Long-term ticagrelor monotherapy versus standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation: rationale and design of the GLOBAL LEADERS trial

AIMS The GLOBAL LEADERS trial is a superiority study in patients undergoing percutaneous coronary intervention, with a uniform use of Biolimus A9-eluting stents (BES) and bivalirudin. GLOBAL LEADERS was designed to assess whether a 24-month antithrombotic regimen with ticagrelor and one month of acetylsalicylic acid (ASA), compared to conventional dual antiplatelet therapy (DAPT), improves outcomes. METHODS AND RESULTS Patients (n >16,000) are randomised (1:1 ratio) to ticagrelor 90 mg twice daily for 24 months plus ASA ≤100 mg for one month versus DAPT with either ticagrelor (acute coronary syndrome) or clopidogrel (stable coronary artery disease) for 12 months plus ASA ≤100 mg for 24 months. The primary outcome is a composite of all-cause mortality or non-fatal, new Q-wave myocardial infarction at 24 months. The key safety endpoint is investigator-reported class 3 or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) definitions. Sensitivity analysis will be carried out to explore potential differences in outcome across geographic regions and according to specific angiographic and clinical risk estimates. CONCLUSIONS The GLOBAL LEADERS trial aims to assess the role of ticagrelor as a single antiplatelet agent after a short course of DAPT for the long-term prevention of cardiac adverse events, across a wide spectrum of patients, following BES implantation.

Arterial healing following primary PCI using the Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) versus the durable polymer everolimus-eluting metallic stent (XIENCE) in patients with acute ST-elevation myocardial infarction: rationale and design of the randomised TROFI II study

AIMS The Absorb bioresorbable vascular scaffold (Absorb BVS) provides similar clinical outcomes compared with a durable polymer-based everolimus-eluting metallic stent (EES) in stable coronary artery disease patients. ST-elevation myocardial infarction (STEMI) lesions have been associated with delayed arterial healing and impaired stent-related outcomes. The purpose of the present study is to compare directly the arterial healing response, angiographic efficacy and clinical outcomes between the Absorb BVS and metallic EES. METHODS AND RESULTS A total of 191 patients with acute STEMI were randomly allocated to treatment with the Absorb BVS or a metallic EES 1:1. The primary endpoint is the neointimal healing (NIH) score, which is calculated based on a score taking into consideration the presence of uncovered and malapposed stent struts, intraluminal filling defects and excessive neointimal proliferation, as detected by optical frequency domain imaging (OFDI) six months after the index procedure. The study will provide 90% power to show non-inferiority of the Absorb BVS compared with the EES. CONCLUSIONS This will be the first randomised study investigating the arterial healing response following implantation of the Absorb BVS compared with the EES. The healing response assessed by a novel NIH score in conjunction with results on angiographic efficacy parameters and device-oriented events will elucidate disease-specific applications of bioresorbable scaffolds.

Efficiency in Managing the Environment and the Opportunity Cost of Pollution Abatement

Using the directional distance function we study a cross section of 110 countries to examine the efficiency of management of the tradeoffs between pollution and income. The DEA model is reformulated to permit 'reverse disposability' of the bad output. Further, we interpret the optimal solution of the multiplier form of the DEA model as an iso-inefficiency line. This permits us to measure the shadow cost of the bad output for a country that is in the interior, rather than on the frontier of the production possibilities set. We also compare the relative environmental performance of countries in terms of emission intensity adjusted for technical efficiency. Only 10% of the countries are found to be on the frontier. Also, there is considerable inter-country variation in the imputed opportunity cost of CO2 reduction. Further, differences in technical efficiency contribute substantially to differences in the observed levels of CO2 intensity.

AN ASSESSMENT OF AFLATOXIN B1, AND OTHER SELECTED VARIABLES, IN A RURAL ENVIRONMENT AND ASSOCIATED CANCER RISK (TEXAS)

A study to assess possible exposure to carcinogenic metabolites (aflatoxins) from a mold Aspergillus flavus has been made in a rice producing area of Brazoria County, Texas. One hundred samples of unmilled rice were analyzed by thin-layer chromatography (TLC) for the amount of aflatoxin produced by the mold during rice growth and storage. Two well water samples and two rice elevator dust samples were also checked for possible aflatoxin content. The mortality rates from gastrointestinal and urinary tract cancers in the rice-growing part of the county were compared with mortality rates in the nonrice-producing areas of the same county.^ This study was an outgrowth of an earlier investigation by Cech and co-workers in Brazoria County which focused on environmental differences, specifically on the quality of drinking water in the former residences of decedents from primary liver cancer. It also compared subjects who died from other causes. The author of this dissertation participated in this phase of the overall investigation by performing some of the chemical analyses and by preparing synographic maps of water quality, and thus, part of those results from the early phase is also included in this manuscript.^ No aflatoxin was detected by TLC methods. However, when extracts of rice dust were checked for mutagenesis by the Ames Salmonella-microsome assay as a supplement to the TLC analysis, the result suggested that these dusts might have contained mutagenic material. The age-adjusted mortality rates in the rice-growing area were higher than those in the comparison area for both male and female gastrointestinal tract cancer and for male urinary tract cancer, but the differences were not statistically significant. ^

RUNOFF FROM COAL PILES: EFFECTS ON THE ENVIRONMENT AND THE PUBLIC'S HEALTH

The use of coal for fuel in place of oil and natural gas has been increasing in the United States. Typically, users store their reserves of coal outdoors in large piles and rainfall on the coal creates runoffs which may contain materials hazardous to the environment and the public's health. To study this hazard, rainfall on model coal piles was simulated, using deionized water and four coals of varying sulfur content. The simulated surface runoffs were collected during 9 rainfall simulations spaced 15 days apart. The runoffs were analyzed for 13 standard water quality parameters, extracted with organic solvents and then analyzed with capillary column GC/MS, and the extracts were tested for mutagenicity with the Ames Salmonella microsomal assay and for clastogenicity with Chinese hamster ovary cells.^ The runoffs from the high-sulfur coals and the lignite exhibited extremes of pH (acidity), specific conductance, chemical oxygen demand, and total suspended solids; the low-sulfur coal runoffs did not exhibit these extremes. Without treatment, effluents from these high-sulfur coals and lignite would not comply with federal water quality guidelines.^ Most extracts of the simulated surface runoffs contained at least 10 organic compounds including polycyclic aromatic hydrocarbons, their methyl and ethyl homologs, olefins, paraffins, and some terpenes. The concentrations of these compounds were generally less than 50 (mu)g/l in most extracts.^ Some of the extracts were weakly mutagenic and affected both a DNA-repair proficient and deficient Salmonella strain. The addition of S9 decreased the effect significantly. Extracts of runoffs from the low-sulfur coal were not mutagenic.^ All extracts were clastogenic. Extracts of runoffs from the high-sulfur coals were both clastogenic and cytotoxic; those from the low-sulfur coal and the lignite were less clastogenic and not cytotoxic. Clastogenicity occurred with and without S9 activation. Chromosomal lesions included gaps, breaks and exchanges. These data suggest a relationship between the sulfur content of a coal, its mutagenicity and also its clastogenicity.^ The runoffs from actual coal piles should be investigated for possible genotoxic effects in view of the data presented in this study.^

BAYESIAN STATISTICAL METHODS IN GENE-ENVIRONMENT AND GENE-GENE INTERACTION STUDIES

Complex diseases such as cancer result from multiple genetic changes and environmental exposures. Due to the rapid development of genotyping and sequencing technologies, we are now able to more accurately assess causal effects of many genetic and environmental factors. Genome-wide association studies have been able to localize many causal genetic variants predisposing to certain diseases. However, these studies only explain a small portion of variations in the heritability of diseases. More advanced statistical models are urgently needed to identify and characterize some additional genetic and environmental factors and their interactions, which will enable us to better understand the causes of complex diseases. In the past decade, thanks to the increasing computational capabilities and novel statistical developments, Bayesian methods have been widely applied in the genetics/genomics researches and demonstrating superiority over some regular approaches in certain research areas. Gene-environment and gene-gene interaction studies are among the areas where Bayesian methods may fully exert its functionalities and advantages. This dissertation focuses on developing new Bayesian statistical methods for data analysis with complex gene-environment and gene-gene interactions, as well as extending some existing methods for gene-environment interactions to other related areas. It includes three sections: (1) Deriving the Bayesian variable selection framework for the hierarchical gene-environment and gene-gene interactions; (2) Developing the Bayesian Natural and Orthogonal Interaction (NOIA) models for gene-environment interactions; and (3) extending the applications of two Bayesian statistical methods which were developed for gene-environment interaction studies, to other related types of studies such as adaptive borrowing historical data. We propose a Bayesian hierarchical mixture model framework that allows us to investigate the genetic and environmental effects, gene by gene interactions (epistasis) and gene by environment interactions in the same model. It is well known that, in many practical situations, there exists a natural hierarchical structure between the main effects and interactions in the linear model. Here we propose a model that incorporates this hierarchical structure into the Bayesian mixture model, such that the irrelevant interaction effects can be removed more efficiently, resulting in more robust, parsimonious and powerful models. We evaluate both of the 'strong hierarchical' and 'weak hierarchical' models, which specify that both or one of the main effects between interacting factors must be present for the interactions to be included in the model. The extensive simulation results show that the proposed strong and weak hierarchical mixture models control the proportion of false positive discoveries and yield a powerful approach to identify the predisposing main effects and interactions in the studies with complex gene-environment and gene-gene interactions. We also compare these two models with the 'independent' model that does not impose this hierarchical constraint and observe their superior performances in most of the considered situations. The proposed models are implemented in the real data analysis of gene and environment interactions in the cases of lung cancer and cutaneous melanoma case-control studies. The Bayesian statistical models enjoy the properties of being allowed to incorporate useful prior information in the modeling process. Moreover, the Bayesian mixture model outperforms the multivariate logistic model in terms of the performances on the parameter estimation and variable selection in most cases. Our proposed models hold the hierarchical constraints, that further improve the Bayesian mixture model by reducing the proportion of false positive findings among the identified interactions and successfully identifying the reported associations. This is practically appealing for the study of investigating the causal factors from a moderate number of candidate genetic and environmental factors along with a relatively large number of interactions. The natural and orthogonal interaction (NOIA) models of genetic effects have previously been developed to provide an analysis framework, by which the estimates of effects for a quantitative trait are statistically orthogonal regardless of the existence of Hardy-Weinberg Equilibrium (HWE) within loci. Ma et al. (2012) recently developed a NOIA model for the gene-environment interaction studies and have shown the advantages of using the model for detecting the true main effects and interactions, compared with the usual functional model. In this project, we propose a novel Bayesian statistical model that combines the Bayesian hierarchical mixture model with the NOIA statistical model and the usual functional model. The proposed Bayesian NOIA model demonstrates more power at detecting the non-null effects with higher marginal posterior probabilities. Also, we review two Bayesian statistical models (Bayesian empirical shrinkage-type estimator and Bayesian model averaging), which were developed for the gene-environment interaction studies. Inspired by these Bayesian models, we develop two novel statistical methods that are able to handle the related problems such as borrowing data from historical studies. The proposed methods are analogous to the methods for the gene-environment interactions on behalf of the success on balancing the statistical efficiency and bias in a unified model. By extensive simulation studies, we compare the operating characteristics of the proposed models with the existing models including the hierarchical meta-analysis model. The results show that the proposed approaches adaptively borrow the historical data in a data-driven way. These novel models may have a broad range of statistical applications in both of genetic/genomic and clinical studies.

Environment and habitat characteristics of wintering lemmings in the Arctic

Snow cover has dramatic effects on the structure and functioning of Arctic ecosystems in winter. In the tundra, the subnivean space is the primary habitat of wintering small mammals and may be critical for their survival and reproduction. We have investigated the effects of snow cover and habitat features on the distributions of collared lemming (Dicrostonyx groenlandicus) and brown lemming (Lemmus trimucronatus) winter nests, as well as on their probabilities of reproduction and predation by stoats (Mustela erminea) and arctic foxes (Vulpes lagopus). We sampled 193 lemming winter nests and measured habitat features at all of these nests and at random sites at two spatial scales. We also monitored overwinter ground temperature at a subsample of nest and random sites. Our results demonstrate that nests were primarily located in areas with high micro-topography heterogeneity, steep slopes, deep snow cover providing thermal protection (reduced daily temperature fluctuations) and a high abundance of mosses. The probability of reproduction increased in collared lemming nests at low elevation and in brown lemming nests with high availability of some graminoid species. The probability of predation by stoats was density dependent and was higher in nests used by collared lemmings. Snow cover did not affect the probability of predation of lemming nests by stoats, but deep snow cover limited predation attempts by arctic foxes. We conclude that snow cover plays a key role in the spatial structure of wintering lemming populations and potentially in their population dynamics in the Arctic.

Palynology, source vegetation, environment and age of ODP Site 188-1166 sediments

Twenty-three core catcher samples from Site 1166 (Hole 1166A) in Prydz Bay were analyzed for their palynomorph content, with the aims of determining the ages of the sequence penetrated, providing information on the vegetation of the Antarctic continent at this time, and determining the environments under which deposition occurred. Dinocysts, pollen and spores, and foraminiferal test linings were recovered from most samples in the interval from 142.5 to 362.03 meters below seafloor (mbsf). The interval from 142.5 to 258.72 mbsf yielded palynomorphs indicative of a middle-late Eocene age, equivalent to the lower-middle Nothofagidites asperus Zone of the Gippsland Basin of southeastern Australia. The Prydz Bay sequence represents the first well-dated section of this age from East Antarctica. Dinocysts belonging to the widespread "Transantarctic Flora" give a more confident late Eocene age for the interval 142.5-220.5 mbsf. The uppermost two cores within this interval, namely, those from 142.5 and 148.36 mbsf, show significantly higher frequencies of dinocysts than the cores below and suggest that an open marine environment prevailed at the time of deposition. The spore and pollen component may reflect a vegetation akin to the modern rainforest scrubs of Tasmania and New Zealand. Below 267 mbsf, sparse microfloras, mainly of spores and pollen, are equated with the Phyllocladidites mawsonii Zone of southeastern Australia, which is of Turonian to possibly Santonian age. Fluvial to marginal marine environments of deposition are suggested. The parent vegetation from this interval is here described as "Austral Conifer Woodland." The same Late Cretaceous microflora occurs in two of the cores above the postulated unconformity at 267 mbsf. In the core at 249.42 mbsf, the Late Cretaceous spores and pollen are uncontaminated by any Tertiary forms, suggesting that a clast of this older material has been sampled; such a clast may reflect transport by ice during the Eocene. At 258.72 mbsf, Late Cretaceous spores and pollen appear to have been recycled into the Eocene sediments.

Seawater carbonate chemistry and proportion of different dissolution levels in live juvenile Limacina helicina antarctica from the natural environment and ship-board incubations

The carbonate chemistry of the surface ocean is rapidly changing with ocean acidification, a result of human activities. In the upper layers of the Southern Ocean, aragonite-a metastable form of calcium carbonate with rapid dissolution kinetics-may become undersaturated by 2050. Aragonite undersaturation is likely to affect aragonite-shelled organisms, which can dominate surface water communities in polar regions. Here we present analyses of specimens of the pteropod Limacina helicina antarctica that were extracted live from the Southern Ocean early in 2008. We sampled from the top 200 m of the water column, where aragonite saturation levels were around 1, as upwelled deep water is mixed with surface water containing anthropogenic CO2. Comparing the shell structure with samples from aragonite-supersaturated regions elsewhere under a scanning electron microscope, we found severe levels of shell dissolution in the undersaturated region alone. According to laboratory incubations of intact samples with a range of aragonite saturation levels, eight days of incubation in aragonite saturation levels of 0.94-1.12 produces equivalent levels of dissolution. As deep-water upwelling and CO2 absorption by surface waters is likely to increase as a result of human activities, we conclude that upper ocean regions where aragonite-shelled organisms are affected by dissolution are likely to expand.

Development of Efficient Techniques for the Analysis and Design of Antennas in Dual-Reflectarray Configuration

This thesis contributes to the analysis and design of printed reflectarray antennas. The main part of the work is focused on the analysis of dual offset antennas comprising two reflectarray surfaces, one of them acts as sub-reflector and the second one acts as mainreflector. These configurations introduce additional complexity in several aspects respect to conventional dual offset reflectors, however they present a lot of degrees of freedom that can be used to improve the electrical performance of the antenna. The thesis is organized in four parts: the development of an analysis technique for dualreflectarray antennas, a preliminary validation of such methodology using equivalent reflector systems as reference antennas, a more rigorous validation of the software tool by manufacturing and testing a dual-reflectarray antenna demonstrator and the practical design of dual-reflectarray systems for some applications that show the potential of these kind of configurations to scan the beam and to generate contoured beams. In the first part, a general tool has been implemented to analyze high gain antennas which are constructed of two flat reflectarray structures. The classic reflectarray analysis based on MoM under local periodicity assumption is used for both sub and main reflectarrays, taking into account the incident angle on each reflectarray element. The incident field on the main reflectarray is computed taking into account the field radiated by all the elements on the sub-reflectarray.. Two approaches have been developed, one which employs a simple approximation to reduce the computer run time, and the other which does not, but offers in many cases, improved accuracy. The approximation is based on computing the reflected field on each element on the main reflectarray only once for all the fields radiated by the sub-reflectarray elements, assuming that the response will be the same because the only difference is a small variation on the angle of incidence. This approximation is very accurate when the reflectarray elements on the main reflectarray show a relatively small sensitivity to the angle of incidence. An extension of the analysis technique has been implemented to study dual-reflectarray antennas comprising a main reflectarray printed on a parabolic surface, or in general in a curved surface. In many applications of dual-reflectarray configurations, the reflectarray elements are in the near field of the feed-horn. To consider the near field radiated by the horn, the incident field on each reflectarray element is computed using a spherical mode expansion. In this region, the angles of incidence are moderately wide, and they are considered in the analysis of the reflectarray to better calculate the actual incident field on the sub-reflectarray elements. This technique increases the accuracy for the prediction of co- and cross-polar patterns and antenna gain respect to the case of using ideal feed models. In the second part, as a preliminary validation, the proposed analysis method has been used to design a dual-reflectarray antenna that emulates previous dual-reflector antennas in Ku and W-bands including a reflectarray as subreflector. The results for the dualreflectarray antenna compare very well with those of the parabolic reflector and reflectarray subreflector; radiation patterns, antenna gain and efficiency are practically the same when the main parabolic reflector is substituted by a flat reflectarray. The results show that the gain is only reduced by a few tenths of a dB as a result of the ohmic losses in the reflectarray. The phase adjustment on two surfaces provided by the dual-reflectarray configuration can be used to improve the antenna performance in some applications requiring multiple beams, beam scanning or shaped beams. Third, a very challenging dual-reflectarray antenna demonstrator has been designed, manufactured and tested for a more rigorous validation of the analysis technique presented. The proposed antenna configuration has the feed, the sub-reflectarray and the main-reflectarray in the near field one to each other, so that the conventional far field approximations are not suitable for the analysis of such antenna. This geometry is used as benchmarking for the proposed analysis tool in very stringent conditions. Some aspects of the proposed analysis technique that allow improving the accuracy of the analysis are also discussed. These improvements include a novel method to reduce the inherent cross polarization which is introduced mainly from grounded patch arrays. It has been checked that cross polarization in offset reflectarrays can be significantly reduced by properly adjusting the patch dimensions in the reflectarray in order to produce an overall cancellation of the cross-polarization. The dimensions of the patches are adjusted in order not only to provide the required phase-distribution to shape the beam, but also to exploit the crosses by zero of the cross-polarization components. The last part of the thesis deals with direct applications of the technique described. The technique presented is directly applicable to the design of contoured beam antennas for DBS applications, where the requirements of cross-polarisation are very stringent. The beam shaping is achieved by synthesithing the phase distribution on the main reflectarray while the sub-reflectarray emulates an equivalent hyperbolic subreflector. Dual-reflectarray antennas present also the ability to scan the beam over small angles about boresight. Two possible architectures for a Ku-band antenna are also described based on a dual planar reflectarray configuration that provides electronic beam scanning in a limited angular range. In the first architecture, the beam scanning is achieved by introducing a phase-control in the elements of the sub-reflectarray and the mainreflectarray is passive. A second alternative is also studied, in which the beam scanning is produced using 1-bit control on the main reflectarray, while a passive subreflectarray is designed to provide a large focal distance within a compact configuration. The system aims to develop a solution for bi-directional satellite links for emergency communications. In both proposed architectures, the objective is to provide a compact optics and simplicity to be folded and deployed.

Analysis and design of a thrombectomy device by using simulation techniques

Purpose: In this work, we present the analysis, design and optimization of one experimental device recently developed in the UK, called the 'GP' Thrombus Aspiration Device (GPTAD). This device has been designed to remove blood clots without the need to make contact with the clot itself thereby potentially reducing the risk of problems such as downstream embolisation. Method: To obtain the minimum pressure necessary to extract the clot and to optimize the device, we have simulated the performance of the GPTAD analysing the resistances, compliances and inertances effects. We model a range of diameters for the GPTAD considering different forces of adhesion of the blood clot to the artery wall, and different lengths of blood clot. In each case we determine the optimum pressure required to extract the blood clot from the artery using the GPTAD, which is attached at its proximal end to a suction pump. Result: We then compare the results of our mathematical modelling to measurements made in laboratory using plastic tube models of arteries of comparable diameter. We use abattoir porcine blood clots that are extracted using the GPTAD. The suction pressures required for such clot extraction in the plastic tube models compare favourably with those predicted by the mathematical modelling. Discussion & Conclusion: We conclude therefore that the mathematical modelling is a useful technique in predicting the performance of the GPTAD and may potentially be used in optimising the design of the device.