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Predicting the impacts of multiple stressors is important for informing ecosystem management but is impeded by a lack of a general framework for predicting whether stressors interact synergistically, additively or antagonistically. Here, we use process-based models to study how interactions generalise across three levels of biological organisation (physiological, population and consumer-resource) for a two-stressor experiment on a seagrass model system. We found that the same underlying processes could result in synergistic, additive or antagonistic interactions, with interaction type depending on initial conditions, experiment duration, stressor dynamics and consumer presence. Our results help explain why meta-analyses of multiple stressor experimental results have struggled to identify predictors of consistently non-additive interactions in the natural environment. Experiments run over extended temporal scales, with treatments across gradients of stressor magnitude, are needed to identify the processes that underpin how stressors interact and provide useful predictions to management.

Amelogenesis imperfecta (AI) describes a heterogeneous group of developmental enamel defects that typically have Mendelian inheritance. Exome sequencing of 10 families with recessive hypomaturation AI revealed four novel and one known variants in the matrix metallopeptidase 20 (MMP20) gene that were predicted to be pathogenic. MMP20 encodes a protease that cleaves the developing extracellular enamel matrix and is necessary for normal enamel crystal growth during amelogenesis. New homozygous missense changes were shared between four families of Pakistani heritage (c.625G>C; p.(Glu209Gln)) and two of Omani origin (c.710C>A; p.(Ser237Tyr)). In two families of UK origin and one from Costa Rica, affected individuals were homozygous for the previously reported c.954-2A>T; p.(Ile319Phefs*19) variant. For each of these variants, microsatellite haplotypes appeared to exclude a recent founder effect, but elements of haplotype were conserved, suggesting more distant founding ancestors. New compound heterozygous changes were identified in one family of the European heritage: c.809_811+12delinsCCAG; p.(?) and c.1122A>C; p.(Gln374His). This report further elucidates the mutation spectrum of MMP20 and the probable impact on protein function, confirms a consistent hypomaturation phenotype and shows that mutations in MMP20 are a common cause of autosomal recessive AI in some communities.

© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd. Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non-syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix. Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT-variant associated AI.

Amelogenesis imperfecta (AI) is a heterogeneous group of inherited disorders characterized by abnormal formation of dental enamel, either in isolation or as part of a syndrome. Heterozygous variants in laminin subunit beta 3 (LAMB3) cause AI with dominant inheritance in the absence of other cosegregating clinical features. In contrast, biallelic loss-of-function variants in LAMB3 cause recessive junctional epidermolysis bullosa, characterized by life-threatening skin fragility. We identified 2 families segregating autosomal dominant AI with variable degrees of a distinctive hypoplastic phenotype due to pathogenic variants in LAMB3. Whole exome sequencing revealed a nonsense variant (c.3340G>T, p.E1114*) within the final exon in family 1, while Sanger sequencing in family 2 revealed a variant (c.3383-1G>A) in the canonical splice acceptor site of the final exon. Analysis of cDNA from family 2 revealed retention of the final intron leading to a premature termination codon. Two unerupted third molar teeth from individual IV:5 in family 2 were subject to computerized tomography and scanning electron microscopy. LAMB3 molar teeth have a multitude of cusps versus matched controls. LAMB3 enamel was well mineralized but pitted. The architecture of the initially secreted enamel was abnormal, with cervical enamel appearing much less severely affected than coronal enamel. This study further defines the variations in phenotype-genotype correlation for AI due to variants in LAMB3, underlines the clustering of nonsense and frameshift variants causing AI in the absence of junctional epidermolysis bullosa, and highlights the shared AI phenotype arising from variants in genes coding for hemidesmosome proteins.

Objectives: The sources and types of social support that athletes receive during the transition out of sport have been well documented. However, less is known about how athletes perceive, mobilise, and manage supportive relationships. This study aimed therefore to gain a more comprehensive insight into the ways that social support may influence how athletes adjust to life following retirement from elite sport. Design: The study was designed according to the principles of Interpretative Phenomenological Analysis. Method: Eight former British elite athletes (four male and four female) from eight different Olympic sports were recruited using criterion-based purposive sampling strategies. Data collected using semi-structured interviews were analysed to explore subjective experiences of social support during transition. Results: Participants' perception of feeling cared for and understood enabled support to be effective. There were variations in participants' ability to seek out and ask for support and those who found this difficult also found transition a more distressing experience. As transitions progressed, the adjustment process was closely linked to the participant's evolving sense of self. New social relationships and social roles fostered a sense of feeling supported, as well as providing opportunities to support others (e.g., other retired athletes). Providing support helped the participants to experience a sense of growth that facilitated adjustment to life after sport. Conclusions: The content of support was largely dependent on context; that is, perceptions of supporters were just as important, if not more so, than specific support exchanges. Stigma around asking for help was a barrier to support seeking.

Background The management of rectal cancer has evolved over the years, including the recent rise of Transanal Total Mesorectal Excision (TaTME). TaTME addresses the limitations created by the bony confines of the pelvis, bulky tumours, and fatty mesorectum, particularly for low rectal cancers. However, guidance is required to ensure safe implementation and to avoid the pitfalls and potential major morbidity encountered by the early adopters of TaTME. We report a broad international consensus statement, which provides a basis for optimal clinical practice. Methods Forty international experts were invited to participate based on clinical and academic achievements. The consensus statements were developed using Delphi methodology incorporating three successive rounds. Consensus was defined as agreement by 80% or more of the experts. Results A total of 37 colorectal surgeons from 20 countries and 5 continents (Europe, Asia, North and South America, Australasia) contributed to the consensus. Participation to the iterative Delphi rounds was 100%. An expert radiologist, pathologist, and medical oncologist provided recommendations to maximize relevance to current practice. Consensus was obtained on all seven different chapters: patient selection and surgical indication, perioperative management, patient positioning and operating room set up, surgical technique, devices and instruments, pelvic anatomy, TaTME training, and outcomes analysis. Conclusions This multidisciplinary consensus statement achieved more than 80% approval and can thus be graded as strong recommendation, yet acknowledging the current lack of high level evidence. It provides the best possible guidance for safe implementation and practice of Transanal Total Mesorectal Excision.

Although marine protected areas can simultaneously contribute to biodiversity conservation and fisheries management, the global network is biased toward particular ecosystem types because they have been established primarily in an ad hoc fashion. The optimization of trade‐offs between biodiversity benefits and socioeconomic values increases success of protected areas and minimizes enforcement costs in the long run, but it is often neglected in marine spatial planning (MSP). Although the acquisition of spatially explicit socioeconomic data is perceived as a costly or secondary step in MSP, it is critical to account for lost opportunities by people whose activities will be restricted, especially fishers. We developed an easily reproduced habitat‐based approach to estimate the spatial distribution of opportunity cost to fishers in data‐poor regions. We assumed the most accessible areas have higher economic and conservation values than less accessible areas and their designation as no‐take zones represents a loss of fishing opportunities. We estimated potential distribution of fishing resources from bathymetric ranges and benthic habitat distribution and the relative importance of the different resources for each port of total catches, revenues, and stakeholder perception. In our model, we combined different cost layers to produce a comprehensive cost layer so that we could evaluate of trade‐offs. Our approach directly supports conservation planning, can be applied generally, and is expected to facilitate stakeholder input and community acceptance of conservation.

In March 2010, four days of GNSS data were gathered on the Severn Suspension Bridge. The GNSS antennas were located on the tops of the four support towers, as well as five locations on the suspension cables. The Severn Bridge has a main suspended span of 998m long. The GNSS data were gathered at rates of 10Hz and 20Hz between the 10th to the 12th and on the morning of the 18th March 2010. In addition to the GNSS data, the air and steel temperatures were gathered every 10 minutes. The GNSS data were processed in an On The Fly manner relative to a reference GNSS receiver located on a solid building adjacent to the Bridge.

A significant unmet clinical need in orthopaedic traumatology is improved bone screw fixation in poor quality bone. It is estimated that over 100 million1 screws are implanted worldwide annually. Loosening & migration are significant clinical complications in osteoporotic fractures. In the proximal humerus and femur failure rates may be as high as 40% and 7% respectively2,3. Bone screws should assure adequate fixation at early (days) and late (weeks) time points, as well as easy removal at revision. It should be possible to design screws/techniques that would improve fixation in weak bone but this is an area neglected by the manufacturers. Paradoxically bone screws are contraindicated for use in osteoporotic bone in instructions for use (IFU) although osteoporotic fractures are the most frequent application for screw fixation. Techniques that may enhance screw stability in weak bone, such as the addition of cement at the time of surgery or use of hydroxyapatite coatings have long been under consideration. This paper considers bone augmentation, what has been learned and goes on to suggest what could be done to gain clinical acceptance of these techniques.

Variation of Crack Tip Opening Displacement (CTOD) test values can have a significant effect on the Engineering Critical Assessment of a structure. This paper examines the development of CTOD with increasing load in an austenitic stainless steel. The silicone replication method giving variation of CTOD across the specimen thickness, and Digital Image Correlation (DIC) are compared to each other, and in turn to clip gauge measurements from tests. Results from Finite Element models are also presented. Estimations of CTOD from BS 7448-1, ISO 12135 and ASTM E1820, and a proposed modification from JWES are compared to the experimental data from the crack cast in silicone compound – assumed to be the actual CTOD. The DIC measurement showed consistency with crack replicas, and a formula is given to estimate CTOD using DIC. For high strain hardening austenitic stainless steel, both the JWES and ASTM E1820 estimations provide adequate accuracy for CTOD. The authors wish to acknowledge the funding and facility provided by TWI and NSIRC for this work.

Question: Do variations of income impact rates of perforation in patients with acute appendicitis? Are variations in appendiceal perforation related to income consistent across these 2 countries? Design: Cohort study using administrative data. Data sources: Canadian Institute for Health Information (CIHI) database (102 692 patients) and the US Nationwide Inpatient Sample (NIS; 276 890 patients). Patient sample: Patients with acute appendicitis diagnosed from 2001 to 2005 were identified using ICD-9 codes. Patients were characterized further by age, sex, insurance status, race and socioeconomic status. Results: In Canada, there was no difference in the odds of perforation among income levels. In the United States, there was a significant, inverse relation between income level and the odds of perforation. The odds of perforation in the lowest income bracket were significantly higher than those in the highest income bracket (odds ratio 1.20, 95% confidence iterval 1.16–1.24). Conclusion: The results suggest that access to emergency operative care is related to socioeconomic status in the United States, but not in Canada. This difference could result from the concern over the ability to pay medical bills or the lack of a stable relationship with a primary care provider that can occur outside of a universal health care system.

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University. This work deals with the underlying physical mechanisms and processes that dominate the fracture of cement based materials and their electrical properties. Electric current emissions were recorded when hardened cement pastes and cement mortars suffered mechanical loading in various modes. Such electric current emissions are known as Pressure Stimulated Currents (PSC) when the applied loading is compressional while they are mentioned as Bending Stimulated Currents (BSC) when the material suffers bending loadings. The physical mechanism responsible for the PSC and BSC emissions can be interpreted in terms of the Moving Charged Dislocations model that correlates mechanical deformation and electric charge distortions in the sample bulk. Laboratory experiments were designed based on the mechanical and physical properties of cement. To conduct the experiments all the background material concerning cement fracture mechanics, the microstructure of the hardened cement paste and the Interfacial Transition Zone of cement mortar were taken into consideration. Additionally, the experience of the PSC technique when it was applied on marble samples was used to guide the experimental procedures and compare qualitatively and quantitatively the experimental results. The relationship between the emitted PSC and the strain was established for the very first time for cement based materials in the present work. When the material was stressed within the range where stress and strain are linearly related a linear relation between PSC and stress rate (d/dt) was observed. Deviation from this linearity appeared when the applied stress was in the range where the applied stress and the yielded strain were not linearly related. Slightly before fracture, intense, non-linear PSC emissions were detected. The damage of the sample structure due to excessive loading in the plastic region significantly affected the recorded phenomena. Bending tests proved that similar electric current emissions are detected when a sample beam suffers 3 Point Bending Tests. The dependence of the emitted electric current on the way of fracture (i.e. compressional or tensional) was proved. It was also shown that the magnitude of the emitted electric current is directly related to the magnitude of damage due to the external loading. Thus, as it was expected, the electric current emitted from the tensed zone is significantly greater than the corresponding emitted from the compressed zone.

This thesis was submitted for the degree of Doctor of Philosophy and was awarded by Brunel University. An intramedullary nail is a trauma treatment device used for fracture fixation of long bones. These devices are subject to failure, including lag screw cut-out and failure at the lag screw insertion hole from high stress concentrations in that region. Clinical developments for such devices are frequently based on a trial and error method, which often results in failure before improvement. However, the finite element method can be used for the development of trauma treatment devices, and their interaction with bone, by providing a large data set at a relatively low cost. Also, parameters can be changed to assess the relative benefits of one device to another. A novel finite element model has been developed that can be used for the analysis of intramedullary nails inserted into long bones. A commercially available finite element package, ANSYS, has been used to implement the modelling strategy. The finite element modelling technique has been applied to fractures of the proximal femur, but the model is generic, and can be developed to deal with any form of intramedullary device where contact between the bone and implant is important. The finite element strategy can be used in pre-clinical trials to test a new device, or for the design optimisation of existing devices. The finite element model consists of the device surrounded by a thin layer of bone, which forms a 'base' model component that is re-usable. This 'base' component can be mathematically connected to any long bone model, forming an integrated implant and bone construct. The construct can be used to assess which device is best suited to a particular fracture, for example. Contact elements have been used to allow stresses to develop as contact is achieved within the implant and bone construct. Pre-assignment of contact points is not required. Verification of the finite element model is achieved by comparison to available data from experiments carried out on constructs of bone and device that use intramedullary femoral nails. In this thesis the finite element model has been applied to two areas of proximal femoral nailing. The finite element model is used to analyse the distal end of a Gamma nail, and shows that analyses that do not consider contact may not lead to accurate predictions of stresses. The model has been developed for using configurations with one and two distal locking screws. The most distal locking screw is more critical under axial loading, and the more proximal screw is more important for bending loads. The use of 'softer' screws distributes the load more evenly between them. The finite element model has been used to investigate the mechanical environment of a fracture callus for a femoral neck fracture, and a subtrochanteric fracture. The use of one and two lag screws, fracture gap size and material properties of the nail have been investigated for a stiffening callus. Results show that the use of two lag screws for a neck fracture provides a more rigid support at the early stages of fracture healing, and minimises stress-shielding once the callus has healed. For subtrochanteric fractures there is a critical point at which the fracture callus is able to carry any load. A Titanium nail significantly reduces the peak stress at the lag screw insertion hole, and titanium lag screws share the load more evenly between them. Each two-lag-screw configuration used transfers a similar load into the fracture callus. A configuration using a larger lag screw above a smaller has a significantly higher stress at the upper lag screw insertion hole. Critically, the load shared between two lag screws changes as the fracture callus stiffens and an assessment should be made at different stages of fracture healing to optimise the use of a device. Brunel University

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University. The purpose of this research was to investigate the parameters that influence the structural behaviour of a specific suspension bridge, The Humber Bridge. Three finite element computer models of increasing complexity were created for the analyses. They were validated against field measurements for both static and dynamic loading, and good correlation was obtained. The programs were used to a) Assess the integrity of the bridge as a whole were three failures of certain individual elements, such as a hanger falling under vehicle impact; b) Determine the influence of the sizing of individual components, such as deck plate thickness or main cable diameter, on overall behaviour; c) ascertain the capability of the structure to cope with loading (traffic, wind orthermal), above the original design values; and d) consider the performance of the bridge had other configurations of hangers been adopted in the original design. From the results of this work, recommendations are made which could influence the future design of long-span suspension bridges.

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University. The main aim of this research is directed towards the study of thin-walled rectangular planform silos with a view to maximising their structural efficiency. In thin plates of the type making up the wall, membrane action may increase the load carrying capability and current design guides make no account of this. Designing rectangular silos with this in mind can lead to significant structural savings. The core of the research involves using the finite element method to study the patterns of pressure exerted by the weight of a granular bulk solid on the walls of the silo structure. The stored granular solid must use an elastic-plastic material law in order to account for large deformations that can occur in a thin-walled structure. The need for this type of constitutive law led to the investigation of bulk solid properties and shows that parameters that have previously been used to categorise bulk solids may not be sufficient to describe all aspects of their behaviour. The finite element model created uses material constitutive laws that can be found in a number of packages. The required granular material parameters can be determined from a number of simple tests. This approach aims to enable engineers to routinely use similar models when designing silos. The results obtained from the finite element model exhibited some anomalies that had been observed in previous work. These were mainly apparent in the form of localised pressure peaks near the base of the model. These effects were investigated and possible mechanisms that lead to them were proposed. The results from the finite element model were compared to previous experimental work and existing theories. The model was then used to conduct parametric surveys on square and rectangular planform silos and the distribution of pressure across the wall compared to previous predictive models. Finally, a scale thin-walled metal silo was constructed and pressure measurements on filling with pea gravel made. These are compared to predictions made by the finite element model. Mr Chris Brown

Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species. The predicted protein has significant similarities with proteins involved in neural cell adhesion and axonal pathfinding, as well as with protein kinases and phosphatases, which suggests that this gene could have a specific role in neuronal migration.

X-chromosome inactivation results in the cis-limited dosage compensation of genes on one of the pair of X chromosomes in mammalian females. Although most X-linked genes are believed to be subject to inactivation, several are known to be expressed from both active and inactive X chromosomes. Here we describe an X-linked gene with a novel expression pattern--transcripts are detected only from the inactive X chromosome (Xi) and not from the active X chromosome (Xa). This gene, called XIST (for Xi-specific transcripts), is a candidate for a gene either involved in or uniquely influenced by the process of X inactivation.

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University. The pressure cxcrtcd by the stored material on rcctangular planform flexible walled silos is investigated during filling and discharge. Tests on a large scale steel model silo with a pyramidal hopper showed that the stress state of the stored material is significantly influenced by the wall flexibility and boundary conditions. The measured wall pressures were very different to pressures predicted by traditional theories and existing design codes. This is because traditional theories were developed for rigid walled circular silos and they ignore the effects of stored material/structure interaction. In this thesis the results of tests to measure the stress state throughout the contents of a flexible silo and pyramidal hopper are presenteda nd compared with measurementso f the structural response. The tests show that the redistribution of stresses within the stored material is cxtcnsive and is influenced by the corners in non-circular silos and horizontal and vertical stiffeners. As wall flexibility increases, the ereis increased freedom for stresses imposed by the stored material to redistribute and reduce the structural forces in the wall. The measured pressure in the corners of the model silo were up to nine times the pressure as the centre of the wall at the same level. The failure to incorporate the redistribution in to the model design led to a considerable over estimate of the wall stresses. Many existing measurements of pressures in the stored material in silos were weakened because of inaccurate instrumentation. In this study. considerable care was taken during the selection of pressure cells. Calibration and equilibrium checks to ensure the accuracy of measured data. Pressure was measured in four directions at forty eight positions in the model to determine the total stress state throughout the stored material. The results showed that wall pressures were influenced by five different arching phenomena. It is concludedt hat the cxisting theory is not accurate for pressure calculation in flexible non-circular silos. The use of a more accurate theory for the calculation of wall pressure can lead to extensive savings in the cost of the silo structure.