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Filamin A editing in myeloid cells reduces intestinal inflammation and protects from colitis
No full textPatho-mechanistic origins of ulcerative colitis are still poorly understood. The actin cross-linker filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. Posttranscriptional A-to-I editing generates two forms of FLNA: genome-encoded FLNAQ and FLNAR. FLNA is edited in colon fibroblasts, smooth muscle cells, and endothelial cells. We found that the FLNA editing status determines colitis severity. Editing was highest in healthy colons and reduced during murine and human colitis. Mice that exclusively express FLNAR were highly resistant to DSS-induced colitis, whereas fully FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and microbiome composition, we found that FLNAR exerts protection specifically via myeloid cells, which are physiologically unedited. Introducing fixed FLNAR did not hamper cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. Thus, loss of FLNA editing correlates with colitis severity, and targeted editing of myeloid cells serves as a novel therapeutic approach in intestinal inflammation
Comparison of Computed Tomogram Coronary Angiography (CTCA) alone versus CTCA with selective FFRCT in patients presenting with stable chest pain: a FORECAST trial substudy
No full textAims: the original FORECAST trial was designed to compare a strategy of CTCA and selective FFRCT to standard care in patients attending Rapid Access Chest Pain clinics in UK centres. This is a prespecified analysis of the FORECAST trial to compare outcomes between the patients in the experimental arm (CTCA + selective FFRCT) and patients in the reference arm who underwent CTCA alone as their initial test of choice.Methods and results: the FORECAST trial recruited 1400 patients randomised between 2 strategies: (i) initial test of choice at the discretion of the healthcare provider (standard care arm) or (ii) CTCA +/- FFRCT. Prior to randomization, clinicians stated their preference for choice of the first test if the patient were to be randomized to standard care. 459 patients (66%) in the standard care pathway were selected for CTCA as the first test of choice. Similarly, 453 (65%) of the patients who were subsequently randomised into the experimental arm were selected for CTCA as initial test prior to that randomisation. This comparison is an intention-to-test (ITT) analysis comparing the post randomisation outcomes of the population of patients who were selected for CTCA as the test of first choice prior to randomisation (labeled as the CTCA stratum). The following comparisons were made: (i) primary trial outcomes at 9 months including (a) total cardiac costs, (b) use of other tests, (c) clinical events & (d) time to final management plan; (ii) a comparison between the CTCA stratum groups and the remainder of the standard care arm (i.e. patients randomised to standard care who were selected for an initial test other than CTCA).Of the CTCA stratum patients, there was no significant difference between randomised groups in the median total cardiac costs at 9 months (£594 (IQR 570 – 1,127) in the experimental arm vs £594 (574 –¬ 966) in the usual care arm (P=0.325)). The number of additional non-invasive tests was significantly lower in the experimental group than in the standard care CTCA patients (43 patients (8.9%) vs 72 (16%), (P=0.005)). Time to final management plan was also significantly lower in the experimental arm (median 64 days (IQR 48-110) versus 75 days (55-126) (P<0.001)). There was no significant difference in the rate of adverse cardiac events. Patients randomised to standard care who were not in the CTCA stratum had significantly higher median total cardiac costs when compared to either of the CTCA stratum groups, with median total cardiac costs of £908 (IQR 592 – 1,161) vs £594 (570-1,123) vs £594 (570-966), respectively (P<0.001).Conclusion: in this prespecified FORECAST substudy of patients whose clinicians preferred CTCA as the first test prior to randomisation, the CTCA +/- FFRCT strategy, when compared to CTCA alone, was cost neutral in the UK, and associated with significantly fewer additional noninvasive tests. Time to final management plan was also significantly lower in the experimental arm (median 64 days (IQR 48-110) versus 75 days (55-126) in the standard care CCTA arm (P<0.001)).<br/
The Lea View House Project: heritage and home in crisis
No full textConference poster for the DCDC25 Conferenc
Analysis and optimisation of cellular Kirigami wingbox (CKW) structures for enhanced aeroelastic performance
No full textCellular structures provide lightweight, high-strength and excellent structural stability due to their repetitive modular unit design. By integrating cutting and folding Kirigami techniques with composite and plastic substrates, cellular configurations can significantly enhance the aero-mechanical performance of wing designs. This innovative structural technology shows great promise for unmanned aerial vehicles (UAVs), enabling flexible control and dynamic flight capabilities to meet varying operational conditions. This study presents an analysis and optimisation of the aeroelastic behaviour of cellular Kirigami wingbox (CKW) structures for multifunctional operations of micro-UAV wings to ensure stability and resilience in various dynamic flight conditions. The effect of thickness and internal cell angle of the cellular structure on static and dynamic aeroelastic behaviour is assessed through finite element analysis. By incorporating Bayesian optimisation, the multi-disciplinary design space of the cellular UAV wings has been efficiently explored to achieve optimal structural performance for adaptive UAV wings. The results show that Bayesian optimisation effectively identifies optimal design parameters for different multi-objective design weights, which improves the aeroelastic performance of the CKW structure.</p
Strengthening the UK regulatory framework: enhancing cybersecurity in supply chains
No full textThe increasing risks associated with cybersecurity in global supply chains present a significant problem, threatening the operational integrity and security of organisations on a global scale. The UK’s Network and Information Systems (NIS) Framework, although fundamental in cybersecurity regulation, has significant gaps in effectively addressing the complexities of contemporary global supply chain architectures entangled with quickly advancing cyber threats. In this work, we analyse the UK NIS framework, identify key gaps, and propose solutions drawn from other existing frameworks, e.g., US NIST, EU NIS2. We base this analysis on a comparative evaluation using defined criteria related to supply chain coverage, adaptability, and risk management specificity. We enhanced the cybersecurity in supply chains by proposing novel security requirements plans for each risk profile. Furthermore, we examined various solutions for risk assessments and self-risk assessments for supply chain security. We analysed practical risk assessment approaches, including self-assessment strategies, particularly suited for SMEs. Moreover, we investigated the contracting between supply chains in the context of data and information sharing
The natural archives of La Hague: Cold War legacies, radioactive rivers, and the endless accident
No full textThis thesis introduces the nuclear cluster of La Hague in Normandy, France, to the field of nuclear culture by exploring its complex and ongoing legacies of radioactive contamination. The two sites addressed are a nuclear reprocessing plant (Orano) and a nuclear waste near-surface repository (ANDRA). The ecosystems and natural environment surrounding both sites have been subjected to continuous fallout and toxic spills which, over seventy years of development and constant redeployment, have progressively laced the peninsula with invisible and radiotoxic residues and traces.Rivers and marshlands are pivotal to the research, serving as material witnesses to the slow nuclear violence operating in the peninsula—the wet accident continuously unfolding. The thesis probes the entanglements between nuclear infrastructures and the natural environment, while outlining the relational dimension of residues and the failures of waste management, maintenance, and containment. This is achieved by establishing connections between data provided by the local NGO ACRO, which has monitored the area since 1986, and the rare official documentation of past accidents. The work aims to retrospectively reconstruct the political contexts of spills and accidents as well as to emphasise their long-lasting consequences.Two events take centre stage: a tritium leak that contaminated the St. Hélène River, and a fire at Silo–130, whose contamination was detected by the Ruisseau des Landes thirty years later. In both instances, probing the events and their legacies highlights the voiding of official information and the ways in which, since the Cold War, secrecy has cloaked the nuclear facilities. One isotope, plutonium, helps establish a direct lineage between the reprocessing plant and repository and the French nuclear military programme that led to the French atomic bomb. The research foregrounds the agency of aquifers and rivers as natural entities that coalesce, redistribute, store, and redeploy isotopes in time and space.The radioactive liquidscape of La Hague encompasses past toxic legacies and their future redeployments. In this way, the absence of official data and documentation is alleviated by approaching La Hague’s ecosystem as a natural archive. Sediments, water, and plants possess a material memory open to decipherment and critical political realignment. This endeavour explores and documents La Hague’s nuclear memory, and articulates alternative narratives for its Cold War legacies
Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: results from COV-BOOST trial
No full textBackground: heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines.Methods: participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020–004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster.Results: the BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083–244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5–241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954–74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53–0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9–9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8–4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17–7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules.Conclusions: a BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens
Efficient privacy-preserving conjunctive searchable encryption for cloud-IoT healthcare system
No full textIn cloud-Internet of Things (IoT) healthcare systems, private medical data leakage is a serious concern as the cloud server is not fully trusted. Dynamic searchable symmetric encryption (DSSE), with necessary forward and backward privacy security properties, enables doctors to retrieve ciphertexts while guaranteeing data privacy. However, existing forward and backward private DSSE schemes are not well-suited for cloud-IoT healthcare systems with attribute-value type databases. To this end, we propose an efficient privacy-preserving conjunctive searchable encryption scheme for cloud-IoT healthcare systems, called PC-SE. It is the first conjunctive DSSE scheme designed for attribute-value type databases. Specifically, we design flexible search capabilities for PC-SE to address users’ various search requirements. It can not only achieve precise conjunctive search based on keywords but also realize broad attribute search. Moreover, our scheme achieves fine-grained search for attribute values while maintaining forward and Type-I− backward privacy. This approach reduces the communication burden and minimizes the risk of privacy exposure. To ensure that users with different authorities can only access the corresponding attribute values, we introduce an attribute access control mechanism in PC-SE. Finally, security analysis and experimental results demonstrate that PC-SE is secure and effective
Written response to the UK Parliamentary Inquiry: House of Lords Select Committee on Medicines Security
No full textMedicine supply is vital for individuals living at home in the last year of life (end-of-life). Without this, symptoms cannot be effectively managed, causing high levels of distress. For community pharmacists (CPs), medicine supply to those at end-of-life was central to their role, significantly impacting individuals and their families.Our submission focuses on the issues related to palliative and end of life Medicine Supply including stock levels, the impact of shortages, communication breakdowns, and inadequate stock level monitoring. The ActMed study highlighted significant issues affecting supply of medicines into community pharmacy in the context of end-of-life care
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