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Sophie Williams - Top 30 Publications

The NHS and migrant patients with cancer.

A fast track clinic improves diagnosis and treatment times for those investigated for lung cancer in Northland District Health Board.

In 2009, a Respiratory Fast Track Clinic (RFTC) was introduced successfully by Southern District Health Board. Advancing on this model by incorporating further biopsy methods, we aimed to streamline our investigative cancer pathway.

Patient-specific parameterised cam geometry in finite element models of femoroacetabular impingement of the hip.

Impingement resulting in soft tissue damage has been observed in hips with abnormal morphologies. Geometric parameterisation can be used to automatically generate a range of bone geometries for use in computational models, including femurs with cam deformity on the femoral neck.

Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders.

High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders.

Xpert human papillomavirus test is a promising cervical cancer screening test for HIV-seropositive women.

This study investigated the performance of Cepheid Xpert human papillomavirus (HPV) assay in South African human immunodeficiency virus (HIV)-infected women and compared its performance with that of hybrid capture-2 (hc2).

Nanocrystallography measurements of early stage synthetic malaria pigment.

The recent availability of extremely intense, femtosecond X-ray free-electron laser (XFEL) sources has spurred the development of serial femtosecond nanocrystallography (SFX). Here, SFX is used to analyze nanoscale crystals of β-hematin, the synthetic form of hemozoin which is a waste by-product of the malaria parasite. This analysis reveals significant differences in β-hematin data collected during SFX and synchrotron crystallography experiments. To interpret these differences two possibilities are considered: structural differences between the nanocrystal and larger crystalline forms of β-hematin, and radiation damage. Simulation studies show that structural inhomogeneity appears at present to provide a better fit to the experimental data. If confirmed, these observations will have implications for designing compounds that inhibit hemozoin formation and suggest that, for some systems at least, additional information may be gained by comparing structures obtained from nanocrystals and macroscopic crystals of the same molecule.

An in vitro simulation method for the tribological assessment of complete natural hip joints.

The use of hip joint simulators to evaluate the tribological performance of total hip replacements is widely reported in the literature, however, in vitro simulation studies investigating the tribology of the natural hip joint are limited with heterogeneous methodologies reported. An in vitro simulation system for the complete natural hip joint, enabling the acetabulum and femoral head to be positioned with different orientations whilst maintaining the correct joint centre of rotation, was successfully developed for this study. The efficacy of the simulation system was assessed by testing complete, matched natural porcine hip joints and porcine hip hemiarthroplasty joints in a pendulum friction simulator. The results showed evidence of biphasic lubrication, with a non-linear increase in friction being observed in both groups. Lower overall mean friction factor values in the complete natural joint group that increased at a lower rate over time, suggest that the exudation of fluid and transition to solid phase lubrication occurred more slowly in the complete natural hip joint compared to the hip hemiarthroplasty joint. It is envisaged that this methodology will be used to investigate morphological risk factors for developing hip osteoarthritis, as well as the effectiveness of early interventional treatments for degenerative hip disease.

Measurements of Long-range Electronic Correlations During Femtosecond Diffraction Experiments Performed on Nanocrystals of Buckminsterfullerene.

The precise details of the interaction of intense X-ray pulses with matter are a topic of intense interest to researchers attempting to interpret the results of femtosecond X-ray free electron laser (XFEL) experiments. An increasing number of experimental observations have shown that although nuclear motion can be negligible, given a short enough incident pulse duration, electronic motion cannot be ignored. The current and widely accepted models assume that although electrons undergo dynamics driven by interaction with the pulse, their motion could largely be considered 'random'. This would then allow the supposedly incoherent contribution from the electronic motion to be treated as a continuous background signal and thus ignored. The original aim of our experiment was to precisely measure the change in intensity of individual Bragg peaks, due to X-ray induced electronic damage in a model system, crystalline C60. Contrary to this expectation, we observed that at the highest X-ray intensities, the electron dynamics in C60 were in fact highly correlated, and over sufficiently long distances that the positions of the Bragg reflections are significantly altered. This paper describes in detail the methods and protocols used for these experiments, which were conducted both at the Linac Coherent Light Source (LCLS) and the Australian Synchrotron (AS) as well as the crystallographic approaches used to analyse the data.

Evaluation of a new methodology to simulate damage and wear of polyethylene hip replacements subjected to edge loading in hip simulator testing.

Wear and fatigue of polyethylene acetabular cups have been reported to play a role in the failure of total hip replacements. Hip simulator testing under a wide range of clinically relevant loading conditions is important. Edge loading of hip replacements can occur following impingement under extreme activities and can also occur during normal gait, where there is an offset deficiency and/or joint laxity. This study evaluated a hip simulator method that assessed wear and damage in polyethylene acetabular liners that were subjected to edge loading. The liners tested to evaluate the method were a currently manufactured crosslinked polyethylene acetabular liner and an aged conventional polyethylene acetabular liner. The acetabular liners were tested for 5 million standard walking cycles and following this 5 million walking cycles with edge loading. Edge loading conditions represented a separation of the centers of rotation of the femoral head and the acetabular liner during the swing phase, leading to loading of the liner rim on heel strike. Rim damage and cracking was observed in the aged conventional polyethylene liner. Steady-state wear rates assessed gravimetrically were lower under edge loading compared to standard loading. This study supports previous clinical findings that edge loading may cause rim cracking in liners, where component positioning is suboptimal or where material degradation is present. The simulation method developed has the potential to be used in the future to test the effect of aging and different levels of severity of edge loading on a range of cross-linked polyethylene materials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1456-1462, 2018.

Predicting surgical outcome in patients with glioblastoma multiforme using pre-operative magnetic resonance imaging: development and preliminary validation of a grading system.

The lack of a simple, objective and reproducible system to describe glioblastoma multiforme (GBM) represents a major limitation in comparative effectiveness research. The objectives of this study were therefore to develop such a grading system and to validate it on patients who underwent surgical resection. A systematic review of the literature was performed to identify features on pre-operative magnetic resonance imaging (MRI) that predict the surgical outcome of patients with GBM. In all, the five most important features of GBM on pre-operative MRI were as follows: periventricular or deep location, corpus callosum or bilateral location, eloquent location, size and associated oedema. These were then used to develop a grading system. To validate this grading system, a retrospective cohort study of all adult patients with supratentorial GBM who underwent surgical resection between the 1 January 2014 and the 31 June 2015 was performed. There was a substantial agreement between the two neurosurgeons grading GBM (Cohen's κ was 0.625; standard error 0.066). High-complexity lesions were significantly less likely to result in complete resection of contrast-enhancing tumour than low-complexity lesions (50.0 versus 3.4%; p = 0.0007). The proposed grading system may allow for the standardised communication of anatomical features of GBM identified on pre-operative MRI.

Three-dimensional assessment of impingement risk in geometrically parameterised hips compared with clinical measures.

Abnormal bony morphology is a factor implicated in hip joint soft tissue damage and an increased lifetime risk of osteoarthritis. Standard 2-dimensional radiographic measurements for diagnosis of hip deformities, such as cam deformities on the femoral neck, do not capture the full joint geometry and are not indicative of symptomatic damage. In this study, a 3-dimensional geometric parameterisation system was developed to capture key variations in the femur and acetabulum of subjects with clinically diagnosed cam deformity. The parameterisation was performed for computed tomography scans of 20 patients (10 female and 10 male). Novel quantitative measures of cam deformity were taken and used to assess differences in morphological deformities between males and females. The parametric surfaces matched the more detailed, segmented hip bone geometry with low fitting error. The quantitative severity measures captured both the size and the position of cams and distinguished between cam and control femurs. The precision of the measures was sufficient to identify differences between subjects that could not be seen with the sole use of 2-dimensional imaging. In particular, cams were found to be more superiorly located in males than in females. As well as providing a means to distinguish between subjects more clearly, the new geometric hip parameterisation facilitates the flexible and rapid generation of a range of realistic hip geometries including cams. When combined with material property models, these stratified cam shapes can be used for further assessment of the effect of the geometric variation under impingement conditions.

X-ray laser-induced electron dynamics observed by femtosecond diffraction from nanocrystals of Buckminsterfullerene.

X-ray free-electron lasers (XFELs) deliver x-ray pulses with a coherent flux that is approximately eight orders of magnitude greater than that available from a modern third-generation synchrotron source. The power density of an XFEL pulse may be so high that it can modify the electronic properties of a sample on a femtosecond time scale. Exploration of the interaction of intense coherent x-ray pulses and matter is both of intrinsic scientific interest and of critical importance to the interpretation of experiments that probe the structures of materials using high-brightness femtosecond XFEL pulses. We report observations of the diffraction of extremely intense 32-fs nanofocused x-ray pulses by a powder sample of crystalline C60. We find that the diffraction pattern at the highest available incident power significantly differs from the one obtained using either third-generation synchrotron sources or XFEL sources operating at low output power and does not correspond to the diffraction pattern expected from any known phase of crystalline C60. We interpret these data as evidence of a long-range, coherent dynamic electronic distortion that is driven by the interaction of the periodic array of C60 molecular targets with intense x-ray pulses of femtosecond duration.

The Effect of Sleep on Children's Word Retention and Generalization.

In the first few years of life children spend a good proportion of time sleeping as well as acquiring the meanings of hundreds of words. There is now ample evidence of the effects of sleep on memory in adults and the number of studies demonstrating the effects of napping and nocturnal sleep in children is also mounting. In particular, sleep appears to benefit children's memory for recently-encountered novel words. The effect of sleep on children's generalization of novel words across multiple items, however, is less clear. Given that sleep is polyphasic in the early years, made up of multiple episodes, and children's word learning is gradual and strengthened slowly over time, it is highly plausible that sleep is a strong candidate in supporting children's memory for novel words. Importantly, it appears that when children sleep shortly after exposure to novel word-object pairs retention is better than if sleep is delayed, suggesting that napping plays a vital role in long-term word retention for young children. Word learning is a complex, challenging, and important part of development, thus the role that sleep plays in children's retention of novel words is worthy of attention. As such, ensuring children get sufficient good quality sleep and regular opportunities to nap may be critical for language acquisition.

Influence of hip joint simulator design and mechanics on the wear and creep of metal-on-polyethylene bearings.

Hip joint simulators are used extensively for preclinical testing of hip replacements. The variation in simulator design and test conditions used worldwide can affect the tribological performance of polyethylene. The aim of this study was to assess the effects of simulator mechanics and design on the wear and creep of ultra-high-molecular-weight polyethylene. In the first part of this study, an electromechanical simulator and pneumatic simulator were used to compare the wear and creep of metal-on-polyethylene components under the same standard gait conditions. In the second part of the study, the same electromechanical hip joint simulator was used to investigate the influence of kinematics on wear. Higher wear rates and penetration depths were observed from the electromechanical simulator compared with the pneumatic simulator. When adduction/abduction was introduced to the gait cycle, there was no significant difference in wear with that obtained under the gait cycle condition without adduction/abduction. This study confirmed the influence of hip simulator design and loading conditions on the wear of polyethylene, and therefore direct comparisons of absolute wear rates between different hip joint simulators should be avoided. This study also confirmed that the resulting wear path was the governing factor in obtaining clinically relevant wear rates, and this can be achieved with either two axes or three axes of rotations. However, three axes of rotation (with the inclusion of adduction/abduction) more closely replicate clinical conditions and should therefore be the design approach for newly developed hip joint simulators used for preclinical testing.

The influence of the representation of collagen fibre organisation on the cartilage contact mechanics of the hip joint.

The aim of this study was to develop a finite element (FE) hip model with subject-specific geometry and biphasic cartilage properties. Different levels of detail in the representation of fibre reinforcement were considered to evaluate the feasibility to simplify the complex depth-dependent fibre pattern in the native hip joint. A FE model of a cadaveric hip with subject-specific geometry was constructed through micro-computed-tomography (µCT) imaging. The cartilage was assumed to be biphasic and fibre-reinforced with different levels of detail in the fibre representation. Simulations were performed for heel-strike, mid-stance and toe-off during walking and one-leg-stance over 1500s. It was found that the required level of detail in fibre representation depends on the parameter of interest. The contact stress of the native hip joint could be realistically predicted by simplifying the fibre representation to being orthogonally reinforced across the whole thickness. To predict the fluid pressure, depth-dependent fibre organisation is needed but specific split-line pattern on the surface of cartilage is not necessary. Both depth-dependent and specific surface fibre orientations are required to simulate the strains.

Whole-pattern fitting technique in serial femtosecond nanocrystallography.

Serial femtosecond X-ray crystallography (SFX) has created new opportunities in the field of structural analysis of protein nanocrystals. The intensity and timescale characteristics of the X-ray free-electron laser sources used in SFX experiments necessitate the analysis of a large collection of individual crystals of variable shape and quality to ultimately solve a single, average crystal structure. Ensembles of crystals are commonly encountered in powder diffraction, but serial crystallography is different because each crystal is measured individually and can be oriented via indexing and merged into a three-dimensional data set, as is done for conventional crystallography data. In this way, serial femtosecond crystallography data lie in between conventional crystallography data and powder diffraction data, sharing features of both. The extremely small sizes of nanocrystals, as well as the possible imperfections of their crystallite structure, significantly affect the diffraction pattern and raise the question of how best to extract accurate structure-factor moduli from serial crystallography data. Here it is demonstrated that whole-pattern fitting techniques established for one-dimensional powder diffraction analysis can be feasibly extended to higher dimensions for the analysis of merged SFX diffraction data. It is shown that for very small crystals, whole-pattern fitting methods are more accurate than Monte Carlo integration methods that are currently used.

The 2015 advanced life support guidelines: a summary and evidence for the updates.

The International Liaison Committee on Resuscitation recently released updated 2015 recommendations for resuscitation. The guidelines form the basis for all levels of resuscitation training, now from first aid to advanced life support (ALS), and for trainees of varying medical skills, from schoolchildren to medical students and consultants. We highlight major updates relating to intra-arrest and postarrest care, and the evidence for their recommendation. We also summarise areas of uncertainty in the evidence for ALS, and highlight current discussions that will likely inform the next round of recommendations.

Prospective One Year Follow Up of HIV Infected Women Screened for Cervical Cancer Using Visual Inspection with Acetic Acid, Cytology and Human Papillomavirus Testing in Johannesburg South Africa.

Cervical cancer is the most common cancer in Sub-Saharan Africa. There are little of HIV-infected women one-year after screening using visual inspection with acetic acid (VIA), HPV or cytology in sub-Saharan Africa.

Osteoarthritic bone marrow lesions almost exclusively colocate with denuded cartilage: a 3D study using data from the Osteoarthritis Initiative.

The aetiology of bone marrow lesions (BMLs) in knee osteoarthritis (OA) is poorly understood. We employed three-dimensional (3D) active appearance modelling (AAM) to study the spatial distribution of BMLs in an OA cohort and compare this with the distribution of denuded cartilage.

Seizure control by decanoic acid through direct AMPA receptor inhibition.

The medium chain triglyceride ketogenic diet is an established treatment for drug-resistant epilepsy that increases plasma levels of decanoic acid and ketones. Recently, decanoic acid has been shown to provide seizure control in vivo, yet its mechanism of action remains unclear. Here we show that decanoic acid, but not the ketones β-hydroxybutryate or acetone, shows antiseizure activity in two acute ex vivo rat hippocampal slice models of epileptiform activity. To search for a mechanism of decanoic acid, we show it has a strong inhibitory effect on excitatory, but not inhibitory, neurotransmission in hippocampal slices. Using heterologous expression of excitatory ionotropic glutamate receptor AMPA subunits in Xenopus oocytes, we show that this effect is through direct AMPA receptor inhibition, a target shared by a recently introduced epilepsy treatment perampanel. Decanoic acid acts as a non-competitive antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects. This inhibitory effect is likely to be caused by binding to sites on the M3 helix of the AMPA-GluA2 transmembrane domain; independent from the binding site of perampanel. Together our results indicate that the direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anti-convulsant effect of the medium chain triglyceride ketogenic diet.

Retrospective Cohort Study to Assess Outcomes, Cost-Effectiveness, and Patient Satisfaction in Primary Vaginal Ovarian Cystectomy versus the Laparoscopic Approach.

To compare surgical outcomes, cost-effectiveness, and patient satisfaction in women undergoing primary vaginal or laparoscopic ovarian cystectomy for benign ovarian cysts.

'Everything's from the inside out with PCOS': Exploring women's experiences of living with polycystic ovary syndrome and co-morbidities through Skype™ interviews.

Polycystic ovary syndrome is an endocrine disorder affecting 1 in 10 women. Women with polycystic ovary syndrome can experience co-morbidities, including depressive symptoms. This research explores the experience of living with polycystic ovary syndrome and co-morbidities. Totally, 10 participants with polycystic ovary syndrome took part in Skype™ interviews and analysed using thematic analysis. Four themes emerged from the data: change (to life plans and changing nature of condition); support (healthcare professionals, education and relationships); co-morbidities (living with other conditions and depression, self-harm and suicidal ideation) and identity (feminine identity and us and them). The findings highlight the need for screening of women with polycystic ovary syndrome for depressive disorders.

Development and characterisation of a decellularised bovine osteochondral biomaterial for cartilage repair.

It is proposed that an acellular natural osteochondral scaffold will provide a successful repair material for the early intervention treatment of cartilage lesions, to prevent or slow the progression of cartilage deterioration to osteoarthritis. Here, we investigated the efficacy of methods for the decellularisation of bovine osteochondral plugs. The plugs were subject to four freeze/thaw cycles followed by two cycles of washes in hypotonic solution and low concentration (0.1% w/v) sodium dodecyl sulphate with protease inhibitors. Plugs were treated with nuclease (DNase and RNase) treatment followed by sterilization in peracetic acid. Full tissue decellularisation was achieved as confirmed by histological analysis and DNA quantification, however the resultant acellular matrix had reduced glycosaminoglycan content which led to an increased percent deformation of cartilage. Furthermore, the acellular scaffold was not reproducibly biocompatible. Additional terminal washes were included in the process to improve biocompatibility, however, this led to visible structural damage to the cartilage. This damage was found to be minimised by reducing the cut edge to cartilage area ratio through decellularisation of larger cuts of osteochondral tissue.

The cannabis conundrum: Thinking outside the THC box.

Exploring Carers' Judgements of Responsibility and Control in Response to the Challenging Behaviour of People with Intellectual Disabilities.

This study examines Weiner's recent cognitive emotional model which makes a distinction between judgements of control and responsibility and emphasizes the moderation of control by 'mitigating' factors.

Studies on the catalytic domains of multiple JmjC oxygenases using peptide substrates.

The JmjC-domain-containing 2-oxoglutarate-dependent oxygenases catalyze protein hydroxylation and N(ϵ)-methyllysine demethylation via hydroxylation. A subgroup of this family, the JmjC lysine demethylases (JmjC KDMs) are involved in histone modifications at multiple sites. There are conflicting reports as to the substrate selectivity of some JmjC oxygenases with respect to KDM activities. In this study, a panel of modified histone H3 peptides was tested for demethylation against 15 human JmjC-domain-containing proteins. The results largely confirmed known N(ϵ)-methyllysine substrates. However, the purified KDM4 catalytic domains showed greater substrate promiscuity than previously reported (i.e., KDM4A was observed to catalyze demethylation at H3K27 as well as H3K9/K36). Crystallographic analyses revealed that the N(ϵ)-methyllysine of an H3K27me3 peptide binds similarly to N(ϵ)-methyllysines of H3K9me3/H3K36me3 with KDM4A. A subgroup of JmjC proteins known to catalyze hydroxylation did not display demethylation activity. Overall, the results reveal that the catalytic domains of the KDM4 enzymes may be less selective than previously identified. They also draw a distinction between the N(ϵ)-methyllysine demethylation and hydroxylation activities within the JmjC subfamily. These results will be of use to those working on functional studies of the JmjC enzymes.

Paradigms and progress in conservation science.

Effect of microseparation on contact mechanics in metal-on-metal hip replacements-A finite element analysis.

Some early failures of metal-on-metal (MoM) hip replacements associated with elevated wear have caused concerns for the use of this bearing combination. Simulator studies have shown that microseparation and its associated rim contact and edge loading may produce the most severe wear in MoM bearings. It is generally recognized that this high wear can be attributed to the high contact stress of the head on the rim of the cup. In this study, an improved finite element contact model that incorporates an elastic-perfectly plastic material property for cobalt-chrome alloy of the metal bearing was developed in an attempt to provide an accurate prediction of the stress and strain for the rim contact. The effects of the microseparation displacement (0.1-2 mm), cup inclination angle (25-65°) and cup rim radius (0.5-4 mm) on the contact stress/strain were investigated. The results show that a translational displacement >0.1 mm under a load >0.5 kN can produce a highly concentrated contact stress at the surface of the cup rim which can lead to plastic deformation. This study also suggests that the magnitude of translational displacement was the major factor that determined the severity of the contact conditions and level of stress and strain under microseparation conditions. Future studies will address the effect of surgical translational and rotational malposition and component design on the magnitude of microseparation, contact stress and strain and severity of wear.

Seizure control by derivatives of medium chain fatty acids associated with the ketogenic diet show novel branching-point structure for enhanced potency.

The medium chain triglyceride (MCT) ketogenic diet is a major treatment of drug-resistant epilepsy but is problematic, particularly in adults, because of poor tolerability. Branched derivatives of octanoic acid (OA), a medium chain fat provided in the diet have been suggested as potential new treatments for drug-resistant epilepsy, but the structural basis of this functionality has not been determined. Here we investigate structural variants of branched medium chain fatty acids as new seizure-control treatments. We initially employ a series of methyl-branched OA derivatives, and using the GABAA receptor antagonist pentylenetetrazol to induce seizure-like activity in rat hippocampal slices, we show a strong, branch-point-specific activity that improves upon the related epilepsy treatment valproic acid. Using low magnesium conditions to induce glutamate excitotoxicity in rat primary hippocampal neuronal cultures for the assessment of neuroprotection, we also show a structural dependence identical to that for seizure control, suggesting a related mechanism of action for these compounds in both seizure control and neuroprotection. In contrast, the effect of these compounds on histone deacetylase (HDAC) inhibition, associated with teratogenicity, shows no correlation with therapeutic efficacy. Furthermore, small structural modifications of the starting compounds provide active compounds without HDAC inhibitory effects. Finally, using multiple in vivo seizure models, we identify potent lead candidates for the treatment of epilepsy. This study therefore identifies a novel family of fatty acids, related to the MCT ketogenic diet, that show promise as new treatments for epilepsy control and possibly other MCT ketogenic diet-responding conditions, such as Alzheimer disease.

A snapshot of the lives of women with polycystic ovary syndrome: A photovoice investigation.

Polycystic ovary syndrome affects 6  percent of women. Symptoms include hirsutism, acne, and infertility. This research explores the impact of polycystic ovary syndrome on women's lives using photovoice. Nine participants photographed objects related to their quality of life and made diary entries explaining each photograph. Three themes emerged from thematic analysis of the diaries: control (of symptoms and polycystic ovary syndrome controlling their lives), perception (of self, others, and their situation), and support (from relationships, health care systems, and education). These findings illuminate positive aspects of living with polycystic ovary syndrome and the role pets and social networking sites play in providing support for women with polycystic ovary syndrome.