Patterns of weight change after the diagnosis of type 2 diabetes in Scotland and their relationship with glycaemic control, mortality and cardiovascular outcomes: a retrospective cohort study

Acknowledgements The authors would like to thank the Scottish Diabetes Research Network Epidemiology Group for granting permission to use this database. They also thank the data management team in the University of Aberdeen who were the initial conduit for access to these data and also provided validation to the various data cleaning criteria applied. Jeremy J Walker, University of Edinburgh, was invaluable for the original funding application and initial exploration of data. HSRU is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates. Funding Chief Scientist Office (CSO) reference number: CZG/2/571.

Advanced Techniques for Image Quality Assessment of Modern X-ray Computed Tomography Systems

X-ray computed tomography (CT) imaging constitutes one of the most widely used diagnostic tools in radiology today with nearly 85 million CT examinations performed in the U.S in 2011. CT imparts a relatively high amount of radiation dose to the patient compared to other x-ray imaging modalities and as a result of this fact, coupled with its popularity, CT is currently the single largest source of medical radiation exposure to the U.S. population. For this reason, there is a critical need to optimize CT examinations such that the dose is minimized while the quality of the CT images is not degraded. This optimization can be difficult to achieve due to the relationship between dose and image quality. All things being held equal, reducing the dose degrades image quality and can impact the diagnostic value of the CT examination.

A recent push from the medical and scientific community towards using lower doses has spawned new dose reduction technologies such as automatic exposure control (i.e., tube current modulation) and iterative reconstruction algorithms. In theory, these technologies could allow for scanning at reduced doses while maintaining the image quality of the exam at an acceptable level. Therefore, there is a scientific need to establish the dose reduction potential of these new technologies in an objective and rigorous manner. Establishing these dose reduction potentials requires precise and clinically relevant metrics of CT image quality, as well as practical and efficient methodologies to measure such metrics on real CT systems. The currently established methodologies for assessing CT image quality are not appropriate to assess modern CT scanners that have implemented those aforementioned dose reduction technologies.

Thus the purpose of this doctoral project was to develop, assess, and implement new phantoms, image quality metrics, analysis techniques, and modeling tools that are appropriate for image quality assessment of modern clinical CT systems. The project developed image quality assessment methods in the context of three distinct paradigms, (a) uniform phantoms, (b) textured phantoms, and (c) clinical images.

The work in this dissertation used the “task-based” definition of image quality. That is, image quality was broadly defined as the effectiveness by which an image can be used for its intended task. Under this definition, any assessment of image quality requires three components: (1) A well defined imaging task (e.g., detection of subtle lesions), (2) an “observer” to perform the task (e.g., a radiologists or a detection algorithm), and (3) a way to measure the observer’s performance in completing the task at hand (e.g., detection sensitivity/specificity).

First, this task-based image quality paradigm was implemented using a novel multi-sized phantom platform (with uniform background) developed specifically to assess modern CT systems (Mercury Phantom, v3.0, Duke University). A comprehensive evaluation was performed on a state-of-the-art CT system (SOMATOM Definition Force, Siemens Healthcare) in terms of noise, resolution, and detectability as a function of patient size, dose, tube energy (i.e., kVp), automatic exposure control, and reconstruction algorithm (i.e., Filtered Back-Projection– FPB vs Advanced Modeled Iterative Reconstruction– ADMIRE). A mathematical observer model (i.e., computer detection algorithm) was implemented and used as the basis of image quality comparisons. It was found that image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low-doses, large phantom sizes, and for low-contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose (increase in detectability index by up to 163% depending on iterative strength). The use of automatic exposure control resulted in more consistent image quality with changing phantom size.

Based on those results, the dose reduction potential of ADMIRE was further assessed specifically for the task of detecting small (<=6 mm) low-contrast (<=20 HU) lesions. A new low-contrast detectability phantom (with uniform background) was designed and fabricated using a multi-material 3D printer. The phantom was imaged at multiple dose levels and images were reconstructed with FBP and ADMIRE. Human perception experiments were performed to measure the detection accuracy from FBP and ADMIRE images. It was found that ADMIRE had equivalent performance to FBP at 56% less dose.

Using the same image data as the previous study, a number of different mathematical observer models were implemented to assess which models would result in image quality metrics that best correlated with human detection performance. The models included naïve simple metrics of image quality such as contrast-to-noise ratio (CNR) and more sophisticated observer models such as the non-prewhitening matched filter observer model family and the channelized Hotelling observer model family. It was found that non-prewhitening matched filter observers and the channelized Hotelling observers both correlated strongly with human performance. Conversely, CNR was found to not correlate strongly with human performance, especially when comparing different reconstruction algorithms.

The uniform background phantoms used in the previous studies provided a good first-order approximation of image quality. However, due to their simplicity and due to the complexity of iterative reconstruction algorithms, it is possible that such phantoms are not fully adequate to assess the clinical impact of iterative algorithms because patient images obviously do not have smooth uniform backgrounds. To test this hypothesis, two textured phantoms (classified as gross texture and fine texture) and a uniform phantom of similar size were built and imaged on a SOMATOM Flash scanner (Siemens Healthcare). Images were reconstructed using FBP and a Sinogram Affirmed Iterative Reconstruction (SAFIRE). Using an image subtraction technique, quantum noise was measured in all images of each phantom. It was found that in FBP, the noise was independent of the background (textured vs uniform). However, for SAFIRE, noise increased by up to 44% in the textured phantoms compared to the uniform phantom. As a result, the noise reduction from SAFIRE was found to be up to 66% in the uniform phantom but as low as 29% in the textured phantoms. Based on this result, it clear that further investigation was needed into to understand the impact that background texture has on image quality when iterative reconstruction algorithms are used.

To further investigate this phenomenon with more realistic textures, two anthropomorphic textured phantoms were designed to mimic lung vasculature and fatty soft tissue texture. The phantoms (along with a corresponding uniform phantom) were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Scans were repeated a total of 50 times in order to get ensemble statistics of the noise. A novel method of estimating the noise power spectrum (NPS) from irregularly shaped ROIs was developed. It was found that SAFIRE images had highly locally non-stationary noise patterns with pixels near edges having higher noise than pixels in more uniform regions. Compared to FBP, SAFIRE images had 60% less noise on average in uniform regions for edge pixels, noise was between 20% higher and 40% lower. The noise texture (i.e., NPS) was also highly dependent on the background texture for SAFIRE. Therefore, it was concluded that quantum noise properties in the uniform phantoms are not representative of those in patients for iterative reconstruction algorithms and texture should be considered when assessing image quality of iterative algorithms.

The move beyond just assessing noise properties in textured phantoms towards assessing detectability, a series of new phantoms were designed specifically to measure low-contrast detectability in the presence of background texture. The textures used were optimized to match the texture in the liver regions actual patient CT images using a genetic algorithm. The so called “Clustured Lumpy Background” texture synthesis framework was used to generate the modeled texture. Three textured phantoms and a corresponding uniform phantom were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Images were reconstructed with FBP and SAFIRE and analyzed using a multi-slice channelized Hotelling observer to measure detectability and the dose reduction potential of SAFIRE based on the uniform and textured phantoms. It was found that at the same dose, the improvement in detectability from SAFIRE (compared to FBP) was higher when measured in a uniform phantom compared to textured phantoms.

The final trajectory of this project aimed at developing methods to mathematically model lesions, as a means to help assess image quality directly from patient images. The mathematical modeling framework is first presented. The models describe a lesion’s morphology in terms of size, shape, contrast, and edge profile as an analytical equation. The models can be voxelized and inserted into patient images to create so-called “hybrid” images. These hybrid images can then be used to assess detectability or estimability with the advantage that the ground truth of the lesion morphology and location is known exactly. Based on this framework, a series of liver lesions, lung nodules, and kidney stones were modeled based on images of real lesions. The lesion models were virtually inserted into patient images to create a database of hybrid images to go along with the original database of real lesion images. ROI images from each database were assessed by radiologists in a blinded fashion to determine the realism of the hybrid images. It was found that the radiologists could not readily distinguish between real and virtual lesion images (area under the ROC curve was 0.55). This study provided evidence that the proposed mathematical lesion modeling framework could produce reasonably realistic lesion images.

Based on that result, two studies were conducted which demonstrated the utility of the lesion models. The first study used the modeling framework as a measurement tool to determine how dose and reconstruction algorithm affected the quantitative analysis of liver lesions, lung nodules, and renal stones in terms of their size, shape, attenuation, edge profile, and texture features. The same database of real lesion images used in the previous study was used for this study. That database contained images of the same patient at 2 dose levels (50% and 100%) along with 3 reconstruction algorithms from a GE 750HD CT system (GE Healthcare). The algorithms in question were FBP, Adaptive Statistical Iterative Reconstruction (ASiR), and Model-Based Iterative Reconstruction (MBIR). A total of 23 quantitative features were extracted from the lesions under each condition. It was found that both dose and reconstruction algorithm had a statistically significant effect on the feature measurements. In particular, radiation dose affected five, three, and four of the 23 features (related to lesion size, conspicuity, and pixel-value distribution) for liver lesions, lung nodules, and renal stones, respectively. MBIR significantly affected 9, 11, and 15 of the 23 features (including size, attenuation, and texture features) for liver lesions, lung nodules, and renal stones, respectively. Lesion texture was not significantly affected by radiation dose.

The second study demonstrating the utility of the lesion modeling framework focused on assessing detectability of very low-contrast liver lesions in abdominal imaging. Specifically, detectability was assessed as a function of dose and reconstruction algorithm. As part of a parallel clinical trial, images from 21 patients were collected at 6 dose levels per patient on a SOMATOM Flash scanner. Subtle liver lesion models (contrast = -15 HU) were inserted into the raw projection data from the patient scans. The projections were then reconstructed with FBP and SAFIRE (strength 5). Also, lesion-less images were reconstructed. Noise, contrast, CNR, and detectability index of an observer model (non-prewhitening matched filter) were assessed. It was found that SAFIRE reduced noise by 52%, reduced contrast by 12%, increased CNR by 87%. and increased detectability index by 65% compared to FBP. Further, a 2AFC human perception experiment was performed to assess the dose reduction potential of SAFIRE, which was found to be 22% compared to the standard of care dose.

In conclusion, this dissertation provides to the scientific community a series of new methodologies, phantoms, analysis techniques, and modeling tools that can be used to rigorously assess image quality from modern CT systems. Specifically, methods to properly evaluate iterative reconstruction have been developed and are expected to aid in the safe clinical implementation of dose reduction technologies.

Delivering enhanced efficiency in the synthesis of α-diazosulfoxides by exploiting the process control enabled in flow

Continuous-flow generation of α-diazosulfoxides results in a two- to three-fold increase in yields and decreased reaction times compared to standard batch synthesis methods. These high yielding reactions are enabled by flowing through a bed of polystyrene-supported base (PS-DBU or PS-NMe2) with highly controlled residence times. This engineered solution allows the α-diazosulfoxides to be rapidly synthesized while limiting exposure of the products to basic reaction conditions, which have been found to cause rapid decomposition. In addition to improved yields, this work has the added advantage of ease of processing, increased safety profile, and scale-up potential.

Diffusible Signal Factor (DSF)-dependent quorum sensing in pathogenic bacteria and its exploitation for disease control

Cell-to-cell signals of the Diffusible Signal Factor (DSF) family are cis-2-unsaturated fatty acids of differing chain length and branching pattern. DSF signalling has been described in diverse bacteria to include plant and human pathogens where it acts to regulate functions such as biofilm formation, antibiotic tolerance and the production of virulence factors. DSF family signals can also participate in interspecies signalling with other bacteria and interkingdom signaling such as with the yeast Candida albicans. Interference with DSF signalling may afford new opportunities for the control of bacterial disease. Such strategies will depend in part on detailed knowledge of the molecular mechanisms underlying the processes of signal synthesis, perception and turnover. Here, I review both recent progress in understanding DSF signalling at the molecular level and prospects for translating this knowledge into approaches for disease control.

Upper-Pleistocene terrace deposits in Mediterranean climate: geomorphological and source-rock control on mineral and geochemical signatures (Betic Cordillera, SE Spain)

Mineral and chemical composition of alluvial Upper-Pleistocene deposits from the Alto Guadalquivir Basin (SE Spain) were studied as a tool to identify sedimentary and geomorphological processes controlling its formation. Sediments located upstream, in the north-eastern sector of the basin, are rich in dolomite, illite, MgO and KB2BO. Downstream, sediments at the sequence base are enriched in calcite, smectite and CaO, whereas the upper sediments have similar features to those from upstream. Elevated rare-earth elements (REE) values can be related to low carbonate content in the sediments and the increase of silicate material produced and concentrated during soil formation processes in the neighbouring source areas. Two mineralogical and geochemical signatures related to different sediment source areas were identified. Basal levels were deposited during a predominantly erosive initial stage, and are mainly composed of calcite and smectite materials enriched in REE coming from Neogene marls and limestones. Then the deposition of the upper levels of the alluvial sequences, made of dolomite and illitic materials depleted in REE coming from the surrounding Sierra de Cazorla area took place during a less erosive later stage of the fluvial system. Such modification was responsible of the change in the mineralogical and geochemical composition of the alluvial sediments.

The influence of simulated exploitation onPatella vulgatapopulations: protandric sex change is size-dependent

Grazing mollusks are used as a food resource worldwide, and limpets are harvested commercially for both local consumption and export in several countries. This study describes a field experiment to assess the effects of simulated human exploitation of limpets Patella vulgata on their population ecology in terms of protandry (age-related sex change from male to female), growth, recruitment, migration, and density regulation. Limpet populations at two locations in southwest England were artificially exploited by systematic removal of the largest individuals for 18 months in plots assigned to three treatments at each site: no (control), low, and high exploitation. The shell size at sex change (L50: the size at which there is a 50:50 sex ratio) decreased in response to the exploitation treatments, as did the mean shell size of sexual stages. Size-dependent sex change was indicated by L50 occurring at smaller sizes in treatments than controls, suggesting an earlier switch to females. Mean shell size of P. vulgata neuters changed little under different levels of exploitation, while males and females both decreased markedly in size with exploitation. No differences were detected in the relative abundances of sexual stages, indicating some compensation for the removal of the bigger individuals via recruitment and sex change as no migratory patterns were detected between treatments. At the end of the experiment, 0–15 mm recruits were more abundant at one of the locations but no differences were detected between treatments. We conclude that sex change in P. vulgata can be induced at smaller sizes by reductions in density of the largest individuals reducing interage class competition. Knowledge of sex-change adaptation in exploited limpet populations should underpin strategies to counteract population decline and improve rocky shore conservation and resource management.

The influence of simulated exploitation onPatella vulgatapopulations: protandric sex change is size-dependent

Grazing mollusks are used as a food resource worldwide, and limpets are harvested commercially for both local consumption and export in several countries. This study describes a field experiment to assess the effects of simulated human exploitation of limpets Patella vulgata on their population ecology in terms of protandry (age-related sex change from male to female), growth, recruitment, migration, and density regulation. Limpet populations at two locations in southwest England were artificially exploited by systematic removal of the largest individuals for 18 months in plots assigned to three treatments at each site: no (control), low, and high exploitation. The shell size at sex change (L50: the size at which there is a 50:50 sex ratio) decreased in response to the exploitation treatments, as did the mean shell size of sexual stages. Size-dependent sex change was indicated by L50 occurring at smaller sizes in treatments than controls, suggesting an earlier switch to females. Mean shell size of P. vulgata neuters changed little under different levels of exploitation, while males and females both decreased markedly in size with exploitation. No differences were detected in the relative abundances of sexual stages, indicating some compensation for the removal of the bigger individuals via recruitment and sex change as no migratory patterns were detected between treatments. At the end of the experiment, 0–15 mm recruits were more abundant at one of the locations but no differences were detected between treatments. We conclude that sex change in P. vulgata can be induced at smaller sizes by reductions in density of the largest individuals reducing interage class competition. Knowledge of sex-change adaptation in exploited limpet populations should underpin strategies to counteract population decline and improve rocky shore conservation and resource management.

Flow shop scheduling problems under machine-dependent precedence constraints

Abstract not available

Spatiotemporal control over the co-conformational switching in pH-responsive flavylium-based multistate pseudorotaxanes

A multistate molecular dyad containing flavylium and viologen units was synthesized and the pH dependent thermodynamics of the network completely characterized by a variety of spectroscopic techniques such as NMR, UV-vis and stopped-flow. The flavylium cation is only stable at acidic pH values. Above pH ≈ 5 the hydration of the flavylium leads to the formation of the hemiketal followed by ring-opening tautomerization to give the cis-chalcone. Finally, this last species isomerizes to give the trans-chalcone. For the present system only the flavylium cation and the trans-chalcone species could be detected as being thermodynamically stable. The hemiketal and the cis-chalcone are kinetic intermediates with negligible concentrations at the equilibrium. All stable species of the network were found to form 1 : 1 and 2 : 1 host : guest complexes with cucurbit[7]uril (CB7) with association constants in the ranges 10(5)-10(8) M(-1) and 10(3)-10(4) M(-1), respectively. The 1 : 1 complexes were particularly interesting to devise pH responsive bistable pseudorotaxanes: at basic pH values (≈12) the flavylium cation interconverts into the deprotonated trans-chalcone in a few minutes and under these conditions the CB7 wheel was found to be located around the viologen unit. A decrease in pH to values around 1 regenerates the flavylium cation in seconds and the macrocycle is translocated to the middle of the axle. On the other hand, if the pH is decreased to 6, the deprotonated trans-chalcone is neutralized to give a metastable species that evolves to the thermodynamically stable flavylium cation in ca. 20 hours. By taking advantage of the pH-dependent kinetics of the trans-chalcone/flavylium interconversion, spatiotemporal control of the molecular organization in pseudorotaxane systems can be achieved.

Seep communities from two mud volcanoes in the deep eastern Mediterranean Sea: faunal composition, spatial patterns and environmental control

The Mediterranean Sea constitutes a unique environment to study cold-seep ecosystems due to the presence of different geodynamic settings, from an active margin along the Mediterranean Ridge (MR) to a passive margin in the Nile Deep-Sea Fan (NDSF). We attempted to identify the structure of benthic communities associated with the Napoli and Amsterdam mud volcanoes (MVs) located on the MR and to establish the links between faunal distribution and environmental conditions at different spatial scales. Comparison between the 2 MVs revealed that the faunal distribution seemed to be mainly controlled by the characteristics of the microhabitats. On both geological structures, the variability between the different microhabitats was higher than the variability observed between replicates of the same microhabitat, and the distribution of macro-fauna was apparently linked to gradients in physico-chemical conditions. The peripheral sites from Napoli were generally more oxygenated and harboured lower species richness than the active sites. The reduced sediment microhabitat from Amsterdam presented the highest methane concentrations and was mainly colonised by symbiont-bearing vesicomyid bivalves and heterotrophic dorvilleid polychaetes. Overall, a higher taxonomic diversity was observed on Napoli. Sub-stratum type was hypothesised to be the second factor influencing faunal distribution. The results of this study highlight the high heterogeneity of faunal communities associated with seep ecosystems within this region and the need to pursue investigations at various spatial and temporal scales.

Using landscape metrics to predict hydrologic connectivity patterns between forested wetlands and streams in a coastal plain watershed

Geographically isolated wetlands, those entirely surrounded by uplands, provide numerous ecological functions, some of which are dependent on the degree to which they are hydrologically connected to nearby waters. There is a growing need for field-validated, landscape-scale approaches for classifying wetlands based on their expected degree of connectivity with stream networks. During the 2015 water year, flow duration was recorded in non-perennial streams (n = 23) connecting forested wetlands and nearby perennial streams on the Delmarva Peninsula (Maryland, USA). Field and GIS-derived landscape metrics (indicators of catchment, wetland, non-perennial stream, and soil characteristics) were assessed as predictors of wetland-stream connectivity (duration, seasonal onset and offset dates). Connection duration was most strongly correlated with non-perennial stream geomorphology and wetland characteristics. A final GIS-based stepwise regression model (adj-R2 = 0.74, p < 0.0001) described wetland-stream connection duration as a function of catchment area, wetland area and number, and soil available water storage.

Analysis and control of transient spectra using time-dependent density functional theory.

215 p.

EGCL: an extended G-Code Language with flow control, functions and mnemonic variables

In the context of computer numerical control (CNC) and computer aided manufacturing (CAM), the capabilities of programming languages such as symbolic and intuitive programming, program portability and geometrical portfolio have special importance -- They allow to save time and to avoid errors during part programming and permit code re-usage -- Our updated literature review indicates that the current state of art presents voids in parametric programming, program portability and programming flexibility -- In response to this situation, this article presents a compiler implementation for EGCL (Extended G-code Language), a new, enriched CNC programming language which allows the use of descriptive variable names, geometrical functions and flow-control statements (if-then-else, while) -- Our compiler produces low-level generic, elementary ISO-compliant Gcode, thus allowing for flexibility in the choice of the executing CNC machine and in portability -- Our results show that readable variable names and flow control statements allow a simplified and intuitive part programming and permit re-usage of the programs -- Future work includes allowing the programmer to define own functions in terms of EGCL, in contrast to the current status of having them as library built-in functions

On-demand generation and removal of alginate biocompatible microvalves for flow control in microfluidics

[EN] This paper describes, for the first time, the use of alginate hydrogels as miniaturised microvalves within microfluidic devices. These biocompatible and biodegradable microvalves are generated in situ and on demand, allowing for microfluidic flow control. The microfluidic devices were fabricated using an origami inspired technique of folding several layers of cyclic olefin polymer followed by thermocompression bonding. The hydrogels can be dehydrated at mild temperatures, 37◦C, to slightly open the microvalve and chemically erased using an ethylenediaminetetraacetic acid disodium salt (EDTA) solution, to completely open the channel, ensuring the reusability of the whole device and removal of damaged or defective valves for subsequent regeneration.

Adaptivity and a posteriori error control for bifurcation problems II: Incompressible fluid flow in open systems with Z_2 symmetry

In this article we consider the a posteriori error estimation and adaptive mesh refinement of discontinuous Galerkin finite element approximations of the bifurcation problem associated with the steady incompressible Navier-Stokes equations. Particular attention is given to the reliable error estimation of the critical Reynolds number at which a steady pitchfork or Hopf bifurcation occurs when the underlying physical system possesses reflectional or Z_2 symmetry. Here, computable a posteriori error bounds are derived based on employing the generalization of the standard Dual-Weighted-Residual approach, originally developed for the estimation of target functionals of the solution, to bifurcation problems. Numerical experiments highlighting the practical performance of the proposed a posteriori error indicator on adaptively refined computational meshes are presented.