The continuous manufacture of dispersant coated bioresorbable nanoparticles

This thesis investigates the continuous synthesis and coating of hydroxyapatite nanoparticles (HA NP’s). A range of dispersant molecules were produced and subsequently used in this continuous coating process. Starting with small aliphatic hydrocarbon chains attached to various functional groups a basic understanding of the interactions occurring between the dispersant molecule, the hydroxyapatite surface and a solvent medium was built. It became clear that the length of the hydrocarbon chain, the nature of the functional group and the morphology of the dispersant all had a role to play in the effectiveness and extent of the coating. Using this fundamental understanding the work progressed into the realm of polymeric dispersants. The biodegradable and bioresorbable polymer, polylactic acid (PLA) was utilised in the coating process with the aim of producing HA NP’s that could be dispersed within a polymer matrix. These low molecular weight (Mw) polymers were based on similar chain size and functional groups chemistry. Similar linear morphologies were investigated along with a new six armed, branched morphology. It was concluded that molecular weight of the polymer (chain length), the functional head group (initiator) and morphology of the polymer were all responsible for the dispersant to successfully coat the HA NP’s. However, results indicated that different surface interactions were occurring between the polymeric dispersant chain and HA than those occurring between the hydrocarbon chain and HA. The conclusion that had been drawn from our hydrocarbon coated HA NP’s was that the interaction between dispersant and surface primarily resulted from the functional group. The aliphatic carbon chain would not form any significant surface bonds. This was not the same conclusion drawn from the results of our polymeric dispersants, which appeared to interact favourably with the highly charged nanoparticle surface. A wide range of analytical techniques have been employed in this thesis to fully understand the surface chemistry occurring between dispersant and nanoparticle surface. Gel-permeation chromatography (GPC), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy have been used to explore the chemistry and morphology of the dispersants. Understanding the interactions between the hydroxyapatite surface and the dispersant molecule proved more challenging. Multiple electron microscopy techniques, including scanning electron microscopy (SEM), tunnelling electron microscopy (TEM), electron energy loss (EEL) spectroscopy along with TGA and FTIR spectroscopy provided an insight into the dispersant-surface interactions. Elemental analysis, such as X-ray powder diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDX) also provided support to the theories developed throughout the project. It was vital that such a wide range of analytical techniques were explored as no one technique could provide the full picture of the surface chemistry. Whilst the many conventional analytical approaches directed our focus to a combination of functional groups and chain lengths, the exact nature of the bonds between dispersant and nanoparticle surface remained elusive. Often NMR spectroscopy, being one of the most powerful tools in understanding chemical bonds, would be able to provide such information. Due to the physical nature of our final nanocomposite material, solution state NMR spectroscopic analysis was not possible leading our investigation into the realm of solid-state NMR spectroscopy. With the help of the Nottingham University’s solid-state NMR research group 1H-31P correlation experiments were used to investigate the interactions between the dispersant molecules and the surface of HA NP’s. The spectra revealed that hydrocarbon based dispersant primarily interacted with the surface via their functional head group. PLA based dispersant spectra were dominated by resonances arising from polymer chain – hydroxyapatite surface interactions. Dynamic nuclear polarization (DNP) solid-state NMR selectively enhanced the surface interactions and supported the conclusions drawn from the standard solid-state NMR correlation spectroscopy. Solid-state NMR spectroscopy was able to provide the final crucial piece of evidence that supported the conclusions drawn from Chapter’s 2 and 3

Secular trends in reported portion size of food and beverages consumed by Irish adults

The present analysis aimed to investigate the changes in the reported portion sizes (PS) of foods and beverages commonly consumed by Irish adults (18–64 years) from the North South Ireland Food Consumption Survey (NSIFCS) (1997–2001) and the National Adult Nutrition Survey (NANS) (2008–10). Food PS, which are defined as the weight of food (g) consumed per eating occasion, were calculated for comparable foods and beverages in two nationally representative cross-sectional Irish food consumption surveys and were published in NSIFCS and NANS. Repeated measure mixed model analysis compared reported food PS at the total population level as well as subdivided by sex, age, BMI and social class. A total of thirteen commonly consumed foods were examined. The analysis demonstrated that PS significantly increased for five foods (‘white sliced bread’, ‘brown/wholemeal breads’, ‘all meat, cooked’, ‘poultry, roasted’ and ‘milk’), significantly decreased for three (‘potatoes’, ‘chips/wedges’ and ‘ham, sliced’) and did not significantly change for five foods (‘processed potato products’, ‘bacon/ham’, ‘cheese’, ‘yogurt’ and ‘butter/spreads’) between the NSIFCS and the NANS. The present study demonstrates that there was considerable variation in the trends in reported food PS over this period

Melt-processed PLA/HA platelet nanoparticle composites produced using tailored dispersants

Hydroxyapatite (HA) nanoparticles, similar to those seen in the structure of human bone, have been produced via hydrothermal synthesisand used to produce nanocomposite materials via melt blending with poly(lactic acid)(PLA). Both of these processes are scalable and commercially relevant. Tailored dispersants were developed and used to improve the dispersion of the HA. Modest improvements in flexural properties were observed (max increases 30% of dry modulus, 13% of wet strength). Rheometry is not suggestive of achieving percolation,so there is potential to improve mechanical properties further. It was established that very dry processing conditions are essential to maintaining the molecular weight of the PLA during processing and that the use of the tailored dispersants can also help to mitigateprocess-induced degradation.MicroCT has proved to be a useful quality control tool to support TEM analysis

Pecten as a new substrate for IcPD dating : the Quaternary raised beaches in the Gulf of Corinth, Greece

Intra-crystalline protein diagenesis (IcPD), a recent development of amino acid racemization dating (AAR), is now established as a reliable geochronological tool for the Quaternary. However, extending the method to new biominerals requires extensive testing in order to provide evidence for the closed-system behaviour of the intra-crystalline proteins and to assess the temporal span that can be covered. Here we present results from high-temperature experiments on the IcPD of the bivalve Pecten, demonstrating that a fraction of proteins can be isolated from a bleach-resistant mineral matrix, which effectively operates as a closed system under conditions of accelerated diagenesis in the laboratory. Analyses of Pecten from the well-dated terrace system of the Gulf of Corinth (Greece) provided a pilot test for the integrity of the intra-crystalline fraction in subfossil shells. The small sample sizes in this preliminary study preclude a full assessment of the aminostratigraphic power of Pecten IcPD, but a concordance is observed between the extent of IcPD and sites dating from between MIS 5 and MIS 11. We conclude that Pecten is a potentially good substrate for IcPD dating in the Mediterranean, and that the temporal limit of the technique in this area lies beyond MIS 11

Provenancing Archaeological Wool Textiles from Medieval Northern Europe by Light Stable Isotope Analysis (δ13C, δ15N, δ2H)

We investigate the origin of archaeological wool textiles preserved by anoxic waterlogging from seven medieval archaeological deposits in north-western Europe (c. 700-1600 AD), using geospatial patterning in carbon (δ13C), nitrogen (δ15N) and non-exchangeable hydrogen (δ2H) composition of modern and ancient sheep proteins. δ13C, δ15N and δ2H values from archaeological wool keratin (n = 83) and bone collagen (n = 59) from four sites were interpreted with reference to the composition of modern sheep wool from the same regions. The isotopic composition of wool and bone collagen samples clustered strongly by settlement; inter-regional relationships were largely parallel in modern and ancient samples, though landscape change was also significant. Degradation in archaeological wool samples, examined by elemental and amino acid composition, was greater in samples from Iceland (Reykholt) than in samples from north-east England (York, Newcastle) or northern Germany (Hessens). A nominal assignment approach was used to classify textiles into local/non-local at each site, based on maximal estimates of isotopic variability in modern sheep wool. Light element stable isotope analysis provided new insights into the origins of wool textiles, and demonstrates that isotopic provenancing of keratin preserved in anoxic waterlogged contexts is feasible. We also demonstrate the utility of δ2H analysis to understand the location of origin of archaeological protein samples

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

Common Genetic Variation And Age at Onset Of Anorexia Nervosa

Background Genetics and biology may influence the age at onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to AN age at onset and to investigate the genetic associations between age at onset of AN and age at menarche. Methods A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed which included 9,335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age at onset, early-onset AN (< 13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses. Results Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (SNP-h2) were 0.01-0.04 for age at onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early- and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age at onset and early-onset AN estimated from independent GWASs significantly predicted age at onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early-onset AN. Conclusions Our results provide evidence consistent with a common variant genetic basis for age at onset and implicate biological pathways regulating menarche and reproduction.Peer reviewe

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202