Combinatorial and Robust Optimisation Models and Algorithms for Railway Applications

This thesis deals with an investigation of combinatorial and robust optimisation models to solve railway problems. Railway applications represent a challenging area for operations research. In fact, most problems in this context can be modelled as combinatorial optimisation problems, in which the number of feasible solutions is finite. Yet, despite the astonishing success in the field of combinatorial optimisation, the current state of algorithmic research faces severe difficulties with highly-complex and data-intensive applications such as those dealing with optimisation issues in large-scale transportation networks. One of the main issues concerns imperfect information. The idea of Robust Optimisation, as a way to represent and handle mathematically systems with not precisely known data, dates back to 1970s. Unfortunately, none of those techniques proved to be successfully applicable in one of the most complex and largest in scale (transportation) settings: that of railway systems. Railway optimisation deals with planning and scheduling problems over several time horizons. Disturbances are inevitable and severely affect the planning process. Here we focus on two compelling aspects of planning: robust planning and online (real-time) planning.

Neurons derived from P19 embryonic carcinoma cells as a platform for biosensor applications - optimisation and characterisation

P19 is a mouse-derived embryonal carcinoma cell line capable of differentiation toward ectodermal, mesodermal and endodermal lineages and could thus be differentiated into neurons. Different culture conditions were tested to optimise and increase the efficiency of neuronal differentiation since the population of P19-derived neurons was reported to be heterogeneous with respect to the morphology and neurotransmitters they synthesise. P19-derived neurons were cultured on microelectrode arrays as cell aggregates and as dissociated cells. Improved neuronal maturation was shown by the presence of microtubule associated protein 2, neurofilament and synaptophysin formation when initiation of neuronal differentiation was prolonged. High initial cell density cultures and coating of surfaces with polyethylenimine-laminin further improved neuronal maturation of differentiated P19 cells. Increased spontaneous activities of the P19-derived neurons were correspondingly recorded. Two to three hours recordings were performed between 17 and 25 days when extracellular signals were stabilised. It was found that P19-derived neurons developed network properties as partially synchronised network activities. P19-derived neurons appeared to give inhomogenous response to the 2 major neurotransmitters, -aminobutyric acid (GABA) and glutamate. The P19-derived neuronal networks obtained from optimised protocol in this thesis were predominantly GABAergic. The reproducible long term extracellular recordings performed showed that neurons derived from P19 embryonal carcinoma cells could be applied as a model for cell based biosensor in corporation with microelectrode arrays.

Il monitoraggio della qualità di vita e dei bisogni di pazienti oncologici e caregiver: il caso ANT

La Fondazione ANT rappresenta una delle più ampie esperienze al mondo di assistenza socio-sanitaria gratuita a domicilio ai malati di tumore, tramite équipe di specialisti costituite da medici, psicologi e infermieri. La patologia oncologica ha un enorme impatto sul benessere dei pazienti. Un modo per raggruppare i diversi sintomi di disagio psicologico è utilizzare il concetto di distress, che sarebbe importante monitorare in modo semplice e veloce. Primo studio: 66 pazienti oncologici (40% uomini; età media 54 anni) in cure palliative domiciliari. Il 79% dei pazienti ha mostrato livelli clinicamente significativi di distress. Il 55% dei partecipanti allo studio ha riportato alti livelli di ansia, e l'81% dei pazienti ha riportato alti livelli di depressione. Dall'analisi delle curve ROC il singolo item del Distress Thermometer, con un cut-off maggiore o uguale a 4, è stato in grado di rilevare il 97% dei soggetti con punteggi clinici di ansia e depressione, quindi può essere utilizzato anche come uno strumento di screening precoce rapido ed affidabile per i disturbi dell'umore. I familiari sono la prima risorsa dei malati di tumore, e l'identificazione dei loro bisogni è utile per individuare chi ha maggiore necessità di aiuto ed in quali aree. Secondo studio: 115 caregiver di pazienti oncologici (37% uomini; età media 52 anni). Di seguito i bisogni più frequenti. Salute psicofisica: “preoccupazioni circa il/la paziente” (72%), ansia (53%) e rabbia (52%). Informazioni: “come prendersi cura del paziente” (64%), “terapie alternative e/o complementari” (64%) e “come gestire lo stress” (57%). Servizi e strutture sanitarie: “un operatore di riferimento”, (65%), “cure infermieristiche a domicilio” (62%), “indicazioni su servizi ospedalieri” (57%), ed “assistenza per caregiver, ad esempio consulenza psicologica” (55%). Il monitoraggio dei bisogni consentirebbe un'ottimizzazione dell'assistenza, prevenendo situazioni che potrebbero compromettere il benessere della famiglia e la qualità dell'assistenza fornita al paziente.

L’instrumentum fittile inscriptum della colonia romana di Mutina e del suo territorio

Il presente lavoro è incentrato sulla raccolta e l’analisi dell’instrumentum fittile inscriptum – in particolare laterizi, dolia, lucerne, ceramica fine da mensa, anfore e tappi d’anfora - rinvenuto a Modena e nel suo territorio. L’attenzione è stata concentrata sul materiale bollato e, per quanto riguarda le anfore, anche sullo studio degli esemplari recanti tituli picti. Si è proceduto ad una raccolta di tutto il materiale edito, a cui si è aggiunto lo studio di un’ingente quantità di reperti provenienti da due recenti scavi suburbani: quello presso il Parco Novi Sad, che si segnala soprattutto per la ricchezza del materiale anforico, e quello di Viale Reiter, ove sono venuti alla luce numerosi scarti di cottura di lucerne a canale recanti le firme di alcuni dei più noti produttori di tali oggetti nel mondo romano. A ciascuna categoria di instrumentum è stato dedicato un capitolo, corredato di tabelle in cui è stato raccolto tutto il materiale considerato; inoltre, per i reperti del Parco Novi Sad e di Viale Reiter, è stato realizzato un catalogo corredato di riproduzioni grafiche e fotografiche. Per quanto concerne le iscrizioni dipinte, un capitolo è stato dedicato a quelle presenti sulle anforette adriatiche da pesce; quanto ai tituli picti su anfore di morfologia betica per il trasporto di salse di pesce è stato effettuato un confronto con esemplari rinvenuti in due scavi inediti a Parma, che presentano significative analogie col materiale modenese. Dall’analisi dell’instrumentum inscriptum di Mutina, pur consapevoli dei limiti insiti in una ricerca incentrata unicamente su tale tipo di materiale, è emersa un’immagine della colonia, tra la tarda età repubblicana ed il I sec. d.C., congruente con quella delineata dalle fonti letterarie, dall’epigrafia lapidaria e dai rinvenimenti archeologici, ossia di una città di notevole importanza e ricchezza.

A multi-objective genetic algorithm optimisation using variable speed pumps in water distribution systems

Due to its practical importance and inherent complexity, the optimisation of distribution networks for supplying drinking water has been the subject of extensive study for the past 30 years. The optimization is governed by sizing the pipes in the water distribution network (WDN) and / or optimises specific parts of the network such as pumps, tanks etc. or try to analyse and optimise the reliability of a WDN. In this thesis, the author has analysed two different WDNs (Anytown City and Cabrera city networks), trying to solve and optimise a multi-objective optimisation problem (MOOP). The main two objectives in both cases were the minimisation of Energy Cost (€) or Energy consumption (kWh), along with the total Number of pump switches (TNps) during a day. For this purpose, a decision support system generator for Multi-objective optimisation used. Its name is GANetXL and has been developed by the Center of Water System in the University of Exeter. GANetXL, works by calling the EPANET hydraulic solver, each time a hydraulic analysis has been fulfilled. The main algorithm used, was a second-generation algorithm for multi-objective optimisation called NSGA_II that gave us the Pareto fronts of each configuration. The first experiment that has been carried out was the network of Anytown city. It is a big network with a pump station of four fixed speed parallel pumps that are boosting the water dynamics. The main intervention was to change these pumps to new Variable speed driven pumps (VSDPs), by installing inverters capable to diverse their velocity during the day. Hence, it’s been achieved great Energy and cost savings along with minimisation in the number of pump switches. The results of the research are thoroughly illustrated in chapter 7, with comments and a variety of graphs and different configurations. The second experiment was about the network of Cabrera city. The smaller WDN had a unique FS pump in the system. The problem was the same as far as the optimisation process was concerned, thus, the minimisation of the energy consumption and in parallel the minimisation of TNps. The same optimisation tool has been used (GANetXL).The main scope was to carry out several and different experiments regarding a vast variety of configurations, using different pump (but this time keeping the FS mode), different tank levels, different pipe diameters and different emitters coefficient. All these different modes came up with a large number of results that were compared in the chapter 8. Concluding, it should be said that the optimisation of WDNs is a very interested field that has a vast space of options to deal with. This includes a large number of algorithms to choose from, different techniques and configurations to be made and different support system generators. The researcher has to be ready to “roam” between these choices, till a satisfactory result will convince him/her that has reached a good optimisation point.

Optimisation of chemical lysis protocol for point-of-care leukocyte differentiation

The full blood cell (FBC) count is the most common indicator of diseases. At present hematology analyzers are used for the blood cell characterization, but, recently, there has been interest in using techniques that take advantage of microscale devices and intrinsic properties of cells for increased automation and decreased cost. Microfluidic technologies offer solutions to handling and processing small volumes of blood (2-50 uL taken by finger prick) for point-of-care(PoC) applications. Several PoC blood analyzers are in use and may have applications in the fields of telemedicine, out patient monitoring and medical care in resource limited settings. They have the advantage to be easy to move and much cheaper than traditional analyzers, which require bulky instruments and consume large amount of reagents. The development of miniaturized point-of-care diagnostic tests may be enabled by chip-based technologies for cell separation and sorting. Many current diagnostic tests depend on fractionated blood components: plasma, red blood cells (RBCs), white blood cells (WBCs), and platelets. Specifically, white blood cell differentiation and counting provide valuable information for diagnostic purposes. For example, a low number of WBCs, called leukopenia, may be an indicator of bone marrow deficiency or failure, collagen- vascular diseases, disease of the liver or spleen. The leukocytosis, a high number of WBCs, may be due to anemia, infectious diseases, leukemia or tissue damage. In the laboratory of hybrid biodevices, at the University of Southampton,it was developed a functioning micro impedance cytometer technology for WBC differentiation and counting. It is capable to classify cells and particles on the base of their dielectric properties, in addition to their size, without the need of labeling, in a flow format similar to that of a traditional flow cytometer. It was demonstrated that the micro impedance cytometer system can detect and differentiate monocytes, neutrophils and lymphocytes, which are the three major human leukocyte populations. The simplicity and portability of the microfluidic impedance chip offer a range of potential applications in cell analysis including point-of-care diagnostic systems. The microfluidic device has been integrated into a sample preparation cartridge that semi-automatically performs erythrocyte lysis before leukocyte analysis. Generally erythrocytes are manually lysed according to a specific chemical lysis protocol, but this process has been automated in the cartridge. In this research work the chemical lysis protocol, defined in the patent US 5155044 A, was optimized in order to improve white blood cell differentiation and count performed by the integrated cartridge.

Demography in eusocial Hymenoptera

In my doctoral thesis I investigated the evolution of demographic traits within eusocial Hymenoptera. In the social bees, wasps and ants, eusociality has a unique effect on life span evolution as female larvae with the same genetic background can develop through phenotypic plasticity to a queen or a worker with vastly diverging life-history traits. Ant queens belong to the longest-lived insect species, while workers in most species live only a fraction of the queen’s life span. The average colony size of a species is positively correlated with social complexity, division of labor and diverging morphological female phenotypes all of which also affect life span. Therefore the demographic traits of interest in this thesis were life span and colony size. To understand the evolution of worker life span I applied a trade-off model that includes both hierarchical levels important in eusocial systems, namely the colony- and the individual-level. I showed that the evolution of worker life span may be an adaptive trait on the colony level to optimize resource allocation and therefore fitness in response to different levels of extrinsic mortality. A shorter worker life span as a result of reduced resource investments under high levels of extrinsic mortality increases colony fitness. In a further study I showed that Lasius niger colonies produce different aging phenotypes throughout colony development. Smaller colonies which apply a different foraging strategy than larger colonies produced smaller workers, which in turn have a longer life span as compared to larger workers produced in larger colonies. With the switch to cooperative foraging in growing colonies individual workers become less important for the colony caused by their increasing redundancy. Alternatively a trade of between growth and life span may lead to the results found in this study. A further comparative analysis to study the effect of colony size on life span showed a correlation between queen and worker life span when colony size is taken into account. While neither worker nor queen life span was associated with colony size, the differences between queen and worker life span increase with larger average colony sizes across all eusocial Hymenoptera. As colony size affects both queen and worker life span, I aimed to understand which factors lead to the small colony sizes displayed by some ant species. I therefore analyzed per-capita productivity at different colony sizes of eight cavity dwelling ant species. Most colonies of the study species grew larger than optimal productivity predicted. Larger colony size was shown to increase colony homeostasis, the predictability of future productivity and in turn the survival probability of the colony. I also showed that species that deploy an individual foraging mode may circumvent the density dependent decline in foraging success by splitting the colony to several nest sites.

Cultura materiale ed espansione di Roma: Il caso dell'Ager Gallicus

Lo scritto ha l’obiettivo di definire dinamiche e cronologie di quel complesso processo espansionistico che portò Roma alla conquista dei territori dell’Ager Gallicus, partendo dall’analisi dettagliata della cultura materiale e dei rispettivi contesti di provenienza emersi dalle recenti indagini archeologiche realizzate dal Dipartimento di Storia Culture Civiltà dell’Università degli Studi di Bologna nella città di Senigallia. In armonia con quanto testimoniato dalle sequenze stratigrafiche documentate, si delineano quattro principali fasi di vita dell’abitato: la prima preromana, la seconda riferibile alla prima fase di romanizzazione del sito, la terza inerente allo sviluppo dell’insediamento con la fondazione della colonia romana e l’ultima riferibile all’età repubblicana. Emerge con chiarezza la presenza già dalla fine del IV-inizio III a.C., di un insediamento romano nel territorio della città, sviluppatosi con la fondazione di un’area sacra e la predisposizione di un’area produttiva. La scelta del sito di Sena Gallica fu strategica: un territorio idoneo allo sfruttamento agricolo e utile come testa di ponte per la conquista dei territori del Nord Italia. Inoltre, questo centro aveva già intrecciato rapporti commerciali con gli insediamenti costieri adriatici e mediterranei. La presenza di ceramica di produzione locale, il rinvenimento di elementi distanziatori e le caratteristiche geomorfologiche del sito, fanno ipotizzare la presenza in loco di un’officina ceramica. Ciò risulta di grande importanza dato che tutte le attestazioni ceramiche prodotte localmente e rinvenute nel territorio, fino ad oggi sono attribuite alle officine di Aesis e Ariminum. Dunque Sena Gallica sarebbe stata un centro commerciale e produttivo. La precoce presenza di ceramica a Vernice Nera di tipo romano-laziale prodotte localmente prima dell’istituzione ufficiale della colonia, che permette di ipotizzare uno stanziamento di piccoli gruppi di Romani in territori appena conquistati ma non ancora colonizzati, attestata a Sena Gallica, trova riscontro anche in altri centri adriatici come Ariminum, Aesis, Pisaurum, Suasa e Cattolica.

Development and optimisation of novel 68 Ga-folates - towards early diagnosis of ovarian cancer

Der Folsäure-basierte Radiotracer Etarfolatide (99mTc-EC 20) hat in der Vergangenheit sehr vielversprechende Ergebnisse im Bereich der frühzeitigen Diagnostik von Ovarialkarzinomen gezeigt. Einzelphotonen-Emissionscomputertomographie (SPECT) erlaubt dabei eine Visualisierung der Krankheit in einem sehr frühen Stadium – ermöglicht wird dies durch Folsäure, welche als Target Vektor dient. Um das erfolgreiche Prinzip der Radiofolate auf die Positronen-Emissionstomographie (PET) zu übertragen, welche eine noch höhere räumliche Auflösung ermöglicht, wurden in den letzten fünf Jahren bereits 18F-folate entwickelt. Deren hepatobiliären Exkretionsmuster, verursacht durch die relativ hohe Lipophilie der Strukturen, entsprachen jedoch nicht den Anforderungen. Eine optimierte Bioverteilung der Tracer in vivo kann durch eine generelle Erhöhung der Polarität erfolgen. Die Kombination aus einem polaren 68Ga-Komplex mit Folsäure als Target Vektor stellte den Fokus dieses Projektes dar. Ziel war die Entwicklung eines Radiofolates mit der Tendenz einer raschen renalen Ausscheidung und verringerter hepatobiliärer Anreicherung. Dazu wurde Folsäure regiospezifisch über ihre y-Säure an verschiedene bifunktionelle Chelatoren (BFCs) gekoppelt. Vier verschiedene Reaktionstypen wurden gewählt und durchgeführt: Cu-katalysierte sowie Cu-freie Click Reaktion, Amindbindung und Thioharnstoff Bildung. Es wurden sechs verschiedene Derivate erhalten und mit 68Ga radiomarkiert.

2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.