Biosimulation of Vocal Fold Inflammation and Healing

Personalized, pre-emptive and predictive medicine is the capstone of contemporary medical care. The central aim of this dissertation is to address clinical challenges in prescribing personalized therapy to patients with acute phonotrauma. Inflammation and healing, which are innate tissue responses to mechanical stress/ trauma, are regulated by a complex dynamic system. A systems biology approach, which combines empirical, mathematical and computational tools, was taken to study the biological complexity of this dynamic system in vocal fold injury.Computational agent-based models (ABMs) were developed to quantitatively characterize multiple cellular and molecular interactions around inflammation and healing. The models allowed for tests of various hypothetical effects of motion-based treatments in individuals with acute phonotrauma. A phonotrauma ABM was calibrated and verified with empirical data of a panel of inflammatory mediators, obtained from laryngeal secretions in individuals following experimentally induced phonotrauma and a randomly assigned motion-based treatment. A supplementary ABM of surgically induced vocal fold trauma was developed and subsequently calibrated and verified with empirical data of inflammatory mediators and extracellular matrix substances from rat studies, for the purpose of gaining insight into the &ldquo net effect &rdquo of cellular and molecular responses at the tissue level.ABM simulations reproduced and predicted trajectories of inflammatory mediators and extracellular matrix as seen in empirical data of phonotrauma and surgical vocal fold trauma. The simulation results illustrated a spectrum of inflammatory responses to phonotrauma, surgical trauma and motion-based treatments. The results suggested that resonant voice exercise may optimize the combination of para- and anti-inflammatory responses to accelerate healing. Moreover, the ABMs suggested that hyaluronan fragments might be an early molecular index of tissue damage that is sensitive to varying stress levels - from relatively low phonatory stress to high surgical stress.We propose that this translational application of biosimulation can be used to quantitatively chart individual healing trajectories, test the effects of different treatment options and most importantly provide new understanding of laryngeal health and healing. By placing biology on a firm mathematical foundation, this line of research has potential to influence the contour of scientific thinking and clinical care of vocal fold injury

A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12

Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales

Analyse systématique des données sur le control banding et proposition d’une méthode semi-quantitative selon des critères physico-chimiques et biologiques des nanomatériaux manufacturés

Parmi les méthodologies d’appréciation du danger ayant connu une forte croissance ces dernières décennies figurent le Control Banding (CB). Selon une estimée du NIOSH (National Institute for Occupational Safety and Health), cette approche qualitative a été développé dans l’industrie pharmaceutique dans un but concret de protéger près de 90% de travailleurs n’ayant pas accès à des services de santé, de sécurité et d’hygiène au travail. Actuellement, cette approche peut être adaptée aux spécificités des nanomatériaux (NMs) pour lesquelles peu de connaissances scientifiques sont disponibles sur les risques potentiels pour la santé et pour la sécurité des travailleurs. Au cours des dernières années, différentes études ont porté sur l’application de l’approche CB et plusieurs pays ont développé leur propre méthode adaptée aux NMs. Par contre, tous les modèles développés sont basés sur des critères qualitatifs du danger et de l’exposition. Une approche semi-quantitative permettrait de mieux gérer les dangers liés à la manipulation des NMs. L’objectif de ce mémoire était de développer une approche semi-quantitative d’évaluation des dangers sur la base d’une approche de CB. Pour ce faire, une analyse systématique de la littérature scientifique des 20 dernières années sur l’approche de CB a été effectué. Les bases de données Toxline, Pubmed et Google Scholar ont été consultées, couvrant la période de janvier 1996 à novembre 2016, en utilisant 4 mots-clés: control banding, nanomaterials, physicochemical, biological characteristics. Cette recherche a permis d’identifier 982 articles, dont 11% (91) furent retenus en première intention pour au final en garder 6 % (51/982). Il ressort de cette revue que le CB est une approche complémentaire aux méthodes d’évaluation quantitative et que les outils CB développés pour les NMs sont tous de nature qualitative, en réponse à une exposition. Une approche semi-quantitative où il y a maillage entre la caractérisation biologique avec les tests in vitro et la caractérisation physicochimique par des analyses chimiques pour mieux caractériser le niveau de dangérosité des NMs tel que présenté dans le présent mémoire permettrait une utilisation plus judicieuse du CB. Cette approche novatrice du CB dépasse largement l’utilisation que l’on en fait actuellement en hygiène du travail, devrait accroître la confiance dans le jugement des experts en santé au travail, afin d’orienter les travailleurs et la population générale vers une utilisation sécuritaire des NMs.Among the hazards assessment methodology that has grown exponentially during the last decade, mention Control Banding (CB). According to the National Institute for Occupational Safety and Health (NIOSH), this qualitative approach originally developed in the pharmaceutical industry, aims to protect approximately 90% or 2.7 billion workers that do not have access to occupational safety, health, and hygiene. Currently, this approach can be adapted to the specificities of nanomaterials (NMs), considering the significant lack of scientific knowledge about their potential health and safety risks to workers. In recent years, several CB models have been developed, and many countries have created their own nano-specific CB instruments. However, a semi-quantitative approach would better managing the hazards of handling nanomaterials in the workplace. This thesis aimed to perform a systematic literature review over the past 20 years about the CB approach and then to suggest a semi-quantitative hazard assessment. The official Web pages of the databases Toxline, Pubmed and Google Scholar were used, covering the literature from January 1996 to November 2016, with use of the 4 keywords to locate relevant articles: Control Banding, nanomaterials, physico-chemical, biological characteristics. These searches yielded a total of 982 articles, 11% (91) were retained to eventually retain 6% (51/982). This review shows that the CB approach is an interesting and complementary methodology to quantitative evaluation methods and the CB tools developed for NMs are all qualitative in nature, in response to an exposure and adapted to different work environments. It is possible to make better use by proposing a semi-quantitative approach based on physicochemical and toxicity parameters of NMs to better characterize their degree of dangerousness. We propose here an original methodology proposing the interaction of in vitro tests and chemical analyzes. This innovative Control Banding approach should increase confidence in the judgment of experts and industry, as well as to guide both exposed workers and the uses of NMs in this industry

An Assessment of Factors Influencing Use of Respiratory Protective Equipment in the Norwegian Smelter Industry and the Effect of a Knowledge-based Intervention

Chronic obstructive pulmonary disease (COPD), asthma and other respiratory illness have been shown to be more prevalent in Norwegian smelter workers compared to the general population. There is evidence suggesting that the use of respiratory protective equipment (RPE) can be sub-optimal in occupations with respiratory exposure. This thesis investigated psychological factors thought to influence intention to use RPE, and reported RPE use in a sample of Norwegian smelter workers. Results indicated that RPE use is at times sub-optimal, that disposable RPEs were still commonly used and that there were barriers related to proper use. A modified version of the Theory of Planned Behavior was compiled and structural equation modeling was used to investigate how attitudes, subjective norms, perceived control, safety climate and work experience predicted intention to use RPE. The relationship between intention and reported behavior was also investigated. Results indicated that Attitudes and Subjective norms and safety climate were the best predictors of intention to use respirators. An intervention study was designed aiming to improve intention and use of RPE. Data was collected at four intervals using questionnaires: at baseline and three follow-ups, two weeks, three and nine months post intervention. The results revealed that participants in the two interventions groups showed small but significant improvements over the control group. The thesis concludes that attitudes, subjective norms and safety climate are important predictors of intention to use RPE, and that tailored and interactive interventions may improve knowledge, attitudes, subjective norms, intentions, perceptions of inconvenience and perceptions of organizational support regarding the use of RPE. In addition, the intervention effect was shown to persist throughout the project period.Det er observert hyppigere forekomst av kronisk obstruktiv lungesykdom (KOLS), astma, luftveissykdommer og fall i lungefunksjon blant norske smelteverksarbeidere enn hos den øvrige befolkningen. Det er tidligere rapportert at bruken av åndedrettsvern kan være sub-optimal i andre industrier. Denne avhandlingen undersøkte psykologiske faktorers innflytelse på intensjonen til å bruke, samt rapportert bruk av åndedrettsvern. Studien viste at bruken av åndedrettsvern er sub-optimal blant annet grunnet vanskelige arbeidssituasjoner og uforenlighet med annet sikkerhetsutstyr. En modifisert versjon av Theory of Planned Behavior ble utviklet for å utforske hvordan sammenhengen mellom holdninger, subjektive normer, opplevd kontroll, sikkerhetsklima og arbeidsopplevelse korrelerte med intensjonen til bruk av åndedrettsvern. Forholdet mellom intensjonen og rapportert bruk ble undersøkt ved bruk av regresjon. Resultatene indikerte at holdninger, subjektive normer og sikkerhetsklima var de beste prediktorene for intensjonen til å bruke åndedrettsvern. En intervensjon ble skreddersydd til industrien og arbeidsoppgavene deres for å øke intensjonen og bruken av åndedrettsvern. Spørreskjema ble brukt for å samle inn data, og ble utlevert før intervensjonen og 2 uker, 3- og 9 måneder etter intervensjonen. Funnene indikerte små men signifikante forskjeller mellom intervensjonsgruppene og kontrollgruppen. Avhandlingen konkluderte med at holdninger, subjektive normer og sikkerhetsklima er viktige prediktorer for intensjonen til å bruke åndedrettsvern, og at intervensjoner kan brukes for å øke kunnskap, holdninger, subjektive normer, intensjon, opplevelsen av ulemper og opplevelsen av organisasjon i relasjon til bruken av åndedrettsvern. Effekten av intervensjonen vedvarte over tid

Using chemical structure and inocula characteristics to predictively model biodegradation rate

PhD ThesisPredictive biodegradation models [i.e. Quantitative Structure Biodegradation Relationship (QSBR) models] might be used as an alternative to current regulatory biodegradation tests to predict chemical persistence. Current models are mostly based on the results derived from regulatory Ready Biodegradability Tests (RBTs), which are highly variable and were not designed to provide half-life data and therefore fundamentally undermines efforts to reliably predict chemical persistence. Improvement to existing approaches for developing and verifying predictive models and their reliability, respectively, have been proposed, and the use of functional gene and 16S rRNA amplicon sequencing techniques towards identifying and quantifying the putative chemical degraders have been studied. Several QSBR models for aromatic chemicals were developed according to OECD principles. Models for mono-aromatic chemicals were verified and calibrated with experimentally determined rates (both from pure culture and natural mixed communities). Traditional test methods were combined with functional genes and 16S amplicon sequence analyses to develop a relationship between rate, chemical concentration and competent putative chemical degrader abundance. QSBR models for mono-aromatic chemicals were stable (R2 = 0.8924), robust (Q2LOO = 0.8718) and had good predictive ability (Q2F1 = 0.8829, Q2F2 = 0.8835, and Q2F3 = 0.9178). In these models, biodegradation rates were associated with electronic, lipophilic and steric descriptors, and thus provided information on the mechanisms of different rate-limiting steps associated with the biodegradation process. However, all the variation in biodegradation rates cannot be explained by the structure alone, the prevailing environmental conditions have a significant role in determining the extent of chemical degradation. Biodegradation rates (k) of chemicals in natural mixed communities were significantly correlated with the ratio of abundance of initial putative degrader abundances (X0) and the starting chemical concentration (C0) (Pearson correlation coefficient (r) > 0.9 and p-value < 0.05). Predictive models developed by relating k with X0 and C0 reliably predicted the rate of studied chemicals. Experimentally determined rates further formed the basis towards calibrating the developed QSBR models. The molecular analysis revealed that majority of identified putative chemical degraders were rare taxa, and their enrichment did not necessarily influence the overall biomass count of the microbial community, and therefore biodegradation models that only consider the overall biomass would not account for the kind of relationships found in this study. Application of 16S amplicon sequencing and functional gene analyses techniques in biodegradation studies will help in depth screening of diversity and function of microbial community in an inoculum and enables better understanding of biodegradation outcomes.funded by the Engineering and Physical Sciences Research Counci

The impact of perfectionism on psychological well-being and ill-being in athletes with and without hearing disability

The overarching aim of the current thesis was to assess the well-being and ill-being correlates of two perfectionism dimensions (i.e., self-oriented and socially prescribed perfectionism) in hearing and deaf athletes. In Study One (Chapter Two), a cross-sectional approach revealed the similarities in the relationships between self-oriented and socially prescribed perfectionism and the broader array of burning out symptoms in deaf and hearing athletes. Study Two (Chapter Three) adopted a longitudinal design, and examined whether self-oriented and socially prescribed perfectionism predicted changes in enjoyment and subjective vitality over four months, as well as whether changes in exhaustion over the same time period mediated the hypothesised relationships. A further purpose of study two was to examine whether the hypothesised relationships were invariant across hearing and deaf athletes. Study Three (Chapter Four) adopted qualitative semi-structured interviews to gain a deeper understanding of high self-oriented and socially prescribed perfectionism in deaf and hearing athletes using a self-regulation framework. The majority of the findings suggest that self-oriented and socially prescribed perfectionism function in a similar manner across deaf and hearing athletes. It is hoped that the findings presented in this thesis may inform future research in deaf athletes to help protect this growing population from the perils of perfectionism

Struktur, Funktion und Verhalten dynamischer Modelle der Systembiologie: formale Wissensrepräsentation als Grundlage für computergestützte Modellierung und Simulation

Das Verstehen komplexer biologischer Phänomene auf der Basis dynamischer Modelle ist ohne Computerunterstützung nicht möglich. Seit mehr als einem Jahrzehnt werden enorme Anstrengungen unternommen, eine Softwareinfrastruktur für die systembiologische Modellierung und Simulation zu entwickeln. Die vorliegende Arbeit bietet den dafür notwendigen Standards, formalen Sprachen, Ontologien und auf diesen operierenden Programmen ein wissenschaftstheoretisches Fundament in Gestalt der sogenannten Wissensfacetten von Bio-Modellen. Die Wissensfacetten von Bio-Modellen stellen ein konzeptuelles Schema zur systematischen Beschreibung von Bio-Modellen, ihrer Verwendung und ihres Verhaltens dar. Dabei muss eine vollständige Beschreibung eines Bio-Modells seine Struktur, seine Funktion und sein Verhalten umfassen und seine intrinsische formale Semantik mit der extrinsischen biologischen Wirklichkeit in Beziehung setzen. Die formale Repräsentation der Wissensfacetten von Bio-Modellen bietet eine Grundlage für eine umfassende Computerunterstützung der Modellierung und Simulation in der Systembiologie. Geleitet durch die Wissensfacetten werden existierende Ansätze für die formale Repräsentation relevanter Wissensfragmente eingeordnet und bewertet sowie Defizite an Beschreibungsmitteln identifiziert. Ein großes Defizit liegt im Fehlen formalsprachlicher Mittel zur qualitativen Beschreibung des Verhaltens von Bio-Modellen. Im Rahmen dieser Arbeit wurde die Ontologie TEDDY entwickelt, auf deren Grundlage sich das Verhalten von Bio-Modellen propositional formalisieren lässt. TEDDY stellt eine formale begriffliche Basis der Theorie dynamischer Systeme dar. Die drei Hauptresultate der vorliegenden Arbeit sind eingebettet in grundsätzliche Betrachtungen zur Modellierung und Simulation in der Systembiologie und basieren auf allgemeinen Begriffen und Verfahren der Wissensrepräsentation sowie speziellen Methoden der qualitativen Beschreibung von Dynamik

A personalised and adaptive insulin dosing decision support system for type 1 diabetes

People with type 1 diabetes (T1D) rely on exogenous insulin to maintain stable glucose levels. Despite the advent of diabetes technologies such as continuous glucose monitors and insulin infusion pumps, the majority of people with T1D do not manage to bring back glucose levels into a healthy target after meals. In addition to patient compliance, this is due to the complexity of the decision-making on how much insulin is required. Commercial insulin bolus calculators exist that help with the calculation of insulin for meals but these lack fine-tuning and adaptability. This thesis presents a novel insulin dosing decision support system for people with T1D that is able to provide individualised insulin dosing advice. The proposed research utilises Case-Based Reasoning (CBR), an artificial intelligence methodology, that is able to learn over time based on the behaviour of the patient and optimises the insulin therapy for various diabetes scenarios. The decision support system has been implemented into a user-friendly smartphone-based patient platform and communicates with a clinical platform for remote supervision. In-silico studies are presented demonstrating the overall performance of CBR as well as metrics used to adapt the insulin therapy. Safety and feasibility of the developed system have been assessed incrementally in clinical trials; initially during an eight-hour study in hospital settings followed by a six-week study in the home environment of the user. Human factors play an important role in the clinical adoption of technologies such as the one proposed. System usability and acceptability were evaluated during the second study phase based on feedback obtained from study participants. Results from in-silico tests show the potential of the proposed research to safely automate the process of optimising the insulin therapy for people with T1D. In the six-week study, the system demonstrated safety in maintaining glycemic control with a trend suggesting improvement in postprandial glucose outcomes. Feedback from participants showed favourable outcomes when assessing device satisfaction and usability. A six-month large-scale randomised controlled study to evaluate the efficacy of the system is currently ongoing.Open Acces

Pan European Voice Conference - PEVOC 11

The Pan European VOice Conference (PEVOC) was born in 1995 and therefore in 2015 it celebrates the 20th anniversary of its establishment: an important milestone that clearly expresses the strength and interest of the scientific community for the topics of this conference. The most significant themes of PEVOC are singing pedagogy and art, but also occupational voice disorders, neurology, rehabilitation, image and video analysis. PEVOC takes place in different European cities every two years (www.pevoc.org). The PEVOC 11 conference includes a symposium of the Collegium Medicorum Theatri (www.comet collegium.com