Visuelles Studienmanagement mit dem Trial Outline Builder in ObTiMA

Die heutige klinische Landschaft ist ein Spannungsfeld aus Kosteneffizienz, umfangreichen Dokumentationspflichten, Personalmangel und vieler weiterer Herausforderungen in der Behandlung von Patienten. Mithilfe der heutigen Computertechnologie und ihren Möglichkeiten wird trotz des eingeschränkten Zeitpensums der behandelnden Ärzte versucht, eine möglichst auf den einzelnen Patienten abgestimmte Behandlung zu ermöglichen. Damit in der personalisierten Medizin auf die für den jeweiligen Patienten am besten passende Therapie zur Bekämpfung seiner Erkrankung zurückgegriffen werden kann, sind im Vorfeld klinische Studien über neue Medikamente und Therapieformen notwendig. Diese klinischen Studien benötigen viel Vorbereitungszeit, da zunächst ein Studienprotokoll inklusive eines Behandlungsplans mit entsprechenden Fragestellungen entwickelt werden muss. In größeren Studien erfordert dies den Austausch zwischen Medizinern aus verschiedenen Fachbereichen. Um diesen Planungsmitgliedern schon zu Beginn eine gemeinsame Diskussionsgrundlage auf Basis eines grafischen Behandlungsplans zu ermöglichen, kann der in dieser Arbeit vorgestellte Trial Outline Builder (TOB) dienen. Damit die Anwendbar- und Nützlichkeit dieser Technologie nicht schon in der Anfangsphase einer Studie endet, wurde sie auf das Studienmanagementsystem Ontology-based Trial Management Application (ObTiMA) angepasst und in diese integriert. Für die vorliegende Arbeit wurde im ersten Schritt ObTiMA und der Trial Outline Builder auf den gleichen technischen Stand gebracht. Somit wurde die in ObTiMA vorhandene Struktur von Study Events und ihren Case Report Form (CRF) Fragebögen im TOB nutzbar gemacht. Dies war notwendig geworden, da sich die beiden Anwendungen über die Jahre auseinanderentwickelt hatten. Im zweiten Schritt wurden Kommunikationsschnittstellen zwischen ObTiMA und dem TOB geschaffen, um erstellte Behandlungspläne speichern und erneut laden zu können. Dafür wurde die Patientenansicht des TOBs mit der Möglichkeit erweitert, medizinische Events über einen Representational State Transfer (REST) Service in ObTiMA zu aktivieren. Dies hatte weitreichende Änderungen am ObTiMA Quellcode zur Folge, da dieser bislang ausschließlich für Benutzersessions ausgelegt war und nun auch über das statuslose REST ausführbar sein musste. Während dieser Entwicklung war es immer wieder erforderlich neu entdeckte Bugs im TOB zu korrigieren, die zu einer nicht geladenen TOB Seite oder zu defekten Behandlungsplänen nach der Speicherung in der Datenbank führte. Im letzten Arbeitsteil wurde eine durch Anwender leicht ausführbare Randomisierung von Patienten nach der Minimisationsmethode realisiert, die die jeweiligen Stärken der beiden Anwendungen nutzt. Mit dem Ergebnis dieser Arbeit können nun die in der Studiendesignphase in ObTiMA erstellten Study Events mit einzelnen medizinischen Events zu einem zeitbasierten Behandlungsplan verknüpft werden. Nach Studienstart werden für die Patienten zusätzlich neben der geplanten Behandlung auch eine persönliche Timeline mit allen medizinischen Events angezeigt. Dadurch erhält das Studienpersonal auf einen Blick eine grafische Übersicht über den realen Behandlungsverlauf des jeweiligen Patienten inklusive unerwünschter Ereignisse wie Serious Adverse Events (SAEs), Suspected Unexpected Serious Adverse Reactions (SUSARs), Notoperationen, etc. Im klinischen Alltag kann der behandelnde Arzt damit leichter und effizienter die erfasste Studiendaten auffinden. Diese Verbesserungen dürften in der zukünftigen Anwendung des Trial Outline Builders sowohl dem medizinischen Personal als auch den Patienten zu Gute kommen.Today's clinical landscape is an area of conflict between cost efficiency, extensive documentation requirements, lack of personnel and many other challenges in the treatment of patients. With the help of today's computer technology and its possibilities, an attempt is being made to enable treatment to be tailored as closely as possible to the individual patient, especially, in times when time is very limited for the physicians. Clinical studies on new drugs and forms of therapy have to be performed in advance so that personalised medicine can use the therapy best suited to the patient's illness. These clinical studies require a lot of preparation time, since a Trial Master Protocol must first be developed, including the corresponding research questions and a treatment plan. In larger studies this requires the exchange of information between many physicians from different departments. In order to provide these planning members with a common basis for discussion based on a visual treatment plan right from the start, the Trial Outline Builder presented in this thesis can be used. To ensure that the applicability and usefulness of this technology does not end in the initial phase of a study, it was adapted to and integrated into the Ontology-based Trial Management Application (ObTiMA). In the first step, ObTiMA and the Trial Outline Builder (TOB) were brought to the same level by unifying the structure of study events and Case Report Form (CRF) questionnaires. This had become necessary since the two applications developed into kind of different direction over the past years. In the second step, communication interfaces between ObTiMA and the Trial Outline Builder were implemented for saving and loading treatment plans. Later, the pa-tient view of the TOB was extended with the possibility to activate medical events via a Rep-resentational State Transfer (REST) service in ObTiMA. This resulted in extensive changes in the ObTiMA source code, since it previously was only supposed to work with user sessions. Now this code works with stateless REST services as well. During this whole transformation process, it was often necessary to correct several breaking bugs in the original TOB code, which led to unloaded pages or broken treatment plans after saving. In the last step of this work, an easy user-executable randomization of patients (minimization method) was implemented, which combined the strengths of both applications. With the result of this work, the CRF questionnaires created in the study design phase in ObTiMA can now be linked with individual medical events to form a time-based treatment plan. After the start of the study, patients have a personal timeline with all medical events in addi-tion to the planned treatment. This provides the study staff with a visual overview of the actual treatment process of the respective patient at a glance, including unwanted events such as Serious Adverse Events (SAEs), Suspected Unexpected Serious Adverse Reactions (SUSARs), emergency operations, etc. This allows physicians in charge to find the recorded study data easier and more efficiently in the clinical routine. These improvements should benefit both, clinicians and patients, in the future use of the Trial Outline Builder

Contactless and spatially structured cooling by directing thermal radiation

In recent years, radiative cooling has become a topic of considerable interest for applications in the context of thermal building management and energy saving. The idea to direct thermal radiation in a controlled way to achieve contactless sample cooling for laboratory applications, however, is scarcely explored. Here, we present an approach to obtain spatially structured radiative cooling. By using an elliptical mirror, we are able to enhance the view factor of radiative heat transfer between a room temperature substrate and a cold temperature landscape by a factor of 92. A temperature pattern and confined thermal gradients with a slope of \~ 0.2~°C/mm are created. The experimental applicability of this spatially structured cooling approach is demonstrated by contactless supercooling of hexadecane in a home-built microfluidic sample. This novel concept for structured cooling yields numerous applications in science and engineering as it provides a means of controlled temperature manipulation with minimal physical disturbance

Quality assurance in non-interventional studies

Nowadays, drug research and surveillance after authorisation becomes more and more important for several reasons. Non-interventional studies (NIS) investigate various aspects of drug use including efficacy and safety under real life conditions. Such kind of health services research should be on a high scientific, methodological and organisational level. Therefore accompanying measures to improve or to keep the quality are highly recommended. The aim of quality management is: first to avoid bias of results by using an appropriate study design and an adequate data analysis, second to assure authenticity, completeness and validity of the data and third to identify and resolve deficiencies at an early stage. Basic principles are laid down in corresponding guidelines and recommendations of authorities, institutes and societies. Various guidelines for good epidemiological practice (GEP) were published by the U.S. Food and Drug Administration (FDA) and international and regional societies for epidemiology. In addition in Germany the Federal Institute for Drugs and Medical Devices (BfArM) together with the Paul Ehrlich Institute (PEI) and the German Association of Research-Based Pharmaceutical Companies (VFA) have published respectively recommendations dealing with quality aspects of non-interventional observational studies. Key points are the advanced publishing of information about the project, developing of a study plan/protocol containing the scientific objectives, a sample size justification and a description of the planned analyses and the publishing of a summary of the results timely after completion of the study. The quality of the data can be improved by using standardized case report forms (CRF) and the CRF should be reviewed and tested before start of study by some participants. A source data verification (SDV) should be performed in randomly selected centres – in between 2% and 5% of the centres depending on the number of participating centres. Before start of statistical analysis a statistical analysis plan (SAP) should be created. The use of standardized tables and figures is highly recommended. The basis of the report writing should be the STROBE-statement “Strengthening the Reporting of Observational studies in Epidemiology Initiative” containing a checklist of 22 points to be covered in the report. The development of own standard operating procedures (SOP) describing the processes during planning, conduct and evaluation of a non-interventional study as well as the quality management and the regular training of all involved people is also highly recommended. All accompanying measures to improve or to keep the quality of the NIS should not violate the concept of non-intervention

PRIMUS/Informed Cities: Making research work for local sustainability

The final report of a three year European Commission FP7 project

Monitoring of clinical activities and performances by using international classifications ICD-10 and ICPC-2: Three years experience of the Kigali University Teaching Hospital, Rwanda

peer reviewedMeasuring performances of health professionals and health facilities is a difficult task. However, with the appropriate information management tools, a lot of useful information can be collected from routine data registration activities. Situated in the capital of Rwanda, the Central Kigali University Teaching Hospital developed in January 2006 its electronic patient record using both ICD10 and ICPC2 codes for the structured registration of diseases and procedures. In order to enable synoptic data analysis, individual codes have been grouped into a set of 174 disease groups (KHIRI Pathology Group Set –KPGS). To assess the activities and performances of the different clinical departments, outcome data were analyzed following a number of essential criteria: the caseload, the LOS (length of stay) load and the in-hospital mortality load. A total number of 27784 patients were admitted during the study period. On the 27784 patients a total of respectively 30609 and 29447 diagnoses were recorded in ICPC2 and ICD10. The total of hospitalization days was 395256. 2759 patients died over the 3 years study period. Four ICPC classes covered more than 10% of the encodings each: A (general) 5649, D (digestive system) 6040, L (locomotors system) 3297 and R (respiratory system) counted for 4026 registrations. Comparable results could be obtained in the corresponding ICD classes A+B, K, M+S-T and J. Linking ICD10 and ICPC2 codes to global patient data clearly enables the physicians and the hospital management to produce comparable, standardized and internationally valuable evaluations of the hospital activities and trends. It also opens the perspective of fixing objective priorities in patient management and provides an interesting starting point for comparing health professionals’ clinical performances in a standardized way

Activation of pro-survival metabolic networks by 1,25(OH)2D3 does not hamper the sensitivity of breast cancer cells to chemotherapeutics

Background: We have previously identified 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the bioactive form of vitamin D3, as a potent regulator of energy-utilization and nutrient-sensing pathways in prostate cancer cells. In the current study, we investigated the effects of 1,25(OH)2D3 on breast cancer (BCa) cell metabolism using cell lines representing distinct molecular subtypes, luminal (MCF-7 and T-47D), and triple-negative BCa (MDA-MB-231, MDA-MB-468, and HCC-1143). Methods: 1,25(OH)2D3’s effect on BCa cell metabolism was evaluated by employing a combination of real-time measurements of glycolysis/oxygen consumption rates using a biosensor chip system, GC/MS-based metabolomics, gene expression analysis, and assessment of overall energy levels. The influence of treatment on energy-related signaling molecules was investigated by immunoblotting. Results: We show that 1,25(OH)2D3 significantly induces the expression and activity of the pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase (G6PD) in all BCa cell lines, however differentially influences glycolytic and respiratory rates in the same cells. Although 1,25(OH)2D3 treatment was found to induce seemingly anti-oxidant responses in MCF-7 cells, such as increased intracellular serine levels, and reduce the expression of its putative target gene thioredoxin-interacting protein (TXNIP), intracellular reactive oxygen species levels were found to be elevated. Serine accumulation in 1,25(OH)2D3-treated cells was not found to hamper the efficacy of chemotherapeutics, including 5-fluorouracil. Detailed analyses of the nature of TXNIP’s regulation by 1,25(OH)2D3 included genetic and pharmacological inhibition of signaling molecules and metabolic enzymes including AMP-activated protein kinase and G6PD, as well as by studying the ITCH (E3 ubiquitin ligase)-TXNIP interaction. While these investigations demonstrated minimal involvement of such pathways in the observed non-canonical regulation of TXNIP, inhibition of estrogen receptor (ER) signaling by tamoxifen mirrored the reduction of TXNIP levels by 1,25(OH)2D3, demonstrating that the latter’s negative regulation of ER expression is a potential mechanism of TXNIP modulation. Conclusions: Altogether, we propose that regulation of energy metabolism contributes to 1,25(OH)2D3’s anti-cancer effects and that combining 1,25(OH)2D3 with drugs targeting metabolic networks in tumor cells may lead to synergistic effects

Evolution of compound eye morphology underlies differences in vision between closely related Drosophila species

Background: Insects have evolved complex visual systems and display an astonishing range of adaptations for diverse ecological niches. Species of Drosophila melanogaster subgroup exhibit extensive intra- and interspecific differences in compound eye size. These differences provide an excellent opportunity to better understand variation in insect eye structure and the impact on vision. Here we further explored the difference in eye size between D. mauritiana and its sibling species D. simulans. Results: We confirmed that D. mauritiana have rapidly evolved larger eyes as a result of more and wider ommatidia than D. simulans since they recently diverged approximately 240,000 years ago. The functional impact of eye size, and specifically ommatidia size, is often only estimated based on the rigid surface morphology of the compound eye. Therefore, we used 3D synchrotron radiation tomography to measure optical parameters in 3D, predict optical capacity, and compare the modelled vision to in vivo optomotor responses. Our optical models predicted higher contrast sensitivity for D. mauritiana, which we verified by presenting sinusoidal gratings to tethered flies in a flight arena. Similarly, we confirmed the higher spatial acuity predicted for Drosophila simulans with smaller ommatidia and found evidence for higher temporal resolution. Conclusions: Our study demonstrates that even subtle differences in ommatidia size between closely related Drosophila species can impact the vision of these insects. Therefore, further comparative studies of intra- and interspecific variation in eye morphology and the consequences for vision among other Drosophila species, other dipterans and other insects are needed to better understand compound eye structure–function and how the diversification of eye size, shape, and function has helped insects to adapt to the vast range of ecological niches

Emerging risks from ballast water treatment: The run-up to the International Ballast Water Management Convention

AbstractUptake and discharge of ballast water by ocean-going ships contribute to the worldwide spread of aquatic invasive species, with negative impacts on the environment, economies, and public health. The International Ballast Water Management Convention aims at a global answer. The agreed standards for ballast water discharge will require ballast water treatment. Systems based on various physical and/or chemical methods were developed for on-board installation and approved by the International Maritime Organization. Most common are combinations of high-performance filters with oxidizing chemicals or UV radiation. A well-known problem of oxidative water treatment is the formation of disinfection by-products, many of which show genotoxicity, carcinogenicity, or other long-term toxicity. In natural biota, genetic damages can affect reproductive success and ultimately impact biodiversity. The future exposure towards chemicals from ballast water treatment can only be estimated, based on land-based testing of treatment systems, mathematical models, and exposure scenarios. Systematic studies on the chemistry of oxidants in seawater are lacking, as are data about the background levels of disinfection by-products in the oceans and strategies for monitoring future developments. The international approval procedure of ballast water treatment systems compares the estimated exposure levels of individual substances with their experimental toxicity. While well established in many substance regulations, this approach is also criticised for its simplification, which may disregard critical aspects such as multiple exposures and long-term sub-lethal effects. Moreover, a truly holistic sustainability assessment would need to take into account factors beyond chemical hazards, e.g. energy consumption, air pollution or waste generation

Experimental implementation of a silicon wafer tandem solar cell

We combine aluminum back surface field (Al-BSF) solar cell precursors with an additional rear side infrared active floating emitter in a tandem cell configuration. This emitter is implemented area selectively by fs-laser hyperdoping in a sulfurous atmosphere. Its design as a floating emitter conceals losses induced by the laser process as long as n-doping occurs. All processes are adapted and supplemented by just a single new process step

Quantifying nitrogen fluxes and their influence on the greenhouse gas balance: recent findings of the NitroEurope Integrated Project

The generation of reactive nitrogen (Nr) by human activities to stimulate agricultural productivity and the unintended formation of Nr in combustion processes both have major impacts on the global environment. Effects of excess Nr include the deterioration of air quality, water quality, soil quality and a decline in biodiversity. One of the most controversial impacts of nitrogen, however, is on the greenhouse gas balance. While recent papers have highlighted a possible benefit of nitrogen in enhancing rates of carbon sequestration, there remain many trade-offs between nitrogen and greenhouse gas exchange. The result is that the net effect of Nr on the global radiative balance has yet to be fully quantified. To better understand these relationships requires intense measurement and modelling of Nr fluxes at various temporal and spatial scales in order to make the link between different nitrogen forms and their fate in the environment. It is essential to measure fluxes for a wide range of ecosystems considering the biosphere-atmosphere exchange of the Nr components and greenhouse gases, as well as the fixation of di-nitrogen and its creation by denitrification. Long-term observations are needed for representative ecosystems, together with results from experiments addressing the responses of the key nitrogen and greenhouse gas fluxes to different global change drivers. The NitroEurope Integrated Project (in short NEU IP), funded under the 6th Framework Programme of the European Commission, has developed and applied a strategy for quantifying these different terms on multiple scales. With the project nearing completion, this presentation reports selected preliminary findings. It highlights the first estimates of Nr inputs and net green-house gas exchange for a series of 13 flux ‘supersites’, complemented by the emerging results of Nr concentrations and related N inputs at a network of 58 ‘inferential sites’, which extend the European representativity of the results. In addition, new low cost methods to measure nitrogen fluxes will be reported, which have been extensively tested at those sites. Results from this 3-tier flux network are underpinned by emerging findings from an extensive network of manipulation sites. A combination of modelling at plot, landscape and European scales is used to upscale the results. Finally the talk will illustrate how nitrogen mitigation techniques are being considered at the European scale, including an estimation of the scale of costs involved in simultaneously mitigating nitrous oxide, ammonia and nitrate losse