Traditional clinical trials have been inefficient in their methods of dose finding and dose allocation. In this paper a four-parameter logistic equation is used to model the outcome of Bernoulli-response clinical trials. A Bayesian adaptive design is used to fit the logistic equation to the dose-response curve of Phase II and Phase III clinical trials. Because of inherent restrictions in the logistic model, symmetric candidate densities cannot be used, thereby creating asymmetric jumping rules inside the Markov chain Monte Carlo algorithm. An order restricted Metropolis-Hastings algorithm is implemented to account for these limitations. Modeling clinical trials in a Bayesian framework allows the experiment to be adaptive. In this adaptive design batches of subjects are assigned to doses based on the posterior probability of success for each dose, thereby increasing the probability of receiving advantageous doses. Good posterior fitting is demonstrated for typical dose-response curves and the Bayesian design is shown to properly stop drug trials for clinical futility or clinical success. In this paper we demonstrate that an adaptive Bayesian approach to dose-response studies increases both the statistical and medicinal effectiveness of clinical research.

The production and approval process for the various labels used in clinical trials wastes significant time and resources through the need to outsource label production or rely on large reams of pre-cut label stock for each revision throughout the process. An in-house, on-demand label printing and cutting system is a potential remedy to this waste. Previous work by Cheadle et al. resulted in a functional electomechanical prototype of the label cutting aspect of this research, capable of rudimentary linear cuts. In this continued research, emphasis was placed on improved label cutting capabilities and creating PC control software for label design. Cutting operations were enhanced through the development of an algorithm for circular cuts, proportional motor control, and a prototype graphical user interface (GUI) for simple user control. The changes to cutting methods have improved linear cutting precision to an average of 0.00402-in (s = 0.00602-in, n=26) at minimum. The new method for circular cuts has an average precision of 0.04384-in (s = 0.01471-in, n=26). The target precision for cuts is 0.040-in, suggesting that linear cuts are satisfactory, but circular cuts must still be refined. The prototype user interface developed for this research is capable of driving the label cutting system through RS232 communication and exposes all functionality of the system to date. Overall, this research has enhanced the capabilities of the label cutting system significantly, but further work is required to realize a complete label production solution.

Background: Given that 43-97% of preterm infants face postnatal growth restriction by hospital discharge, monitoring of growth is challenging but critical for clinical management of preterm infants. Currently, serial anthropometric measurements of weight and height are used to monitor growth but lack sensitivity. Thus, by the time significant deviations in growth trajectory are identified, an infant has already reached sub-optimal growth. A biomarker that is predictive of sub-optimal growth can serve as a preventative tool in clinical decision making. Blood urea nitrogen (BUN) may be one such potential metabolic biomarker, as it has been used as a measure of protein adequacy and thus, may additionally indicate quality of growth. While protein intake has a well-established correlation with growth, it is currently unknown if BUN is correlated with postnatal growth and if it can be used as a biomarker for growth. Objectives: 1) to examine the relationship between BUN and macronutrient intake factors such as protein intake, protein-to-energy (P:E) ratios, and carbohydrate to non-protein energy (CHO:NPE %) to better understand BUN response; 2) to examine the potential of using BUN as a predictive metabolic biomarker of growth status in a multiple linear regression. We hypothesize that BUN will positively correlate with protein intake, P:E and negatively with CHO:NPE ratio. It will also be positively correlated with growth parameters: growth velocity, length gain, head circumference gain and fat free mass. Methods: Very low birth weight preterm infants (n=101) born ≤30 weeks of gestation at McMaster Children’s Hospital’s level III NICU were included. BUN was assessed at three time points: baseline (SDay1), study day 14 (SDay14) and study day 21 (SDay21). Intake of protein and energy were collected for the 24-hour period prior to the BUN measure, their averages computed over SDay14 and SDay21 and included as confounding predictor variables. Other confounding variables such as maternal characteristics and baseline study group characteristics were also considered. Growth velocity, length gain and head circumference gain at SDay14 and SDay21, and body composition (FFM%, FFMI) between 36-40 weeks were examined as dependent growth variables. After an initial univariate analysis of baseline and maternal confounders, multiple linear regression models were then developed in a block design as follows: for the analysis of BUN vs macronutrient factors- block 1: 24-hour macronutrient intake factors + relevant baseline and/or maternal confounders; block 2: average macronutrient factors; for the analysis of BUN vs growth- block 3: BUN. Results: In the analysis of BUN and macronutrient intake, BUN was found to have a significant positive correlation with P:E ratio at all time points. Protein intake was positively correlated with BUN only at SDay1 and SDay21. CHO:NPE ratio did not correlated with BUN at any time point. The R2 for the multiple regression of BUN and macronutrient factor analysis at SDay1, SDay14 and SDay21 was 0.19, 0.42 and 0.44 respectively. In the analysis of BUN vs growth, SDay1 BUN had a significant negative correlation with SDay21 growth velocity (p=0.02). The addition of SDay1 BUN to the model of SDay21 growth velocity was significant (p<0.01 of F change statistic, R2= 0.17). SDay21 BUN also had a significant negative correlation with SDay21 growth velocity (p<0.01) and its addition was significant to the model (p<0.01 of F change statistic, R2 =0.22). BUN was not related to SDay 14 growth velocity, or to length gain, head circumference gain or any body composition estimates at any time point. Additionally, P:E was found to be significantly negatively correlated with growth. Conclusion: BUN is a statistically and clinically significant marker of nutritional adequacy, both of protein intake and energy in relation to protein intake. Addition of BUN adds to the explanation of variation in growth, and this is statistically significant, however, the additional variation explained may be too small to be clinically significant. Additionally, we observed that P:E ratio was significantly negatively correlated with growth. Thus, it may be more clinically pertinent to use high BUN values as a marker of inadequate energy to protein intake to prevent future sub-optimal growth. / Thesis / Master of Science (MSc)

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24998号 / 医博第5032号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 山本 洋介, 教授 永井 洋士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Das Ziel dieser randomisierten, klinischen 12-Monatsstudie war die Untersuchung der Performance des Universaladhäsivs iBond® Universal an Restaurationen von nicht-kariöse Zahnhalsläsionen (NCCL) sowohl klinisch mittels FDI Kriterien als auch mittels Analyse des Zahn-Komposit-Verbundversagens mittels optischer Kohärenztomografie (OCT). An 50 Patienten wurden je drei bzw. vier NCCLs mit dem Universaladhäsiv iBond Universal (iBU, Kulzer) in den Konditionierungsmodi self-etch (iBU-SE, n = 50), selective-enamel-etch (iBU-SEE, n = 29) und etch-and-rinse (iBU-ER, n = 50) und mittels des Komposit Venus® Diamond Flow restauriert. Als Referenzadhäsiv (Kontrollgruppe) diente das Etch-and-rinse-Adhäsiv OptiBond™ FL (OFL, Kerr, n = 50). Die quantitative Bewertung der interfazialen Spaltformation an Schmelz und Dentin/Zement mittels OCT begann bereits initial (direkt nach Füllungslegung), nach 14 Tagen, nach sechs und zwölf Monaten, während die klinische Bewertung mittels FDI-Kriterien erst nach 14 Tagen begann und dann parallel zur tomografischen Untersuchung erfolgte. Es wurden die kumulativen Fehlerraten (für Randverfärbung, Randadaptation, Frakturen/Retention) berechnet und Kaplan-Meier-Kurven erstellt sowie die gemittelten adhäsiven Defekte pro Gruppe statistisch ausgewertet. Nach zwölf Monaten waren die kumulativen Fehlerraten mit iBU in allen Applikationsmodi signifikant (iBU-SE, iBU-SEE, Fehlerraten je 0,0%) bzw. nicht signifikant (iBU-ER, Fehlerrate 2,1%) geringer als mit OFL. Es ergaben sich für die Randadaptation und Randverfärbung keine signifikanten Gruppenunterschiede, lediglich bei der Gruppe OFL wurden tendentiell beim Kriterium Randadaptation mehr Restaurationen mit Score 2 bewertet als in der Gruppe iBU-SE. Die interfazialen Spalte nahmen innerhalb von 12 Monaten in allen Gruppen signifikant zu. Am Schmelz wurden für iBU-SE von initial bis zwölf Monate signifikant mehr adhäsive Defekte als in der Gruppe OFL und von t1 bis t3 signifikant mehr im Vergleich zu iBU-ER sowie ab t2 bis t3 mehr gegenüber iBU-SEE festgestellt. Am Dentin/Zement wurden mit iBU in allen Modi signifikant weniger adhäsive Defekte als mit OFL sowie ab t2 bis t3 weniger im Modus SE gegenüber ER festgestellt. Das mit dem Referenzadhäsiv OFL im Vergleich zu iBU signifikant häufigere Verbundversagen an der Dentin/Zement-Komposit-Interface (OCT) korrespondiert mit dem nach 12 Monaten signifikant erhöhten Auftreten von Füllungsverlusten in dieser Gruppe. Mit OCT waren die Gruppenunterschiede bereits initial (iBU-SEE, Dentin) bzw. nach 14 Tagen (alle Modi, Dentin und Dentin/Zement) statistisch verifizierbar. Die klinische Bewertung der Restauration lässt diese Aussage erst nach 12 Monaten für die Gruppen iBU-SE und iBU-ER (Trend) zu. Das gesteigerte Verbundversagen an der Dentin-Komposit- bzw. Dentin/Zement-Komposit-Interface in der Gruppe iBU-ER im Vergleich zur Gruppe iBU-SE hat sich hingegen klinisch nach 12 Monaten noch nicht durch eine geringere Retentionsrate in Gruppe iBU-ER manifestiert. Anhand der geringeren Streuung der Messwerte lässt sich vermuten, dass das Universaladhäsiv iBond Universal insbesondere im Modus SEE gegenüber OFL weniger techniksensitiv ist. Die optische Kohärenztomographie ermöglicht das Monitoring von Restaurationen, insbesondere die Progression des interfazialen Zahn-Komposit-Verbundversagens. Die Bewertung des Zahn-Komposit-Verbundversagens könnte geeignet sein, um die klinische Bewährung eines Adhäsivs frühzeitig zu beurteilen.:1. Einführung in die Thematik 1.1 Adhäsivsysteme 1.2 Methoden zur Bewertung des adhäsiven Verbundes in vivo 1.3 Optische Kohärenztomografie 2. Zielsetzungen und Hypothesen 3. Publikationsmanuskript 4. Zusammenfassung 5. Literaturverzeichnis 6. Darstellung des eigenen Beitrags 7. Selbstständigkeitserklärung 8. Wissenschaftliche Veröffentlichung 9. Lebenslauf 34 10. Danksagung 35

Mål: Målet med den retrospektiva studien var att bedöma den kliniska kvaliteten av metallkeramiska broar i titan-porslin (Ti) och kobolt-krom-porslin (Co-Cr) med en minsta uppföljningstid på två år.Material och metod: 49 patienter behandlades med metallkeramiska broar i Ti och Co-Cr på avdelningen för Oral Protetik på Odontologiska fakulteten i Malmö under perioden 2007-2010. År 2012 kontaktades dessa patienter efter att tandteknikerfakturor gåtts igenom. 21 patienter (10 män och 11 kvinnor), med en medelålder på 59,2 år och 25 broar (13 Ti och 12 Co-Cr), deltog i studien. Broarnas kliniska kvalitet bedömdes med hjälp av en modifierad version av California Dental Association (CDA) kvalitetbedömningssystem. En bedömning av lyckande- och överlevnadsfrekvens genomfördes. Statistisk analys gjordes med hjälp av Fishers’ exact test vid bedömning av skillnaden mellan grupperna. För bedömning av skillnaden mellan bedömarna beräknades kappa värdet.Resultat: Det förelåg ingen statistiskt signifikant skillnad mellan grupperna vad gäller bedömningen med CDA kvalitetbedömningssystem. Sju broar i Ti-gruppen, och åtta i Co-Cr-gruppen bedömdes som ”acceptable”. Sex Ti-broar och tre Co-Cr-broar bedömdes vara i behov av revision (”correct/replace”). Överlevnadsfrekvensen var 81,3 % för Ti-broarna och 92,3 % för Co-Cr-broarna. Tre Ti-broar och två Co-Cr-broar hade frakturer i fasadporslinet – s.k. "chip-off”-frakturer. Inom vardera grupp fanns en bro med karies på stödtänderna.Slutsatser: Broarna visade acceptabel kvalitet inom båda grupperna. Med tanke på begränsningarna för den här studien bör försiktighet vidtas när man drar slutsatser utifrån resultaten. / Aim: The aim of this retrospective study was to evaluate the clinical quality of titanium (Ti) metal-ceramic and cobalt-chromium (Co-Cr) metal-ceramic fixed dental prostheses(FDPs) with a minimum follow up period of 2 years.Methods: In 2012, 49 patients treated with FDPs during 2007-2010 at the Department of Prosthetic Dentistry, Faculty of Odontology, Malmö University, Sweden, were contacted after auditing dental technician bills. Twenty-one patients with a mean age of 59.2 years with 25 FDPs (13 Ti and 12 Co-Cr FDPs) agreed to participate in the study (10 men and 11 women). Evaluation of the metal-ceramic FDPs was made using a modified version of the California Dental Association (CDA) evaluation system. Success and survival rates were assessed. Statistical analysis was performed using Fisher’s exact test for differences between groups and for inter-examiner reliability the kappa value was calculated.Results: The two groups did not differ significantly concerning the ratings according to the CDA evaluation system. Seven FDPs in the Ti group were evaluated as acceptable while there were 8 in the Co-Cr group. Six Ti and 3 Co-Cr FDPs were evaluated as correct/replace. The survival rate for the Ti FDPs was 81.3% and for the Co-Cr FDPs 92.3%. Three Ti FDPs showed chip-off fractures while two were recorded in the Co-Cr group. In either group one FDP exhibited caries on the abutment teeth.Conclusions: Within the limitations of this study the clinical quality of the fixed dental prostheses was acceptable in both groups.

<p>Context: It is unclear whether the construct of a randomized controlled trial (RCT) itself could confer benefit or harm to trial participants beyond any effect of the experimental treatment under study (trial effect).</p> <p>Objective: To determine whether there is a trial effect appreciated by RCT participants (insiders) compared to similar patients who do not participate (outsiders). Although we are most interested in the pragmatic comparison of insiders to outsiders, we will also conduct the explanatory comparison of insiders to outsiders when the intervention is the same.</p> <p>Data Sources: We searched electronic health research databases, including CENTRAL (1960-2010), MEDLINE (1966-2010), EMBASE(1980-2010) and PsycINFO (1880- 2010).</p> <p>Study Selection: Eligible studies included those that reported the outcomes of insiders and a group of parallel or consecutive outsiders and reported the same health outcome at the same endpoint.</p> <p>Results: We included 147 articles out of the 42493 identified in our initial search. Five out of the 147 studies randomized patients to be insiders or outsiders, the remaining were observational designs. The heterogeneity of our overall result was reduced by grouping studies based on whether the intervention being investigated was effective and whether treatment inside and outside of the RCT was the same or different. There was no significant difference in outcomes between insiders and outsiders when the experimental intervention was ineffective (standard mean difference [95% confidence interval]: -0.03 [-0.1, 0.04]), or when it was effective and received by both insiders and outsiders (0.04 [-0.04,0.13]). If the experimental intervention was effective but was not administered to outsiders, they experienced worse health outcomes (-0.36 [-0.61, -0.12]).</p> <p>Conclusions: There is no evidence to support any benefit or harm associated with trial participation. There is some evidence that better outcomes are experienced by insiders who had access to effective treatments not offered or available to outsiders.</p> / Master of Health Sciences (MSc)

Until recently, academic and practitioner research on clinical trial supply chains focused on identifying innovative models and solutions in providing comparator and study drugs to global clinical sites. Due to the expansion of outsourcing efforts by pharmaceutical organizations, newly enacted global laws and regulations, and the continued push to increase the speed at which new drugs gain market approval, a new and extremely complex global “ancillary” supply chain has emerged. This manuscript focuses on the clinical trial ancillary supply chain: a supply chain that develops the end-to-end process resulting in the distribution and quality management of medical products and devices, consumable supplies, and patient giveaways to global clinical trial sites. Based on a series of quantitative analyses, this research assesses the influence of the customer, country, and product on the overall success of the supply chain. Three factors emerged from these analyses as having a direct influence on the clinical trial ancillary supply chain; product characteristics, magnitude (components of size), and stability (components of changes in scope). Part II of this research sought to understand the success of the supply chain by evaluating the moderating effects of knowledge management, organizational culture, therapeutic area, and type of shipment. Assessments of 444 customer and server surveys yielded components of a sense of shared culture, shared communication and transparency, and feeling educated and supported. Quantitative data analysis supported that these components had a moderating influence on success during the pre-trial phase of the supply chain. These research findings provide insight into the internal and external drivers of success within the complex and emergent clinical trial supply chain – a supply chain that helps pharmaceutical organizations bring innovative therapies to market and most important, those patients in need of such therapies to improve or even save their lives. / Business Administration/Interdisciplinary