VoxLogicA : A Spatial Model Checker for Declarative Image Analysis

Spatial and spatio-temporal model checking techniques have a wide range of application domains, among which large scale distributed systems and signal and image analysis.We explore a new domain, namely (semi-)automatic contouring in Medical Imaging, introducing the tool VoxLogicA which merges the state-of-the-art library of computational imaging algorithms ITK with the unique combination of declarative specification and optimised execution provided by spatial logic model checking. The result is a rapid, logic based analysis development methodology. The analysis of an existing benchmark of medical images for segmentation of brain tumours shows that simple VoxLogicA analysis can reach state-of-the-art accuracy, competing with best-in-class algorithms, with the advantage of explainability and easy replicability. Furthermore, due to a two-orders-of-magnitude speedup compared to the existing generalpurpose spatio-temporal model checker topochecker, VoxLogicA enables interactive development of analysis of 3D medical images, which can greatly facilitate the work of professionals in this domain

Descrizione di nuclei leggeri come sistemi a due e tre corpi

Il concetto di ``sistema nucleare composto da pochi corpi' non è limitato a descrivere nuclei composti da pochi nucleoni, ma si adatta a descrivere anche nuclei più complessi visti come aggregazione di nuclei più piccoli, che per le loro caratteristiche possono essere considerati, almeno approssimativamente, un corpo unico. Nel caso di nuclei leggeri, è possibile considerare in questo modo il nucleo di {^4}He, particella alpha, che presenta un unico stato legato molto profondo. Così, ad esempio, il nucleo di {^6}Li può essere visto come un sistema a tre corpi, alpha+n+p. In questo lavoro ho studiato la diffusione nucleone nucleone, N-N, alpha-N, e alpha-alpha, e gli stati legati del deutone e alpha+alpha ({^8}Be), considerati come sistemi composti di due corpi. A tale scopo ho utilizzato diversi potenziali, presenti in letteratura, che descrivono ragionevolmente i parametri di diffusione a bassa energia. Successivamente, ho studiato il sistema di tre nucleoni, {^3}H, e quelli compositi {^6}He e {^12}C, considerati rispettivamente come alpha+n+n e alpha+alpha+alpha. Nelle descrizioni sono stati utilizzati i potenziali studiati in precedenza per i sistemi a due corpi. Particolare attenzione è stata posta nel caso dei sistemi alpha+N+N per eliminare i cosiddetti stati spuri, in quanto tutti i potenziali alpha-N utilizzati hanno presentato uno stato legato di cinque nucleoni con momento angolare l=0 proibito dal principio di Pauli

Polymorphisms in CYP1A2, CYP2C9 and ABCB1 affect agomelatine pharmacokinetics

[Background]: Agomelatine is an agonist of the melatoninergic receptors used for the treatment of depression. Our aim was to evaluate the effect of genetic polymorphisms in metabolising enzymes and the P-glycoprotein transporter on agomelatine pharmacokinetics and pharmacodynamics.[Methods]: Twenty-eight healthy volunteers receiving a single 25 mg oral dose of agomelatine, were genotyped for nine polymorphisms in cytochrome P450 enzymes (CYP1A2, CYP2C9 and CYP2C19) and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), by real-time polymerase chain reaction. Agomelatine concentrations were measured by high performance liquid chromatography coupled to a tandem mass spectrometry detector.[Results]: We calculated a CYP1A2 activity score that was directly correlated with agomelatine pharmacokinetics. Individuals with a decreased enzyme activity (*1C carriers) had a lower clearance and accumulated higher concentrations of agomelatine. In contrast, individuals with a high CYP1A2 inducibility (*1F or *1B carriers) showed an extensive clearance and lower agomelatine concentrations. The apparently marked differences between races were due to the different CYP1A2 genotype distribution. CYP2C9 intermediate/poor metabolisers showed a higher area under the concentration-time curve and maximum concentration. ABCB1 G2677T/A polymorphism affected the time to reach maximum concentration, as subjects carrying A/A+A/T genotypes showed higher values. No association was found for CYP2C19 phenotype. Agomelatine did not produce any change in blood pressure, heart rate or QT interval.[Conclusions]: CYP1A2 polymorphisms affect agomelatine pharmacokinetics. CYP1A2 phenotype inferred from the genotyping of CYP1A2*1C, *1F and *1B alleles might be a potential predictor of agomelatine exposure. ABCB1 G2677T/A could affect agomelatine absorption, as subjects with A/A+A/T genotypes had lower agomelatine concentration and they take more time to reach the maximum concentration.D. Koller is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grant. P. Zubiaur is co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social EuropeoPeer reviewe

Effect of ABCB1 C3435T polymorphism on pharmacokinetics of antipsychotics and antidepressants

P‐glycoprotein, encoded by ABCB1, is an ATP‐dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P‐glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real‐time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9‐OH‐risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro‐aripiprazole and trazodone area under the concentration‐time curve, along with lower half‐life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro‐aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P‐glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants.F. Abad‐Santos and D. Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen‐Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. D. Koller is co‐financed by the H2020 Marie Sklodowska‐Curie Innovative Training Network 721236 grant. M. Saiz‐Rodríguez and P. Zubiaur are co‐financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo.Peer reviewe

Polymorphisms associated with fentanyl pharmacokinetics, pharmacodynamics and adverse effects

Fentanyl is an agonist of the μ‐opioid receptor commonly used in the treatment of moderate‐severe pain. In order to study whether pharmacogenetics explains some of the variability in the response to fentanyl, several genes related to fentanyl receptors, transporters and metabolic enzymes have been analysed. Thirty‐five healthy volunteers (19 men and 16 women) receiving a single 300 μg oral dose of fentanyl were genotyped for 9 polymorphisms in cytochrome P450 (CYP) enzymes (CYP3A4 and CYP3A5), ATP‐binding cassette subfamily B member 1 (ABCB1), opioid receptor mu 1 (OPRM1), catechol‐O‐methyltransferase (COMT) and adrenoceptor beta 2 (ADRB2) by real‐time PCR. Fentanyl concentrations were measured by ultra‐performance liquid chromatography combined with tandem mass spectrometry (UPLC‐MS/MS). Fentanyl pharmacokinetics is affected by sex. Carriers of the CYP3A4*22 allele, which is known to reduce the mRNA expression, showed higher area under the concentration‐time curve (AUC) and lower clearance (Cl) values. Although this finding might be of importance, its validity needs to be confirmed in other similar settings. Furthermore, carriers of the ABCB1 C1236T T/T genotype presented a lower AUC and higher Cl, as well as lower half‐life (T1/2). As volunteers were blocked with naltrexone, the effect of fentanyl on pharmacodynamics might be biased; however, we could observe that fentanyl had a hypotensive effect. Moreover, ADRB2 C523A A allele carriers showed a tendency towards reducing systolic blood pressure. Likewise, OPRM1 and COMT minor allele variants were risk factors for the development of somnolence. CYP3A5*3, ABCB1 C3435T and ABCB1 G2677T/A were not associated with fentanyl's pharmacokinetics, pharmacodynamics and safety profile.F. Abad‐Santos and D. Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen‐Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. D. Koller is co‐financed by the H2020 Marie Sklodowska‐Curie Innovative Training Network 721236 grant. P. Zubiaur is co‐financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo.Peer reviewe

Artificial intelligence applications in medical imaging: A review of the medical physics research in Italy

Purpose: To perform a systematic review on the research on the application of artificial intelligence (AI) to imaging published in Italy and identify its fields of application, methods and results. Materials and Methods: A Pubmed search was conducted using terms Artificial Intelligence, Machine Learning, Deep learning, imaging, and Italy as affiliation, excluding reviews and papers outside time interval 2015-2020. In a second phase, participants of the working group AI4MP on Artificial Intelligence of the Italian Association of Physics in Medicine (AIFM) searched for papers on AI in imaging. Results: The Pubmed search produced 794 results. 168 studies were selected, of which 122 were from Pubmed search and 46 from the working group. The most used imaging modality was MRI (44%) followed by CT(12%) ad radiography/mammography (11%). The most common clinical indication were neurological diseases (29%) and diagnosis of cancer (25%). Classification was the most common task for AI (57%) followed by segmentation (16%). 65% of studies used machine learning and 35% used deep learning. We observed a rapid increase of research in Italy on artificial intelligence in the last 5 years, peaking at 155% from 2018 to 2019