Development of Clinical Decision Support Systems based on Mathematical Models of Physiological Systems

In the last years of research, I focused my studies on different physiological problems. Together with my supervisors, I developed/improved different mathematical models in order to create valid tools useful for a better understanding of important clinical issues. The aim of all this work is to develop tools for learning and understanding cardiac and cerebrovascular physiology as well as pathology, generating research questions and developing clinical decision support systems useful for intensive care unit patients. I. ICP-model Designed for Medical Education We developed a comprehensive cerebral blood flow and intracranial pressure model to simulate and study the complex interactions in cerebrovascular dynamics caused by multiple simultaneous alterations, including normal and abnormal functional states of auto-regulation of the brain. Individual published equations (derived from prior animal and human studies) were implemented into a comprehensive simulation program. Included in the normal physiological modelling was: intracranial pressure, cerebral blood flow, blood pressure, and carbon dioxide (CO2) partial pressure. We also added external and pathological perturbations, such as head up position and intracranial haemorrhage. The model performed clinically realistically given inputs of published traumatized patients, and cases encountered by clinicians. The pulsatile nature of the output graphics was easy for clinicians to interpret. The manoeuvres simulated include changes of basic physiological inputs (e.g. blood pressure, central venous pressure, CO2 tension, head up position, and respiratory effects on vascular pressures) as well as pathological inputs (e.g. acute intracranial bleeding, and obstruction of cerebrospinal outflow). Based on the results, we believe the model would be useful to teach complex relationships of brain haemodynamics and study clinical research questions such as the optimal head-up position, the effects of intracranial haemorrhage on cerebral haemodynamics, as well as the best CO2 concentration to reach the optimal compromise between intracranial pressure and perfusion. We believe this model would be useful for both beginners and advanced learners. It could be used by practicing clinicians to model individual patients (entering the effects of needed clinical manipulations, and then running the model to test for optimal combinations of therapeutic manoeuvres). II. A Heterogeneous Cerebrovascular Mathematical Model Cerebrovascular pathologies are extremely complex, due to the multitude of factors acting simultaneously on cerebral haemodynamics. In this work, the mathematical model of cerebral haemodynamics and intracranial pressure dynamics, described in the point I, is extended to account for heterogeneity in cerebral blood flow. The model includes the Circle of Willis, six regional districts independently regulated by autoregulation and CO2 reactivity, distal cortical anastomoses, venous circulation, the cerebrospinal fluid circulation, and the intracranial pressure-volume relationship. Results agree with data in the literature and highlight the existence of a monotonic relationship between transient hyperemic response and the autoregulation gain. During unilateral internal carotid artery stenosis, local blood flow regulation is progressively lost in the ipsilateral territory with the presence of a steal phenomenon, while the anterior communicating artery plays the major role to redistribute the available blood flow. Conversely, distal collateral circulation plays a major role during unilateral occlusion of the middle cerebral artery. In conclusion, the model is able to reproduce several different pathological conditions characterized by heterogeneity in cerebrovascular haemodynamics and can not only explain generalized results in terms of physiological mechanisms involved, but also, by individualizing parameters, may represent a valuable tool to help with difficult clinical decisions. III. Effect of Cushing Response on Systemic Arterial Pressure. During cerebral hypoxic conditions, the sympathetic system causes an increase in arterial pressure (Cushing response), creating a link between the cerebral and the systemic circulation. This work investigates the complex relationships among cerebrovascular dynamics, intracranial pressure, Cushing response, and short-term systemic regulation, during plateau waves, by means of an original mathematical model. The model incorporates the pulsating heart, the pulmonary circulation and the systemic circulation, with an accurate description of the cerebral circulation and the intracranial pressure dynamics (same model as in the first paragraph). Various regulatory mechanisms are included: cerebral autoregulation, local blood flow control by oxygen (O2) and/or CO2 changes, sympathetic and vagal regulation of cardiovascular parameters by several reflex mechanisms (chemoreceptors, lung-stretch receptors, baroreceptors). The Cushing response has been described assuming a dramatic increase in sympathetic activity to vessels during a fall in brain O2 delivery. With this assumption, the model is able to simulate the cardiovascular effects experimentally observed when intracranial pressure is artificially elevated and maintained at constant level (arterial pressure increase and bradicardia). According to the model, these effects arise from the interaction between the Cushing response and the baroreflex response (secondary to arterial pressure increase). Then, patients with severe head injury have been simulated by reducing intracranial compliance and cerebrospinal fluid reabsorption. With these changes, oscillations with plateau waves developed. In these conditions, model results indicate that the Cushing response may have both positive effects, reducing the duration of the plateau phase via an increase in cerebral perfusion pressure, and negative effects, increasing the intracranial pressure plateau level, with a risk of greater compression of the cerebral vessels. This model may be of value to assist clinicians in finding the balance between clinical benefits of the Cushing response and its shortcomings. IV. Comprehensive Cardiopulmonary Simulation Model for the Analysis of Hypercapnic Respiratory Failure We developed a new comprehensive cardiopulmonary model that takes into account the mutual interactions between the cardiovascular and the respiratory systems along with their short-term regulatory mechanisms. The model includes the heart, systemic and pulmonary circulations, lung mechanics, gas exchange and transport equations, and cardio-ventilatory control. Results show good agreement with published patient data in case of normoxic and hyperoxic hypercapnia simulations. In particular, simulations predict a moderate increase in mean systemic arterial pressure and heart rate, with almost no change in cardiac output, paralleled by a relevant increase in minute ventilation, tidal volume and respiratory rate. The model can represent a valid tool for clinical practice and medical research, providing an alternative way to experience-based clinical decisions. In conclusion, models are not only capable of summarizing current knowledge, but also identifying missing knowledge. In the former case they can serve as training aids for teaching the operation of complex systems, especially if the model can be used to demonstrate the outcome of experiments. In the latter case they generate experiments to be performed to gather the missing data.

Fellow travelers: an ethnographic study of the dynamics of inter-organizational collaboration

The research is a 13-months ethnographic field work on the early operations of a Multi-party alliance active in the global field of indoor positioning. The study aims to understand and investigate empirically the challenges that at the individual and group level influence the organizing principle guiding the alliance operations and evolution. Its contribution rests on the dynamics affecting ecosystems of innovation and collaborative spaces of value co-creation in inter-organizational projects.

Neo-commodification of persons: exploitation of personal data and impact on the sharing economy

The notion of commodification is a fascinating one. It entails many facets, ranging from subjective debates on desirability of commodification to in depth economic analyses of objects of value and their corresponding markets. Commodity theory is therefore not just defined by a single debate, but spans a plethora of different discussions. This thesis maps and situates those theories and debates and selects one specific strain to investigate further. This thesis argues that commodity theory in its optima forma deals with the investigation into what sets commodities apart from non-commodities. It proceeds to examine the many given answers to this question by scholars ranging from the mid 1800’s to the late 2000’s. Ultimately, commodification is defined as a process in which an object becomes an element of the total wealth of societies in which the capitalist mode of production prevails. In doing so, objects must meet observables, or indicia, of commodification provided by commodity theories. Problems arise when objects are clearly part of the total wealth in societies without meeting established commodity indicia. In such cases, objects are part of the total wealth of a society without counting as a commodity. This thesis examines this phenomenon in relation to the novel commodities of audiences and data. It explains how these non-commodities (according to classical theories) are still essential elements of industry. The thesis then takes a deep dive into commodity theory using the theory on the construction of social reality by John Searle.

Ruolo delle cellule staminali mesenchimali in modelli cellulari e animali di nefropatia

Background. Mesenchymal stem cells (MSC) may be of value in regeneration of renal tissue after damage, however lack of biological knowledge and variability of results in animal models limit their utilization. Methods. We studied the effects of MSC on podocytes ‘in vitro’ and ‘in vivo’ utilizing adriamycin (ADR) as a model of renal toxicity. The ‘in vivo’ experimental approach was carried out in male Sprague Dawley rats (overall 60 animals) treated with different ADR schemes to induce acute and chronic nephrosis. MSC were given a) concomitantly to ADR in tail vein or b) in aorta and c) in tail vein 60 days after ADR. Homing was assessed with PKH26-MSC. Results. MSC rescued podocytes from apoptosis induced by ADR ‘in vitro’. The maximal effect (80% rescue) was obtained with MSC/Podocytes co-culture ratio of 1:1 for 72 hours. All rats treated with ADR developed nephrosis. In no case MSC modified the clinical parameters (i.e. proteinuria, serum creatinine, lipids) but protected the kidney from severe glomerulosclerosis when given concomitantly to ADR. Rats given MSC 60 days after ADR developed the same severe renal damage. Only few MSC were found in renal tubule-interstitial areas after 1-24 hours from injection and no MSC was detected in glomeruli. Conclusions. MSC reduced apoptosis of podocytes treated with ADR ‘in vitro’. Early and repeated MSC infusion blunted glomerular damage in chronic ADR nephropathy. MSC did not modify proteinuria and progression to renal failure, that implies lack of regenerative potential in this model.

Capitale sociale e sistema del valore: Il caso del pesce azzurro in Puglia

The aim of my project is to find operational strategies for increasing the commercial exploitation of fish in Apulia region and to acquire a thorough knowledge of several important aspects of this system order to propose concrete, suitable and appropriate development tools. The plan is to analyze the impact that the socio-economic context has on blue fish systems of fishing and marketing in the various maritime regions. The sector of fishery is typified by a settled downward trend due to both communitarian policies driving towards a reduction of the fishery effort and to reduction of fishing resources. In the same time in Italy a increasing of costs (expecially fuel) and a reduction of market prices, because of the increasing of imports, are observed. Although a big part of Italian fishing fleet is to be referred to Apulia region, this dynamics are worsen, here, also because of market inefficiency and lack of integration and cooperation among fishermen. In this first part of my work I have investigated two areas that are relevant for regional fishery. On a first step I have evaluated fish amount for each kind of dealer working in each one of the two areas than, according to Porter's value chain analysis theory. Than i have applied the approach of value system to evaluate the value chains of the firm's supplier, the firm of fishery itself, and the firms distribution channels. Distribution of value has been resulted different but very unfavorable to fisherman in both investigated areas. The second step of my study has been the evaluation of the social capital value in both areas, defining the networks of fishery consistence and number of their mutual relationship. Results lay stress on a relation to an higher social capital value and a distribution of value system more profitable for fishermen.

La ricerca del valore nell'impresa cooperativa di lavorazione e trasformazione: cooperative e imprese capitalistiche a confronto

La ricerca si propone un duplice obbiettivo: 1. provare, attraverso l’applicazione di un metodo teorico tradizionale di analisi economico-finanziaria, il livello ottimale di equilibrio finanziario fra accesso al credito esterno e capitale proprio; 2. mostrare l’utilità di alcuni strumenti finanziari partecipativi per la ricapitalizzazione dell’impresa cooperativa. Oggetto di studio è l’impresa cooperativa che si occupa di una o più fasi del processo di lavorazione, trasformazione e prima commercializzazione del prodotto agricolo conferito dai soci, confrontata con le imprese di capitali che svolgono la medesima attività. La società cooperativa e quella capitalistica saranno, pertanto analizzate in termini di liquidità generata, redditività prodotta e grado di indebitamento, attraverso il calcolo e l’analisi di una serie di indici, tratti dai rispettivi bilanci d’esercizio. È opportuno sottolineare che nella seguente trattazione sarà riservato uno spazio al tema della ricerca del valore nell’impresa cooperativa inteso come espressione della ricchezza creata dai processi aziendali in un determinato periodo di tempo tentando di definire, se esiste, una struttura finanziaria ottimale , ossia uno specifico rapporto tra indebitamento finanziario e mezzi propri, che massimizzi il valore dell’impresa. L’attenzione verso la struttura finanziaria, pertanto, non sarà solo rivolta al costo esplicito del debito o dell’equity, ma si estenderà anche alle implicazioni delle scelte di finanziamento sulle modalità di governo dell’impresa. Infatti molti studi di economia aziendale, e in particolar modo di gestione d’impresa e finanza aziendale, hanno trattato il tema dell’attività di governo dell’impresa, quale elemento in grado di contribuire alla creazione di valore non solo attraverso la selezione dei progetti d’investimento ma anche attraverso la composizione della struttura finanziaria.

Gold and the Stock Market: 3 Essays on Gold Investments

This thesis gives an overview of the history of gold per se, of gold as an investment good and offers some institutional details about gold and other precious metal markets. The goal of this study is to investigate the role of gold as a store of value and hedge against negative market movements in turbulent times. I investigate gold’s ability to act as a safe haven during periods of financial stress by employing instrumental variable techniques that allow for time varying conditional covariance. I find broad evidence supporting the view that gold acts as an anchor of stability during market downturns. During periods of high uncertainty and low stock market returns, gold tends to have higher than average excess returns. The effectiveness of gold as a safe haven is enhanced during periods of extreme crises: the largest peaks are observed during the global financial crises of 2007-2009 and, in particular, during the Lehman default (October 2008). A further goal of this thesis is to investigate whether gold provides protection from tail risk. I address the issue of asymmetric precious metal behavior conditioned to stock market performance and provide empirical evidence about the contribution of gold to a portfolio’s systematic skewness and kurtosis. I find that gold has positive coskewness with the market portfolio when the market is skewed to the left. Moreover, gold shows low cokurtosis with the market returns during volatile periods. I therefore show that gold is a desirable investment good to risk averse investors, since it tends to decrease the probability of experiencing extreme bad outcomes, and the magnitude of losses in case such events occur. Gold thus bears very important and under-researched characteristics as an asset class per se, which this thesis contributed to address and unveil.

All'origine dello squilibrio di potere negoziale della parte agricola nella food supply chain: il caso della suinicoltura in Emilia-Romagna

Il settore suinicolo ricopre un ruolo rilevante nel contesto nazionale, con ricadute economiche e sociali di primaria importanza in varie regioni. Tuttavia da alcuni anni il settore si trova in crisi a causa dell’instabilità dei mercati internazionali, dello scarso coordinamento tra gli attori della filiera, della progressiva riduzione della redditività dei prodotti trasformati a Denominazione di Origine, della mancata valorizzazione dei tagli di carne fresca, nonché della difficoltà di aggredire i mercati esteri. Altre criticità riguardano la distribuzione del valore lungo la filiera e la scarsa efficacia delle politiche di coordinamento finora adottate. L'obiettivo della ricerca è quello di identificare gli elementi che possono garantire maggiore equilibrio di potere negoziale tra allevatori suinicoli e macellatori rispetto alla situazione attuale: verificati gli elementi critici che caratterizzano la relazione commerciale tra allevatori e macellatori, si avanzano alcune proposte operative utili al superamento delle fratture tra la componente agricola e quella dei macelli in Emilia Romagna. La struttura della tesi è la seguente: (capitolo 1) si descrive il quadro economico del settore suinicolo a livello internazionale e nazionale. Successivamente (capitolo 2) si passano in rassegna le teorie economiche utili a comprendere le ragioni alla base del malfunzionamento dei rapporti tra gli attori della filiera agroalimentare, mentre nel terzo capitolo è richiamato il quadro normativo comunitario, nazionale e regionale all’interno del quale tali relazioni si configurano. Nel quarto capitolo si elabora un modello interpretativo al fine di spiegare le fratture che oggi contraddistinguono le relazioni in essere tra gli attori della filiera: il “modello delle fratture”. Alla luce di questa concettualizzazione è stata svolta un’indagine diretta svolta presso gli operatori aderenti all’Organizzazione Interprofessionale del Gran Suino Italiano, i cui risultati hanno consentito di valutare l’efficacia del modello interpretativo e di fornire indicazioni migliorative della strategia di governance delle relazioni tra allevatori e macellatori.

Dall'uomo esposto al soggetto esposto: il concetto di interfaccia in alcuni filoni di riflessione sulla tecnica dal Settecento a Marcel Mauss

La nozione di ambiente non è una nozione recente. Al giorno d’oggi il riferimento all’ambiente compare in maniera sempre più diffusa nei dibattiti, nelle opere scientifiche e artistiche, negli spazi di divulgazione e sempre più entra all’interno degli spazi affettivi individuali e all’interno delle teorie e delle prassi politiche individuali e collettive. L’ambiente tanto entra nel campo assiologico, quanto vi entra come elemento fragile, indissociabile dall’azione antropica individuale e collettiva, attraverso ciò che noi riassumiamo con la nozione di crisi ambientale. La crisi ambientale permette di riaprire degli ambiti di valore e di interesse nel presente, allo stesso tempo provoca una reinterpretazione e un riorientamento delle teorie e delle prassi del passato. Dal nostro presente di crisi ambientale, è possibile rintracciare delle figure che, nel passato, hanno rappresentato l’inerenza degli enti con il loro ambiente e, tra questi, dell’uomo con il suo ambiente di vita. Sono due le principali figure attraverso le quali si intende riprendere un rapporto con il nostro passato letto attraverso la crisi ambientale: la figura dell’interfaccia come ciò che demarca un rapporto di inerenza e di separazione tra un interno e un esterno che hanno un rapporto tra loro necessario e tuttavia contingente, e la figura della relazione di “esposizione”, tramite la quale si vuole pensare a forme di soggettività vulnerabili, esposte alle relazioni e ai concatenamenti nei quali sono inserite e che tuttavia non possono che esporre a loro volta le altre soggettività e l’ambiente di vita comune a continue modificazioni. Tramite i concetti di interfaccia e di esposizione abbiamo potuto seguire il prodursi di forme di sapere relative all’inerenza tra forme e modi dell’interiorità rispetto all’ambiente che si sono prodotte nella storia e che sono emerse tramite la provocazione di un passato indotto dalla trasformazione che è il nostro presente di crisi ambientale.

Non-Equilibrium Atmospheric Plasma As A Novel Route To Nanomaterial Synthesis And Processing For Biomedical Applications

Since last century, the rising interest of value-added and advanced functional materials has spurred a ceaseless development in terms of industrial processes and applications. Among the emerging technologies, thanks to their unique features and versatility in terms of supported processes, non-equilibrium plasma discharges appear as a key solvent-free, high-throughput and cost-efficient technique. Nevertheless, applied research studies are needed with the aim of addressing plasma potentialities optimizing devices and processes for future industrial applications. In this framework, the aim of this dissertation is to report on the activities carried out and the results achieved concerning the development and optimization of plasma techniques for nanomaterial synthesis and processing to be applied in the biomedical field. In the first section, the design and investigation of a plasma assisted process for the production of silver (Ag) nanostructured multilayer coatings exhibiting anti-biofilm and anti-clot properties is described. With the aim on enabling in-situ and on-demand deposition of Ag nanoparticles (NPs), the optimization of a continuous in-flight aerosol process for particle synthesis is reported. The stability and promising biological performances of deposited coatings spurred further investigation through in-vitro and in-vivo tests which results are reported and discussed. With the aim of addressing the unanswered questions and tuning NPs functionalities, the second section concerns the study of silver containing droplet conversion in a flow-through plasma reactor. The presented results, obtained combining different analysis techniques, support a formation mechanism based on droplet to particle conversion driven by plasma induced precursor reduction. Finally, the third section deals with the development of a simulative and experimental approach used to investigate the in-situ droplet evaporation inside the plasma discharge addressing the main contributions to liquid evaporation in the perspective of process industrial scale up.

Costituzionalismo democratico e diritto sovranazionale: la questione sociale in Europa.

La presente tesi affronta l’evoluzione dei rapporti tra costituzionalismo democratico e diritto sovranazionale in Europa. L’ipotesi della ricerca si basa sull’idea che l’aumentare sempre più incessante negli ultimi decenni di conflitti costituzionali tra i due ordinamenti sia dovuto ad una loro differenza di fondo, di cui una parte importante è rappresentata dall’assenza della questione sociale nel diritto sovranazionale. Il primo capitolo si occupa di analizzare le principali teorie giuridiche che hanno fornito l’habitus teorico per leggere il processo di integrazione, giustificando l’adozione di una lettura delle dinamiche ordinamentali attraverso il prisma dei conflitti e della costituzione materiale. Nel secondo capitolo si volge lo sguardo all’analisi del diritto giurisprudenziale, suddiviso in due blocchi: un primo in cui – dopo aver approfondito alcuni capisaldi del diritto sovranazionale – si confrontano i due sistemi, in maniera statica, su alcuni temi (principio di non discriminazione, libertà di impresa e il bilanciamento con interessi collettivi, i diritti di pressione democratica, ecc.) per mettere in luce i diversi approcci; un secondo blocco in cui, invece, si studiano, in maniera più dinamica, le diverse perturbazioni che hanno interessato i rapporti tra ordinamenti, di cui una prima si è sviluppata sul rispetto dei diritti fondamentali da parte del diritto sovranazionale, mentre una seconda, ancora in corso, si concentra sul discorso sull’identità costituzionale. Nel terzo capitolo, in chiusura, si prova a sviluppare – sulla base delle risultanze del dibattito teorico e dell’analisi giurisprudenziale – una proposta finale che cerchi di unire la questione sociale e il discorso sull’identità costituzionale nel diritto pubblico europeo, che abbia alla sua base un nuovo e più centrale ruolo che dovranno svolgere le Corti costituzionali nello sviluppo delle dinamiche ordinamentali, al fine di far emergere alcuni conflitti di valore assenti nello spazio pubblico europeo.

Le nozioni autonome di diritto europeo nel sistema dell'imposta sul valore aggiunto

Il presente lavoro intende indagare la formulazione di nozioni autonome di diritto europeo nell’ambito dell’imposta sul valore aggiunto elaborate dalla Corte di giustizia. Più specificamente si intende proporre una tassonomia convenzionale delle nozioni autonome, utile alla loro sistematizzazione e miglior comprensione, fondata sulla distinzione fondamentale tra nozioni autonome e nozioni proprie. A questo scopo il lavoro propone un’ampia analisi delle nozioni nella giurisprudenza europea che vengono distinte a seconda che l’obiettivo finale dell’autonomia sia quello di limitare la discrezionalità applicativa degli Stati relativamente a ipotesi derogatorie, nel caso delle nozioni autonome in senso stretto; oppure che l’obiettivo ultimo sia quello di meglio definire l’ambito di applicazione di nozioni fondamentali nella struttura dell’imposta, nel caso delle nozioni proprie. Lo scopo del lavoro è dimostrare che la definizione funzionalistica risponde a obiettivi diversi, accomunati dal fatto di far valere comunque il primato dell'ordinamento europeo. L’analisi e la sistematizzazione proposte possono essere uno strumento utile nell’attuazione, interpretazione e applicazione delle nozioni. In questo senso, il lavoro esamina anche esempi tratti dalle esperienze nazionali che dimostrino, da un lato, che gli interventi della Corte relativi alle nozioni influenzano gli ordinamenti nazionali; dall’altro, che permangono ancora disallineamenti. L’analisi della giurisprudenza europea e dei regimi nazionali, infine, vuole dimostrare che l’elaborazione di nozioni autonome si inserisce nel processo verso un’armonizzazione sempre più incisiva in ambito IVA, di cui è protagonista la Corte di giustizia. Questo processo, cui l’elaborazione di un “tessuto concettuale europeo” contribuisce, comporta una limitazione della discrezionalità degli Stati, e quindi del principio di attribuzione, in nome dell’efficacia e della primazia del diritto europeo.

Cleavage Politics in Changing Times. Political Realignment Processes in Western European Countries

The dissertation fits the political realignment literature and aims to pro-vide further insights into cleavage politics by investigating voting behaviour in the Western European countries’ national elections. In particular, the dis-sertation focuses on the class and value voting patterns and on the change of these patterns in different countries and over the course of time. Peculiar pro-cesses affected all Western European party systems: whilst the «traditional» cleavage theory accounts for National and Industrial revolutions, those pro-cesses assumed to constitute the «societal modernization» determined chang-es in electoral competitions that questioned the relevance of individuals’ so-cial positions to study electoral preferences. Since the associations between social positions and voting behaviour underpin the so-called political cleav-age, the dealignment perspective assumes them to have been eroding since the second half of the XX century. On the other hand, the realignment perspective argues that the cleavage theory still accounts for individuals’ vote choices: of the four «traditional» cleavages, this perspective hypothesizes new class vot-ing patterns and alignments between electoral preferences and a new line of conflict, that is based on values. The dissertation provides a theoretical ac-count of the realignment of the class cleavage and a new conceptualization of value voting. Then, class and value voting patterns are explored. The analyses employ European Social Survey data and detect general and country-specific patterns. The dissertation adopts a mediation perspective and aims to observe how class voting patterns change when controlling for value orientations. The results are provided with a sensitivity analysis, indeed two versions of the measures computed for value orientations are compared. The findings show that social class continues to affect voting behaviour and that value orienta-tions both mediate this effect and affect electoral preferences.