Studio prospettico osservazionale sull'interruzione volontaria farmacologica di gravidanza: fattori predittivi di dolore pelvico durante il trattamento

INTRODUZIONE Pochi studi in Letteratura hanno indagato la correlazione tra la sintomatologia dolorosa associata all’interruzione farmacologica di gravidanza (IVG) e i livelli d’ansia pre-trattamento. L’obiettivo primario del nostro studio è stato di valutare la correlazione tra la sintomatologia dolorosa in corso di IVG farmacologica e i livelli d’ansia pre-trattamento. Inoltre, sono stati indagati i fattori predittivi di dolore e la correlazione con l’epoca gestazionale. MATERIALI E METODI È stato condotto uno studio osservazionale, prospettico, multicentrico presso l’Unità Operativa di Ostetricia e Ginecologia dell’Azienda USL e presso l’Unità Operativa di Ginecologia dell’IRCCS Sant’Orsola Malpighi di Bologna. Sono state incluse le pazienti sottoposte a IVG farmacologica tra giugno 2021 e novembre 2021, che rispettassero i criteri di inclusione ed esclusione. Sono stati somministrati 5 questionari (GHQ-12, GAD-7, STAI-6, VAS) e raccolti i dati anamnestici ed ecografici. I potenziali fattori di rischio sono stati, quindi, selezionati per l’inclusione nell'analisi di regressione multivariata. RISULTATI Delle 242 pazienti incluse, il 38,0% ha riferito una sintomatologia dolorosa severa (VAS >70). Dall’analisi di regressione multivariata, la dismenorrea intensa è risultata essere il fattore di rischio più forte per il dolore (OR = 6,30, IC 95% 2,66 – 14,91), seguita da alti livelli di ansia valutati mediante il punteggio del GHQ-12 > 9 (OR = 3,33, IC 95% 1,43 – 7,76). Al contrario, la nostra analisi ha confermato che un precedente parto vaginale rappresentava una caratteristica protettiva contro il dolore (OR 0,26, IC 95% 0,14 – 0,50). CONCLUSIONI Nel nostro studio alti livelli d’ansia pre-trattamento e la dismenorrea sono associati ad intensa sintomatologia dolorosa, mentre il parto vaginale è risultato protettivo. L’IVG farmacologica è una metodica efficace e sicura, ma spesso associata a sintomatologia dolorosa. È quindi fondamentale delineare fattori di predittivi di dolore ed individuare le pazienti a maggior rischio a cui somministrare un’idonea terapia antalgica.

Evaluating non-price effects of regulatory and competition enforcement interventions

This thesis provides an ex-post evaluation of the effects of regulatory and competition policy enforcement interventions on non-price dimensions of competition. Chapter 1 examines the effects of a merger between two large Dutch supermarket chains on the variety and composition of product assortment. Chapter 2 and Chapter 3 investigate, both theoretically and empirically, the effects of access regulation in fixed telecoms markets on incentives to invest in superior infrastructure technologies. Non-price effects, together with price effects, are crucial to shed light on the extent of competition in a market and assess the effectiveness of regulatory and competition authorities' interventions. When evaluating non-price effects, however, it is harder to draw conclusions on the overall impact on consumers' welfare.

Preclinical neuroblastoma models for a pharmacological study of a new MYCN oncogene inhibitor

Background. Neuroblastoma is the most deadly solid tumor of childhood. In the 25% of cases it is associated with MYCN amplification (MA), resulting in the disregulation of several genes involved in cancer progression, chemotherapy resistance and poor prognosis causing the disregulation of several genes involved in cancer progression and chemotherapy resistance and resulting in a poor prognosis. Moreover, in this contest, therapy-related p53 mutations are frequently found in relapsed cases conferring an even stronger aggressiveness. For this reason, the actual therapy requires new antitumor molecules. Therefore, rapid, accurate, and reproducible preclinical models are needed to evaluate the evolution of the different subtypes and the efficacy of new pharmacological strategies. Procedures. We report the real-time tumorigenesis of MA Neuroblastoma mouse models: transgenic TH-MYCN mice and orthotopic xenograft models with either p53wt or p53mut, by non-invasive micro PET and bioluminescent imaging, respectively. Characterization of MYCN amplification and expression was performed on every collected sample. We tested the efficacy of a new MYCN inhibitor in vitro and in vivo. Results. MicroPET in TH-MYCN mice permitted the identification of Neuroblastoma at an early stage and offered a sensitive method to follow metabolic progression of tumors. The MA orthotopic model harboring multitherapy-related p53 mutations showed a shorter latency and progression and a stronger aggressiveness respect to the p53wt model. The presence of MA and overexpression was confirmed in each model and we saw a better survival in the TH-MYCN homozigous mice treated with the inhibitor. Conclusions. The mouse models obtained show characteristics of non-invasiveness, rapidity and sensitivity that make them suitable for the in vivo preclinical study of MA-NB. In particular, our firstly reported p53mut BLI xenograft orthotopic mouse model offers the possibility to evaluate the role of multitherapy-related p53 mutations and to validate new p53 independent therapies for this highly aggressive Neuroblastoma subtype. Moreover, we have shown potential clinical suitability of an antigene strategy through its cellular and molecular activity, ability to specifically inhibit transcription and in vivo efficacy with no evidence of toxicity.

Non Invasive Tools for Early Detection of Autism Spectrum Disorders

Autism Spectrum Disorders (ASDs) describe a set of neurodevelopmental disorders. ASD represents a significant public health problem. Currently, ASDs are not diagnosed before the 2nd year of life but an early identification of ASDs would be crucial as interventions are much more effective than specific therapies starting in later childhood. To this aim, cheap an contact-less automatic approaches recently aroused great clinical interest. Among them, the cry and the movements of the newborn, both involving the central nervous system, are proposed as possible indicators of neurological disorders. This PhD work is a first step towards solving this challenging problem. An integrated system is presented enabling the recording of audio (crying) and video (movements) data of the newborn, their automatic analysis with innovative techniques for the extraction of clinically relevant parameters and their classification with data mining techniques. New robust algorithms were developed for the selection of the voiced parts of the cry signal, the estimation of acoustic parameters based on the wavelet transform and the analysis of the infant’s general movements (GMs) through a new body model for segmentation and 2D reconstruction. In addition to a thorough literature review this thesis presents the state of the art on these topics that shows that no studies exist concerning normative ranges for newborn infant cry in the first 6 months of life nor the correlation between cry and movements. Through the new automatic methods a population of control infants (“low-risk”, LR) was compared to a group of “high-risk” (HR) infants, i.e. siblings of children already diagnosed with ASD. A subset of LR infants clinically diagnosed as newborns with Typical Development (TD) and one affected by ASD were compared. The results show that the selected acoustic parameters allow good differentiation between the two groups. This result provides new perspectives both diagnostic and therapeutic.

Induction of Hebbian associative plasticity through paired non-invasive brain stimulation of premotor-motor areas to elucidate the network's functional role

The ventral premotor cortex (PMv) is believed to play a pivotal role in a multitude of visuomotor behaviors, such as sensory-guided goal-directed visuomotor transformations, arbitrary visuomotor mapping, and hyper-learnt visuomotor associations underlying automatic imitative tendencies. All these functions are likely carried out through the copious projections connecting PMv to the primary motor cortex (M1). Yet, causal evidence investigating the functional relevance of the PMv-M1 network remains elusive and scarce. In the studies reported in this thesis we addressed this issue using a transcranial magnetic stimulation (TMS) protocol called cortico-cortical paired associative stimulation (ccPAS), which relies on multisite stimulation to induce Hebbian spike-timing dependent plasticity (STDP) by repeatedly stimulating the pathway connecting two target areas to manipulate their connectivity. Firstly, we show that ccPAS protocols informed by both short- and long-latency PMv-M1 interactions effectively modulate connectivity between the two nodes. Then, by pre-activating the network to apply ccPAS in a state-dependent manner, we were able to selectively target specific functional visuo-motor pathways, demonstrating the relevance of PMv-M1 connectivity to arbitrary visuomotor mapping. Subsequently, we addressed the PMv-to-M1 role in automatic imitation, and demonstrated that its connectivity manipulation has a corresponding impact on automatic imitative tendencies. Finally, by combining dual-coil TMS connectivity assessments and ccPAS in young and elderly individuals, we traced effective connectivity of premotor-motor networks and tested their plasticity and relevance to manual dexterity and force in healthy ageing. Our findings provide unprecedent causal evidence of the functional role of the PMv-to-M1 network in young and elderly individuals. The studies presented in this thesis suggest that ccPAS can effectively modulate the strength of connectivity between targeted areas, and coherently manipulate a networks’ behavioral output. Results open new research prospects into the causal role of cortico-cortical connectivity, and provide necessary information to the development of clinical interventions based on connectivity manipulation.