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Lifelike or Like Life: Votive Terracotta Figurines and the Societal Ideals of Ancient Greek Women from the Archaic to Classical Era
No full textThis doctoral thesis examines how votive terracotta figurines, dedicated at select religious settings in Ancient Greece, reflect societal ideals relating to women. These ideals are explored via eight sanctuaries in Attica and the Corinthia. The studies focus primarily on figurines dating from the Archaic to the Classical period and consider popular handmade and mould-made coroplast styles.
My research explores the relevance of some popular characteristics of figurine designs depicting women. This evaluation considers aspects of the figurines’ depicted body language, fashions worn, and the significance of incorporated popular symbols and attributes. It explores what the figurines can reveal regarding the real-life aspirations of women and the development of societal expectations concerning their lives.
A local case study approach supports a consideration of why these ideals and expectations were relevant at the sanctuaries where they were dedicated, and how sanctuaries could be involved in reinforcing these ideals within their respective communities. In addition, it allows for comparison between regions, leading to a deeper understanding of the importance of local nuance versus more universal dynamics.
One argument underpinning this thesis is that popular, mass-produced figurine designs were often thematic images representing the ideal woman that reflect the societal expectations of the period and location they relate to. Devotees used figurines for various ritual purposes, which we can more fully understand by examining the entire ritual context within which they were dedicated. The iconography of many of the mass-produced figurines was sufficiently indeterminate to allow them to represent goddesses or mortal women. Often, the popularity of figurine designs rested in their connection to widely spread symbolic themes important to the community rather than a connection to a specific character. Furthermore, characteristics evident in popular designs often connect to common ideals and stereotypes regarding the behaviour and predisposition of women during these periods
Mapping the Molecular Landscape of Early Diabetic Retinopathy: A Multi-layered Analysis of the Human Retina
No full textBackground: The early stages of diabetic retinopathy are not well understood, and studies in humans are limited by the scarcity of post-mortem retinal tissue, variable post-mortem delays, and differences among donors. Under these real-world conditions, many spatial and sequencing methods that work well in model systems either fail or behave unpredictably. This thesis defines the technical limits of multilayer molecular profiling in the human diabetic retina and develops a decision framework to guide future studies. /
Methods: Three approaches were tested on FFPE and OCT-embedded human retina: high-plex immunohistochemistry (IBEX), RNA-focused spatial methods (Light-Seq and HCR-RNA-FISH), and genome-wide DNA methylation profiling using the Infinium MethylationEPIC v2.0 array. I judged feasibility by whether signals were reproducible across donors, whether there were clear quality-control readouts (RIN/DV200 for RNA, DIN for DNA), and whether the differential methylation patterns were biologically interpretable. /
Results: In archival retina, IBEX and spatial RNA methods were usable but not reliable as first-line discovery tools. IBEX provided informative maps of blood vessels and glial cells, but it was limited by antibody specificity, antigen retrieval conditions, autofluorescence, and donor-to-donor variability. Several spatial transcriptomics methods were tested and found to be unsuitable due to poor mRNA quality impacting on reverse transcription and library preparation; only short-amplicon imaging on promptly fixed tissue was consistently robust. In contrast, genome-wide DNA methylation profiling with the MethylationEPIC v2 array was technically robust and reproduced validated signals, including changes in the ten-eleven translocation (TET) pathway, which plays a crucial role in DNA demethylation and epigenetic regulation.
epigenome‑wide significance. /
Conclusion: IBEX, spatial RNA, and DNA methylation provide complementary but not equivalent information in the human post-mortem retina. Under typical tissue constraints, DNA methylation emerged as the most robust discovery readout. In a small pilot study this approach detected differences between diabetic and control samples in stress response and demethylation pathways and indicated heterogeneous epigenetic age acceleration in diabetic retina, but did not reach epigenome wide significance. On the other hand, IBEX and spatial RNA were better suited to localise and testing selected pathways in high-quality samples. Overall, this thesis established a framework that links tissue quality to method choice and defines realistic performance limits for each assay type in human post-mortem retina. This is already influencing local practice. RNA/DNA quality control, in situ screening, and the MethylationEPIC v2 analysis pipeline are now used in our institute to triage donor tissue and design new studies. More broadly, this thesis offers a platform for planning studies using scarce and variable human retinal tissue
Testing the Source of Ingress Traffic at Internet Service Providers
No full textInternet Service Providers (ISPs) may notice traffic entering their network from certain sources at unexpected locations but cannot tell whether it reflects a real routing problem or is spoofed noise, making it difficult to act. Existing monitoring systems do not account for spoofed traffic, which limits their reliability and often leads to false positives. This thesis addresses two high-level challenges: (i) how to build a mechanism that reliably detects non-spoofed traffic while keeping the impact on genuine flows minimal and handling the oddities of real-world conditions and (ii) how to scale the application of this mechanism to ISP workloads, where potentially thousands of prefixes need to be tested in parallel under strict resource constraints.
To address the first challenge, we introduce Penny, an active probabilistic traffic checker that identifies non-spoofed traffic entering ISP networks. The idea is simple: when traffic arrives at an unexpected point, Penny deliberately drops a few TCP packets. Non-spoofed TCP flows will retransmit, while spoofed ones will not. However, building a robust test from this simple concept presents subtle challenges. We demonstrate how to address conflicting goals: minimising performance degradation for genuine flows, accounting for external conditions such as path changes and remote loss, and ensuring robustness against spoofers attempting to evade the test. The second challenge is addressed with Quid, a system that relies on Penny and incorporates a resource-aware scheduler customised to the challenges and specificities of Penny tests. This scheduler supports both on-demand traffic testing and routine background monitoring, enabling applications such as detecting routing misconfigurations, identifying unprofitable paths, improving security, and informing infrastructure planning
Fetal exome sequencing for prenatal diagnosis in the NHS: identifying challenges, benefits and barriers to ensure appropriate implementation
No full textBACKGROUND:
Since October 2020 rapid prenatal exome sequencing (pES) has been offered through seven National Health Service (NHS) genomic laboratory hubs (GLHs) in England for pregnancies complicated by fetal anomalies with a likely monogenic aetiology. pES can increase prenatal diagnoses of monogenic disorders, providing valuable information to inform parental counselling, decision-making and clinical management. This is the first time pES has been offered in a national public healthcare system and research is needed to
determine how best to deliver it to maximise benefit to patients, while optimising NHS resources.
AIMS:
This research studied how the pES service was delivered in the North Thames GLH in its first year, aiming to identify successes, challenges, and areas requiring further research.
METHODS:
This project used mixed methods to study the delivery of pES through service evaluation (including analysis of pregnancy outcomes), a healthcare professional survey to map care pathways, and qualitative interviews with parents and professionals to explore stakeholder views and experiences. This was combined with examination of laboratory pipelines, including the development of a fetal anomalies gene panel.
KEY FINDINGS:
In the first year of the pES service 240 cases were referred to the North Thames GLH, 121 were sequenced and a diagnosis was made in 48/121 (39.7%) with a median turnaround time of 14 days. Results influenced clinical management for 59% of
sequenced cases. Analysis using a gene panel minimised but did not eliminate incidental findings. In interviews, parents and health professionals welcomed the opportunity to use pES to gain information about the cause of fetal anomalies and highlighted the need for close multidisciplinary working between fetal medicine and genetics, ongoing professional education, and support for parents throughout the testing process. These data will inform further guideline development to ensure acceptable, equitable, effective and efficient delivery of pES in the NHS
Pensions and economic status among the 1958 birth cohort prior to reaching State Pension age (SPa)
No full textIn the UK, extensive legislation introduced in the last 20 years has transformed the retirement and pension landscape. Key changes include reforms to the State Pension (SP) eligibility age and structure, the introduction of automatic enrolment into a workplace pension scheme, and greater flexibility in how and when individuals can access their private pensions. While these reforms aimed to improve pension provision, their consequences for different groups of society and people at different stages of the lifecourse remain underexplored. With further reforms on the horizon, including the forthcoming Pension Schemes Bill 2025 and the launch of a new Pensions Commission, this report has also highlighted key areas requiring attention.
The National Child Development Study, which follows the lives of 17,415 babies born in 1958, offers a unique opportunity to explore how life experiences relate to retirement outcomes as this cohort approaches State Pension age (SPa). The most recent survey, conducted at age 62 to 65, included detailed information on pension provision. Ten earlier waves of interviews conducted at key stages of the lifecourse collected extensive information on various life domains, including detailed work histories. Drawing on this rich, nationally representative cohort study, this report offers a comprehensive account of how individuals affected by recent legislative reforms are navigating the transition from work to retirement, establishing a benchmark for comparisons with future generations.
Across 6 substantive chapters, this report examines how retirement outcomes vary based on study members’ current characteristics and their experiences over the lifecourse, illuminating several disadvantaged groups. These include: women, who were more likely to be undersavers and whose average pension savings were much lower than men’s; those who spent the majority of their working lives between age 20 and 55 as self-employed, many of whom expected to still be in paid employment at age 68 or later; and those who spent time out of work due to poor health and caring responsibilities, many of whom did not reach the minimum Retirement Living Standards (RLS) and were expected to rely on the SP for most of their retirement income
Identifying the Molecular Mechanisms of Mitochondria-Lysosome Membrane Contact Sites and Their Effect on Mitophagy
No full textNiemann-Pick disease Type C (NPC) is a rare but devastating neurodegenerative disorder caused by loss-of-function mutations in the lysosomal lipid transport proteins NPC1 or NPC2. At the cellular level, NPC is characterized by the accumulation of cholesterol and sphingolipids within lysosomes, with secondary mitochondrial dysfunction, including reduced ATP production and elevated reactive oxygen species (ROS), although the underlying mechanisms remain poorly understood.
Membrane contact sites, where organelles are tethered in close apposition, play a key role in maintaining cellular homeostasis by facilitating exchange of lipids and signalling molecules. Increased mitochondria–lysosome contact sites (MLCs), dependent on the endo/lysosomal lipid transport protein STARD3, have been reported in NPC1-inhibited cells. This project aimed to improve understanding of MLC regulation to determine their role in mitochondrial dysfunction in NPC.
MLCs were increased in NPC1-deficient ARPE19 cells but striking disassembly was induced by release of lysosomal calcium, in a GSK3β-dependent manner. A STARD3-targeted APEX2 proximity labelling screen identified hexokinase-domain containing protein 1 (HKDC1) which was upregulated in NPC1-knockout cells and was required for the calcium-mediated untethering, revealing an additional layer of regulation.
Disruption of these contacts through calcium signalling led to increased mitophagosomes observed via transmission electron microscopy (TEM), suggesting upregulation of mitophagy. Further investigation revealed a relationship between MLCs and mitophagy, which was restricted by MLC expansion, suggesting that excessive tethering at MLCs impairs mitochondrial quality control by limiting mitophagy, potentially revealing a novel mechanism contributing to mitochondrial dysfunction in NPC.
By elucidating the molecular mechanisms of MLCs, we seek to reverse the extended contacts, increase mitophagy and reduce mitochondrial dysfunction as a potential therapeutic strategy for NPC, as well as more broadly for diseases where lipid accumulation is a key phenotype
The Yield and Clinical Impact of Genetic Testing in Older Patients with Dilated Cardiomyopathy
No full textAIMS: Genetic testing in patients with dilated cardiomyopathy (DCM) is increasingly used to guide clinical management, but international guidance does not endorse genetic testing for older patients. This study sought to explore the yield and impact of genetic testing in older patients with DCM. METHODS AND RESULTS: Consecutive and unrelated genotyped patients with DCM were retrospectively recruited in a single referral centre. The yield of genetic testing was examined by age group. Genotype positive patients above and below 55 years of age were compared for a primary composite endpoint of end-stage heart failure (ESHF) or malignant ventricular arrhythmia (MVA).Six hundred and eighty-six patients (62.1% male, median [IQR] age 50 [37, 59] years) were recruited; 166 (24.2%) were genotype-positive. Sixty of 308 (19.5%) patients over 55 years of age were genotype-positive with 18 (30%) harbouring variants in genes associated with a higher risk of MVA.During a median follow-up of 50 months, twenty-one of 148 (14.2%) genotype-positive patients without baseline MVA had the primary composite endpoint with no significant difference between age groups (11/94 (11.7%) of those aged <55 years and 10/54 (18.5%) ≥55 years, log rank p value = 0.4). CONCLUSIONS: One fifth of older patients with DCM carry disease causing genetic variants, including those associated with a higher risk of MVA. Adverse event rates in older genotype-positive patients with DCM are comparable to their younger counterparts. These data highlight the value of extending genetic testing to older patients with DCM
Nintedanib in systemic sclerosis-associated interstitial lung disease: real-world cohort study on tolerability and discontinuation
No full textOBJECTIVES:
Nintedanib slows progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD), but its tolerability in this patient group is a potential concern.
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METHODS:
This multicentre study evaluated tolerability and treatment-related interruptions in SSc-ILD patients receiving nintedanib. Factors associated with interruption were analysed by logistic regression, with multivariable adjustment for potential confounders. Fisher’s exact test was used when complete separation precluded logistic regression. Cox regression assessed time to first interruption. Weight changes before and after treatment were compared using the Wilcoxon signed-rank test.
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RESULTS:
Among 63 patients (mean age 56.5±13.8 years, 22% male), 76% received nintedanib 150 mg twice daily, the remainder 100 mg twice daily; 86% were on mycophenolate. Over a median 22.2-month follow-up (95% CI 18.1-26.2), 51% experienced nintedanib interruptions. Patient-reported reasons for treatment interruption included diarrhoea (33.3%), nausea/vomiting (20.6%), weight loss (9.5%) and reflux (1.6%). Older age (p< 0.03) and BMI <18.5 kg/m2 (p=0.024) were independently associated with interruption. BMI <18.5 kg/m2 was also independently linked to shorter time to interruption. Permanent discontinuation occurred in 20.6%, with no significant predictors identified. Weight loss in the 12±6 months after treatment initiation (mean 2.05 kg) was significantly greater than in the preceding 12±6 months (1.09 kg) (p=0.001).
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CONCLUSIONS:
Adverse effects frequently led to treatment interruptions in SSc-ILD patients. Older age and lower BMI were predictors of interruption, while no clear predictors of permanent discontinuation were identified. Most patients resumed treatment, highlighting the need for close monitoring and supportive care to manage side effects and maintain treatment continuity
Characteristics of mental health service users attending Recovery Colleges in England: baseline findings from Recovery Colleges Characterisation and Testing (RECOLLECT)
No full textAims and method: Recovery Colleges are adult education initiatives supporting personal recovery for individuals with mental health difficulties. We characterised a national (England) inception cohort of mental health service users, students from the Recovery Colleges Characterisation and Testing 2 programme, and compared those attending different Recovery College types on sociodemographic, clinical, service use and student-reported outcomes over the 4 months prior to enrolment. Mixed-effects regression models were used to assess differences. / /
Results: The cohort comprised 498 students from 36 Recovery Colleges across England; 77.7% attended strengths-oriented Recovery Colleges. Mean age was 39 years (s.d. 12); most were female (72.1%) and White (81.5%). Common diagnoses were mood (31.3%) and anxiety disorders (29.7%). No significant differences were found between students attending strengths- versus community-oriented Recovery Colleges. / /
Clinical implications: Strengths- and community-oriented Recovery Colleges have similar service user student populations. Certain groups that may be underrepresented in Recovery Colleges and Recovery College research include older adults, men, those with developmental disorders and ethnic minority populations