Constant power - continuously variable transmission (CP-CVT): Optimisation and simulation

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.A novel continuously variable transmission has previously been designed that is capable of addressing a number of concerns within the automotive industry such as reduced emissions. At the commencement of this research, the design was in the early stages of development and little attempt had been previously made to optimise the design to meet specific measurable targets. This thesis utilises and modifies several design approaches to take the design from the concept stage to a usable product. Several optimisation techniques are adapted and created to analyse the CVT from both a design and tribological prospective. A specially designed optimisation algorithm has been created that is capable of quickly improving each critical component dimension in parallel to fulfil multiple objectives. This algorithm can be easily adapted for alternative applications and objectives. The validity of the optimised design is demonstrated through a simulation-tool that has been created in order to model the behaviour of the CVT in a real automotive environment using multiple fundamental theories and models including tire friction and traction behaviour. This powerful simulation tool is capable of predicting transmission and vehicular behaviour, and demonstrates a very good correlation with real-world data. A design critique is then performed that assesses the current state of the CVT design, and looks to address some of the concerns that have been found through the various methods used. A specific prototype design is also presented, based on the optimisation techniques developed, although the actual creation of a prototype is not presented here. Additional complementary research looks at the accuracy of the tire friction models through the use of a specially design tire friction test rig. Furthermore, a monitoring system is proposed for this particular CVT design (and similar) that is capable of continuously checking the contact film thickness between adjacent elements to ensure that there is sufficient lubricant to avoid metal-on-metal contact. The system, which is based around capacitance, requires the knowledge of the behaviour of the lubricant’s permittivity at increased pressure. This behaviour is studied through the use of a specially-designed experimental test rig.Thomas Gerald Gray Charitable Trus

Constant power-continuously variable transmission (CP-CVT) : optimisation and simulation

A novel continuously variable transmission has previously been designed that is capable of addressing a number of concerns within the automotive industry such as reduced emissions. At the commencement of this research, the design was in the early stages of development and little attempt had been previously made to optimise the design to meet specific measurable targets. This thesis utilises and modifies several design approaches to take the design from the concept stage to a usable product. Several optimisation techniques are adapted and created to analyse the CVT from both a design and tribological prospective. A specially designed optimisation algorithm has been created that is capable of quickly improving each critical component dimension in parallel to fulfil multiple objectives. This algorithm can be easily adapted for alternative applications and objectives. The validity of the optimised design is demonstrated through a simulation-tool that has been created in order to model the behaviour of the CVT in a real automotive environment using multiple fundamental theories and models including tire friction and traction behaviour. This powerful simulation tool is capable of predicting transmission and vehicular behaviour, and demonstrates a very good correlation with real-world data. A design critique is then performed that assesses the current state of the CVT design, and looks to address some of the concerns that have been found through the various methods used. A specific prototype design is also presented, based on the optimisation techniques developed, although the actual creation of a prototype is not presented here. Additional complementary research looks at the accuracy of the tire friction models through the use of a specially design tire friction test rig. Furthermore, a monitoring system is proposed for this particular CVT design (and similar) that is capable of continuously checking the contact film thickness between adjacent elements to ensure that there is sufficient lubricant to avoid metal-on-metal contact. The system, which is based around capacitance, requires the knowledge of the behaviour of the lubricant’s permittivity at increased pressure. This behaviour is studied through the use of a specially-designed experimental test rig.EThOS - Electronic Theses Online ServiceThomas Gerald Gray Charitable TrustGBUnited Kingdo

Intrinsic calf factors associated with the behavior of healthy pre-weaned group-housed dairy-bred calves

Technology-derived behaviors are researched for disease detection in artificially-reared calves. Whilst existing studies demonstrate differences in behaviors between healthy and diseased calves, intrinsic calf factors (e.g., sex and birthweight) that may affect these behaviors have received little systematic study. This study aimed to understand the impact of a range of calf factors on milk feeding and activity variables of dairy-bred calves. Calves were group-housed from ~7 days to 39 days of age. Seven liters of milk replacer was available daily from an automatic milk feeder, which recorded feeding behaviors and live-weight. Calves were health scored daily and a tri-axial accelerometer used to record activity variables. Healthy calves were selected by excluding data collected 3 days either side of a poor health score or a treatment event. Thirty-one calves with 10 days each were analyzed. Mixed models were used to identify which of live-weight, age, sex, season of birth, age of inclusion into the group, dam parity, birthweight, and sire breed type (beef or dairy), had a significant influence on milk feeding and activity variables. Heavier calves visited the milk machine more frequently for shorter visits, drank faster and were more likely to drink their daily milk allowance than lighter calves. Older calves had a shorter mean standing bout length and were less active than younger calves. Calves born in summer had a longer daily lying time, performed more lying and standing bouts/day and had shorter mean standing bouts than those born in autumn or winter. Male calves had a longer mean lying bout length, drank more slowly and were less likely to consume their daily milk allowance than their female counterparts. Calves that were born heavier had fewer lying and standing bouts each day, a longer mean standing bout length and drank less milk per visit. Beef-sired calves had a longer mean lying bout length and drank more slowly than their dairy sired counterparts. Intrinsic calf factors influence different healthy calf behaviors in different ways. These factors must be considered in the design of research studies and the field application of behavior-based disease detection tools in artificially reared calves

“What if There's Something Wrong with Her?”‐How Biomedical Technologies Contribute to Epistemic Injustice in Healthcare

While there is a steadily growing literature on epistemic injustice in healthcare, there are few discussions of the role that biomedical technologies play in harming patients in their capacity as knowers. Through an analysis of newborn and pediatric genetic and genomic sequencing technologies (GSTs), I argue that biomedical technologies can lead to epistemic injustice through two primary pathways: epistemic capture and value partitioning. I close by discussing the larger ethical and political context of critical analyses of GSTs and their broader implications for just and equitable healthcare delivery

Identification of DEK as a potential therapeutic target for neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer which does not respond to hormone therapy. Research of NEPC has been hampered by a lack of clinically relevant in vivo models. Recently, we developed a first-in-field patient tissue-derived xenograft model of complete neuroendocrine transdifferentiation of prostate adenocarcinoma. By comparing gene expression profiles of a transplantable adenocarcinoma line (LTL331) and its NEPC subline (LTL331R), we identified DEK as a potential biomarker and therapeutic target for NEPC. In the present study, elevated DEK protein expression was observed in all NEPC xenograft models and clinical NEPC cases, as opposed to their benign counterparts (0%), hormonal naïve prostate cancer (2.45%) and castration-resistant prostate cancer (29.55%). Elevated DEK expression was found to be an independent clinical risk factor, associated with shorter disease-free survival of hormonal naïve prostate cancer patients. DEK silencing in PC-3 cells led to a marked reduction in cell proliferation, cell migration and invasion. The results suggest that DEK plays an important role in the progression of prostate cancer, especially to NEPC, and provides a potential biomarker to aid risk stratification of prostate cancer and a novel target for therapy of NEPC

Assessing agreement between malaria slide density readings

BACKGROUND: Several criteria have been used to assess agreement between replicate slide readings of malaria parasite density. Such criteria may be based on percent difference, or absolute difference, or a combination. Neither the rationale for choosing between these types of criteria, nor that for choosing the magnitude of difference which defines acceptable agreement, are clear. The current paper seeks a procedure which avoids the disadvantages of these current options and whose parameter values are more clearly justified. METHODS AND RESULTS: Variation of parasite density within a slide is expected, even when it has been prepared from a homogeneous sample. This places lower limits on sensitivity and observer agreement, quantified by the Poisson distribution. This means that, if a criterion of fixed percent difference criterion is used for satisfactory agreement, the number of discrepant readings is over-estimated at low parasite densities. With a criterion of fixed absolute difference, the same happens at high parasite densities. For an ideal slide, following the Poisson distribution, a criterion based on a constant difference in square root counts would apply for all densities. This can be back-transformed to a difference in absolute counts, which, as expected, gives a wider range of acceptable agreement at higher average densities. In an example dataset from Tanzania, observed differences in square root counts correspond to a 95% limits of agreement of -2,800 and +2,500 parasites/microl at average density of 2,000 parasites/microl, and -6,200 and +5,700 parasites/microl at 10,000 parasites/microl. However, there were more outliers beyond those ranges at higher densities, meaning that actual coverage of these ranges was not a constant 95%, but decreased with density. In a second study, a trial of microscopist training, the corresponding ranges of agreement are wider and asymmetrical: -8,600 to +5,200/microl, and -19,200 to +11,700/microl, respectively. By comparison, the optimal limits of agreement, corresponding to Poisson variation, are +/- 780 and +/- 1,800 parasites/microl, respectively. The focus of this approach on the volume of blood read leads to other conclusions. For example, no matter how large a volume of blood is read, some densities are too low to be reliably detected, which in turn means that disagreements on slide positivity may simply result from within-slide variation, rather than reading errors. CONCLUSIONS: The proposed method defines limits of acceptable agreement in a way which allows for the natural increase in variability with parasite density. This includes defining the levels of between-reader variability, which are consistent with random variation: disagreements within these limits should not trigger additional readings. This approach merits investigation in other settings, in order to determine both the extent of its applicability, and appropriate numerical values for limits of agreement

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Large-scale sequencing of SARS-CoV-2 genomes from one region allows detailed epidemiology and enables local outbreak management.

The COVID-19 pandemic has spread rapidly throughout the world. In the UK, the initial peak was in April 2020; in the county of Norfolk (UK) and surrounding areas, which has a stable, low-density population, over 3200 cases were reported between March and August 2020. As part of the activities of the national COVID-19 Genomics Consortium (COG-UK) we undertook whole genome sequencing of the SARS-CoV-2 genomes present in positive clinical samples from the Norfolk region. These samples were collected by four major hospitals, multiple minor hospitals, care facilities and community organizations within Norfolk and surrounding areas. We combined clinical metadata with the sequencing data from regional SARS-CoV-2 genomes to understand the origins, genetic variation, transmission and expansion (spread) of the virus within the region and provide context nationally. Data were fed back into the national effort for pandemic management, whilst simultaneously being used to assist local outbreak analyses. Overall, 1565 positive samples (172 per 100 000 population) from 1376 cases were evaluated; for 140 cases between two and six samples were available providing longitudinal data. This represented 42.6 % of all positive samples identified by hospital testing in the region and encompassed those with clinical need, and health and care workers and their families. In total, 1035 cases had genome sequences of sufficient quality to provide phylogenetic lineages. These genomes belonged to 26 distinct global lineages, indicating that there were multiple separate introductions into the region. Furthermore, 100 genetically distinct UK lineages were detected demonstrating local evolution, at a rate of ~2 SNPs per month, and multiple co-occurring lineages as the pandemic progressed. Our analysis: identified a discrete sublineage associated with six care facilities; found no evidence of reinfection in longitudinal samples; ruled out a nosocomial outbreak; identified 16 lineages in key workers which were not in patients, indicating infection control measures were effective; and found the D614G spike protein mutation which is linked to increased transmissibility dominates the samples and rapidly confirmed relatedness of cases in an outbreak at a food processing facility. The large-scale genome sequencing of SARS-CoV-2-positive samples has provided valuable additional data for public health epidemiology in the Norfolk region, and will continue to help identify and untangle hidden transmission chains as the pandemic evolves.The sequencing costs were funded by the COVID-19 Genomics UK (COG-UK) Consortium which is supported by funding from the Medical Research Council (MRC) part of UK Research and Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute

GEO-6 assessment for the pan-European region

Through this assessment, the authors and the United Nations Environment Programme (UNEP) secretariat are providing an objective evaluation and analysis of the pan-European environment designed to support environmental decision-making at multiple scales. In this assessment, the judgement of experts is applied to existing knowledge to provide scientifically credible answers to policy-relevant questions. These questions include, but are not limited to the following:• What is happening to the environment in the pan-European region and why?• What are the consequences for the environment and the human population in the pan-European region?• What is being done and how effective is it?• What are the prospects for the environment in the future?• What actions could be taken to achieve a more sustainable future?<br/

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes