Efficient ultrasonic signal processing techniques for aided medical diagnostics

Ultrasound imaging is widely used in medical diagnostics as it is the fastest, least invasive, and least expensive imaging modality. However, ultrasound images are intrinsically difficult to be interpreted. In this scenario, Computer Aided Detection (CAD) systems can be used to support physicians during diagnosis providing them a second opinion. This thesis discusses efficient ultrasound processing techniques for computer aided medical diagnostics, focusing on two major topics: (i) Ultrasound Tissue Characterization (UTC), aimed at characterizing and differentiating between healthy and diseased tissue; (ii) Ultrasound Image Segmentation (UIS), aimed at detecting the boundaries of anatomical structures to automatically measure organ dimensions and compute clinically relevant functional indices. Research on UTC produced a CAD tool for Prostate Cancer detection to improve the biopsy protocol. In particular, this thesis contributes with: (i) the development of a robust classification system; (ii) the exploitation of parallel computing on GPU for real-time performance; (iii) the introduction of both an innovative Semi-Supervised Learning algorithm and a novel supervised/semi-supervised learning scheme for CAD system training that improve system performance reducing data collection effort and avoiding collected data wasting. The tool provides physicians a risk map highlighting suspect tissue areas, allowing them to perform a lesion-directed biopsy. Clinical validation demonstrated the system validity as a diagnostic support tool and its effectiveness at reducing the number of biopsy cores requested for an accurate diagnosis. For UIS the research developed a heart disease diagnostic tool based on Real-Time 3D Echocardiography. Thesis contributions to this application are: (i) the development of an automated GPU based level-set segmentation framework for 3D images; (ii) the application of this framework to the myocardium segmentation. Experimental results showed the high efficiency and flexibility of the proposed framework. Its effectiveness as a tool for quantitative analysis of 3D cardiac morphology and function was demonstrated through clinical validation.

Design and Characterization of New Luminescent Sensors and Labels

The aim of this Ph.D. project has been the design and characterization of new and more efficient luminescent tools, in particular sensors and labels, for analytical chemistry, medical diagnostics and imaging. Actually both the increasing temporal and spatial resolutions that are demanded by those branches, coupled to a sensitivity that is required to reach the single molecule resolution, can be provided by the wide range of techniques based on luminescence spectroscopy. As far as the development of new chemical sensors is concerned, as chemists we were interested in the preparation of new, efficient, sensing materials. In this context, we kept developing new molecular chemosensors, by exploiting the supramolecular approach, for different classes of analytes. In particular we studied a family of luminescent tetrapodal-hosts based on aminopyridinium units with pyrenyl groups for the detection of anions. These systems exhibited noticeable changes in the photophysical properties, depending on the nature of the anion; in particular, addition of chloride resulted in a conformational change, giving an initial increase in excimeric emission. A good selectivity for dicarboxylic acid was also found. In the search for higher sensitivities, we moved our attention also to systems able to perform amplification effects. In this context we described the metal ion binding properties of three photoactive poly-(arylene ethynylene) co-polymers with different complexing units and we highlighted, for one of them, a ten-fold amplification of the response in case of addition of Zn2+, Cu2+ and Hg2+ ions. In addition, we were able to demonstrate the formation of complexes with Yb3+ an Er3+ and an efficient sensitization of their typical metal centered NIR emission upon excitation of the polymer structure, this feature being of particular interest for their possible applications in optical imaging and in optical amplification for telecommunication purposes. An amplification effect was also observed during this research in silica nanoparticles derivatized with a suitable zinc probe. In this case we were able to prove, for the first time, that nanoparticles can work as “off-on” chemosensors with signal amplification. Fluorescent silica nanoparticles can be thus seen as innovative multicomponent systems in which the organization of photophysically active units gives rise to fruitful collective effects. These precious effects can be exploited for biological imaging, medical diagnostic and therapeutics, as evidenced also by some results reported in this thesis. In particular, the observed amplification effect has been obtained thanks to a suitable organization of molecular probe units onto the surface of the nanoparticles. In the effort of reaching a deeper inside in the mechanisms which lead to the final amplification effects, we also attempted to find a correlation between the synthetic route and the final organization of the active molecules in the silica network, and thus with those mutual interactions between one another which result in the emerging, collective behavior, responsible for the desired signal amplification. In this context, we firstly investigated the process of formation of silica nanoparticles doped with pyrene derivative and we showed that the dyes are not uniformly dispersed inside the silica matrix; thus, core-shell structures can be formed spontaneously in a one step synthesis. Moreover, as far as the design of new labels is concerned, we reported a new synthetic approach to obtain a class of robust, biocompatible silica core-shell nanoparticles able to show a long-term stability. Taking advantage of this new approach we also showed the synthesis and photophysical properties of core-shell NIR absorbing and emitting materials that proved to be very valuable for in-vivo imaging. In general, the dye doped silica nanoparticles prepared in the framework of this project can conjugate unique properties, such as a very high brightness, due to the possibility to include many fluorophores per nanoparticle, high stability, because of the shielding effect of the silica matrix, and, to date, no toxicity, with a simple and low-cost preparation. All these features make these nanostructures suitable to reach the low detection limits that are nowadays required for effective clinical and environmental applications, fulfilling in this way the initial expectations of this research project.

Analysis and modeling techniques for ultrasonic tissue characterization

This thesis introduces new processing techniques for computer-aided interpretation of ultrasound images with the purpose of supporting medical diagnostic. In terms of practical application, the goal of this work is the improvement of current prostate biopsy protocols by providing physicians with a visual map overlaid over ultrasound images marking regions potentially affected by disease. As far as analysis techniques are concerned, the main contributions of this work to the state-of-the-art is the introduction of deconvolution as a pre-processing step in the standard ultrasonic tissue characterization procedure to improve the diagnostic significance of ultrasonic features. This thesis also includes some innovations in ultrasound modeling, in particular the employment of a continuous-time autoregressive moving-average (CARMA) model for ultrasound signals, a new maximum-likelihood CARMA estimator based on exponential splines and the definition of CARMA parameters as new ultrasonic features able to capture scatterers concentration. Finally, concerning the clinical usefulness of the developed techniques, the main contribution of this research is showing, through a study based on medical ground truth, that a reduction in the number of sampled cores in standard prostate biopsy is possible, preserving the same diagnostic power of the current clinical protocol.

Quantifying the Economics of Medical Malpractice - A View from a Civil Law Perspective

Life is full of uncertainties. Legal rules should have a clear intention, motivation and purpose in order to diminish daily uncertainties. However, practice shows that their consequences are complex and hard to predict. For instance, tort law has the general objectives of deterring future negligent behavior and compensating the victims of someone else's negligence. Achieving these goals are particularly difficult in medical malpractice cases. To start with, when patients search for medical care they are typically sick in the first place. In case harm materializes during the treatment, it might be very hard to assess if it was due to substandard medical care or to the patient's poor health conditions. Moreover, the practice of medicine has a positive externality on the society, meaning that the design of legal rules is crucial: for instance, it should not result in physicians avoiding practicing their activity just because they are afraid of being sued even when they acted according to the standard level of care. The empirical literature on medical malpractice has been developing substantially in the past two decades, with the American case being the most studied one. Evidence from civil law tradition countries is more difficult to find. The aim of this thesis is to contribute to the empirical literature on medical malpractice, using two civil law countries as a case-study: Spain and Italy. The goal of this thesis is to investigate, in the first place, some of the consequences of having two separate sub-systems (administrative and civil) coexisting within the same legal system, which is common in civil law tradition countries with a public national health system (such as Spain, France and Portugal). When this holds, different procedures might apply depending on the type of hospital where the injury took place (essentially whether it is a public hospital or a private hospital). Therefore, a patient injured in a public hospital should file a claim in administrative courts while a patient suffering an identical medical accident should file a claim in civil courts. A natural question that the reader might pose is why should both administrative and civil courts decide medical malpractice cases? Moreover, can this specialization of courts influence how judges decide medical malpractice cases? In the past few years, there was a general concern with patient safety, which is currently on the agenda of several national governments. Some initiatives have been taken at the international level, with the aim of preventing harm to patients during treatment and care. A negligently injured patient might present a claim against the health care provider with the aim of being compensated for the economic loss and for pain and suffering. In several European countries, health care is mainly provided by a public national health system, which means that if a patient harmed in a public hospital succeeds in a claim against the hospital, public expenditures increase because the State takes part in the litigation process. This poses a problem in a context of increasing national health expenditures and public debt. In Italy, with the aim of increasing patient safety, some regions implemented a monitoring system on medical malpractice claims. However, if properly implemented, this reform shall also allow for a reduction in medical malpractice insurance costs. This thesis is organized as follows. Chapter 1 provides a review of the empirical literature on medical malpractice, where studies on outcomes and merit of claims, costs and defensive medicine are presented. Chapter 2 presents an empirical analysis of medical malpractice claims arriving to the Spanish Supreme Court. The focus is on reversal rates for civil and administrative decisions. Administrative decisions appealed by the plaintiff have the highest reversal rates. The results show a bias in lower administrative courts, which tend to focus on the State side. We provide a detailed explanation for these results, which can rely on the organization of administrative judges career. Chapter 3 assesses predictors of compensation in medical malpractice cases appealed to the Spanish Supreme Court and investigates the amount of damages attributed to patients. The results show horizontal equity between administrative and civil decisions (controlling for observable case characteristics) and vertical inequity (patients suffering more severe injuries tend to receive higher payouts). In order to execute these analyses, a database of medical malpractice decisions appealed to the Administrative and Civil Chambers of the Spanish Supreme Court from 2006 until 2009 (designated by the Spanish Supreme Court Medical Malpractice Dataset (SSCMMD)) has been created. A description of how the SSCMMD was built and of the Spanish legal system is presented as well. Chapter 4 includes an empirical investigation of the effect of a monitoring system for medical malpractice claims on insurance premiums. In Italy, some regions adopted this policy in different years, while others did not. The study uses data on insurance premiums from Italian public hospitals for the years 2001-2008. This is a significant difference as most of the studies use the insurance company as unit of analysis. Although insurance premiums have risen from 2001 to 2008, the increase was lower for regions adopting a monitoring system for medical claims. Possible implications of this system are also provided. Finally, Chapter 5 discusses the main findings, describes possible future research and concludes.

Indagini forensi in tema di scambio di file pedopornografici mediante software di file sharing a mezzo peer-to-peer

La prova informatica richiede l’adozione di precauzioni come in un qualsiasi altro accertamento scientifico. Si fornisce una panoramica sugli aspetti metodologici e applicativi dell’informatica forense alla luce del recente standard ISO/IEC 27037:2012 in tema di trattamento del reperto informatico nelle fasi di identificazione, raccolta, acquisizione e conservazione del dato digitale. Tali metodologie si attengono scrupolosamente alle esigenze di integrità e autenticità richieste dalle norme in materia di informatica forense, in particolare della Legge 48/2008 di ratifica della Convenzione di Budapest sul Cybercrime. In merito al reato di pedopornografia si offre una rassegna della normativa comunitaria e nazionale, ponendo l’enfasi sugli aspetti rilevanti ai fini dell’analisi forense. Rilevato che il file sharing su reti peer-to-peer è il canale sul quale maggiormente si concentra lo scambio di materiale illecito, si fornisce una panoramica dei protocolli e dei sistemi maggiormente diffusi, ponendo enfasi sulla rete eDonkey e il software eMule che trovano ampia diffusione tra gli utenti italiani. Si accenna alle problematiche che si incontrano nelle attività di indagine e di repressione del fenomeno, di competenza delle forze di polizia, per poi concentrarsi e fornire il contributo rilevante in tema di analisi forensi di sistemi informatici sequestrati a soggetti indagati (o imputati) di reato di pedopornografia: la progettazione e l’implementazione di eMuleForensic consente di svolgere in maniera estremamente precisa e rapida le operazioni di analisi degli eventi che si verificano utilizzando il software di file sharing eMule; il software è disponibile sia in rete all’url http://www.emuleforensic.com, sia come tool all’interno della distribuzione forense DEFT. Infine si fornisce una proposta di protocollo operativo per l’analisi forense di sistemi informatici coinvolti in indagini forensi di pedopornografia.

Fattori prognostici in corso di malattia renale cronica (ckd) nel cane

Negli ultimi anni si è assistito ad un miglioramento della qualità di vita dei piccoli animali che, oltre ad aumentarne l'aspettativa di vita, ha determinato un aumento della frequenza di patologie associate all'età medio-avanzata, quali le patologie renali croniche. Il presente studio si fonda sulla necessità, sempre più sentita nella pratica clinica veterinaria, di poter fornire al proprietario del paziente affetto da CKD, una serie di parametri che, oltre a fungere da target terapeutico, possano aiutare a comprenderne la prognosi. Lo studio ha valutato una popolazione di cani affetti da CKD e ne ha seguito o ricostruito il follow-up, per tutto il periodo di sopravvivenza fino al momento dell’exitus. Di tali soggetti sono stati raccolti dati relativi ad anamnesi, esame clinico, misurazione della pressione arteriosa, diagnostica per immagini, esami ematochimici, analisi delle urine ed eventuale esame istologico renale. È stato possibile individuare alcuni importanti fattori prognostici per la sopravvivenza in pazienti con CKD. Oltre a fattori ben noti in letteratura, come ad esempio elevati valori di creatinina e fosforo, o la presenza di proteinuria, è stato possibile anche evidenziare il ruolo prognostico negativo di alcuni parametri meno noti, ed in particolare delle proteine di fase acuta positive e negative, e del rapporto albumina/globuline. Una possibile spiegazione del valore prognostico di tali parametri risiede nel ruolo prognostico negativo dell’infiammazione nel paziente con CKD: tale ruolo è stato suggerito e dimostrato nell’uomo e avrebbe alla base numerosi possibili meccanismi (sviluppo di anemia, complicazioni gastroenteriche, neoplasie, etc.), ma dati analoghi sono mancanti in medicina veterinaria. Una seconda possibile spiegazione risiede nel fatto che potenzialmente i livelli delle proteine di fase acuta possono essere influenzati dalla presenza di proteinuria nel paziente con CKD e di conseguenza potrebbero essere una conferma di come la proteinuria influenzi negativamente l'outcome.