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Rethinking calcium fluoride chemistry: from structural and mechanistic studies to applied methodologies
No full textThe research in this thesis centres around an overarching theme of rethinking (nucleophilic) fluoride chemistry. It has been carried out at the interface between fundamental- and application-driven science, and brings together key themes from organic and inorganic chemistry, with strong mechanistic emphasis. Little fundamental understanding of the reactivity of Ca–F moieties is available to guide methodology development to use CaF2 directly with well-defined molecular species containing Ca–F bonds being extremely rare. Furthermore, existing examples are strongly aggregated and evidence no nucleophilic fluoride delivery. Here, accessible structural motifs have been expanded to include monomeric complexes (unlocking the first examples of nucleophilic delivery) and terminal Ca–F systems, resulting in the first calcium-catalysed fluorination. Systematic control of fluoride lability proved crucial in this system, a theme also central to the development of the first catalytic Appel-type fluorination, which exploits a phosphorus-based delivery vehicle
Harmonic-decomposition approach to dynamical friction for eccentric orbits
Get PDFCompact objects evolving in an astrophysical environment experience a gravitational drag force known as dynamical friction. We present a multipole-frequency decomposition to evaluate the orbit-averaged energy and angular momentum dissipation experienced by point masses on periodic orbits within a homogeneous, fluidlike background. Our focus is on eccentric Keplerian trajectories. Although our approach is currently restricted to linear response theory, it is fully consistent within that framework. We validate our theoretical expressions for the specific case of an ideal fluid, using semi-numerical simulations of the linear response acoustic wake. We demonstrate that, for a finite-time perturbation switched on at t=0, a steady dissipation state is reached after a time bounded by twice the sound crossing time of the apocenter distance. We apply our results to model the secular evolution of compact eccentric binaries in a gaseous medium, assuming low-density conditions where the orbital elements evolve adiabatically. For unequal-mass systems with moderate initial eccentricity, the late-time eccentricity growth is significantly delayed compared to the equal-mass case, due to the binary components becoming transonic at different times along their orbital trajectory. Our approach offers a computationally efficient alternative to full simulations of the linear response wake
An Active Galaxy Cluster Merger at Cosmic Noon Revealed by JWST Weak Lensing and Multiwavelength Probes
Get PDFThe galaxy cluster XLSSC 122 is a rare system at z = 1.98, hosting surprisingly evolved member galaxies when the Universe was only one-third of its present age. Leveraging deep JWST/NIRCam imaging, we perform a weak-lensing analysis and reconstruct the cluster’s mass distribution, finding a mass peak that coincides with both the X-ray peak and the position of the brightest cluster galaxy. Consistent with recent strong-lensing analyses, we obtain a mass estimate of 1.60 ± 0.30 (stat.) ± 0.26 (LSS) × 1014 M⊙ and an implied concentration of c200c = 6.3 ± 0.4, where the uncertainty represents the propagation of the mass error through the adopted concentration–mass relation and excludes intrinsic scatter. Placing our weak-lensing mass map in the context of Chandra X-ray data, MeerKAT radio imaging, Atacama Large Millimeter/submillimeter Array + Atacama Compact Array/Atacama Cosmology Telescope Sunyaev–Zel’dovich (SZ) mapping, and new JWST intracluster light measurements, we identify consistent NE–SW elongation across datasets and a pronounced offset along the same axis between the SZ and mass/X-ray peaks, pointing to significant merger activity. XLSSC 122 thus serves as a JWST pilot study for high-z lensing, demonstrating the telescope’s unique ability to map cluster mass distributions at z ∼ 2. The concordance of the multiwavelength analysis here, together with the high concentration relative to ΛCDM expectations, motivates a uniform sample of analogous systems with joint lensing, X-ray, SZ, and radio data to probe cluster assembly at cosmic noon
Transforming transfusion safety: Insights from implementing bedside electronic checks at a large UK National Health Service trust
Get PDFBackground and Objectives: Bedside electronic transfusion checks (BETC) enhance transfusion safety by reducing errors associated with manual processes. Despite national recommendations, BETC adoption in the United Kingdom remains limited. This study reports on the implementation of BETC at four hospitals at Barts Health NHS Trust, aiming to share insights on the implementation process. Materials and Methods: The main implementation was split into three phases: (1) pre‐pilot, (2) pilot and (3) main implementation (2022–2025). Staff surveys on training satisfaction and key performance indicators (KPIs) on transfusion activity were used to evaluate the uptake of the BETC system. Statistical process control (SPC) charts were used to identify trends, variation and patterns in the data following the implementation of BETC. Results: A total of 5079 staff were trained and 404 personal digital assistant (PDA) devices deployed across four hospitals. Early implementation highlighted that training 60% of staff was insufficient for optimal system use, increasing this threshold to 80% improved adoption. BETC was initially more commonly used for blood administration than group and screen (G&S) sample labelling. Over time, increased usage of BETC for G&S labelling correlated with a marked reduction in sample rejection rates across all sites. Staff reported high satisfaction with training, with 99.5% rating it positively. Conclusion: Early adopters played a pivotal role, but achieving widespread adoption required extended training and support. Addressing technical and workflow barriers, coupled with mandatory system use, could enhance the speed of impact of BETC. These insights offer guidance for future adopters aiming to improve transfusion safety and efficiency
CASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids
Get PDFGestational transfer of brain‐reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin‐associated protein‐like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been proposed to interfere with fetal neurodevelopment. However, the impact of CASPR2 antibodies on human brain development remains largely unknown. Here, to better understand the neurophysiological changes that occur in the presence of these pathogenic autoantibodies, we cultured unguided human neural organoids for a period of 6‐months in media containing anti‐CASPR2 antibodies. We then performed neurophysiological characterization via whole‐cell patch‐clamp and calcium imaging in acute organoid slices. Our results reveal that CASPR2 antibody exposure increased spontaneous synaptic activity, enhanced the maximal frequency of action potential firing and of spontaneous network activity. These findings are consistent with a state of neuronal hyperexcitability, a phenotype which is observed in several models of neurodevelopmental disorders. Mechanistically, the alterations observed in action potential waveform are in accordance with a role for CASPR2 in the regulation of voltage‐gated potassium channels and a pathological role for CASPR2 autoantibodies in driving neuronal hyperexcitability. imag
Benchmarking Large Language Models Using a Best Evidence Topic Report in a Patient With Early Non-Small Cell Lung Cancer
Get PDFObjectives: Large language models (LLMs) are generative-AI which generate text output like a human conversation. We wanted to assess the ability of LLMs to answer patient’s questions and benchmark their output using a best evidence topic (BET). Methods: We asked LLMs whether robot-assisted thoracic surgery (RATS) or video-assisted thoracoscopic surgery (VATS) lobectomy had better perioperative outcomes for postoperative pain, length of hospital stay (LOS) and mortality. A BET was constructed according to a structured protocol for the same questions. An initial search yielded 324 papers, 12 represented the best evidence. Results: LLM outputs are almost instantaneous while a BET took many hours of searching a database for relevant evidence. However, current iterations and models of LLMs did not provide relevant outputs, suffered from hallucinations, and could be restricted by copyright and paywall issues. The BET, on the other hand, was tailored to the scenario by specialist human oversight and therefore more reliable and nuanced. Conclusions: There were no major differences between RATS and VATS lobectomy for T1cN0M0 NSCLC apart from shorter LOS following RATS. Current LLMs may not be entirely reliable for answering clinical questions. An LLM-BET protocol could be used as a standardized process to compare LLM outputs for different clinical scenarios, each benchmarked with a BET. It can also be used to analyse outputs of different models of current and future LLMs
Random graphs with additional structure evolving in time
Get PDFThis thesis comprises three projects concerning random graphs and random processes on graphs.In Chapter 2 we prove that if the offspring distribution of a Bienaymé tree is critical and admits a finite third moment, then under a suitable tail condition on the displacements, any globally centered size-conditioned discrete snake with finite global variance converges (upon suitable rescaling) to the Brownian snake driven by a normalized Brownian excursion. We also consider displacement distributions with heavier tails, for which we instead prove convergence in distribution to a variant of the hairy snake introduced by Janson and Marckert. We further give two applications of our main result. Namely, we obtain a scaling limit for the difference between the height function and the Łukasiewicz path of a size-conditioned critical Bienaymé tree; and we obtain a scaling limit for the difference between the height function of a size-conditioned critical Bienaymé tree and the height function of its associated looptree.In Chapter 3 we prove a threshold for the existence of monotone increasing paths between all pairs of vertices in temporal random geometric graphs. Our result reveals that temporal connectivity appears when the edge density is significantly larger than that required for simple connectivity of the underlying graph. This contrasts with temporal connectivity thresholds for Erdős–Rényi random graphs which occur when the edge density is a constant multiple of that required for connectivity of the underlying graph. Our results hold for a wide family of soft random geometric graphs as well as the standard random geometric graph, and in general dimensions d≥2.In Chapter 4 we prove rapid mixing for a lazy simple symmetric random walk on the set of Coxeter tournaments with a given score sequence. Coxeter tournaments serve as generalizations of standard tournaments, where in addition to competitive games, pairs of players can play collaborative games, and individual players can play solitary games. We obtain our main result by an intricate application of Bubley and Dyer’s method of path coupling, using a re-weighting of the graph metric
Investigating the void lattice phenomenon in nuclear irradiated materials
Get PDFIn the 1950s, the pioneering computer scientist and mathematician, Alan Turing proposed a method to describe the observed phenomenon of pattern formation in reaction--diffusion systems: a Turing instability or a reaction--diffusion instability. The mechanism states that two or more species must be present within the system and be able to interact and move around. Pattern formation in these systems can occur when the diffusion rates between two (or more) species significantly differ in magnitude. In liquid chemical reactions, the diffusion rates are similar, so pattern formation within these systems is rare. In the solid state, however, the diffusion rate is D ∝ exp(−E_mig / k_B T), where E_mig is the energy of the migration barrier of the species and T is the temperature of the system. As a result, the diffusion rates are enormous, often orders of magnitude apart, and the criteria for pattern formation are satisfied.Void and gas bubble superlattices are phenomena observed in nuclear-irradiated materials when a random distribution of pre-existing voids or gas bubbles moves and self-order themselves into a long-range periodic superlattice, often mimicking the crystal structure of the host lattice. This transition from a random distribution into a long-range ordered system, at first, would appear to violate the second law of thermodynamics; as such, it stands to reason that there must be one or more mechanisms driving this pattern formation, however, to date, no mechanisms have yet been proven. The mechanism behind the formation of void and gas bubble superlattices remains a mystery. In this thesis, I propose that a Turing-like instability can explain the emergent pattern of a void superlattice in a nuclear-irradiated material. I do this in two stages. First, by following the derivation notes of M. Cross and H. Greenside, I perform a linear stability analysis on a pair of Cahn-Hilliard partial differential equations. The equations are coupled by an annihilation term and include a creation term. They describe the evolution of the vacancy and the self-interstitial atom concentrations in a nuclear-irradiated material.I show that such a system will support pattern formation due to the Turing-like instability for a particular selection of parameter values. Secondly, a phase-field model is used to explore the non-linear post-bifurcation regime using the finite-element framework MOOSE (Multiphysics Object Oriented Simulation Environment), allowing me to numerically solve the coupled pair of Cahn-Hilliard partial differential equations via the implicit method of backward Euler time integration, demonstrating the formation and development of a void superlattice.My model, although simple and minimal, as it neglects features like driving advective terms or refinements such as the elastic interactions between voids or the anisotropic mobility of the self-interstitial atoms, can successfully explain almost all of the qualitative behaviours of a void superlattice, such as their ordered formation from a random distribution of pre-existing voids; their periodicity and structure, which are in agreement with experimental observations, and the temperature window of their formation. Combined, this model suggests that a Turing-like instability is, in fact, the driving mechanism for void superlattices in nuclear-irradiated materials and, given that widely differing mobilities are so typical in solid-state materials, could be the driving mechanism for many of the patterns observed in solid-state systems
Characterising the impact of shift work on diet and glucose variability in healthcare employees living with type 2 diabetes: The Shift‐Diabetes study
Get PDFAims: To characterise differences in dietary intake, glucose variability, and activity in free‐living healthcare shift workers with type 2 diabetes (T2D) across varying work conditions. Methods: Healthcare shift workers with T2D were monitored over 10 days, covering night shifts, day shifts, and rest days. Data were collected using blinded continuous glucose monitoring, activity trackers, and diet/sleep diaries. Within‐person comparisons were made for mean glucose (MG), coefficient of variation (CV), mean absolute glucose change (MAG), mean amplitude of glycaemic excursion (MAGE), continuous overlapping net glycaemic action (CONGA), dietary intake (food choices, nutrient intake), and activity/rest periods. Results: The study sample (n = 37; 89.2% women) were mainly employed as nurses or midwives (62.2%). Energy intake was highest (2199 kcal SD 648) on a day when a night shift was worked. Percentage of energy intake from sweet snacks was higher on a night shift compared with a rest day after a night shift (13.4 SD 12.0% vs. 7.8 SD 11.8%, p = 0.013). Night shifts had the highest eating occasions (7.0 SD 2.2) and rest after night (RAN) the lowest (3.4 SD 1.6), p < 0.001. No differences were reported for MG, MAGE, or CV. MAG and CONGA were higher for night shift compared with RAN shift (p = 0.029). Step counts were higher on night shift days (13,775, SD 4270 p = 0.016), and participants were awake longer (22.2 h SD 2.4 h, p < 0.001) compared with other day types. Conclusions: Night shifts are associated with prolonged wakefulness, increased activity, and distinct dietary behaviours. Tailored interventions are needed to support night shift workers with T2D in managing their condition effectively