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Gene–Environment Interaction Affects Risk of Atopic Eczema: Population and In Vitro Studies
Get PDFBackground: Multiple environmental and genetic factors play a role in the pathogenesis of atopic eczema (AE). We aimed to investigate gene–environment interactions (G × E) to improve understanding of the pathophysiology. Methods: We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modeling to independently assess findings. Results: The discovery analysis (including 25,339 individuals) showed suggestive evidence for interaction (p < 0.05) between seven environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total. In the replication analysis (254,532 individuals) dog exposure × rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (OR interaction = 0.91 [0.83–0.99] p = 0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (OR interaction = 0.84 [0.75–0.94] p = 0.003), but replication analysis was under-powered (OR interaction = 1.09 [0.82–1.46]). rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. Conclusion: Interaction analysis and functional assessment provide preliminary evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G × E studied here implies only weak effects are likely to occur.</p
In-situ tailored repair of thermoplastic composites by overprinting of continuous carbon fibre reinforced polymer filaments
Get PDFThis study proposes an efficient and convenient in-situ repair approach for damaged thermoplastic composites by 3D overprinting. Continuous carbon fibre reinforced polyphenylene sulphide (CCF/PPS) filament was employed to overprint repair patches onto conventionally manufactured woven polyamide 6 (PA6) laminates. The process window was optimised through thermal analysis of the target polymers, with a temperature range spanning from the melting point of PA6 (216.8°C) to the crystallisation point of PPS (227.6°C). A nominated interface temperature of 220 °C was evidenced as the most effective, raising the tensile strength of repaired specimens to 205.9 MPa, an improvement of 35 % compared to open-hole laminates and a recovery of nearly 50 % of the strength lost relative to undamaged specimens. Additionally, bio-inspired spider web printing paths were tailored for static indention loading, restoring 94 % of the original laminate strength while reducing material usage by 67 % compared to conventional unidirectional patches. This novel overprinting approach offers a highly efficient and flexible solution for repairing damaged thermoplastic structures
Islands of solidarity? Migration and activism in Malta
Get PDFHow does geography shape possibilities for migration-related activism and advocacy? In this article, we investigate this question through a case study of the Maltese Islands. Though located on the edge of the European Union, Malta has long considered itself at the centre of a ‘migration crisis’ in the Mediterranean. Maltese politicians have denounced what they perceive as a lack of solidarity from ‘EUrope’ and argued that they carry a disproportionate ‘migration burden’. In response, they have adopted systematic practices of maritime abandonment and non-assistance of migrant boats in distress. While Maltese activist and advocacy groups and organisations voice criticism of Malta’s non-engagement at sea, their work largely focuses on the treatment of migrants within the island-nation. Investigating this limited engagement with the Mediterranean border and search and rescue activities, we explore how actors in Malta navigate the politically contentious issue of migration. Through this empirical focus, and by bringing social movements and island studies scholarship into conversation, we show how Malta’s specific island geography, its socio-political environment, as well as dominant maritime imaginaries condition forms of advocacy and activism. We argue that Malta’s islandness and its geographic location within the central Mediterranean borderzone are, perhaps counterintuitively, key factors in constraining Maltese engagement with maritime rescue.</p
Memcontrol:Mitigating memorization in medical diffusion models via automated parameter selection
Get PDFDiffusion models excel in generating images that closely resemble their training data but are also susceptible to data memorization, raising privacy, ethical, and legal concerns, particularly in sensitive domains such as medical imaging. We hypothesize that this memorization stems from the overparameterization of deep models and propose that regularizing model capacity during fine-tuning can mitigate this issue. Firstly, we empirically show that regulating the model capacity via Parameter-efficient fine-tuning (PEFT) mitigates memorization to some extent, however, it further requires the identification of the exact parameter subsets to be fine-tuned for high-quality generation. To identify these subsets, we introduce a bi-level optimization framework, MemControl, that automates parameter selection using memorization and generation quality metrics as rewards during fine-tuning. The parameter subsets discovered through MemControl achieve a superior tradeoff between generation quality and memorization. For the task of medical image generation, our approach outperforms existing state-of-the-art memorization mitigation strategies by fine-tuning as few as 0.019% of model parameters. Moreover, we demonstrate that the discovered parameter subsets are transferable to non-medical domains. Our framework is scalable to large datasets, agnostic to reward functions, and can be integrated with existing approaches for further memorization mitigation. To the best of our knowledge, this is the first study to empirically evaluate memorization in medical images and propose a targeted yet universal mitigation strategy. The code is available at https://github.com/Raman1121/Diffusion_Memorization_HPO
Choroidal and retinal vascular changes in adults with Down syndrome:Insights into the Alzheimer's disease continuum
Get PDFINTRODUCTION: Retinal and choroidal vascular changes have been proposed as a non-invasive central nervous system (CNS) proxy for clinical trials in Alzheimer's disease (AD). However, their role in Down syndrome (DS), the largest genetically predisposed group for AD, remains unclear.METHODS: We conducted ultra-widefield and optical coherence tomography imaging on 24 individuals with DS and 17 controls and extracted various vascular parameters. Data were analyzed using logistic and linear regression models.RESULTS: The DS retinae exhibited supernumerary vessels that were wider and thinned more rapidly along their paths (p = 0.01). There was a more complex central retinal (p = 0.047) and a less complex peripheral retinal vascular tree (p = 0.001), with increased numbers of peripheral microvascular abnormalities (p = 0.038) and reduced choroid vascularity index in DS (p < 0.001).DISCUSSION: We found that retinal and choroidal vascular changes are present in DS adults before the clinical onset of AD and might become early surrogates for cerebral vascular abnormalities.HIGHLIGHTS: Eye imaging in DS showed retinal and choroidal changes seen in AD. Far peripheral retinal microaneurysms and hemorrhages associated to DS. Wider and faster thinning vessels associated to DS. Reduced vascular tree complexity in the peripheral retina linked to DS. Lower choroidal vascularity associated with DS.</p
Unique Nash equilibrium of a nonlinear model of opinion dynamics on networks with friction-inspired stubbornness
Get PDFThe modeling of opinion dynamics has seen much study in varying academic disciplines. Understanding the complex ways information can be disseminated is a complicated problem for mathematicians as well as social scientists. We present a nonlinear model of opinion dynamics that utilizes an environmental averaging protocol similar to the DeGroot and Freidkin-Johnsen models. Indeed, the way opinions evolve is complex and nonlinear effects ought to be considered when modeling. For this model, the nonlinearity destroys the translation invariance of the equations, as well as the convexity of the associated payout functions. The standard theory for well-posedness and convergence no longer applies and we must utilize the Brouwer topological degree and nonconvex analysis in order to achieve these results. Numerical simulations of the model reveal that the nonlinearity behaves similarly to the well-known Friedkin-Johnsen for so-called ‘reasonable’ opinions, but better models the way agents that hold ‘extreme’ opinions are more stubborn than their reasonable counterparts.</p
Tackling poverty across the United Kingdom. Devolution, difference and discourse
Get PDFThe UK welfare state is often considered as being highly centralised, yet the design and administration of UK social security involves significant spatial variations in law, policy, and practice. As such, where you live in the UK can affect the value of benefits and cash transfers you are entitled to, as well as how you experience benefit administration. In this article we advocate for greater consideration of spatial variations in social security and draw attention to existing policy differences in the devolved nations and across localities. The article explores policy discourse and design differences to identify competing narratives and to encourage greater consideration of spatial policy developments in social security. Drawing attention to the Safety Nets research project, it argues that a better understanding of the causes and outcomes of spatial variation in social security provision is necessary in the context of governance reforms to increase devolution and decentralistion including the rise of mayoral regions in England
Examining zoonotic notifications in Aboriginal and Torres Strait Islander populations over time: An analysis of the National Notifiable Diseases Surveillance System from 1996-2021
Get PDFObjective: This paper utilised the National Notifiable Diseases Surveillance System database to analyse the commonly notified zoonotic disease presentations in Aboriginal and Torres Strait Islander populations over 25 years, from 1996-2021. Methods: We analysed the top four zoonotic notifications using a descriptive analysis, a time series analysis assessing the trends and seasonal indices, and a de-seasonalised analysis to assess the years contributing to an increase above the trend. Results: Results show an increase in notifications for salmonellosis and campylobacteriosis over the last 10 years. On average, all diseases saw an increase in notifications above the trend in Q1 (Jan-Mar) and less so Q2 (Apr-Jun), and a decrease in notifications below the trend in Q3 (Jul-Sep) and less so in Q4 (Oct-Dec), which is aligned with increases in zoonotic notifications in Australia's hotter and wetter months. Conclusion: The results present zoonotic notifications in Aboriginal and Torres Strait Islander populations over time and highlight potential implications of climate change due to increasing notifications, and increasing temperatures and extreme weather events in recent years. Implications for public health: The findings can inform preventative health approaches for zoonoses in Indigenous populations, with One Health approaches recommended.</p
The perceptions of European geriatricians on the co-occurrence and links between dementia, delirium and frailty
Get PDFPurposeThis study aimed to explore the perceptions of geriatricians and experienced geriatric trainees in Europe of the complex relationship between dementia, delirium and frailty, including their relative prevalence, overlaps and causality.MethodsAn online anonymous survey was administered across 30 European countries, via the mailing list of the European Geriatric Medicine Society (EuGMS), national member groups and the authors’ professional networks. Questions were framed in the context of recently hospitalised 80-year-old patients.ResultsWithin the 440 included surveys, respondents particularly over-estimated frailty prevalence in older hospitalised patients, with two-thirds choosing between 41 and 80% prevalence, when the literature suggests only 23–46%, but paradoxically underestimated the frequency of frailty in people with delirium (more than three quarters of responses across 21–80%; literature suggests 71–93%). Severe dementia and previous delirium were correctly considered the strongest risks for future inpatient delirium. However, many considered pre-frailty a moderate (44%) or even strong (19%) risk for future delirium, while a minority considered severe dementia a low risk. Respondents viewed delirium superimposed on dementia (DSD) as having the strongest influence on in-hospital mortality and discharge to residential care, dementia as having the strongest influence on future residential care admission, and frailty as the condition most strongly influencing future mortality.ConclusionGeriatricians and experienced geriatric trainees across Europe gave varied responses to questions about delirium, dementia and frailty prevalence, co-occurrence and consequences. This indicates a need for the performance and wide dissemination of robust, prospective research examining all three conditions in older hospital cohorts. We suggest a merging of selective delirium-frailty and dementia-delirium interests to the dementia-delirium-frailty triumvirate
Physical science of the didodecyldimethylammonium bromide-water system:1. Equilibrium phase behaviour
Get PDFSurfactant molecules in solvents self-assemble into a large variety of structures depending on their chemical composition, concentration and temperature, summarized in the system's equilibrium phase diagram. However, the occurrence of long-lived metastable states can lead to incomplete or partly incorrect phase diagrams. By applying a set of complementary techniques and recording changes on different length scales, we determine an improved aqueous equilibrium phase diagram of the widely used double-chain surfactant didodecyldimethylammonium bromide (DDAB) over a broad concentration range (ϕDDAB = 3-100 wt%). We reveal that DDAB molecules exist as zero-hydrates in the room temperature solid state and decompose above 90 °C: the upper temperature of the phase diagram. Differential scanning calorimetry was used to characterise the transition's heat energy, kinetics and temperature, while the structure of the phases was characterized by small angle X-ray scattering and microscopy. Raman spectroscopy combined with computational techniques provided information regarding the conformational properties of the surfactant molecules. Our results were in good agreement with the literature phase diagram for moderate temperatures and surfactant concentrations. At 16 °C, a transition from a frozen lamellar phase (Lβ) to a fluid lamellar phase Lα has previously been suggested across all concentrations (Dubois et al. 1998), with Tm coinciding with the Krafft temperature (Tc) determined in dilute systems. Here, we characterize for the first time the low temperature equilibrium phase for ϕDDAB > 3 wt% as a crystalline dispersion, and determine the position and shape of the Krafft eutectic. The equilibrium phase below 14.1 °C is now assigned to a coexistence region of surfactant hydrate crystals and water XWn + W. At intermediate temperatures, the crystal hydrates XWn melt gradually into the previously reported Lα phase, leaving a narrow coexistence region in the phase diagram XWn + Lα. In conclusion, an amended broad equilibrium phase diagram is presented, combining our new results with those previously reported in the literature.</p
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