Modelling the impact of treatment uncertainties in radiotherapy

Uncertainties are inevitably part of the radiotherapy process. Uncertainty in the dose deposited in the tumour exists due to organ motion, patient positioning errors, fluctuations in machine output, delineation of regions of interest, the modality of imaging used, and treatment planning algorithm assumptions among others; there is uncertainty in the dose required to eradicate a tumour due to interpatient variations in patient-specific variables such as their sensitivity to radiation; and there is uncertainty in the dose-volume restraints that limit dose to normal tissue. This thesis involves three major streams of research including investigation of the actual dose delivered to target and normal tissue, the effect of dose uncertainty on radiobiological indices, and techniques to display the dose uncertainty in a treatment planning system. All of the analyses are performed with the dose distribution from a four-field box treatment using 6 MV photons. The treatment fields include uniform margins between the clinical target volume and planning target volume of 0.5 cm, 1.0 cm, and 1.5 cm. The major work is preceded by a thorough literature review on the size of setup and organ motion errors for various organs and setup techniques used in radiotherapy. A Monte Carlo (MC) code was written to simulate both the treatment planning and delivery phases of the radiotherapy treatment. Using MC, the mean and the variation in treatment dose are calculated for both an individual patient and across a population of patients. In particular, the possible discrepancy in tumour position located from a single CT scan and the magnitude of reduction in dose variation following multiple CT scans is investigated. A novel convolution kernel to include multiple pretreatment CT scans in the calculation of mean treatment dose is derived. Variations in dose deposited to prostate and rectal wall are assessed for each of the margins and for various magnitudes of systematic and random error, and penumbra gradients. The linear quadratic model is used to calculate prostate Tumour Control Probability (TCP) incorporating an actual (modelled) delivered prostate dose. The Kallman s-model is used to calculate the normal tissue complication probability (NTCP), incorporating actual (modelled) fraction dose in the deforming rectal wall. The impact of each treatment uncertainty on the variation in the radiobiological index is calculated for the margin sizes.Thesis (Ph.D.)--Department of Physics and Mathematical Physics, 2002

Where’s My Favorite Dictator? An Analysis of the American Empire In Post-Revolution Egypt

In 2011, Egypt became the epicenter of a regional wave of uprisings demanding an end to corruption, inequality, and undemocratic governance. The Egyptian revolution marked the hopeful beginning of a democratization process. However, in 2013 a military coup by General Abdel Fatah El-Sisi deposed the elected president and ended Egypt’s democratic experiment (DeSmet 2021). Despite the deterioration in U.S.-Egypt relations during the Obama administration and the erosion of political freedoms and economic stability over the last decade, the Trump administration enthusiastically embraced El-Sisi’s regime. Did Trump\u27s claim that El-Sisi was his “favorite dictator” signal a profound shift in American policy? In this case study of American foreign policy in Egypt during the Trump administration, I argue that the United States has pursued a strategy of democracy prevention to secure American interests and incorporate Egypt into a regional neoliberal order. Trump maintained the imperial approach of his predecessors by deepening security ties with the Egyptian military, accelerating the securitization of foreign aid, and outsourcing imperialism to the IMF and the Gulf. Nevertheless, Trump’s America First foreign policy departed from past presidents by promoting Sisi’s authoritarianism, rejecting democracy promotion and soft power, and aggressively deterring Egypt from aligning with American rivals. I assert that the Trump administration’s foreign policy strategy responded to declining American influence in the Middle East and North Africa. America First foreign policy was an aggressive but contradictory and limited strategy to sustain American dominance in a region characterized by increasing multipolarity

Assembling practice in clinical placements at a new medical school

Sociological studies of undergraduate medical education classically concentrated on students and tutors in the clinical environment and paid scant attention to course structures, systems of assessment or the institutional context in which medical education is embedded (Merton, Becker, Foucault, Atkinson, Bosk). Like them, this thesis offers a close ethnographic focus on the clinical experience, but combines it with a sociology of associations that explores the network of institutions and processes that impinge on it. Employing an ‘extended case method’ it focuses on the creation of a new medical school, and building on previous studies applies new materialist perspectives to explore the development and processes of regulation, the organization of supervision and assessment, and the embodied nature of practice (Burawoy). After an analysis of the original aims and development of the GMC’s Tomorrows’ Doctors it examines the school’s early years, focusing on the assessment of professionalism. It shows how the need to transfer information between the school and the NHS shaped assessment, and explores the clinical legitimation of the types of assessment to inform a discussion of their exchange-value and use-value. It presents the results of observations in clinical placements through Foucault’s perspective of the gaze and the ‘implicit labour of language’ in the assembly of practice, and by treating the senses used in patient consultations as mediators. It shows how patient-centered practice continues to reproduce a traditional individualized medicine and its hierarchy, and argues that patients in the community of practice serve as exemplars for comparison, learning, and the definition of the field of medicine itself. Following Kuhn’s assertion that scientific communities are best discovered by examining patterns of education and communication, this broader perspective makes an original contribution to the sociology of knowledge as well as to the fields of professional education and healthcare provision

Cyber resiliency for digital enterprises: A strategic leadership perspective

As organizations increasingly view information as one of their most valuable assets, which supports the creation and distribution of their products and services, information security will be an integral part of the design and operation of organizational business processes. Yet, risks associated with cyber attacks are on the rise. Organizations that are subjected to attacks can suffer significant reputational damage as well as loss of information and knowledge. As a consequence, effective leadership is cited as a critical factor for ensuring corporate level attention for information security. However, there is a lack of empirical understanding as to the roles strategic leaders play in shaping and supporting the cyber security strategy. This study seeks to address this gap in the literature by focusing on how senior leaders support the cyber security strategy. The authors conducted a series of exploratory interviews with leaders in the positions of Chief Information Officer, Chief Security Information Officer, and Chief Technology Officer. The findings revealed that leaders are engaged in both transitional, where the focus is on improving governance and integration, and transformational support, which involves fostering a new cultural mindset for cyber resiliency and the development of an ecosystem approach to security thinking. Managerial relevance statement Our findings provide interesting insights for managers particularly those in the role of Chief Information Officers (CIOs), Chief Security Information Officers (CSIOs), and Chief Technology Officers (CTOs). We propose a Cyber Security Strategy Framework (CSSF) which can be used by these information/technology managers to design an effective organizational strategy to develop cyber resilience in their organization. Our framework suggests that managers should focus on transitional and transformational support. The transitional support focuses on improving governance and integration whereas transformational support focuses on the emphasis of fostering a new cultural mindset for cyber resiliency and the development of an ecosystem approach to security thinking. Our findings provide good evidence showing how leaders can support more effective cyber security initiatives

Effects of Bni5 Binding on Septin Filament Organization

AbstractSeptins are a protein family found in all eukaryotes (except higher plants) that have roles in membrane remodeling and formation of diffusion barriers and as a scaffold to recruit other proteins. In budding yeast, proper execution of cytokinesis and cell division requires the formation of a collar of circumferential filaments at the bud neck. These filaments are assembled from apolar septin hetero-octamers. Currently, little is known about the mechanisms that control the arrangement and dynamics of septin structures. In this study, we utilized both Förster resonance energy transfer and electron microscopy to analyze the biophysical properties of the septin-binding protein Bni5 and how its association with septin filaments affects their organization. We found that the interaction of Bni5 with the terminal subunit (Cdc11) at the junctions between adjacent hetero-octamers in paired filaments is highly cooperative. Both the C-terminal end of Bni5 and the C-terminal extension of Cdc11 make important contributions to their interaction. Moreover, this binding may stabilize the dimerization of Bni5, which, in turn, forms cross-filament braces that significantly narrow, and impose much more uniform spacing on, the gap between paired filaments

Comparing and Integrating Constraint Programming and Temporal Planning for Quantum Circuit Compilation

Recently, the makespan-minimization problem of compiling a general class of quantum algorithms into near-term quantum processors has been introduced to the AI community. The research demonstrated that temporal planning is a strong solution approach for the studied class of quantum circuit compilation (QCC) problems. In this paper, we explore the use of methods from operations research, specifically constraint programming (CP), as an alternative and complementary approach to temporal planning. We also extend previous work by introducing two new problem variations that incorporate important characteristics identified by the quantum computing community. We apply temporal planning and CP to the baseline and extended QCC problems as both stand-alone and hybrid approaches. The hybrid method uses solutions found by temporal planning to warm-start CP, leveraging the ability of temporal planning to find satisficing solutions to problems with a high degree of task optionality, an area that CP typically struggles with. These solutions are then used to seed the CP formulation which significantly benefits from inferred bounds on planning horizon and task counts provided by the warm-start. Our extensive empirical evaluation indicates that while stand-alone CP is not competitive with temporal planning, except for the smallest problems, CP in a hybrid setting is beneficial for all temporal planners in all problem classes

The interaction of Epstein-Barr virus encoded transcription factor EBNA2 with multiple sclerosis risk loci is dependent on the risk genotype

Background: Epstein-Barr virus (EBV) infection may be necessary for the development of Multiple sclerosis (MS). Earlier we had identified six MS risk loci that are co-located with binding sites for the EBV transcription factor Epstein-Barr Nuclear Antigen 2 (EBNA2) in EBV-infected B cells (lymphoblastoid cell lines – LCLs). Methods: We used an allele-specific chromatin immunoprecipitation PCR assay to assess EBNA2 allelic preference. We treated LCLs with a peptide inhibitor of EBNA2 (EBNA2-TAT), reasoning that inhibiting EBNA2 function would alter gene expression at these loci if it was mediated by EBNA2. Findings: We found that EBNA2 binding was dependent on the risk allele for five of these six MS risk loci (p < 0·05). Treatment with EBNA2-TAT significantly altered the expression of TRAF3 (p < 0·05), CD40 (p < 0·001), CLECL1 (p <0·0001), TNFAIP8 (p < 0·001) and TNFRSF1A (p < 0·001). Interpretation: These data suggest that EBNA2 can enhance or reduce expression of the gene depending on the risk allele, likely promoting EBV infection. This is consistent with the concept that these MS risk loci affect MS risk through altering the response to EBNA2. Together with the extensive data indicating a pathogenic role for EBV in MS, this study supports targeting EBV and EBNA2 to reduce their effect on MS pathogenesis

Return to drug use and overdose after release from prison: a qualitative study of risk and protective factors

BACKGROUND: Former inmates are at high risk for death from drug overdose, especially in the immediate post-release period. The purpose of the study is to understand the drug use experiences, perceptions of overdose risk, and experiences with overdose among former prisoners. METHODS: This qualitative study included former prison inmates (N = 29) who were recruited within two months after their release. Interviewers conducted in-person, semi-structured interviews which explored participants' experiences and perceptions. Transcripts were analyzed utilizing a team-based method of inductive analysis. RESULTS: The following themes emerged: 1) Relapse to drugs and alcohol occurred in a context of poor social support, medical co-morbidity and inadequate economic resources; 2) former inmates experienced ubiquitous exposure to drugs in their living environments; 3) intentional overdose was considered "a way out" given situational stressors, and accidental overdose was perceived as related to decreased tolerance; and 4) protective factors included structured drug treatment programs, spirituality/religion, community-based resources (including self-help groups), and family. CONCLUSIONS: Former inmates return to environments that strongly trigger relapse to drug use and put them at risk for overdose. Interventions to prevent overdose after release from prison may benefit from including structured treatment with gradual transition to the community, enhanced protective factors, and reductions of environmental triggers to use drugs

The interaction of human and Epstein–Barr virus miRNAs with Multiple Sclerosis risk loci

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly