Modelling and verification of doses delivered to deformable moving targets in radiotherapy

During the last two decades, advanced treatment techniques have been developed in radiotherapy to achieve more conformal beam targeting of cancerous lesions. The advent of these techniques, such as intensity modulated radiotherapy (IMRT), volumetric modulated arc radiothreapy (VMAT), Tomotherapy etc., allows more precise localisation of higher doses to complex-shaped target volumes, thereby sparing more healthy tissue. In this context, motion management is a critical issue in contemporary radiotherapy (RT). That anatomic structures move during respiration is well known and much research is presently being devoted to strategies to contend with organ motion. However, moving structures are typically regarded as rigid bodies. The fact that many structures deform as a result of motion makes their resultant dose distributions difficult to measure and calculate, and has not been fully accounted for. The potential for ineffective treatments that do not take into account motion and anatomic deformation is self-evident. This thesis addresses the pressing need to investigate dose distributions in targets that deform during and/or between treatments, to ensure robust calculations for dose accumulation and delivery, thus providing the most positive outcomes for patients. This involves the direct measurement of complex and re-distributed dose in deforming objects (an experimental model), as well as calculations of the deformed dose distribution (a mathematical model). The comparison thereof aims to validate the dose deformation technique, thereby to apply the method to a clinical example such as liver stereotactic body radiotherapy. To facilitate four-dimensional deformable dosimetry for both external beam radiotherapy and brachytherapy, methodologies for three-dimensional deformed dose measurements were developed and employed using radiosensitive polymer gel combined with a cone beam optical computed tomography (CT) scanner. This includes the development of a novel prototype deformable target volume using a tissue-equivalent, deformable gel dosimetric phantom, dubbed “defgel”. This can reproducibly simulate targets subject to a range of mass- and density-conserving deformations representative of those observable in anatomical targets. This novel tool was characterised in terms of its suitability for the measurement of dose in deforming geometries. It was demonstrated that planned doses could be delivered to the deformable gel dosimeter in the presence of different deformations and complex spatial re-distributions of dose in all three dimensions could be quantified. For estimating the cumulative dose in different deformed states, deformable image registration (DIR) algorithms were implemented to ‘morph’ a dose distribution calculated by a treatment planning system. To investigate the performance of DIR and dose-warping technique, two key studies were undertaken. The first was to systematically assess the accuracy of a range of different DIR algorithms available in the public domain and quantitatively examine, in particular, low-contrast regions, where accuracy had not previously been established. This work investigates DIR algorithms in 3D via a systematic evaluation process using defgel suitable for verification of mass- and density-conserving deformations. The second study was a full three-dimensional experimental validation of the dose-warping technique using the evaluated DIR algorithm and comparing it to directly measured deformed dose distributions from defgel. It was shown that the dose-warping can be accurate, i.e. over 95% passing rate of 3D-gamma analysis with 3%/3mm criteria for given extents of deformation up to 20 mm For the application of evaluating patient treatment planning involving tumour motion/deformation, two key studies were undertaken in the context of liver stereotactic body radiotherapy. The first was a 4D evaluation of conventional 3D treatment planning, combined with 4D computed tomography, in order to investigate the extent of dosimetric differences between conventional 3D-static and path-integrated 4D-cumulative dose calculation. This study showed that the 3D planning approach overestimated doses to targets by ≤ 9% and underestimated dose to normal liver by ≤ 8%, compared to the 4D methodology. The second study was to assess a consequent reduction of healthy tissue sparing, which may increase risk for surrounding healthy tissues. Estimates for normal tissue complications probabilities (NTCP) based on the two dose calculation schemes are provided. While all NTCP were low for the employed fractionation scheme, analysis of common alternative schemes suggests potentially larger uncertainties exist in the estimation of NTCP for healthy liver and that substantial differences in these values may exist across the different fractionation schemes. These bodies of work have shown the potential to quantify such issues of under- and/or over-dosages which are quite patient dependent in RT. Studies presented in this work consolidate gel dosimetry, image guidance, DIR, dose-warping and consequent dose accumulation calculation to investigate the dosimetric impact and make more accurate evaluation of conventional 3D treatment plans. While liver stereotactic body radiotherapy (SBRT) was primarily concerned for immediate clinical application, the findings of this thesis are also applicable to other organs with various RT techniques. Most importantly, however, it is hoped that the outcomes of this thesis will help to improve treatment plan accuracy. By considering both computation and measurement, it is also hoped that this work will open new windows for future work and hence provide building blocks to further enhance the benefit of radiotherapy treatment

Update on the current status of onchocerciasis in Cote d’Ivoire following 40 years of intervention: Progress and challenges

Background Onchocerciasis control in Côte d’Ivoire started with aerial insecticide spraying in 1974 and continued with community directed treatment with ivermectin (CDTi) from 1992 to the present. Onchocerciasis and lymphatic filariasis (LF) are co-endemic in 46 of the 81 health districts in the country. Fourteen and 12 districts are endemic for only LF or onchocerciasis, respectively. This paper aims to review the impact of past interventions on onchocerciasis in Côte d’Ivoire between 1975 and 2013, and review plans for disease elimination. Methods We reviewed microfilaria (MF, skin snip) prevalence and community microfilarial load (CMFL) data from published reports from 53 health districts during two major epidemiological assessment periods. Data from 1975 through 1991 provided information on the impact of vector control, and data from 1992 through 2016 provided information on the impact of CDTi. Results Weekly aerial insecticide spraying in 8 endemic districts between 1975 and 1991 reduced the overall MF prevalence by 68.1% from 43.5% to 13.9%. The CMFL also decreased in 7 out of 8 surveyed communities by 95.2% from 9.24 MF/snip to 0.44 MF/snip. Ivermectin distribution started in 1992. The coverage targets for control (65% of the total population) was reached in most endemic districts, and some areas achieved 80% coverage. Two sets of surveys were conducted to assess the impact of CDTi. Results from the first repeat surveys showed a significant decrease in overall MF prevalence (by 75.7%, from 41.6% to 10.1%). The second follow-up evaluation showed further improvement in most endemic districts and also documented major reductions in CMFL compared to baseline. Conclusions Extensive data collected over many years document the very significant impact of interventions conducted by the National Onchocerciasis and other Eyes Diseases Control Programme during challenging times with periods of civil unrest. The Health Ministry has now integrated efforts to control neglected tropical diseases and adopted the goal of onchocerciasis elimination

Towards Subject and Diagnostic Identifiability in the Alzheimer’s Disease Spectrum Based on Functional Connectomes

Alzheimer’s disease (AD) is the only major cause of mortality in the world without an effective disease modifying treatment. Evidence supporting the so called “disconnection hypothesis” suggests that functional connectivity biomarkers may have clinical potential for early detection of AD. However, known issues with low test-retest reliability and signal to noise in functional connectivity may prevent accuracy and subsequent predictive capacity. We validate the utility of a novel principal component based diagnostic identifiability framework to increase separation in functional connectivity across the Alzheimer’s spectrum by identifying and reconstructing FC using only AD sensitive components or connectivity modes. We show that this framework (1) increases test-retest correspondence and (2) allows for better separation, in functional connectivity, of diagnostic groups both at the whole brain and individual resting state network level. Finally, we evaluate a posteriori the association between connectivity mode weights with longitudinal neurocognitive outcomes

Is there a Phase Transition to the Flux Lattice State?

The sharp drops in the resistance and magnetization which are usually attributed to a phase transition from the vortex liquid state to a crystal state are explained instead as a crossover between three and two dimensional behavior, which occurs when the phase coherence length in the liquid becomes comparable to the sample thickness. Estimates of the width of the crossover region and the phase coherence length scales are in agreement with experiment.Comment: 4 pages, RevTe

Metastable Dynamics above the Glass Transition

The element of metastability is incorporated in the fluctuating nonlinear hydrodynamic description of the mode coupling theory (MCT) of the liquid-glass transition. This is achieved through the introduction of the defect density variable $n$ into the set of slow variables with the mass density $\rho$ and the momentum density ${\bf g}$. As a first approximation, we consider the case where motions associated with $n$ are much slower than those associated with $\rho$. Self-consistently, assuming one is near a critical surface in the MCT sense, we find that the observed slowing down of the dynamics corresponds to a certain limit of a very shallow metastable well and a weak coupling between $\rho$ and $n$. The metastability parameters as well as the exponents describing the observed sequence of time relaxations are given as smooth functions of the temperature without any evidence for a special temperature. We then investigate the case where the defect dynamics is included. We find that the slowing down of the dynamics corresponds to the system arranging itself such that the kinetic coefficient $\gamma_v$ governing the diffusion of the defects approaches from above a small temperature-dependent value $\gamma^c_v$.Comment: 38 pages, 14 figures (6 figs. are included as a uuencoded tar- compressed file. The rest is available upon request.), RevTEX3.0+eps

Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Modelling of content-aware indicators for effective determination of shot boundaries in compressed MPEG videos

In this paper, a content-aware approach is proposed to design multiple test conditions for shot cut detection, which are organized into a multiple phase decision tree for abrupt cut detection and a finite state machine for dissolve detection. In comparison with existing approaches, our algorithm is characterized with two categories of content difference indicators and testing. While the first category indicates the content changes that are directly used for shot cut detection, the second category indicates the contexts under which the content change occurs. As a result, indications of frame differences are tested with context awareness to make the detection of shot cuts adaptive to both content and context changes. Evaluations announced by TRECVID 2007 indicate that our proposed algorithm achieved comparable performance to those using machine learning approaches, yet using a simpler feature set and straightforward design strategies. This has validated the effectiveness of modelling of content-aware indicators for decision making, which also provides a good alternative to conventional approaches in this topic

Deoxyribonucleic Acid as a Universal Electrolyte for Bio-Friendly Light-Emitting Electrochemical Cells [in press]

In the search for bio and eco‐friendly light sources, light‐emitting electrochemical cells (LECs) are promising candidates for the implementation of biomaterials in their device architecture thanks to their low fabrication complexity and wide range of potential technological applications. In this work, the use of the DNA derivative DNA‐cetyltrimethylammonium (DNA‐CTMA) is introduced as the ion‐solvating component of the solid polymer electrolyte (SPE) in the active layer of solution‐processed LECs. The focus is particularly on the investigation of its electrochemical and ionic conductivity properties demonstrating its suitability for device fabrication and correlation with thin film morphology. Furthermore, upon blending with the commercially available emissive polymer Super Yellow, the structure property relationship between the microstructure and the ionic conductivity is investigated and yields an optimized LEC performance. The large electrochemical stability window of DNA‐CTMA enables a stable device performance for a variety of emitters covering the complete visible spectral range, thus highlighting the universal character of this naturally sourced SPE

Genomic analysis of natural intra-specific hybrids among Ethiopian isolates of Leishmania donovani.

Parasites of the genus Leishmania (Kinetoplastida: Trypanosomatidae) cause widespread and devastating human diseases. Visceral leishmaniasis due to Leishmania donovani is endemic in Ethiopia where it has also been responsible for major epidemics. The presence of hybrid genotypes has been widely reported in surveys of natural populations, genetic variation reported in a number of Leishmania species, and the extant capacity for genetic exchange demonstrated in laboratory experiments. However, patterns of recombination and the evolutionary history of admixture that produced these hybrid populations remain unclear. Here, we use whole-genome sequence data to investigate Ethiopian L. donovani isolates previously characterized as hybrids by microsatellite and multi-locus sequencing. To date there is only one previous study on a natural population of Leishmania hybrids based on whole-genome sequences. We propose that these hybrids originate from recombination between two different lineages of Ethiopian L. donovani occurring in the same region. Patterns of inheritance are more complex than previously reported with multiple, apparently independent, origins from similar parents that include backcrossing with parental types. Analysis indicates that hybrids are representative of at least three different histories. Furthermore, isolates were highly polysomic at the level of chromosomes with differences between parasites recovered from a recrudescent infection from a previously treated individual. The results demonstrate that recombination is a significant feature of natural populations and contributes to the growing body of data that shows how recombination, and gene flow, shape natural populations of Leishmania