Sviluppo di una piattaforma per la diagnosi prenatale non invasiva di malattie genetiche in epoca gestazionale precoce

Prenatal diagnosis of aneuploidies and monogenic diseases is usually performed by amniocentesis or chorionic villous sampling. However, these procedures are associated with 0.5%-2% risk of miscarriage. The discovery of cell free fetal DNA (cffDNA) in maternal plasma in 1997 has provided a new source of fetal genetic material that can be safely obtained from maternal blood and successfully processed for non invasive genetic diagnosis (NIPD). In this study is described a new approach for non invasive prenatal diagnosis of β- thalassemia which is based on semiconductor sequencing (Ion Torrent PGM) and fetal haplotype inference. In particular, the approach is based on target sequencing of the mutation site, the β°39 non sense mutation of the HBB gene, and several informative SNPs spread in the β-globin gene cluster. The data analysis of each cffDNA sample and the inference of the most likely inherited haplotypes were determined by an automated pipeline which firstly constructs the parental haplotypes, using the sequencing data from the parental DNAs and an haplotype reference panel previously created. The pipeline, then, quantifies the allele counts observed in each site sequenced in the corresponding cffDNA sample and finally predicts the two haplotypes most likely inherited by the fetus using a hidden Markov Model (HMM). The results were finally compared with the sequencing data of the fetal DNA obtained by villocentesis. Using these approaches we have analyzed 30 out of 37 cffDNA samples; in seven samples, in fact, the pipeline could not proceed because of the lack of informative sites or of other parameters useful for downstream analysis. The fetal β°39 genotype was correctly predicted in 24/30 (80%) samples, while it was incorrectly defined in 6/30 (20%) cases. The incorrect results obtained in these last samples was due to the erroneus inference of the maternal haplotype. On the contrary, the paternal haplotype was correctly detected in all 30 samples processed. In the next future we are planning to improve the protocol by increasing the number of potentially informative SNPs and to process a higher number of Sardinian β°39 carriers in order to expand the haplotype reference panel. This haplotype-based approach has given encouraging results and we think that it could be a starting point for eventual future application of NIPD also to other monogenic disorders

Characterizing the effects of water distribution system topology modifications on its dynamic behaviour through connectivity metrics

[EN] Water distribution networks (WDNs) are complex combinations of nodes and links and their structure has an impact on their behaviour, considering both quantitative (i.e. related to pipe flows and nodal pressures) and qualitative (i.e. related to water age and quality) aspects. The complexity of WDNs has been the basis of several studies that have resorted to the graph theory to relate connectivity properties to system behaviour (e.g. its reliability and water age/quality), evaluated under the assumption of steady-state conditions. Within this framework, in recent years the tendency toward reducing network interconnection through the closure of isolation valves has emerged, mainly to (i) facilitate its monitoring and management, and (ii) increase flow velocity and reduce water age. However, changes in the topology of a network can affect not only aspects evaluated under the assumption of steady-state conditions, but also its dynamic behaviour. Based on these considerations, the present study investigates whether some metrics derived from graph theory, already applied in the context of networks’ steady-state analyses, can also provide useful indications for assessing the effects of changes in the topological structure, which could be consequences of branching operations, on the dynamic response of a network subjected to users’ activity. The analyses highlight that connectivity metrics can reflect the pressure dynamic behaviour of the hydraulic systems and support in their macroscopic understanding during design and management operations. Thus, their application can be effectively extended from the steady-state to the dynamic framework.Marsili, V.; Alvisi, S.; Maietta, F.; Capponi, C.; Meniconi, S.; Brunone, B.; Franchini, M. (2024). Characterizing the effects of water distribution system topology modifications on its dynamic behaviour through connectivity metrics. Editorial Universitat Politècnica de València. https://doi.org/10.4995/WDSA-CCWI2022.2022.1401

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO2/FiO2 ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Modellazione in moto vario di una rete di distribuzione idrica soggetta all'attività dell'utenza

Le reti di distribuzione idrica sono continuamente soggette a transitori di pressione che si instaurano ogni volta che nel sistema viene effettuata una manovra o un'azione programmata o accidentale, come ad esempio, l'accensione o lo spegnimento di un gruppo di pompaggio, l'apertura o la chiusura di una valvola ma anche in conseguenza alla semplice attività dell'utenza. In questo lavoro, è presentato un approccio finalizzato alla modellazione in moto vario di reti di distribuzione soggette a transitori indotti dall'attività dell'utenza. L'approccio è applicato alla rete a servizio del centro urbano di Gorino Ferrarese (Ferrara, Italia). La rete serve circa 300 utenti ed è stata sottoposta ad un monitoraggio delle pressioni ad alta frequenza e dei consumi idrici dei singoli utenti a passo del minuto per una durata di due giorni. In particolare, durante il periodo di monitoraggio, la rete era sottoposta a condizioni ordinarie di funzionamento, ovvero le sole richieste idriche delle utenze agivano come forzante per il sistema

Laboratory Simulation of Transients in Looped Water Distribution Network

This paper analyses some tests carried out in a looped water distribution network (WDN) at the Water Engineering Laboratory of the University of Perugia. Specifically, the aim of such tests is to evaluate the effect of transients generated by a water consumption change, i. e., a complete and fast closure of a valve simulating an end-user maneuver. This end-user was located at the downstream end section of a service line placed in three different sections of the WDN. The tests allow examining the effect of the network topology and the location of the transient generation point