the first UK lockdown, which began on 23rd March 2020.
Structured interviews were conducted with five writers, with an additional person responding to the questions in writing. This group included writers of fiction and non-fiction, as well as poets. Interviewees were at various points of their careers, ranging from an undergraduate creative writing student to a prize-winning author who has been publishing for over thirty years. Through these interviews, the impact of the pandemic on writing was explored in three main areas: the impact of emotions on the writing process; the effect Covid had on conditions needed for writing; and the ability of writers to find and/or act on inspiration.
Incorporating evidence from these interviews – as well as from writing anthologies, newspaper articles, and literature relating to the pandemic – this study demonstrates that the pandemic did have a noticeable impact on writers’ creativity. Although two writers wrote more during lockdown, nearly all described the negative impact emotions had on their ability and/or motivation to write. Where the pandemic disrupted the conditions they need to write, writers wrote nothing, or significantly less than pre-pandemic; writers whose children lived with them during this time were most affected. Some noticed a negative correlation between finding/acting on inspiration and social distancing restrictions. Writers reflected on the impact of the pandemic and were able to identify positive and negative aspects that were a result of the restrictions, such as the benefits in terms of inclusion at literary events. The findings presented in the final section show the importance of learning from and recording the pandemic through writing."This work was supported by the Ewan and Christine Brown Postgraduate Studentship in the Arts and Humanities. I would, therefore, like to express my heartfelt gratitude to Ewan and Christine Brown for the financial support that allowed me to undertake this doctoral research.”--Fundin
Exploring Similarities and Differences Between Methods That Exploit Patterns of Local Genetic Correlation to Identify Shared Causal Loci Through Application to Genome-Wide Association Studies of Multiple Long Term Conditions
Full text linkGenetic correlation analysis can provide useful insight into the shared genetic basis between traits or conditions of interest. However, most genome-wide analyses only inform about the degree of global (overall) genetic similarity and do not identify the specific genomic regions that give rise to this similarity. Identification of the key genomic regions contributing to shared genetic correlation between traits could allow the genes in these regions to be prioritised for investigation of potential shared biological mechanisms. In recent years, several statistical tools (e.g. LAVA, ρ-HESS, SUPERGNOVA and LOGODetect) have been developed to investigate local (in contrast to global) genetic correlation. These tools partition the genome into multiple segments and provide estimates of the genetic correlation captured by each individual segment. We applied these tools to publicly available European ancestry genome-wide association study (GWAS) summary statistics for three pairs of commonly occurring conditions: hypertension with atrial fibrillation and flutter, hypertension with chronic kidney disease, and hypertension with type 2 diabetes. Despite each of the methods aiming to address the same question, the results were found to be inconsistent across tools, with some identified regions overlapping and others implicated only by a single tool. Computer simulations using genetic data from UK Biobank, carried out under known generating conditions, suggest that LAVA and, to a lesser extent, ρ-HESS, provide the most reliable identification of genuine shared genetic factors. A newly-developed tool, HDL-L, also performed highly competitively. Here we highlight the similarities and differences between the results obtained from these methods and discuss some potential reasons underlying these differences
Zinc transport and diabetes risk
No full textGenome-wide association studies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk. A rare variant association study has now established the direction of effect, surprisingly showing that loss-of-function mutations in SLC30A8 are protective against diabetes.</p
Disfluency in dialogue:an intentional signal from the speaker?
Full text linkDisfluency is a characteristic feature of spontaneous human speech, commonly seen as a consequence of problems with production. However, the question remains open as to why speakers are disfluent: Is it a mechanical by-product of planning difficulty, or do speakers use disfluency in dialogue to manage listeners' expectations? To address this question, we present two experiments investigating the production of disfluency in monologue and dialogue situations. Dialogue affected the linguistic choices made by participants, who aligned on referring expressions by choosing less frequent names for ambiguous images where those names had previously been mentioned. However, participants were no more disfluent in dialogue than in monologue situations, and the distribution of types of disfluency used remained constant. Our evidence rules out at least a straightforward interpretation of the view that disfluencies are an intentional signal in dialogue
Fossil fuel divestment, directors’ duties, and derivative claims: McGaughey and Davies v. USS Ltd and its directors
No full textA Climate Change Laws of the World insight In July 2023, at that time the hottest ever month in human history, the UK Court of Appeal gave judgment in McGaughey and Davies v. USS Ltd and its Directors [2023] EWCA Civ 873. The author of this note, Professor Ewan McGaughey, and his colleague, Professor Neil Davies, had undertaken the largest crowdfunded drive in the UK so far, to sue the board of directors personally to reverse (the roughly) 30% cuts to defined benefit pensions, and to require the UK’s biggest pension fund, the Universities Superannuation Scheme (USS), to divest of its fossil fuels assets. Out of court, after the Truss mini-budget, years of strikes, and shortly after the complainants got leave to the Court of Appeal, USS capitulated: the CEO announced his resignation, and USS declared it would reverse the pension cuts. Despite this victory, McGaughey and Davies went on to lose in the Court of Appeal, but by then they had already succeeded in most of their goals. The key issue where they had limited success was in fossil fuel divestment. The focus of this Climate Change Laws of the World note is why they lost on the fossil fuel claim, but also how the case sets a positive precedent for beneficiaries seeking to uphold directors’ duties, thus it may be instructive for the future wave of litigation against directors complicit in climate damage
Pengaruh Sikap Terhadap Pencapaian Akademik Pelajar Kursus Secara Sambilan Berdasarkan Model Andragogi Knowles / Mohd Effendi @ Ewan Mohd Matore
Full text linkKajian ini mengkaji pengaruh sikap pelajar terhadap pencapaian akademik pelajar Kursus Secara Sambilan (KSS) di Politeknik Kota Kinabalu, Sabah berdasarkan Model Andragogi oleh Knowles yang merangkumi enam elemen iaitu keperluan ingin tahu, penyempurnaan kendiri, peranan pengalaman, kesediaan belajar, orientasi pembelajaran, peranan motivasi dan elemen andragogi secara keseluruhan. Kajian ini melibatkan kesemua 47 orang responden di Jabatan Kejuruteraan Mekanikal sebagai sampel kajian. Data diproses dengan The Statistical Package for Social Science (SPSS) versi 14.0 menggunakan Ujian Korelasi Pearson Product Momen, Ujian Regresi Pelbagai dan min deskriptif. Nilai pekali Alpha Cronbach untuk kajian ini ialah 0.888. Dapatan kajian mendapati, min skor bagi semua aspek menunjukkan bahawa tahap sikap pelajar pada prinsip pembelajaran utama andragogi secara keseluruhannya berada di tahap yang baik. Dapatan menunjukkan korelasi yang sangat kuat bagi elemen keperluan ingin tahu dan prinsip pembelajaran keseluruhan terhadap pencapaian akademik. Bagi elemen lain seperti penyempurnaan kendiri, peranan pengalaman, orientasi pembelajaran dan peranan motivasi pula menunjukkan korelasi yang kuat iaitu nilai r antara 0.71 sehingga 0.90. Hanya elemen kesediaan belajar yang memiliki kekuatan korelasi yang sederhana. Analisis regresi pelbagai menunjukkan bahawa pembolehubah peramal iaitu Keperluan ingin tahu dan penyempurnaan kendiri adalah peramal yang mempunyai korelasi dan sumbangan yang signifikan terhadap pencapaian akademik pelajar KSS di Jabatan Kejuruteraan Mekanikal, Politeknik Kota Kinabalu
Dorothy Hodgkin Lecture 2021:Drugs, genes and diabetes
Full text linkGlycaemic response to metformin and sulphonylureas is heritable – with ~34%–37% of variation explainable by common genetic variation. The premise of this review is that by understanding how genetic variation contributes to drug response we can gain insights into the mechanisms of action of diabetes drugs. Here, I focus on two old drugs, metformin and sulphonylureas, where I would suggest we still have a lot to learn about their mechanism of action or their optimal use in clinical care. The fact that reduced function variants of the key transporter that takes metformin into the liver (OCT1) do not alter glycaemic response to metformin suggests that metformin does not need to get into the liver to work. A subsequent GWAS of metformin response identifies a robust variant that alters GLUT2 expression – which may support increasing evidence that metformin works primarily in the gut. For sulphonylureas, observation from patients with neonatal diabetes due to activating KATP channel mutations treated with sulphonylureas identified a novel role for sulphonylureas to enable β-cell incretin response. This work led to recent studies of low-dose sulphonylurea (20 mg gliclazide) in T2DM, which identified that at this dose sulphonylureas augment the incretin effect and increase β-cell glucose sensitivity, without increasing hypoglycaemia risk. This work, prompted by studies in monogenic diabetes, suggests that we have historically been using sulphonylureas at too high a dose. With increasing availability of genetic data pharmacogenomic studies in patients with diabetes should reveal mechanistic insights into old and new diabetes drugs, with the potential for optimized use and novel therapies.</p
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