Determinants of cesarean delivery, a population-based study in the Emilia Romagna Region

Cesarean Delivery (CD) rates are rising in many parts of the world. In order to define strategies to reduce them, it is important to explore the role of clinical and organizational factors. This thesis has the objective to describe the contemporary CD practice and study clinical and organizational variables as determinants of CD in all women who gave birth between 2005 and June 2010 in the Emilia Romagna region (Italy). All hospital discharge abstracts of women who delivered between 2005 and mid 2010 in the region were selected and linked with birth certificates. In addition to descriptive statistics, in order to study the role of clinical and organizational variables (teaching or non-teaching hospital, birth volumes, time and day of delivery) multilevel Poisson regression models and a classification tree were used. A substantial inter-hospital variability in CD rate was found, and this was only partially explained by the considered variables. The most important risk factors of CD were: previous CD (RR 4,95; 95%CI: 4,85-5,05), cord prolapse (RR 3,51; 95% CI:2,96-4,16), and malposition/malpresentation (RR 2,72; 95%CI: 2,66-2,77). Delivery between 7 pm and 7 am and during non working days protect against CD in all subgroups including those with a small number of elective CDs while delivery at a teaching hospital and birth volumes were not statistically significant risk factors. The classification tree shows that previous CD and malposition/malpresentation are the most important variables discriminating between high and low risk of CD. These results indicate that other not considered factors might explain CD variability and do not provide clear evidence that small hospitals have a poor performance in terms of CD rate. Some strategies to reduce CD could be found by focusing on the differences in delivery practice between day and night and between working and no-working day deliveries.

Spectroscopic studies on Cyclodextrin and Metal Organic Framework based potential nanovectors for delivery of Anticancer and Antiviral drugs

The aim of this work is to contribute to the development of new multifunctional nanocarriers for improved encapsulation and delivery of anticancer and antiviral drugs. The work focused on water soluble and biocompatible oligosaccharides, the cyclodextrins (CyDs), and a new family of nanostructured, biodegradable carrier materials made of porous metal-organic frameworks (nanoMOFs). The drugs of choice were the anticancer doxorubicin (DOX), azidothymidine (AZT) and its phosphate derivatives and artemisinin (ART). DOX possesses a pharmacological drawback due to its self-aggregation tendency in water. The non covalent binding of DOX to a series of CyD derivatives, such as g-CyD, an epichlorohydrin crosslinked b-CyD polymer (pb-CyD) and a citric acid crosslinked g-CyD polymer (pg-CyD) was studied by UV visible absorption, circular dichroism and fluorescence. Multivariate global analysis of multiwavelength data from spectroscopic titrations allowed identification and characterization of the stable complexes. pg-CyD proved to be the best carrier showing both high association constants and ability to monomerize DOX. AZT is an important antiretroviral drug. The active form is AZT-triphosphate (AZT-TP), formed in metabolic paths of low efficiency. Direct administration of AZT-TP is limited by its poor stability in biological media. So the development of suitable carriers is highly important. In this context we studied the binding of some phosphorilated derivatives to nanoMOFs by spectroscopic methods. The results obtained with iron(III)-trimesate nanoMOFs allowed to prove that the binding of these drugs mainly occurs by strong iono-covalent bonds to iron(III) centers. On the basis of these and other results obtained in partner laboratories, it was possible to propose this highly versatile and “green” carrier system for delivery of phosphorylated nucleoside analogues. The interaction of DOX with nanoMOFs was also studied. Finally the binding of the antimalarial drug, artemisinin (ART) with two cyclodextrin-based carriers,the pb-CyD and a light responsive bis(b-CyD) host, was also studied.

Maternal Smoking Impact on the Delivery Cost: a population-based study in the Emilia-Romagna region

This doctoral thesis is devoted to the study of the causal effects of the maternal smoking on the delivery cost. The interest of economic consequences of smoking in pregnancy have been studied fairly extensively in the USA, and very little is known in European context. To identify the causal relation between different maternal smoking status and the delivery cost in the Emilia-Romagna region two distinct methods were used. The first - geometric multidimensional - is mainly based on the multivariate approach and involves computing and testing the global imbalance, classifying cases in order to generate well-matched comparison groups, and then computing treatment effects. The second - structural modelling - refers to a general methodological account of model-building and model-testing. The main idea of this approach is to decompose the global mechanism into sub-mechanisms though a recursive decomposition of a multivariate distribution.

Tissue engineering strategies for biomaterial-based anticancer drug delivery and enhancement of angiogenesis in tumor-resected bone

Patienten, die an Osteosarkom leiden werden derzeit mit intravenös applizierten krebstherapeutischen Mitteln nach Tumorresektion behandelt, was oftmals mit schweren Nebenwirkungen und einem verzögerten Knochenheilungsprozess einhergeht. Darüber hinaus treten vermehrt Rezidive aufgrund von verbleibenden neoplastischen Zellen an der Tumorresektionsstelle auf. Erfolgreiche Knochenregeneration und die Kontrolle von den im Gewebe verbleibenden Krebszellen stellt eine Herausforderung für das Tissue Engineering nach Knochenverlust durch Tumorentfernung dar. In dieser Hinsicht scheint der Einsatz von Hydroxyapatit als Knochenersatzmaterial in Kombination mit Cyclodextrin als Medikamententräger, vielversprechend. Chemotherapeutika können an Biomaterial gebunden und direkt am Tumorbett über einen längeren Zeitraum freigesetzt werden, um verbliebene neoplastische Zellen zu eliminieren. Lokal applizierte Chemotherapie hat diverse Vorteile, einschließlich der direkten zytotoxischen Auswirkung auf lokale Zellen, sowie die Reduzierung schwerer Nebenwirkungen. Diese Studie wurde durchgeführt, um die Funktionsfähigkeit eines solchen Arzneimittelabgabesystems zu bewerten und um Strategien im Bereich des Tissue Engineerings zu entwickeln, die den Knochenheilungsprozess und im speziellen die Vaskularisierung fördern sollen. Die Ergebnisse zeigen, dass nicht nur Krebszellen von der chemotherapeutischen Behandlung betroffen sind. Primäre Endothelzellen wie zum Beispiel HUVEC zeigten eine hohe Sensibilität Cisplatin und Doxorubicin gegenüber. Beide Medikamente lösten in HUVEC ein tumor-unterdrückendes Signal durch die Hochregulation von p53 und p21 aus. Zudem scheint Hypoxie einen krebstherapeutischen Einfluss zu haben, da die Behandlung sensitiver HUVEC mit Hypoxie die Zellen vor Zytotoxizität schützte. Der chemo-protektive Effekt schien deutlich weniger auf Krebszelllinien zu wirken. Diese Resultate könnten eine mögliche chemotherapeutische Strategie darstellen, um den Effekt eines zielgerichteten Medikamenteneinsatzes auf Krebszellen zu verbessern unter gleichzeitiger Schonung gesunder Zellen. Eine erfolgreiche Integration eines Systems, das Arzneimittel abgibt, kombiniert mit einem Biomaterial zur Stabilisierung und Regeneration, könnte gesunden Endothelzellen die Möglichkeit bieten zu proliferieren und Blutgefäße zu bilden, während verbleibende Krebszellen eliminiert werden. Da der Prozess der Knochengeweberemodellierung mit einer starken Beeinträchtigung der Lebensqualität des Patienten einhergeht, ist die Beschleunigung des postoperativen Heilungsprozesses eines der Ziele des Tissue Engineerings. Die Bildung von Blutgefäßen ist unabdingbar für eine erfolgreiche Integration eines Knochentransplantats in das Gewebe. Daher ist ein umfangreich ausgebildetes Blutgefäßsystem für einen verbesserten Heilungsprozess während der klinischen Anwendung wünschenswert. Frühere Experimente zeigen, dass sich die Anwendung von Ko-Kulturen aus humanen primären Osteoblasten (pOB) und humanen outgrowth endothelial cells (OEC) im Hinblick auf die Bildung stabiler gefäßähnlicher Strukturen in vitro, die auch effizient in das mikrovaskuläre System in vivo integriert werden konnten, als erfolgreich erweisen. Dieser Ansatz könnte genutzt werden, um prä-vaskularisierte Konstrukte herzustellen, die den Knochenheilungsprozess nach der Implantation fördern. Zusätzlich repräsentiert das Ko-Kultursystem ein exzellentes in vitro Model, um Faktoren, welche stark in den Prozess der Knochenheilung und Angiogenese eingebunden sind, zu identifizieren und zu analysieren. Es ist bekannt, dass Makrophagen eine maßgebliche Rolle in der inflammatorisch-induzierten Angiogenese spielen. In diesem Zusammenhang hebt diese Studie den positiven Einfluss THP-1 abgeleiteter Makrophagen in Ko-Kultur mit pOB und OEC hervor. Die Ergebnisse zeigten, dass die Anwendung von Makrophagen als inflammatorischer Stimulus im bereits etablierten Ko-Kultursystem zu einer pro-angiogenen Aktivierung der OEC führte, was in einer signifikant erhöhten Bildung blutgefäßähnlicher Strukturen in vitro resultierte. Außerdem zeigte die Analyse von Faktoren, die in der durch Entzündung hervorgerufenen Angiogenese eine wichtige Rolle spielen, eine deutliche Hochregulation von VEGF, inflammatorischer Zytokine und Adhäsionsmoleküle, die letztlich zu einer verstärkten Vaskularisierung beitragen. Diese Resultate werden dem Einfluss von Makrophagen zugeschrieben und könnten zukünftig im Tissue Engineering eingesetzt werden, um den Heilungsprozess zu beschleunigen und damit die klinische Situation von Patienten zu verbessern. Darüber hinaus könnte die Kombination der auf Ko-Kulturen basierenden Ansätze für das Knochen Tissue Engineering mit einem biomaterial-basierenden Arzneimittelabgabesystem zum klinischen Einsatz kommen, der die Eliminierung verbliebener Krebszellen mit der Förderung der Knochenregeneration verbindet.

Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.

Polyethylenimine-based polyplex delivery of self-replicating RNA vaccines

Self-amplifying replicon RNA (RepRNA) are large molecules (12-14kb); their self-replication amplifies mRNA template numbers, affording several rounds of antigen production, effectively increasing vaccine antigen payloads. Their sensitivity to RNase-sensitivity and inefficient uptake by dendritic cells (DCs) - absolute requirements for vaccine design - were tackled by condensing RepRNA into synthetic, nanoparticulate, polyethylenimine (PEI)-polyplex delivery vehicles. Polyplex-delivery formulations for small RNA molecules cannot be transferred to RepRNA due to its greater size and complexity; the N:P charge ratio and impact of RepRNA folding would influence polyplex condensation, post-delivery decompaction and the cytosolic release essential for RepRNA translation. Polyplex-formulations proved successful for delivery of RepRNA encoding influenza virus hemagglutinin and nucleocapsid to DCs. Cytosolic translocation was facilitated, leading to RepRNA translation. This efficacy was confirmed in vivo, inducing both humoral and cellular immune responses. Accordingly, this paper describes the first PEI-polyplexes providing efficient delivery of the complex and large, self-amplifying RepRNA vaccines.

Verification of the clinical implementation of the respiratory gated beam delivery technique with synchrotron-based proton irradiation

The clinical advantage for protons over conventional high-energy x-rays stems from their unique depth-dose distribution, which delivers essentially no dose beyond the end of range. In order to achieve it, accurate localization of the tumor volume relative to the proton beam is necessary. For cases where the tumor moves with respiration, the resultant dose distribution is sensitive to such motion. One way to reduce uncertainty caused by respiratory motion is to use gated beam delivery. The main goal of this dissertation is to evaluate the respiratory gating technique in both passive scattering and scanning delivery mode. Our hypothesis for the study was that optimization of the parameters of synchrotron operation and respiratory gating can lead to greater efficiency and accuracy of respiratory gating for all modes of synchrotron-based proton treatment delivery. The hypothesis is tested in two specific aims. The specific aim #1 is to assess the efficiency of respiratory-gated proton beam delivery and optimize the synchrotron operations for the gated proton therapy. A simulation study was performed and introduced an efficient synchrotron operation pattern, called variable Tcyc. In addition, the simulation study estimated the efficiency in the respiratory gated scanning beam delivery mode as well. The specific aim #2 is to assess the accuracy of beam delivery in respiratory-gated proton therapy. The simulation study was extended to the passive scattering mode to estimate the quality of pulsed beam delivery to the residual motion for several synchrotron operation patterns with the gating technique. The results showed that variable Tcyc operation can offer good reproducible beam delivery to the residual motion at a certain phase of the motion. For respiratory gated scanning beam delivery, the impact of motion on the dose distributions by scanned beams was investigated by measurement. The results showed the threshold for motion for a variety of scan patterns and the proper number of paintings for normal and respiratory gated beam deliveries. The results of specific aims 1 and 2 provided supporting data for implementation of the respiratory gating beam delivery technique into both passive and scanning modes and the validation of the hypothesis.

Route-back delivery protocol for collection tree protocol-based applications

We propose the Route-back Delivery (RBD) protocol; a routing mechanism to create reverse routes exploiting the Collection Tree Protocol to allow unicast data dissemination from the sink. The main goal of this work is to provide a mechanism to enable bi-directional communications among the root(s) and specific sensor nodes in data gathering applications that does not use broadcast only mechanisms. The main objective of the root-to-remote-nodes route creation is to disseminate short messages to change application parameters in a unicast fashion. This facilitates remote configurability in heterogeneous WSN deployments.

SOA-Based Model for Value-Added ITS Services Delivery

Integration is currently a key factor in intelligent transportation systems (ITS), especially because of the ever increasing service demands originating from the ITS industry and ITS users. The current ITS landscape is made up of multiple technologies that are tightly coupled, and its interoperability is extremely low, which limits ITS services generation. Given this fact, novel information technologies (IT) based on the service-oriented architecture (SOA) paradigm have begun to introduce new ways to address this problem. The SOA paradigm allows the construction of loosely coupled distributed systems that can help to integrate the heterogeneous systems that are part of ITS. In this paper, we focus on developing an SOA-based model for integrating information technologies (IT) into ITS to achieve ITS service delivery. To develop our model, the ITS technologies and services involved were identified, catalogued, and decoupled. In doing so, we applied our SOA-based model to integrate all of the ITS technologies and services, ranging from the lowest-level technical components, such as roadside unit as a service (RS S), to the most abstract ITS services that will be offered to ITS users (value-added services). To validate our model, a functionality case study that included all of the components of our model was designed.

Market based transit facility design : final report /

"DOT-T-89-12."