Steel fibre reinforced concrete pipes. Part 2: numerical model to simulate the crushing test

This paper is part of an extensive work about the technological development, experimental analysis and numerical modeling of steel fibre reinforced concrete pipes. The first part ("Steel fibre reinforced concrete pipes. Part 1: technological analysis of the mechanical behavior") dealt with the technological development of the experimental campaign, the test procedure and the discussion of the structural behavior obtained for each of the dosages of fibre used. This second part deals with the aspects of numerical modeling. In this respect, a numerical model called MAP, which simulates the behavior of fibre reinforced concrete pipes with medium-low range diameters, is introduced. The bases of the numerical model are also mentioned. Subsequently, the experimental results are contrasted with those produced by the numerical model, obtaining excellent correlations. It was possible to conclude that the numerical model is a useful tool for the design of this type of pipes, which represents an important step forward to establish the structural fibres as reinforcement for concrete pipes. Finally, the design for the optimal amount of fibres for a pipe with a diameter of 400 mm is presented as an illustrating example with strategic interest.

Primary stability in cementless total hip replacement: measurement techniques and aided-surgery

Primary stability of stems in cementless total hip replacements is recognized to play a critical role for long-term survival and thus for the success of the overall surgical procedure. In Literature, several studies addressed this important issue. Different approaches have been explored aiming to evaluate the extent of stability achieved during surgery. Some of these are in-vitro protocols while other tools are coinceived for the post-operative assessment of prosthesis migration relative to the host bone. In vitro protocols reported in the literature are not exportable to the operating room. Anyway most of them show a good overall accuracy. The RSA, EBRA and the radiographic analysis are currently used to check the healing process of the implanted femur at different follow-ups, evaluating implant migration, occurance of bone resorption or osteolysis at the interface. These methods are important for follow up and clinical study but do not assist the surgeon during implantation. At the time I started my Ph.D Study in Bioengineering, only one study had been undertaken to measure stability intra-operatively. No follow-up was presented to describe further results obtained with that device. In this scenario, it was believed that an instrument that could measure intra-operatively the stability achieved by an implanted stem would consistently improve the rate of success. This instrument should be accurate and should give to the surgeon during implantation a quick answer concerning the stability of the implanted stem. With this aim, an intra-operative device was designed, developed and validated. The device is meant to help the surgeon to decide how much to press-fit the implant. It is essentially made of a torsional load cell, able to measure the extent of torque applied by the surgeon to test primary stability, an angular sensor that measure the relative angular displacement between stem and femur, a rigid connector that enable connecting the device to the stem, and all the electronics for signals conditioning. The device was successfully validated in-vitro, showing a good overall accuracy in discriminating stable from unstable implants. Repeatability tests showed that the device was reliable. A calibration procedure was then performed in order to convert the angular readout into a linear displacement measurement, which is an information clinically relevant and simple to read in real-time by the surgeon. The second study reported in my thesis, concerns the evaluation of the possibility to have predictive information regarding the primary stability of a cementless stem, by measuring the micromotion of the last rasp used by the surgeon to prepare the femoral canal. This information would be really useful to the surgeon, who could check prior to the implantation process if the planned stem size can achieve a sufficient degree of primary stability, under optimal press fitting conditions. An intra-operative tool was developed to this aim. It was derived from a previously validated device, which was adapted for the specific purpose. The device is able to measure the relative micromotion between the femur and the rasp, when a torsional load is applied. An in-vitro protocol was developed and validated on both composite and cadaveric specimens. High correlation was observed between one of the parameters extracted form the acquisitions made on the rasp and the stability of the corresponding stem, when optimally press-fitted by the surgeon. After tuning in-vitro the protocol as in a closed loop, verification was made on two hip patients, confirming the results obtained in-vitro and highlighting the independence of the rasp indicator from the bone quality, anatomy and preserving conditions of the tested specimens, and from the sharpening of the rasp blades. The third study is related to an approach that have been recently explored in the orthopaedic community, but that was already in use in other scientific fields. It is based on the vibration analysis technique. This method has been successfully used to investigate the mechanical properties of the bone and its application to evaluate the extent of fixation of dental implants has been explored, even if its validity in this field is still under discussion. Several studies have been published recently on the stability assessment of hip implants by vibration analysis. The aim of the reported study was to develop and validate a prototype device based on the vibration analysis technique to measure intra-operatively the extent of implant stability. The expected advantages of a vibration-based device are easier clinical use, smaller dimensions and minor overall cost with respect to other devices based on direct micromotion measurement. The prototype developed consists of a piezoelectric exciter connected to the stem and an accelerometer attached to the femur. Preliminary tests were performed on four composite femurs implanted with a conventional stem. The results showed that the input signal was repeatable and the output could be recorded accurately. The fourth study concerns the application of the device based on the vibration analysis technique to several cases, considering both composite and cadaveric specimens. Different degrees of bone quality were tested, as well as different femur anatomies and several levels of press-fitting were considered. The aim of the study was to verify if it is possible to discriminate between stable and quasi-stable implants, because this is the most challenging detection for the surgeon in the operation room. Moreover, it was possible to validate the measurement protocol by comparing the results of the acquisitions made with the vibration-based tool to two reference measurements made by means of a validated technique, and a validated device. The results highlighted that the most sensitive parameter to stability is the shift in resonance frequency of the stem-bone system, showing high correlation with residual micromotion on all the tested specimens. Thus, it seems possible to discriminate between many levels of stability, from the grossly loosened implant, through the quasi-stable implants, to the definitely stable one. Finally, an additional study was performed on a different type of hip prosthesis, which has recently gained great interest thus becoming fairly popular in some countries in the last few years: the hip resurfacing prosthesis. The study was motivated by the following rationale: although bone-prosthesis micromotion is known to influence the stability of total hip replacement, its effect on the outcome of resurfacing implants has not been investigated in-vitro yet, but only clinically. Thus the work was aimed at verifying if it was possible to apply to the resurfacing prosthesis one of the intraoperative devices just validated for the measurement of the micromotion in the resurfacing implants. To do that, a preliminary study was performed in order to evaluate the extent of migration and the typical elastic movement for an epiphyseal prosthesis. An in-vitro procedure was developed to measure micromotions of resurfacing implants. This included a set of in-vitro loading scenarios that covers the range of directions covered by hip resultant forces in the most typical motor-tasks. The applicability of the protocol was assessed on two different commercial designs and on different head sizes. The repeatability and reproducibility were excellent (comparable to the best previously published protocols for standard cemented hip stems). Results showed that the procedure is accurate enough to detect micromotions of the order of few microns. The protocol proposed was thus completely validated. The results of the study demonstrated that the application of an intra-operative device to the resurfacing implants is not necessary, as the typical micromovement associated to this type of prosthesis could be considered negligible and thus not critical for the stabilization process. Concluding, four intra-operative tools have been developed and fully validated during these three years of research activity. The use in the clinical setting was tested for one of the devices, which could be used right now by the surgeon to evaluate the degree of stability achieved through the press-fitting procedure. The tool adapted to be used on the rasp was a good predictor of the stability of the stem. Thus it could be useful for the surgeon while checking if the pre-operative planning was correct. The device based on the vibration technique showed great accuracy, small dimensions, and thus has a great potential to become an instrument appreciated by the surgeon. It still need a clinical evaluation, and must be industrialized as well. The in-vitro tool worked very well, and can be applied for assessing resurfacing implants pre-clinically.

Essays on the political economy of European integration

Recently, a rising interest in political and economic integration/disintegration issues has been developed in the political economy field. This growing strand of literature partly draws on traditional issues of fiscal federalism and optimum public good provision and focuses on a trade-off between the benefits of centralization, arising from economies of scale or externalities, and the costs of harmonizing policies as a consequence of the increased heterogeneity of individual preferences in an international union or in a country composed of at least two regions. This thesis stems from this strand of literature and aims to shed some light on two highly relevant aspects of the political economy of European integration. The first concerns the role of public opinion in the integration process; more precisely, how economic benefits and costs of integration shape citizens' support for European Union (EU) membership. The second is the allocation of policy competences among different levels of government: European, national and regional. Chapter 1 introduces the topics developed in this thesis by reviewing the main recent theoretical developments in the political economy analysis of integration processes. It is structured as follows. First, it briefly surveys a few relevant articles on economic theories of integration and disintegration processes (Alesina and Spolaore 1997, Bolton and Roland 1997, Alesina et al. 2000, Casella and Feinstein 2002) and discusses their relevance for the study of the impact of economic benefits and costs on public opinion attitude towards the EU. Subsequently, it explores the links existing between such political economy literature and theories of fiscal federalism, especially with regard to normative considerations concerning the optimal allocation of competences in a union. Chapter 2 firstly proposes a model of citizens’ support for membership of international unions, with explicit reference to the EU; subsequently it tests the model on a panel of EU countries. What are the factors that influence public opinion support for the European Union (EU)? In international relations theory, the idea that citizens' support for the EU depends on material benefits deriving from integration, i.e. whether European integration makes individuals economically better off (utilitarian support), has been common since the 1970s, but has never been the subject of a formal treatment (Hix 2005). A small number of studies in the 1990s have investigated econometrically the link between national economic performance and mass support for European integration (Eichenberg and Dalton 1993; Anderson and Kalthenthaler 1996), but only making informal assumptions. The main aim of Chapter 2 is thus to propose and test our model with a view to providing a more complete and theoretically grounded picture of public support for the EU. Following theories of utilitarian support, we assume that citizens are in favour of membership if they receive economic benefits from it. To develop this idea, we propose a simple political economic model drawing on the recent economic literature on integration and disintegration processes. The basic element is the existence of a trade-off between the benefits of centralisation and the costs of harmonising policies in presence of heterogeneous preferences among countries. The approach we follow is that of the recent literature on the political economy of international unions and the unification or break-up of nations (Bolton and Roland 1997, Alesina and Wacziarg 1999, Alesina et al. 2001, 2005a, to mention only the relevant). The general perspective is that unification provides returns to scale in the provision of public goods, but reduces each member state’s ability to determine its most favoured bundle of public goods. In the simple model presented in Chapter 2, support for membership of the union is increasing in the union’s average income and in the loss of efficiency stemming from being outside the union, and decreasing in a country’s average income, while increasing heterogeneity of preferences among countries points to a reduced scope of the union. Afterwards we empirically test the model with data on the EU; more precisely, we perform an econometric analysis employing a panel of member countries over time. The second part of Chapter 2 thus tries to answer the following question: does public opinion support for the EU really depend on economic factors? The findings are broadly consistent with our theoretical expectations: the conditions of the national economy, differences in income among member states and heterogeneity of preferences shape citizens’ attitude towards their country’s membership of the EU. Consequently, this analysis offers some interesting policy implications for the present debate about ratification of the European Constitution and, more generally, about how the EU could act in order to gain more support from the European public. Citizens in many member states are called to express their opinion in national referenda, which may well end up in rejection of the Constitution, as recently happened in France and the Netherlands, triggering a European-wide political crisis. These events show that nowadays understanding public attitude towards the EU is not only of academic interest, but has a strong relevance for policy-making too. Chapter 3 empirically investigates the link between European integration and regional autonomy in Italy. Over the last few decades, the double tendency towards supranationalism and regional autonomy, which has characterised some European States, has taken a very interesting form in this country, because Italy, besides being one of the founding members of the EU, also implemented a process of decentralisation during the 1970s, further strengthened by a constitutional reform in 2001. Moreover, the issue of the allocation of competences among the EU, the Member States and the regions is now especially topical. The process leading to the drafting of European Constitution (even if then it has not come into force) has attracted much attention from a constitutional political economy perspective both on a normative and positive point of view (Breuss and Eller 2004, Mueller 2005). The Italian parliament has recently passed a new thorough constitutional reform, still to be approved by citizens in a referendum, which includes, among other things, the so called “devolution”, i.e. granting the regions exclusive competence in public health care, education and local police. Following and extending the methodology proposed in a recent influential article by Alesina et al. (2005b), which only concentrated on the EU activity (treaties, legislation, and European Court of Justice’s rulings), we develop a set of quantitative indicators measuring the intensity of the legislative activity of the Italian State, the EU and the Italian regions from 1973 to 2005 in a large number of policy categories. By doing so, we seek to answer the following broad questions. Are European and regional legislations substitutes for state laws? To what extent are the competences attributed by the European treaties or the Italian Constitution actually exerted in the various policy areas? Is their exertion consistent with the normative recommendations from the economic literature about their optimum allocation among different levels of government? The main results show that, first, there seems to be a certain substitutability between EU and national legislations (even if not a very strong one), but not between regional and national ones. Second, the EU concentrates its legislative activity mainly in international trade and agriculture, whilst social policy is where the regions and the State (which is also the main actor in foreign policy) are more active. Third, at least two levels of government (in some cases all of them) are significantly involved in the legislative activity in many sectors, even where the rationale for that is, at best, very questionable, indicating that they actually share a larger number of policy tasks than that suggested by the economic theory. It appears therefore that an excessive number of competences are actually shared among different levels of government. From an economic perspective, it may well be recommended that some competences be shared, but only when the balance between scale or spillover effects and heterogeneity of preferences suggests so. When, on the contrary, too many levels of government are involved in a certain policy area, the distinction between their different responsibilities easily becomes unnecessarily blurred. This may not only leads to a slower and inefficient policy-making process, but also risks to make it too complicate to understand for citizens, who, on the contrary, should be able to know who is really responsible for a certain policy when they vote in national,local or European elections or in referenda on national or European constitutional issues.

Sviluppo di metodologie di localizzazione nel contesto del Comprehensive Nuclear Test-Ban Treaty

Since the first underground nuclear explosion, carried out in 1958, the analysis of seismic signals generated by these sources has allowed seismologists to refine the travel times of seismic waves through the Earth and to verify the accuracy of the location algorithms (the ground truth for these sources was often known). Long international negotiates have been devoted to limit the proliferation and testing of nuclear weapons. In particular the Treaty for the comprehensive nuclear test ban (CTBT), was opened to signatures in 1996, though, even if it has been signed by 178 States, has not yet entered into force, The Treaty underlines the fundamental role of the seismological observations to verify its compliance, by detecting and locating seismic events, and identifying the nature of their sources. A precise definition of the hypocentral parameters represents the first step to discriminate whether a given seismic event is natural or not. In case that a specific event is retained suspicious by the majority of the State Parties, the Treaty contains provisions for conducting an on-site inspection (OSI) in the area surrounding the epicenter of the event, located through the International Monitoring System (IMS) of the CTBT Organization. An OSI is supposed to include the use of passive seismic techniques in the area of the suspected clandestine underground nuclear test. In fact, high quality seismological systems are thought to be capable to detect and locate very weak aftershocks triggered by underground nuclear explosions in the first days or weeks following the test. This PhD thesis deals with the development of two different seismic location techniques: the first one, known as the double difference joint hypocenter determination (DDJHD) technique, is aimed at locating closely spaced events at a global scale. The locations obtained by this method are characterized by a high relative accuracy, although the absolute location of the whole cluster remains uncertain. We eliminate this problem introducing a priori information: the known location of a selected event. The second technique concerns the reliable estimates of back azimuth and apparent velocity of seismic waves from local events of very low magnitude recorded by a trypartite array at a very local scale. For the two above-mentioned techniques, we have used the crosscorrelation technique among digital waveforms in order to minimize the errors linked with incorrect phase picking. The cross-correlation method relies on the similarity between waveforms of a pair of events at the same station, at the global scale, and on the similarity between waveforms of the same event at two different sensors of the try-partite array, at the local scale. After preliminary tests on the reliability of our location techniques based on simulations, we have applied both methodologies to real seismic events. The DDJHD technique has been applied to a seismic sequence occurred in the Turkey-Iran border region, using the data recorded by the IMS. At the beginning, the algorithm was applied to the differences among the original arrival times of the P phases, so the cross-correlation was not used. We have obtained that the relevant geometrical spreading, noticeable in the standard locations (namely the locations produced by the analysts of the International Data Center (IDC) of the CTBT Organization, assumed as our reference), has been considerably reduced by the application of our technique. This is what we expected, since the methodology has been applied to a sequence of events for which we can suppose a real closeness among the hypocenters, belonging to the same seismic structure. Our results point out the main advantage of this methodology: the systematic errors affecting the arrival times have been removed or at least reduced. The introduction of the cross-correlation has not brought evident improvements to our results: the two sets of locations (without and with the application of the cross-correlation technique) are very similar to each other. This can be commented saying that the use of the crosscorrelation has not substantially improved the precision of the manual pickings. Probably the pickings reported by the IDC are good enough to make the random picking error less important than the systematic error on travel times. As a further justification for the scarce quality of the results given by the cross-correlation, it should be remarked that the events included in our data set don’t have generally a good signal to noise ratio (SNR): the selected sequence is composed of weak events ( magnitude 4 or smaller) and the signals are strongly attenuated because of the large distance between the stations and the hypocentral area. In the local scale, in addition to the cross-correlation, we have performed a signal interpolation in order to improve the time resolution. The algorithm so developed has been applied to the data collected during an experiment carried out in Israel between 1998 and 1999. The results pointed out the following relevant conclusions: a) it is necessary to correlate waveform segments corresponding to the same seismic phases; b) it is not essential to select the exact first arrivals; and c) relevant information can be also obtained from the maximum amplitude wavelet of the waveforms (particularly in bad SNR conditions). Another remarkable point of our procedure is that its application doesn’t demand a long time to process the data, and therefore the user can immediately check the results. During a field survey, such feature will make possible a quasi real-time check allowing the immediate optimization of the array geometry, if so suggested by the results at an early stage.

The Time-Of-Flight detector of ALICE at LHC: construction, test and commissioning with cosmic rays

The Time-Of-Flight (TOF) detector of ALICE is designed to identify charged particles produced in Pb--Pb collisions at the LHC to address the physics of strongly-interacting matter and the Quark-Gluon Plasma (QGP). The detector is based on the Multigap Resistive Plate Chamber (MRPC) technology which guarantees the excellent performance required for a large time-of-flight array. The construction and installation of the apparatus in the experimental site have been completed and the detector is presently fully operative. All the steps which led to the construction of the TOF detector were strictly followed by a set of quality assurance procedures to enable high and uniform performance and eventually the detector has been commissioned with cosmic rays. This work aims at giving a detailed overview of the ALICE TOF detector, also focusing on the tests performed during the construction phase. The first data-taking experience and the first results obtained with cosmic rays during the commissioning phase are presented as well and allow to confirm the readiness state of the TOF detector for LHC collisions.

Preclinical development of cancer vaccines

Triplex cell vaccine is a cancer immunopreventive cell vaccine that can prevent almost completely mammary tumor onset in HER-2/neu transgenic mice. A future translation of cancer immunoprevention from preclinical to clinical studies should take into account several aspects. The work reported in this thesis deals with the study of three of these aspects: vaccine schedule, activity in a therapeutic set-up and second-generation DNA vaccines. An important element in determining human acceptance and compliance of a treatment protocol is the number of vaccinations. In order to improve the vaccination schedule a minimal protocol was searched, i.e. a schedule consisting of a lower number of administrations than standard protocol but with a similar efficacy. A candidate optimal protocol was identified by the use of an in silico model, SimTriplex simulator. The in vivo test of this schedule in HER-2/neu transgenic mice only partially confirmed in silico predictions. This result shows that in silico models have the potential ability to aid in searching of optimal treatment protocols, provided that they will be further tuned on experimental data. As a further result this preclinical study highlighted that kinetic of antibody response plays a major role in determining cancer prevention, leading to the hypothesis of a threshold that must be reached rapidly and maintained lifetime. Early clinical trials would be performed in a therapeutic, rather than preventive, setting. Thus, the activity of Triplex vaccine was investigated against experimental lung metastases in HER-2/neu transgenic mice in order to evaluate if the immunopreventive Triplex vaccine could be effective also against a pre-existing tumor mass. This preclinical model of aggressive metastatic development showed that the vaccine was an efficient treatment also 4 for the cure of micrometastases. However the immune mechanisms activated against tumor mass were not antibody dependent, i.e. different from those preventing the onset of primary mammary carcinoma. DNA vaccines could be more easily used than cellular ones. A second generation of Triplex vaccine based on DNA plasmids was evaluated in an aggressive preclinical model (BALBp53neu female mice) and compared with the preventive ability of cellular Triplex vaccine. It was observed that Triplex DNA vaccine was as effective as Triplex cell vaccine, exploiting a more restricted immune stimulation.

Development of Software Tools for the Test of Ultra Wide Band Receivers

In the last years, the importance of locating people and objects and communicating with them in real time has become a common occurrence in every day life. Nowadays, the state of the art of location systems for indoor environments has not a dominant technology as instead occurs in location systems for outdoor environments, where GPS is the dominant technology. In fact, each location technology for indoor environments presents a set of features that do not allow their use in the overall application scenarios, but due its characteristics, it can well coexist with other similar technologies, without being dominant and more adopted than the others indoor location systems. In this context, the European project SELECT studies the opportunity of collecting all these different features in an innovative system which can be used in a large number of application scenarios. The goal of this project is to realize a wireless system, where a network of fixed readers able to query one or more tags attached to objects to be located. The SELECT consortium is composed of European institutions and companies, including Datalogic S.p.A. and CNIT, which deal with software and firmware development of the baseband receiving section of the readers, whose function is to acquire and process the information received from generic tagged objects. Since the SELECT project has an highly innovative content, one of the key stages of the system design is represented by the debug phase. This work aims to study and develop tools and techniques that allow to perform the debug phase of the firmware of the baseband receiving section of the readers.

Towards a new test of time dilation: Laser spectroscopy on lithium ions stored at a velocity of 33.8 % of the speed of light

The subject of the presented thesis is the accurate measurement of time dilation, aiming at a quantitative test of special relativity. By means of laser spectroscopy, the relativistic Doppler shifts of a clock transition in the metastable triplet spectrum of ^7Li^+ are simultaneously measured with and against the direction of motion of the ions. By employing saturation or optical double resonance spectroscopy, the Doppler broadening as caused by the ions' velocity distribution is eliminated. From these shifts both time dilation as well as the ion velocity can be extracted with high accuracy allowing for a test of the predictions of special relativity. A diode laser and a frequency-doubled titanium sapphire laser were set up for antiparallel and parallel excitation of the ions, respectively. To achieve a robust control of the laser frequencies required for the beam times, a redundant system of frequency standards consisting of a rubidium spectrometer, an iodine spectrometer, and a frequency comb was developed. At the experimental section of the ESR, an automated laser beam guiding system for exact control of polarisation, beam profile, and overlap with the ion beam, as well as a fluorescence detection system were built up. During the first experiments, the production, acceleration and lifetime of the metastable ions at the GSI heavy ion facility were investigated for the first time. The characterisation of the ion beam allowed for the first time to measure its velocity directly via the Doppler effect, which resulted in a new improved calibration of the electron cooler. In the following step the first sub-Doppler spectroscopy signals from an ion beam at 33.8 %c could be recorded. The unprecedented accuracy in such experiments allowed to derive a new upper bound for possible higher-order deviations from special relativity. Moreover future measurements with the experimental setup developed in this thesis have the potential to improve the sensitivity to low-order deviations by at least one order of magnitude compared to previous experiments; and will thus lead to a further contribution to the test of the standard model.

Leben mit Phenprocoumon — optimal versorgt? : Untersuchung der Qualität und Effektivität der Phenprocoumon-Therapie im ambulanten Sektor

In Deutschland wird zur oralen Vitamin-K-Antagonistentherapie überwiegend der Wirkstoff Phenprocoumon (PPC) eingesetzt und die meisten Patienten werden durch ihren Hausarzt betreut. In einer deskriptiven, nicht-interventionellen Studie wurde die Ist-Situation der Versorgung von PPC-Patienten im ambulanten Sektor untersucht. Ziel war es, die Qualität und Effektivität der bisherigen Standardtherapie zu evaluieren. In Anbetracht der Einführung der neuen oralen Antikoagulantien (NOAC) ist die Untersuchung der PPC-Therapie von besonderem Interesse. Dem „Throughput-Modell“ folgend sollten „Input“- und „Outcome“-Parameter analysiert werden. rnIn einer klinischen Studie wurden 50 ambulant behandelte Patienten mit PPC-Therapie jeweils über einen Zeitraum von 3 Jahren retrospektiv beobachtet. In 5 niedergelassenen Arztpraxen in Rheinland-Pfalz wurden dazu 10 Patienten pro Praxis rekrutiert. Anhand der Patientenakte wurde eine Dokumentenanalyse durchgeführt. Die Selbstmedikation wurde mit einem eigens erstellten Fragebogen erfasst. rnIm Studienkollektiv wurden im Median 3 Comorbiditäten ermittelt. Die mediane Wochendosis betrug 4,0 Tabletten à 3 mg PPC. Die Patienten wurden im Median mit weiteren 15 verschiedenen Wirkstoffen therapiert, einer davon wurde in Selbstmedikation eingenommen. Im gesamten Beobachtungszeitraum fanden pro Patient im Median 57 Arztbesuche statt, die durch die Phenprocoumon-Therapie bedingt waren. INR (International normalized ratio)-Messungen (Median 47) waren der häufigste Grund für die Arztbesuche, so dass ein 3-Wochen-Rhythmus vom Gesamtkollektiv zu 97% erreicht wurde. Die „stabile“ INR-Einstellung wurde im Median nach 94 Tagen erreicht. Die prozentuale Rate (INR (%)) für die Einhaltung des INR-Zielbereiches (ZSB) erreichte internationale Benchmark-Werte, was auf eine gute Versorgungsqualität hindeutete. Die genauere Analyse ergab jedoch große interindividuelle Schwankungen. Während der „stabilen“ INR-Einstellung wurden bessere Ergebnisse als im Gesamtbeobachtungszeitraum erzielt. Drei Patienten (6%) erreichten die „stabile“ INR-Einstellung innerhalb von 3 Jahren nie. Die Auswertung für den erweiterten ZSB (ZSB ± 0,2) ergab bessere INR (%)-Ergebnisse als für den ZSB. Die Zeit im INR-ZSB (TTR (%)) erreichte mit 75% höhere Werte als INR (%) im ZSB mit 70%. Tendenziell war das Patientenkollektiv eher unter- als übertherapiert (Median „Under-INR“ 18% bzw. „Over-INR“ 8%). Erkrankungen und Impfungen stellten die wichtigsten der zahlreichen Einflussfaktoren für INR-Shifts hin zu Werten außerhalb des ZSB dar. Patienten, die Comedikation mit hohem Interaktionspotential einnahmen, erreichten in den INR-Qualitätsindikatoren schlechtere Ergebnisse als Patienten ohne potentiell interagierende Comedikation (Mann-Whitney-U-Test; p-Wert=0,003 für TTR (%), p=0,008 für INR (%)). In Zeitintervallen der „stabilen“ INR-Einstellung war der Unterschied nur für TTR (%) auffällig (Mann-Whitney-U-Test; p=0,015). Für den erweiterten ZSB waren die Unterschiede bezüglich beider INR-Qualitätsindikatoren nicht auffällig. Insgesamt wurden 41 unerwünschte Ereignisse (UAW) beobachtet, davon 24 (59%) in der Phase der „stabilen“ INR-Einstellung (21 leichte Blutungen, 1 schwere Blutung, 2 thromboembolische Ereignisse (TE)). Je 4 leichte Blutungen (19%) wurden in einen möglichen bzw. sicheren kausalen Zusammenhang mit der VKA-Therapie gebracht, wenn ein Zeitintervall von 3 Tagen zwischen der INR-Messung und Auftreten der UAW geprüft wurde. Ein TE wurde als sicher kausal gewertet. Von insgesamt 5 Krankenhausaufenthalten waren 3 bzw. 2 durch Blutungen bzw. TE veranlasst. Des Weiteren wurde im 3-Tage-Zeitintervall für 4 INR-Shifts hin zu Werten außerhalb des ZSB eine Interaktion mit verordneter CM als in sicherem oder möglichem kausalen Zusammenhang bewertet. Bei 49% der beobachteten Grippeimpfungen wurde ein INR-Shift festgestellt, der in ca. 60% der Fälle zu einem subtherapeutischen INR-Wert führte. Insgesamt war das klinische Ergebnis nicht optimal. rnDas „Outcome“ in Form der gesundheitsbezogenen Lebensqualität (LQ) wurde retrospektiv-prospektiv mittels SF-36-Fragebogen ermittelt. Die Patienten zeigten gegenüber der Normalbevölkerung einen Verlust an LQ auf körperlicher Ebene bzw. einen Gewinn auf psychischer Ebene. Das humanistische Ergebnis erfüllte bzw. übertraf damit die Erwartungen. rnInsgesamt wiesen die Ergebnisse darauf hin, dass Qualität und Effektivität der Antikoagulationstherapie mit PPC im ambulanten Sektor weiterer Optimierung bedürfen. Mit intensivierten Betreuungsmodellen lässt sich ein besseres Outcome erzielen. rn

Anpassung des Metamodells PerPot an den ausdauerorientierten Laufsport zur Trainings- und Wettkampfoptimierung

Schon seit einigen Jahrzehnten wird die Sportwissenschaft durch computergestützte Methoden in ihrer Arbeit unterstützt. Mit der stetigen Weiterentwicklung der Technik kann seit einigen Jahren auch zunehmend die Sportpraxis von deren Einsatz profitieren. Mathematische und informatische Modelle sowie Algorithmen werden zur Leistungsoptimierung sowohl im Mannschafts- als auch im Individualsport genutzt. In der vorliegenden Arbeit wird das von Prof. Perl im Jahr 2000 entwickelte Metamodell PerPot an den ausdauerorientierten Laufsport angepasst. Die Änderungen betreffen sowohl die interne Modellstruktur als auch die Art der Ermittlung der Modellparameter. Damit das Modell in der Sportpraxis eingesetzt werden kann, wurde ein Kalibrierungs-Test entwickelt, mit dem die spezifischen Modellparameter an den jeweiligen Sportler individuell angepasst werden. Mit dem angepassten Modell ist es möglich, aus gegebenen Geschwindigkeitsprofilen die korrespondierenden Herzfrequenzverläufe abzubilden. Mit dem auf den Athleten eingestellten Modell können anschliessend Simulationen von Läufen durch die Eingabe von Geschwindigkeitsprofilen durchgeführt werden. Die Simulationen können in der Praxis zur Optimierung des Trainings und der Wettkämpfe verwendet werden. Das Training kann durch die Ermittlung einer simulativ bestimmten individuellen anaeroben Schwellenherzfrequenz optimal gesteuert werden. Die statistische Auswertung der PerPot-Schwelle zeigt signifikante Übereinstimmungen mit den in der Sportpraxis üblichen invasiv bestimmten Laktatschwellen. Die Wettkämpfe können durch die Ermittlung eines optimalen Geschwindigkeitsprofils durch verschiedene simulationsbasierte Optimierungsverfahren unterstützt werden. Bei der neuesten Methode erhält der Athlet sogar im Laufe des Wettkampfs aktuelle Prognosen, die auf den Geschwindigkeits- und Herzfrequenzdaten basieren, die während des Wettkampfs gemessen werden. Die mit PerPot optimierten Wettkampfzielzeiten für die Athleten zeigen eine hohe Prognosegüte im Vergleich zu den tatsächlich erreichten Zielzeiten.

Toward optimal display of physiologic status in critical care: I. Recreating bedside displays from archived physiologic data

BACKGROUND: Physiologic data display is essential to decision making in critical care. Current displays echo first-generation hemodynamic monitors dating to the 1970s and have not kept pace with new insights into physiology or the needs of clinicians who must make progressively more complex decisions about their patients. The effectiveness of any redesign must be tested before deployment. Tools that compare current displays with novel presentations of processed physiologic data are required. Regenerating conventional physiologic displays from archived physiologic data is an essential first step. OBJECTIVES: The purposes of the study were to (1) describe the SSSI (single sensor single indicator) paradigm that is currently used for physiologic signal displays, (2) identify and discuss possible extensions and enhancements of the SSSI paradigm, and (3) develop a general approach and a software prototype to construct such "extended SSSI displays" from raw data. RESULTS: We present Multi Wave Animator (MWA) framework-a set of open source MATLAB (MathWorks, Inc., Natick, MA, USA) scripts aimed to create dynamic visualizations (eg, video files in AVI format) of patient vital signs recorded from bedside (intensive care unit or operating room) monitors. Multi Wave Animator creates animations in which vital signs are displayed to mimic their appearance on current bedside monitors. The source code of MWA is freely available online together with a detailed tutorial and sample data sets.

Hierarchical Approach for Survivable Network Design

A central design challenge facing network planners is how to select a cost-effective network configuration that can provide uninterrupted service despite edge failures. In this paper, we study the Survivable Network Design (SND) problem, a core model underlying the design of such resilient networks that incorporates complex cost and connectivity trade-offs. Given an undirected graph with specified edge costs and (integer) connectivity requirements between pairs of nodes, the SND problem seeks the minimum cost set of edges that interconnects each node pair with at least as many edge-disjoint paths as the connectivity requirement of the nodes. We develop a hierarchical approach for solving the problem that integrates ideas from decomposition, tabu search, randomization, and optimization. The approach decomposes the SND problem into two subproblems, Backbone design and Access design, and uses an iterative multi-stage method for solving the SND problem in a hierarchical fashion. Since both subproblems are NP-hard, we develop effective optimization-based tabu search strategies that balance intensification and diversification to identify near-optimal solutions. To initiate this method, we develop two heuristic procedures that can yield good starting points. We test the combined approach on large-scale SND instances, and empirically assess the quality of the solutions vis-à-vis optimal values or lower bounds. On average, our hierarchical solution approach generates solutions within 2.7% of optimality even for very large problems (that cannot be solved using exact methods), and our results demonstrate that the performance of the method is robust for a variety of problems with different size and connectivity characteristics.

Global Reuse and Optimal Waste Policy

Electronic waste generated from the consumption of durable goods in developed countries is often exported to underdeveloped countries for reuse, recycling and disposal with unfortunate environmental consequences. The lack of efficient disposal policies within developing nations coupled with global free trade agreements make it difficult for consumers to internalize these costs. This paper develops a two-country model, one economically developed and the other underdeveloped, to solve for optimal tax policies necessary to achieve the efficient allocation of economic resources in an economy with a durable good available for global reuse without policy measures in the underdeveloped country. A tax in the developed country on purchases of the new durable good combined with a waste tax set below the domestic external cost of disposal is sufficient for global efficiency. The implication of allowing free global trade in electronic waste is also examined, where optimal policy resembles a global deposit-refund system.

The Optimal Confidence Region for a Random Parameter

Under a two-level hierarchical model, suppose that the distribution of the random parameter is known or can be estimated well. Data are generated via a fixed, but unobservable realization of this parameter. In this paper, we derive the smallest confidence region of the random parameter under a joint Bayesian/frequentist paradigm. On average this optimal region can be much smaller than the corresponding Bayesian highest posterior density region. The new estimation procedure is appealing when one deals with data generated under a highly parallel structure, for example, data from a trial with a large number of clinical centers involved or genome-wide gene-expession data for estimating individual gene- or center-specific parameters simultaneously. The new proposal is illustrated with a typical microarray data set and its performance is examined via a small simulation study.

GENE SET ENRICHMENT ANALYSIS MADE SIMPLE

Among the many applications of microarray technology, one of the most popular is the identification of genes that are differentially expressed in two conditions. A common statistical approach is to quantify the interest of each gene with a p-value, adjust these p-values for multiple comparisons, chose an appropriate cut-off, and create a list of candidate genes. This approach has been criticized for ignoring biological knowledge regarding how genes work together. Recently a series of methods, that do incorporate biological knowledge, have been proposed. However, many of these methods seem overly complicated. Furthermore, the most popular method, Gene Set Enrichment Analysis (GSEA), is based on a statistical test known for its lack of sensitivity. In this paper we compare the performance of a simple alternative to GSEA.We find that this simple solution clearly outperforms GSEA.We demonstrate this with eight different microarray datasets.