Pharmacogenetic testing provides an outstanding opportunity to improve prescribing safety and efficacy. In Public health policy pharmacogenetics is relevant for personalized therapy and to maximize therapeutic benefit minimizing adverse events. CYP2D6 is known to be a key enzyme responsible for the biotransformation of about 25-30% of extensively used drugs and genetic variations in genes coding for drug-metabolizing enzymes might lead to adverse drug reactions, toxicity or therapeutic failure of pharmacotherapy. Significant interethnic differences in CYP2D6 allele distribution are well established, but immigration is reshaping the genetic background due to interethnic admixture which introduces variations in individual ancestry resulting in distinct level of population structure. The present thesis deals with the genetic determination of the CYP2D6 alleles actually present in the Emilia-Romagna resident population providing insights into the admixture process. A random sample of 122 natives and 175 immigrants from Africa, Asia and South America where characterized considering the present scenario of migration and back migration events. The results are consistent with the known interethnic genetic variation, but introduction of ethnic specific variants by immigrants predicts a heterogeneous admixed population scenario requiring, for drugs prescription and pharmacogenetics studies, an interdisciplinary approach applied in a properly biogeographical and anthropological frame. To translate pharmacogenetics knowledge into clinical practice requires appropriated public health policies, possibly guiding clinicians to evaluate prospectively which patients have the greatest probability of expressing a variant genotype.

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La farmacogenetica fornisce un importante strumento utile alla prescrizione farmacologica, migliorando l’efficacia terapeutica ed evitando le reazioni avverse. Il citocromo P450 gioca un ruolo centrale nel metabolismo di molti farmaci utilizzati nella pratica clinica e il suo polimorfismo genetico spiega in gran parte le differenze interindividuali nella risposta ai farmaci. Con riferimento alla terapia della narcolessia, occorre premettere che la narcolessia con cataplessia è una ipersonnia del Sistema Nervoso Centrale caratterizzata da eccessiva sonnolenza diurna, cataplessia, paralisi del sonno, allucinazioni e sonno notturno disturbato. Il trattamento d’elezione per la narcolessia include stimolanti dopaminergici per la sonnolenza diurna e antidepressivi per la cataplessia, metabolizzati dal sistema P450. Peraltro, poiché studi recenti hanno attestato un’alta prevalenza di disturbi alimentari nei pazienti affetti da narcolessia con cataplessia, è stata ipotizzata una associazione tra il metabolismo ultrarapido del CYP2D6 e i disturbi alimentari. Lo scopo di questa ricerca è di caratterizzare il polimorfismo dei geni CYP2D6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 e ABCB1 coinvolti nel metabolismo e nel trasporto dei farmaci in un campione di 108 pazienti affetti da narcolessia con cataplessia, e valutare il fenotipo metabolizzatore in un sottogruppo di pazienti che mostrano un profilo psicopatologico concordante con la presenza di disturbi alimentari. I risultati hanno mostrato che il fenotipo ultrarapido del CYP2D6 non correla in maniera statisticamente significativa con i disturbi alimentari, di conseguenza il profilo psicopatologico rilevato per questo sottogruppo di pazienti potrebbe essere parte integrante del fenotipo sintomatologico della malattia. I risultati della tipizzazione di tutti i geni analizzati mostrano un’alta frequenza di pazienti con metabolismo intermedio, elemento potenzialmente in grado di influire sulla risposta terapeutica soprattutto in caso di regime politerapico, come nel trattamento della narcolessia. In conclusione, sarebbe auspicabile l’esecuzione del test farmacogenetico in pazienti affetti da narcolessia con cataplessia. / Pharmacogenetics represents an important tool to improve prescribing decisions, enhancing treatment outcomes and avoiding adverse drug reactions. Cytochrome P450 enzymes play a central role in drug metabolism and its genetic polymorphism explains a large portion of interindividual differences in drug response. Referring to the therapy of narcolepsy, it should be specified that narcolepsy with cataplexy is a serious central nervous system hypersomnia characterized by severe daytime sleepiness, cataplexy, sleep paralysis, hallucinations and awakening during sleep. First-line treatment of narcolepsy includes dopaminergic stimulants for excessive sleepiness and antidepressants for cataplexy, which are extensively metabolized by the cytochrome P450 system. Moreover, due to the high prevalence of eating disorders in narcoleptic patients showed by recent studies, an association between CYP2D6 UM phenotype and eating disorders has been hypothesized. The aim of this study was to characterize the polymorphism of CYP2D6, CYP2C9, CYP2C19, CYP3A4, CYP3A5 and ABCB1 genes, involved in drug metabolism and transport, in a total of 108 samples belonging to narcoleptic patients, and evaluate the metabolizer status in a subgroup of patients displaying a psychopathologic profile consistent with eating disorders. The results show no statistical association between CYP2D6 ultrarapid metabolism and eating disorders in narcoleptic patients, proving that these disorders seems to be an integral part of the narcolepsy phenotype. Results from genotyping of all genes analyzed in the study show a an high frequency of patients with intermediate metabolism, potentially affecting therapeutic response especially in case of polytherapy, as in narcolepsy treatment. In conclusion, pharmacogenetic testing it would be beneficial in patients with narcolepsy with cataplexy.

L’abuso dell’anziano è una condizione estremamente diffusa e ha un grande costo umano e finanziario. La dimensione reale del problema del maltrattamento dell’anziano non è stata correttamente definita, in particolare i casi segnalati ufficialmente di abuso sono solo la "punta dell'iceberg". In questi anni il problema è stato riconosciuto a livello internazionale come un fenomeno comune, che viene sottostimato e degno di attenzione da parte della comunità scientifica. In Italia non ci sono molti dati, la prevalenza degli abusi e maltrattamenti può essere circa il 5% e il problema è ampiamente sottovalutato, perché sono scarse le segnalazioni di abusi. Le evidenze disponibili dimostrano che l'abuso sugli anziani in Italia costituisce una questione pubblica, tuttavia, la legislazione e le politiche per affrontare il fenomeno sono scarse, riflettendo la mancanza di una strategia nazionale coerente e globale. Il codice civile italiano non contiene alcun riferimento esplicito a persone anziane, e pochi sono anche gli articoli del codice penale che riguardano le persone anziane. Gli articoli più rilevanti interessate sono le seguenti: art. 572: "Maltrattamenti contro familiari e conviventi" e art. 643: "circonvenzione di persone incapaci". Il presente studio ha lo scopo di analizzare la situazione attuale del fenomeno nel nostro Paese, al fine di valutare la dimensione del problema e le relazioni di abuso e maltrattamenti tra vittime, caregiver e operatori sanitari alle autorità. / Elder abuse is an extremely widespread condition and has a big human and financial price. The real dimension of the problem of elder maltreatment has not been properly defined, notably the officially reported cases of abuse are only the “tip of the iceberg”. In these years the problem has been recognized on an international level as a common phenomenon, which is underestimated and worthy of attention by the scientific community. In Italy there are not a lot of data, the prevalence of elder abuse and mistreatment may be around 5% and the problem is widely underestimated because there are few reports of abuse. The evidence available shows that elder abuse in Italy constitutes a public issue; nevertheless, legislation and policies tackling the phenomenon are scattered, reflecting the lack of a coherent and comprehensive national strategy. Moreover the elderly are not specifically protected by law. The Italian Civil Code does not contain any explicit reference to elderly people, very few articles of the Penal Code consider elderly people. The most relevant articles concerned are: art. 572: “Mistreatment of family members or children” and art. 643: “Circumvention of incapacitated persons”. The present study aim to analyze the actual situation of the phenomena in our country in order to evaluate the dimension of the problem and the reports of elder abuse and mistreatment by the victims, caregivers or health operators to the authorities.

Con questo mio lavoro di tesi ho voluto esplorare il fenomeno del maltrattamento e dell’abuso sui minori delineandone, sulla base della letteratura scientifica nazionale ed internazionale, gli aspetti clinici, epidemiologici ed i fattori di rischio. Un breve excursus giuridico illustrerà, poi, gli articoli di legge relativi alla tutela dei minori; in particolare, ci si soffermerà ad illustrare quegli articoli che normano i doveri dei sanitari nei confronti dell’autorità giudiziaria nel caso si sospetti un abuso su minori. La conoscenza della semeiotica dell’abuso, il suo riconoscimento all’interno di una diagnostica differenziale clinico-forense, la corretta repertazione e la consapevolezza che, un approccio autenticamente tutelante verso la vittima, deve sempre realizzarsi all’interno di una cornice giuridica fanno si che, il ruolo della medicina legale, competente in tutti questi ambiti, diventi senza ombra di dubbio “primum inter pares” all’interno dei team multidisciplinari ed interistituzionali che si occupano di minori vitti. Il gruppo scientifico in cui sono stata inserita e con cui si è proceduto alla redazione del manuale è il Gruppo di lavoro per l’abuso e il maltrattamento dell’infanzia coordinato dalla dott.ssa Maria Rosa Giolito ed ha coinvolto professionisti italiani afferenti a tre differenti aree sanitarie: quella ginecologica, quella medico-legale e quella pediatrica. Il testo elaborato è stato immaginato come un aiuto ai professionisti medici che si trovano a valutare un soggetto prepubere con sospetto di abuso sessuale. Non costituisce una linea-guida per la diagnosi di abuso sessuale, ma definisce alcuni requisiti essenziali e diffonde alcune conoscenze per evitare errori che possano ripercuotersi negativamente sulla valutazione clinica e sull’eventuale conseguente iter giudiziario. / With my thesis I wanted to explore the phenomenon of child abuse and child abuse by sketching on the basis of national and international scientific literature, clinical, and epidemiological risk factors. A brief review will discuss legal, then the statutory provisions relating to the protection of minors, in particular, we will look to illustrate those articles that organize the duties of health in relation to the judicial authority in cases of suspected child abuse. The semiotics of knowledge of the abuse, its identification in a forensic clinical differential diagnosis, the correct repertazione and the realization that a truly tutelante approach towards the victim, must always take place within a legal framework makes it that the role of forensic medicine, competent in all these areas, without a doubt become "first among equals" within multidisciplinary teams and institutions that deal with child victims. The Panel in which they are inserted and which is being drafted in the manual is the Working Group for the abuse and mistreatment of children coordinated by Dr. Maria Rosa Giolito and involved professionals belonging to three different Italian areas of health: the gynecological, the forensic and the children. The text drafted was imagined as an aid to medical professionals who are evaluating a person suspected of prepubertal sexual abuse. This is not a guideline for the diagnosis of sexual abuse, but it defines the essential requirements and disseminates knowledge to avoid some errors that could adversely affect the clinical evaluation and possible subsequent judicial process.

Seguendo l’approccio metodologico della grounded theory sono stati esplorati i dati relativi a 32 relazioni psicodiagnostiche a fini peritali per casi di disadattamento lavorativo. I dati sembrano evidenziare ipotesi teoriche riguardanti dinamiche e caratteristiche intrapsichiche coinvolte nei processi di fronteggiamento degli eventi avversativi in ambito lavorativo, come ad esempio il mobbing. In particolare il costrutto di resilienza e le concettualizzazioni tipiche della psicologia dello sviluppo lungo l’arco di vita sembrano essere elementi teorici che integrati nelle tradizioni di ricerca sul disadattamento lavorativo tipiche della psicologia clinica, psicologia sociale e medicina legale possono apportare nuove prospettive, ipotesi di ricerca e proposte operative. Parallelamente viene presentato uno studio di caso singolo che comprende un arco temporale di osservazione di più di 3 anni dal termine di un mobbing fino a due anni dopo il termine di un percorso psicoterapeutico cognitivo-comportamentale. / According to grounded theory methodology 32 psychodiagnostic assessments of compensation claimants who present with complaints of bullying, burnout or work related stress. Data analysis shows possible new theoretical hypothesis about intrapsychic dynamics and characteristics involved in coping with occupational stressor. Resilience and life-long developmental theories fit with data and emerging hypothesis. This theoretical development and traditional research approach in fields like clinical psychology, social psychology and forensic medicine, when integrated on each other give new prospectives, research hypothesis and working proposals. At the same time a single case study is analyzed. A 3 years long monitoring of a bullying victim started up at the end of the harassment and concluded 2 years after the end of a Cognitive and Behavioural Therapy.

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.