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Using gene-environment interactions to explore pathways for colorectal cancer risk
No full textBackground
Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.
Methods
We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].
Findings
A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms.
Interpretation
The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies.
Funding
This study was funded by Cancer Research UK (CRUK; grant number: PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements
Forward-looking life cycle assessment of novel bauxite residue-incorporated cementitious materials
No full textBauxite residue (BR) is emerging as a raw material with significant potential for developing cementitious materials, including supplementary cementitious materials (SCMs). While laboratory and pilot-scale technologies have shown promise for incorporating BR into cement, their environmental performance remains poorly explored. Therefore, forward-looking environmental assessments are necessary to evaluate the potential benefits of BR utilisation in cements, which is explored in this thesis. First, an ex-ante life cycle assessment (LCA) was conducted to assess the environmental performance of BR vitrification technology to produce a reactive SCM at different scales. Upscaling laboratory to pilot and industrial scales reduced environmental impacts by 83% and 94%, respectively. Various upscaling approaches were explored, showing that with appropriate parameters, proxy modelling can perform comparably to complex process models, supporting its suitability in early-stage assessments with limited data. Second, prospective LCA of traditional cement production was performed, incorporating several decarbonisation measures: increasing clinker substitution, increasing alternative fuels, improving kiln efficiency, carbon capture and storage (CCS), and electricity grid decarbonisation. The results showed that clinker substitution could potentially reduce CO2-eq. emissions by 42% between 2020 and 2050. Combining all decarbonisation measures could reduce CO2-eq. emissions to below 0.01 kg per kg of cement by 2050. Third, ex-ante LCA was conducted on three BR processing technologies: (i) co-calcination with kaolin clay, (ii) vitrification, and (iii) reductive smelting, producing BR-based SCMs for up to 30% clinker replacement. Environmental performance was influenced by energy requirements and sources, raw material composition, and clinker replacement ratio. Composite cements were analysed by combining environmental and mechanical performance, showing that optimising fineness and material composition can reduce impacts without compromising strength. The thesis demonstrated the importance of early-stage environmental assessments in identifying hotspots, guiding optimisation, and supporting upscaling. Its findings offer benchmarks for comparing emerging BR technologies with conventional practices and quantifying their environmental benefits.Open Acces
Rethinking energy infrastructure: the value of holistic locally integrated cross-vector flexibility
No full textThe energy transition is expanding beyond electricity to address high-emission sectors such as heat and transport. While electrification is key to decarbonisation, it risks overloading infrastructure and increasing costs for end-
users. Flexibility remains a critical barrier to integrating low-carbon technologies at scale. This paper explores the role of cross-vector flexibility, the coordinated use of electricity, heat, and transport systems, in reducing infrastructure strain and supporting decarbonisation. Using the REMeDY district energy business model, applied to Southend-on-Sea, the study evaluates distribution network impacts. Results show that cross-vector flexibility delivers greater value than decentralised approaches, offering reduced reinforcement needs, enhanced system flexibility,
and lower investment costs. Stand-alone applications provide limited benefits, whereas integrated, whole-systems deployment achieves significantly higher value. The findings highlight the importance of strategic local planning and holistic energy management. Follow-up analyses further confirm the potential of cross-vector flexibility to reduce system costs and support efficient, scalable decarbonisation
Certified robustness to data poisoning in gradient-based training
No full textModern machine learning pipelines leverage large amounts of public data, making it infeasible to guarantee data quality and leaving models open to poisoning and backdoor attacks. Provably bounding the behavior of learning algorithms under such attacks remains an open problem. In this work, we address this challenge by developing the first framework providing provable guarantees on the behavior of models trained with potentially manipulated data without modifying the model or learning algorithm. In particular, our framework certifies robustness against untargeted and targeted poisoning, as well as backdoor attacks, for bounded and unbounded manipulations of the training inputs and labels. Our method leverages convex relaxations to over-approximate the set of all possible parameter updates for a given poisoning threat model, allowing us to bound the set of all reachable parameters for any gradient-based learning algorithm. Given this set of parameters, we provide bounds on worst-case behavior, including model performance and backdoor success rate. We demonstrate our approach on multiple real-world datasets from applications including energy consumption, medical imaging, and autonomous driving
On the MMP for rank one foliations on threefolds
No full textWe prove existence of flips for log canonical foliated pairs of rank one on a Q-factorial projective klt threefold.
This, in particular, provides a proof of the existence of a minimal model for a rank one foliation on a threefold for
a wider range of singularities, after McQuillan
Conventional versus pump-controlled retrograde trial off (PCRTO) weaning in V-A ECMO: exploring feasibility, physiological insights and benefits
No full textThermally drawn steerable soft robotic fiber for multi-purpose minimally invasive surgery
No full textSoft robotic instruments offer unique advantages for minimally invasive surgery (MIS), including safe tissue interaction and adaptability within confined anatomical spaces. However, achieving both miniaturization and functionality within a single device remains a significant engineering challenge. This work presents a monolithically fabricated, tendon-driven fiber robot produced via thermal drawing, integrating rigid polycarbonate (PC) and compliant Styrene-Ethylene-Butylene-Styren (SEBS) elastomer into a continuous, multi-lumen structure. The resulting platform enables remote steering of the fiber tip while supporting channels for additional diagnostic or therapeutic functions. Three purpose-specific fiber variants were developed and evaluated in anatomical phantoms: transvaginal tumor ablation requiring high-precision motion control, gastrointestinal optical diagnosis with spectroscopic sensing, and endovascular navigation with targeted liquid delivery. These demonstrations validate the robot's precision, adaptability, and clinical relevance across multiple MIS scenarios. The proposed thermally drawn fiber offers a scalable approach for rapid prototyping and development of compact, multi-purpose medical devices
Investigating the beneficial effects of a WO3 seed layer on the mechanical and photoelectrochemical stability of WO3|BiVO4|NiFeOOH photoanodes under operational conditions
No full textScalable and durable photoelectrodes are essential for technological breakthroughs in photoelectrochemical systems, yet the fragility of nanostructured photocatalyst materials in industrially relevant operating conditions is rarely explored. Herein, we advance understanding of the importance of morphology and temperature on stability and performance of nanostructured WO3|BiVO4|NiFeOOH photoanodes. The integration of a planar WO3 seed layer beneath nanostructured WO3, improved mechanical stability at 40°C with flowing electrolyte approximately twofold compared with materials where a seed layer was not integrated. This work provides a pathway through which robust photoelectrode systems can be engineered to enable the advancement of up-scaled photoelectrochemical water splitting
The impact of precipitation on ANC service utilisation and healthcare access in Malawi
No full textMalawi is vulnerable to climate-related shocks, which are projected to worsen. Whilst some dimensions of this vulnerability have been characterised, little is known about healthcare sector resilience. Coupling facility-specific data on antenatal care (ANC) service provision in Malawi with gridded precipitation data from 2012-2024 we use linear regression analyses to characterise the historic relationship between precipitation and healthcare access. We estimate that precipitation negatively impacted ANC service utilisation in Malawi, with up to 1 in 20 appointments disrupted annually in some districts. Projecting further to 2060 indicates that, cumulatively, up to 250,000 pregnancies could be affected. Notably, if precipitation patterns from 1941 to 1953 had persisted into the 21st century, disruptions between 2012 and 2024 would be a hundred times less frequent, highlighting the significant influence of anthropogenic climate change on healthcare access. In a country already facing high maternal and neonatal mortality, such disruptions could further hinder access to care and worsen health outcomes. To mitigate this, interventions should focus on preserving or improving the physical accessibility of facilities, particularly through resilient transport services and road networks
Catecholaminergic nucleus integrity and Alzheimer's pathology, symptoms, and progression
No full textBACKGROUND
The noradrenergic locus coeruleus (LC) accumulates pathology early in Alzheimer's disease (AD), with LC dysfunction contributing to symptoms and disease progression. We investigated LC and substantia nigra (SN) integrity in healthy controls and AD participants.
METHODS
Ninety-three AD participants and 29 controls underwent neuromelanin magnetic resonance imaging. LC and SN contrast, reflecting nucleus integrity, related to cognitive and neuropsychiatric symptoms, as well as cognitive decline and atrophy rates.
RESULTS
LC – but not SN – integrity was reduced in AD versus controls (b = −0.39, p = 0.001) and within AD was associated with global cognition (b = 8.53, p = 0.04) and neuropsychiatric symptoms, accounting for SN. An AD subgroup with reduced SN integrity had worse cognition. LC integrity predicted plasma phosphorylated tau protein 217 (b = −0.30, p = 0.03). Lower LC and SN integrities were both related to faster cognitive decline (LC: b = −4.74, p = 0.048; SN: b = −2.27, p = 0.03), accounting for one another.
DISCUSSION
Catecholaminergic nucleus integrity plays an important role in AD. Both systems are relevant to cognitive performance and decline. LC, in particular, relates closely to symptoms, pathology, and rate of progression.
Highlights
In symptomatic AD, LC integrity reflects cortical AD pathology, measured by pTau217.
LC integrity predicts cognitive function in AD, independent of cortical atrophy.
LC and SN integrity independently relate to attentional performance.
Symptoms of anxiety, depression, and apathy are associated with lower LC integrity.
LC and SN relate to cognitive decline rate and left LC predicts atrophy rate