Le travail de cette thése a montré d'une part le rôle significatif du mécanisme de \underline{Fusion-Fission Asymétrique} dans les collisions entre ions lourds légers (A$_{\rm NC} \le$60) et, d'autre part, le \underline{Désalignement des Spins} dans un systéme {\it oblate-oblate} mettant en évidence pour \underline{la premiére fois le {\it mode papillon} lors de la réaction dans les résonances quasi-moléculaires}. Ces deux aspects, l'un macroscopique l'autre beaucoup plus lié á des effets microscopiques, sont certes différents d'un point de vue conceptuel, mais tout á fait complémentaires pour une compréhension globale des systémes di-nucléaires. \par \hspace*{0.5cm}Dans la premiére partie, les réactions $^{35}$Cl $+$ $^{12}$C et $^{35}$Cl $+$ $^{24}$Mg á 8 MeV/nucléon (expérience effectuée á Saclay) ont fait l'objet de mesures inclusives et de mesures exclusives. La nature des produits donnant naissance au mécanisme de fusion-fission asymétrique a été vérifiée. Il a été également démontré que dans ce domaine en énergie le processus \underline{ternaire} est trés faible. La deuxiéme partie est consacrée á l'étude de la réaction $^{28}$Si $+$ $^{28}$Si réalisée sur une énergie de résonance E$_{\rm lab.}$~=~111.6 MeV auprés de l'accélérateur VIVITRON de Strasbourg avec le multidétecteur EUROGAM Phase II. Le moment angulaire J$^{\pi}$ = 38$^{+}$ a été mesuré pour les voies inélastique et mutuelles de la voie de sortie $^{28}$Si $+$ $^{28}$Si. La mise en évidence du \underline{désalignement} \underline{des spins} a été interprété á l'aide du modéle moléculaire par le \underline{mouvement papillon}''mouvement Butterfly''. La spectroscopie $\gamma$ semble indiquer une nouvelle transition $\gamma$ dans la désexcitation du $^{32}$S qui est $0^{+} (8507.8\ keV) \to 2^{+}_{1} (2230.2\ keV) $.

The clinical trial is the most import study for the development of successful novel drugs. The aim of this dissertation is to develop innovative statistical methods to overcome the three main obstacles in clinical trials: (1) lengthy trial duration and inaccurate maximum tolerated dose (MTD) in phase I trials; (2) heterogeneity in drug effect when patients are given the same prescription and same dose; and (3) high failure rates of expensive phase III confirmatory trials due to the discrepancy in the endpoints adopted in phase II and III trials. Towards overcoming the first obstacle, we originally develop a hybrid design for the time-to-event dose escalation method with overdose control using a normalized equivalent toxicity score (NETS) system. This hybrid design can substantially reduce sample size, shorten study length, and estimate accurate MTD by employing a parametric model and adaptive Bayesian approach. Toward overcoming the second obstacle, we propose a new approach to incorporate patients’ characteristic using our proposed design in phase I clinical trials which considers the personalized information for patients who participant in the trials. To conquer the third obstacle, we propose a novel two-stage screening design for phase II trials whereby the endpoint of percent change in of tumor size is used in an initial screening to select potentially effective agents within a short time interval followed by a second screening stage where progression free survival is estimated to confirm the efficacy of agents. These research projects will substantially benefit both cancer patients and researchers by improving clinical trial efficiency and reducing cost and trial duration. Moreover, they are of great practical meaning since cancer medicine development is of paramount importance to human health care.

Statistical process control (SPC) is a toolbox to detect changes in the output of a process distribution. It can serve as a valuable resource to maintain high quality in a manufacturing process. This report is based on the work on evaluating and implementing methods for SPC in the process of chromatography instrument manufacturing at GE Healthcare, Umeå. To handle low volume and non-normally distributed process output data, non-parametric methods are considered. Eight control charts, three for for Phase I analysis, and five for Phase II analysis, are evaluated in this study. The usability of the charts are assessed based on ease of interpretation and the performance to detect distributional changes. The later is evaluated with simulations. The result of the project is the implementation of the RS/P-chart, suggested by Capizzi et al (2013), for Phase I analysis. Of the considered Phase I methods (and simulation scenarios), the RS/P-chart has the highest overall probability, of detecting a variety of distributional changes. Further, the RS/P-chart is easily interpreted, facilitating the analysis. For Phase II analysis, the use of two control charts, one based on the Mann-Whitney U statistic, suggested by Chakraborti et al (2008), and one on the Mood test statistic for dispersion, suggested by Ghute et al (2014), have been implemented. These are chosen mainly based on the ease of interpretation. To reduce the detection time for changes in the process distribution, the change-point chart based on the Cramer Von Mises statistic, suggested by Ross et al (2012), could be used instead. Using single observations, instead of larger samples, this chart is updated more frequently. However, this efficiently increases the false alarm rate and the chart is also considered much more difficult to interpret for the SPC practitioner. / Statistisk processkontroll (SPC) är en samling verktyg för att upptäcka förändringar, i fördelningen, hos utfallen i en process. Det kan fungera som en värdefull resurs för att upprätthålla en hög kvalitet i en tillverkningsprocess. Denna rapport är baserad på arbetet med att utvärdera och implementera metoder för SPC i en monteringsprocess av kromatografiinstrument på GE Healthcare, Umeå. Åtta styrdiagram, tre för för fas I analys, och fem för fas II analys, studeras i denna rapport. Användbarheten hos styrdiagrammen bedöms efter hur enkla de är att tolka och förmågan att upptäcka fördelningsförändringar. Den senare utvärderas med simuleringar. Resultatet av projektet är införandet av RS/P-metod, utvecklad av Capizzi et al (2013), för analysen i fas I. Av de utvärderade metoderna, (och simuleringsscenarier), har RS/P-diagrammet den högsta övergripande sannolikheten, för att upptäcka en mängd olika fördelningsförändringar. Vidare är metodens grafiska diagram lätt att tolka, vilket underlättar analysen. För fas II analys, har två styrdiagram, ett baserat på Mann-Whitney's U teststatistika, som föreslagits av Chakraborti et al (2008), och ett på Mood's teststatistika för spridning, som föreslagits av Ghute et al (2014), implementerats. Styrkan i dessa styrdiagram ligger främst i dess enkla tolkning. För snabbare identifiering av processförändringar kan styrdiagrammet baserat på Cramer von Mises teststatistika, som föreslagits av Ross et al (2012), användas. Baserat på enskilda observationer, istället för stickprov, har styrdiagrammet en högre uppdateringsfrekvens. Detta leder dock till ett ökat antal falska larm och styrdiagrammet anses dessutom vara avsevärt mycket svårare att tolka för SPC-utövaren.

The body of work presented here is a compendium of the multiple steps required for an investigator initiated trial of an existing medication (Valproic Acid- VPA) for a new indication (Retinitis Pigmentosa – RP). The chapters are listed in logical and chronological order of the process. In order to access patient records an expedited Institutional Review Board (IRB) application for retrospective chart review was submitted (Chapter 1). These records enabled the statistical analysis which not only laid the framework for the trial design, but also became the basis for two manuscripts (Chapter 2). Protocol development informed by the preliminary human studies (Chapter 3) was an instrumental part of the Investigational New Drug (IND) application (Chapter 3.5). This protocol along with the extensive case report forms that detail the intended data to be collected are included in the IND application. Because the Phase II clinical trial proposed attempting to identify the specific RP mutations of the subjects utilizing a National Eye Institute (NEI) study that enabled free genotyping services, two IRB applications were submitted (Chapter 3.6). The first was for approval of the NEI genotyping protocol, the second involved the VPA intervention. Two very different sources of funding for this trial were attempted (Chapter 4) – the NIH via the Challenge Grant mechanism and a private eye disease foundation (Foundation Fighting Blindness). In Chapter 5 I detail the alternate study designs that were considered and developed for this trial (and ultimately abandoned). Finally, in Chapter 6, I formally detail my suggestions to aid in the development of a comprehensive investigator initiated core facility at UMMMC. The goal of this project was two-fold. The first was to learn the entire process of trial and protocol design both from a Umass Institutional perspective as well as from the perspective of the FDA. The second goal was the very real prospect of helping patients with a blinding disease. This work was successful on both counts. IRB approval was received for all the submitted applications. The complexity and uniqueness of many aspects of these submissions culminated in a comprehensive learning experience. The process of working with the Umass Research Pharmacy as well as developing the industry contacts and know-how to develop a workable and financially feasible placebo were both particularly important learning experiences. FDA approval of the IND submission was also received, and the process of pre-communication and delving into the considerable and ever-changing rules and regulations resulted in an extensive and valuable knowledge base. While the practicality of funding has limited the ability of this trial to move forward at this point, given the extensive framework laid by this body of work, we are actively pursuing other opportunities. The third outcome of this work, while not as intentional, was the considerable process of determining the specific competencies and infrastructure that exist at UMMMC to enable investigator initiated drug intervention studies. While this institution is clearly moving rapidly in the direction of translational research, the many needs of these studies are often only clearly understood when the process is specifically undertaken. In completing the approval of this Phase II clinical trial, I was not only able to better understand and define the existing capabilities of UMMMC for this kind of research, I was able to add to that infrastructure when the existing knowledge or skill set was not available. In this manner, I was able to inform and guide many of the support personnel who guided me and have become a part of the strategic direction of UMMMC towards clinical translational research.

This thesis deals with phase II of IFRS 4 Insurance contracts. The aim of the standard is to establish the principles that an entity should apply to report useful information to users of its financial statements about the nature, amount, timing and uncertainty of cash flows from insurance contracts, so that the financial statements of the entity are comparable with financial statements of other entities. Therefore IASB introduced building blocks measurement model, where an insurance contract is measured based on the present value of expected fulfillment cash flows, risk margin and contractual service margin. The building blocks model is based on making extensive judgments when measuring the insurance contracts. To explain the judgments, the standard requires the entity to disclose details about the judgments in the footnotes to the financial statements. The building blocks model is used mainly for life insurance contracts. For contracts that last one year or less (usually non-life insurance contracts) the standard allows the entities to use a simplified approach for measuring insurance contracts that is similar as the current practice of measuring non-life insurance contracts. Revenues from insurance contracts should depict the transfer of promised services arising from the insurance contract in an amount that reflects the consideration to which the entity expects to be entitled in exchange for those services (this approach is in line with the prepared IFRS 15 Revenue from Contracts with Customers).

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Im Jahr 2026 beginnt im Rahmen der Phase-II Erweiterung der Ausbau des Large Hadron Colliders, damit dieser zukünftig mit dem bis zu 7.5-fachen seiner nominellen Luminosität betrieben werden kann. Der Beginn der Datenaufnahme für den sogenannten High-Luminosity Large Hadron Collider ist für 2029 vorgesehen. Durch die Erweiterung wird eine wesentliche Zunahme der Kollisionsrate und damit der Kollisionsdaten erwartet, welche die heutige Auffassung von Theorien jenseits des Standardmodells der Teilchenphysik verbessern wird. Zusammen mit der Steigerung interessanter Ereignisse werden jedoch auch Proton-Proton-Kollisionen mit meist niederenergetischen hadronischen Teilchen im Endzustand und damit Signalüberlappungen zunehmen. Am ATLAS-Experiment führt dies zu höheren Anforderungen an die Detektorelektronik und die Echtzeit-Datenverarbeitung. Für die Flüssig-Argon-Kalorimeter ist ein Austausch der gesamten Elektronik vorgesehen. Studien konnten zeigen, dass der Optimalfilter, der derzeit zur Energierekonstruktion eingesetzt wird, einen erheblichen Leistungsabfall verzeichnen wird. Eine zuverlässige Energieinformation ist jedoch essentiell, insbesondere auch für das Triggersystem. Im Rahmen dieser Arbeit wurden sogenannte Faltungsnetzwerke für die Rekonstruktion von Energiedepositionen in Flüssig-Argon-Kalorimeterzellen entwickelt. Da diese auf Field Programmable Gate Arrays (FPGAs) mit strengen Ressourcenbeschränkungen implementiert werden sollen, müssen diese nicht nur eine hohe Rekonstruktionsgenauigkeit zeigen, sondern auch einen geringen Ressourcenverbrauch haben. Eine Hyperparametersuche wird präsentiert, die das Bestimmen geeigneter Netzwerkarchitekturen ermöglicht. Für das Trainieren und Testen von Faltungsnetzwerken wurden Daten mit realistischen Signalszenarien anhand der AREUS-Simulationssoftware generiert. Die verschiedenartigen Signalbedingungen und Leistungsanforderungen machen eine umfassende Untersuchung des Energierekonstruktionsalgorithmus erforderlich. Die Reproduzierbarkeit der Trainingsergebnisse der Faltungsnetzwerke stellt eine weitere Anwendungsvoraussetzung dar. Infolgedessen beschreibt diese Arbeit ein umfangreiches Qualifizierungsprozedere, welches für jedweden Energierekonstruktionsalgorithmus angewandt werden kann. Die präsentierten Faltungsnetzwerke erfüllen die FPGA Ressourcenbeschränkungen und zeigen darüber hinaus essentielle Leistungsverbesserungen gegenüber dem Optimalfilter. Das Faltungsnetz mit der besten Leistung besteht aus zwei Schichten und nutzt Dilatation, um den einfließenden Signalbereich auszudehnen. Dies erlaubt dem Netzwerk, mehr Informationen von vergangenen Signalereignissen zu erhalten, während gleichzeitig die Zahl der Netzwerkparameter niedrig gehalten wird. Es wird gezeigt, dass das zweischichtige Faltungsnetzwerk Verbesserungen hinsichtlich Signaleffizienz und Energieauflösung, insbesondere für überlappende Signale, liefert. Des Weiteren wird die Robustheit gegenüber variierenden Signalankunftszeiten und sich verändernden Untergrundbedingungen vorgestellt, sowie die Erfüllung der Trainingsreproduzierbarkeit demonstriert. Zusammengefasst beschreibt diese Arbeit die systematische Entwicklung und Erprobung von Faltungsnetzwerken für die Energierekonstruktion von Flüssig-Argon-Kalorimetersignalen am ATLAS-Detektor. In diesem Rahmen wurden allgemeine Qualifizierungskriterien erarbeitet, die das Potential der Faltungsnetzwerke gegenüber der aktuellen Methode, dem Optimalfilter, aufzeigen. / In 2026, the expansion of the Large Hadron Collider will begin as part of the Phase II extension so that it can be operated at up to 7.5 times its nominal luminosity in future. The start of data acquisition for the so-called High-Luminosity Large Hadron Collider is scheduled for 2029. The expansion is expected to significantly increase the collision rate and thus the collision data, which will improve the current understanding of theories beyond the standard model of particle physics. However, together with the increase in interesting events, proton-proton collisions with mostly low-energy hadronic particles in the final state and thus signal overlaps will also increase. At the ATLAS experiment, this will lead to higher demands on the detector electronics and real-time data processing. The entire electronics for the liquid argon calorimeters will be replaced. Studies have shown that the optimal filter, which is currently used for energy reconstruction, will experience a considerable drop in performance. However, reliable energy information is essential, especially for the trigger system. As part of this work, so-called convolutional networks were developed for the reconstruction of energy depositions in liquid argon calorimeter cells. Since these are to be implemented on field programmable gate arrays (FPGAs) with strict resource constraints, they must not only show a high reconstruction accuracy but also have a low resource consumption. A hyperparameter search is presented, which enables the determination of suitable network architectures. For the training and testing of convolutional networks, data with realistic signal scenarios were generated using the AREUS simulation software. The different signal conditions and performance requirements necessitate a comprehensive investigation of the energy reconstruction algorithm. The reproducibility of the training results of the convolutional networks is a further application requirement. Consequently, this thesis describes a comprehensive qualification procedure that can be applied to any energy reconstruction algorithm.

Background Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. Methods/design This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. Discussion The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Trial registration Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

Background Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. Methods/design This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. Discussion The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Trial registration Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016.

A quantitative, exploratory, descriptive and contextual research study was conducted to establish the effect of reinforcement of information in phase II cardiac rehabilitation of myocardial infarction patients. Its aim was to determine the sufficiency of patient education during hospitalisation and the necessity for reinforcing information during follow-up sessions after the patient's discharge from hospital. Patients from two private hospitals in Gauteng were involved in the study. A quasi-experimental research design, namely the comparison group posttest-only design, was implemented with no random assignment of subjects to the experimental and control groups. A convenient non-probability sampling method was used and data was collected by means of questionnaires. The data analysis revealed that patients received sufficient education during hospitalisation, but that discharged patients still believed follow-up sessions to be a necessity. No significant difference was found in the knowledge levels of the experimental and control groups. / 'n Kwantitatiewe, verkennende, beskrywende en kontekstuele studie is uitgevoer om ondersoek in te stel na die effek van inligtingversterking in Fase II kardialerehabilitasie van miokardiale-infarksie-pasiente. Hiermee wou die navorser bepaal of pasientonderrig in die hospitaal voldoende was, en of die opvolging van pasiente na ontslag uit twee privaat hospitale in Gauteng noodsaaklik was om inligting te versterk. Vir die implementering van die studie is van 'n kwasi-eksperimentele navorsingsontwerp, naamlik die tweegroep-posttoets-ontwerp, gebruik gemaak. Respondente is nie ewekansig aan 'n eksperimentele en 'n kontrolegroep toegewys nie. 'n Nie-waarskynlike gerieflikheidsteekproeftrekking is gedoen, en data is ingesamel deur middel van die voltooiing van 'n vraelys. Die data-analise het getoon dat die pasientonderrig in die hospitaal voldoende was, maar dat pasiente steeds van mening was dat opvolging na ontslag noodsaaklik is. Geen beduidende verskil is gevind in die kennisvlakke van die eksperimentele en die kontrolegroep nie. / Health Sciences / M.A. (Nursing)