Machine learning based longitudinal virtual diagnostics at SwissFEL.

The bunch length in a linac driven Free Electron Laser (FEL) is a major parameter to be characterized to optimize the final accelerator performance. In linear machines, this observable is typically determined from the beam imaged on a screen located downstream of a Transverse Deflecting Structure (TDS) used to impinge a time dependent kick along the longitudinal coordinate of the beam. This measurement is typically performed during the machine setup and only sporadically to check the beam duration, but it cannot be continuously repeated because it is time consuming and invasive. A non-invasive method to determine the electron bunch length has already been presented in the past. This method is based on the analysis of the synchrotron radiation light spot emitted by the bunch passing through a magnetic chicane, provided that the energy chirp impinged on the bunch by the upstream radio frequency structures is known. In order to overcome a systematic discrepancy affecting the synchrotron radiation monitor based results compared to the absolute TDS based ones, we implemented and optimized a machine learning approach to predict the bunch length downstream of the two SwissFEL compression stages-from about 10 fs up to about 2 ps-as well as the beam longitudinal profile at the first one.

From bench to bedside: in vitro and in vivo evaluation of a neonate-focused nebulized surfactant delivery strategy.

BACKGROUND: Non-invasive delivery of nebulized surfactant has been a neonatology long-pursued goal. Nevertheless, the clinical efficacy of nebulized surfactant remains inconclusive, in part, due to the great technical challenges of depositing nebulized drugs in the lungs of preterm infants. The aim of this study was to investigate the feasibility of delivering nebulized surfactant (poractant alfa) in vitro and in vivo with an adapted, neonate-tailored aerosol delivery strategy. METHODS: Particle size distribution of undiluted poractant alfa aerosols generated by a customized eFlow-Neos nebulizer system was determined by laser diffraction. The theoretical nebulized surfactant lung dose was estimated in vitro in a clinical setting replica including a neonatal continuous positive airway pressure (CPAP) circuit, a cast of the upper airways of a preterm neonate, and a breath simulator programmed with the tidal breathing pattern of an infant with mild respiratory distress syndrome (RDS). A dose-response study with nebulized surfactant covering the 100-600 mg/kg nominal dose-range was conducted in RDS-modelling, lung-lavaged spontaneously-breathing rabbits managed with nasal CPAP. The effects of nebulized poractant alfa on arterial gas exchange and lung mechanics were assessed. Exogenous alveolar disaturated-phosphatidylcholine (DSPC) in the lungs was measured as a proxy of surfactant deposition efficacy. RESULTS: Laser diffraction studies demonstrated suitable aerosol characteristics for inhalation (mass median diameter, MMD = 3 µm). The mean surfactant lung dose determined in vitro was 13.7% ± 4.0 of the 200 mg/kg nominal dose. Nebulized surfactant delivered to spontaneously-breathing rabbits during nasal CPAP significantly improved arterial oxygenation compared to animals receiving CPAP only. Particularly, the groups of animals treated with 200 mg/kg and 400 mg/kg of nebulized poractant alfa achieved an equivalent pulmonary response in terms of oxygenation and lung mechanics as the group of animals treated with instilled surfactant (200 mg/kg). CONCLUSIONS: The customized eFlow-Neos vibrating-membrane nebulizer system efficiently generated respirable aerosols of undiluted poractant alfa. Nebulized surfactant delivered at doses of 200 mg/kg and 400 mg/kg elicited a pulmonary response equivalent to that observed after treatment with an intratracheal surfactant bolus of 200 mg/kg. This bench-characterized nebulized surfactant delivery strategy is now under evaluation in Phase II clinical trial (EUDRACT No.:2016-004547-36).

Non-Invasive Assessment of Liver Injury in Non-Alcoholic Fatty Liver Disease: A Review of Literature.

NAFLD (Non-Alcoholic Fatty Liver Disease) is an increasingly significant public health issue, regarded as the most relevant liver disease of the twenty-first century. Approximately 20%-30% of NAFLD subjects develop a NASH (Non-Alcoholic Steato-Hepatitis), a condition which can potentially evolve to liver cirrhosis and hepatocellular carcinoma. For these reasons a proper evaluation of liver damage is a key point for diagnosis and prognosis and liver biopsy still remains the "gold standard" procedure both for discrimination between steatosis and steatohepatitis and assessment of the degree of liver fibrosis. Nonetheless, given it is an invasive, painful and costly procedure, a great research efforts have been made in order to develop non-invasive methods for the assessment of NAFLD presence and/or severity by serum markers and imaging techniques. In this review we aimed to perform a comprehensive review of the literature about strengths and weaknesses of the main tools available for the non-invasive assessment of NAFLD patients.

Mechanistic evaluation of the transfection barriers involved in lipid-mediated gene delivery: interplay between nanostructure and composition.

Here we present a quantitative mechanism-based investigation aimed at comparing the cell uptake, intracellular trafficking, endosomal escape and final fate of lipoplexes and lipid-protamine/deoxyribonucleic acid (DNA) (LPD) nanoparticles (NPs) in living Chinese hamster ovary (CHO) cells. As a model, two lipid formulations were used for comparison. The first formulation is made of the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic lipid dioleoylphosphocholine (DOPC), while the second mixture is made of the cationic 3ß-[N-(N,N-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) and the zwitterionic helper lipid dioleoylphosphatidylethanolamine (DOPE). Our findings indicate that lipoplexes are efficiently taken up through fluid-phase macropinocytosis, while a less efficient uptake of LPD NPs occurs through a combination of both macropinocytosis and clathrin-dependent pathways. Inside the cell, both lipoplexes and LPD NPs are actively transported towards the cell nucleus, as quantitatively addressed by spatio-temporal image correlation spectroscopy (STICS). For each lipid formulation, LPD NPs escape from endosomes more efficiently than lipoplexes. When cells were treated with DOTAP-DOPC-containing systems the majority of the DNA was trapped in the lysosome compartment, suggesting that extensive lysosomal degradation was the rate-limiting factors in DOTAP-DOPC-mediated transfection. On the other side, escape from endosomes is large for DC-Chol-DOPE-containing systems most likely due to DOPE and cholesterol-like molecules, which are able to destabilize the endosomal membrane. The lipid-dependent and structure-dependent enhancement of transfection activity suggests that DNA is delivered to the nucleus synergistically: the process requires both the membrane-fusogenic activity of the nanocarrier envelope and the employment of lipid species with intrinsic endosomal rupture ability.

[Surgical interventions in dialysis patients in Piedmont: data from the Regional Registry. Working Group of the Piedmont Registry of Dialysis and Transplantation]. / Interventi chirurgici nei pazienti in dialisi in Piemonte: dati dal Registro Regionale (RPDT). Gruppo di lavoro dell'RPDT.

In this work surgical events in a large population of chronic dialysis patients are analysed. Data are obtained from the Regional (Piedmont) Registry of Dialysis and Transplantation (RPDT), that has collected information since 1981 about all chronic dialysis patients in the Region. Since 1984, causes of admission to-hospital are registered. Surgical causes of hospitalization, for purposes not related to uremia, were 538 (20% of all surgical admissions). In patients younger than 65 years, these hospitalizations account for about 6% of the cases, whereas in patients older than 65 they are less than 5%. As expected, a higher number of surgical operations is observed in diabetics, while on the contrary the lowest is performed in nephroangiosclerosis patients. Cardiovascular and bowel diseases represent almost 50% of all surgical needs. Postoperative mortality was 5.8% within 45 days from admission. Cardiac and infectious diseases and cachexia represent the more frequent causes of death. In 27 out of 28 cases at least one high risk condition was present.

[Diagnosis of delayed upper left ventricular activation: limits of electrocardiography and usefulness of vectorcardiography]. / La diagnosi di ritardo di attivazione ventricolare sinistra superiore: limiti dell'elettrocardiografia e utilità della vettorcardiografia.

The electrocardiographic (ECG) diagnosis of delayed ventricular left superior activation (DVLSA) is often difficult and uncertain, even when all the criteria proposed in clinical literature are fulfilled. The vectorcardiography (VCG) always permits an accurate diagnostic evaluation because the contour of the QRS loop describes successively the various phases of ventricular depolarization. Sensitivity and specificity of ECG in diagnosing DVLSA have been calculated referring to VCG analysis. The QRS loop initial forces orientation in the frontal plane, a VCG highly reliable criterion, was considered especially significant for this purpose. The sensitivity and specificity of ECG were, respectively, 75% and 95%. Moreover, this study has confirmed the low performance of frontal plane QRS axis criterion and the necessity of polyparametric method for a correct ECG-VCG diagnosis of DVLSA. However, the VCG is more reliable than ECG in such diagnosis because it allows thoroughly to analyze QRS-loop initial forces.