Trajectory-Oriented Approach to Managing Traffic Complexity: Operational Concept and Preliminary Metrics Definition

This document describes preliminary research on a distributed, trajectory-oriented approach for traffic complexity management. The approach is to manage traffic complexity in a distributed control environment, based on preserving trajectory flexibility and minimizing constraints. In particular, the document presents an analytical framework to study trajectory flexibility and the impact of trajectory constraints on it. The document proposes preliminary flexibility metrics that can be interpreted and measured within the framework

Human Red Blood Cells as Oxygen Carriers to Improve Ex-Situ Liver Perfusion in a Rat Model

Ex-situ machine perfusion (MP) has been increasingly used to enhance liver quality in different settings. Small animal models can help to implement this procedure. As most normothermic MP (NMP) models employ sub-physiological levels of oxygen delivery (DO2), the aim of this study was to investigate the effectiveness and safety of different DO2, using human red blood cells (RBCs) as oxygen carriers on metabolic recovery in a rat model of NMP. Four experimental groups (n = 5 each) consisted of (1) native (untreated/control), (2) liver static cold storage (SCS) 30 min without NMP, (3) SCS followed by 120 min of NMP with Dulbecco-Modified-Eagle-Medium as perfusate (DMEM), and (4) similar to group 3, but perfusion fluid was added with human RBCs (hematocrit 15%) (BLOOD). Compared to DMEM, the BLOOD group showed increased liver DO2 (p = 0.008) and oxygen consumption ( V O \u2d9 2) (p < 0.001); lactate clearance (p < 0.001), potassium (p < 0.001), and glucose (p = 0.029) uptake were enhanced. ATP levels were likewise higher in BLOOD relative to DMEM (p = 0.031). V O \u2d9 2 and DO2 were highly correlated (p < 0.001). Consistently, the main metabolic parameters were directly correlated with DO2 and V O \u2d9 2. No human RBC related damage was detected. In conclusion, an optimized DO2 significantly reduces hypoxic damage-related effects occurring during NMP. Human RBCs can be safely used as oxygen carriers

Radiation hardening techniques for rare-earth based optical fibers and amplifiers

Er/Yb doped fibers and amplifiers have been shown to be very radiation sensitive, limiting their integration in space. We present an approach including successive hardening techniques to enhance their radiation tolerance. The efficiency of our approach is demonstrated by comparing the radiation responses of optical amplifiers made with same lengths of different rare-earth doped fibers and exposed to gamma-rays. Previous studies indicated that such amplifiers suffered significant degradation for doses exceeding 10 krad. Applying our techniques significantly enhances the amplifier radiation resistance, resulting in a very limited degradation up to 50 krad. Our optimization techniques concern the fiber composition, some possible pre-treatments and the interest of simulation tools used to harden by design the amplifiers. We showed that adding cerium inside the fiber phosphosilicate-based core strongly decreases the fiber radiation sensitivity compared to the standard fiber. For both fibers, a pre-treatment with hydrogen permits to enhance again the fiber resistance. Furthermore, simulations tools can also be used to improve the tolerance of the fiber amplifier by helping identifying the best amplifier configuration for operation in the radiative environment

The value of the multidisciplinary team in metastatic renal cell carcinoma: paving the way for precision medicine in toxicities management

The new landscape of treatments for metastatic clear cell renal carcinoma (mRCC) is constantly expanding, but it is associated with the emergence of novel toxicities, adding to up to those observed in the tyrosine-kinase inhibitor (TKI) era. Indeed, the introduction of immune checkpoint inhibitors (ICIs) alone or in combination has been associated with the development of immune-related adverse events (irAEs) involving multiple-organ systems which, even if rarely, had led to fatal outcomes. Moreover, due to the relatively recent addition of ICIs to the previously available treatments, the potential additive adverse effects of these combinations are still unknown. A prompt recognition and management of these toxicities currently represents a fundamental issue in oncology, since it correlates with the outcome of cancer patients. Even if clinical guidelines provide indications for the management of irAEs, no specific protocol to evaluate the individual risk of developing an adverse event during therapy is currently available. A multidisciplinary approach addressing appropriate interventions aimed at reducing the risk of any insidious, severe, and/or dose-limiting toxicity might represent the most efficacious strategy to timely prevent and manage severe irAEs, allowing indirectly to improve both patients' cancer-specific survival and quality of life. In this review, we reported a five-case series of toxicity events that occurred at our center during treatment for mRCC followed by the remarks of physicians from different specialties, pinpointing the relevant role of an integrated and extended multidisciplinary team in a modern model of mRCC patient management

Fenomeno Caulerpa 2010-2013. Rapporto sull'evoluzione delle specie aliene nel Canale di Sicilia

Gli studi effettuati da ARPA-Sicilia, ISPRA e CNR-IAMC hanno perseguito l’obiettivo principale di monitorare e valutare l’impatto della diffusione delle alghe indagate, attraverso l’analisi dell’evoluzione spazio-temporale del fenomeno e la caratterizzazione eco-tossicologica delle aree di pesca maggiormente interessate dalla presenza delle caulerpe. In particolare Le ricerche di ARPA-Sicilia sono state mirate a: - Definire le aree di studio principalmente interessate dal fenomeno di diffusione delle due alghe aliene; - Caratterizzare da un punto di vista ambientale le aree oggetto d’indagine; - Valutare le pressioni antropiche che insistono lungo le coste delle aree indagate; - Stimare l’influenza che le pressioni antropiche possono esercitare sulla diffusione della Caulerpa; - Indagare l’andamento spazio-temporale della distribuzione di Caulerpa in specifiche aree di indagine. Gli studi condotti da ISPRA hanno puntato a: - Valutare possibili interferenze dell’alga con le attività di pesca, l’intasamento delle reti e la riduzione della pescabilità dell’attrezzo; - Rilevare l’eventuale diversità tra aree con insediamento e prive di insediamento; - Avviare l’introduzione di buone pratiche per evitare che la pesca possa rappresentare un ulteriore vettore di invasioni secondarie attraverso disseminazione dei frammenti e propaguli dell’alga; - Definire comportamenti alieutici nel tempo utili alla mitigazione del potenziale impatto della pesca sulle risorse nelle aree colpite; - Istituire in tutta l’area di studio e, in particolare, nell’arcipelago delle Pelagie, un “Osservatorio delle Specie Aliene” per svolgere attività di monitoraggio sulla diffusione delle specie aliene, al fine di formulare proposte gestionali mirate alla salvaguardia degli ecosistemi e delle attività economiche di pesca. Le indagini realizzate dal CNR-IAMC hanno avuto come obiettivi principali: - Confrontare le caratteristiche dei popolamenti bentonici associati a praterie di Posidonia oceanica della Sicilia meridionale interessate dall’invasione di Caulerpa taxifolia var. distichophylla con quelle di popolamenti associati a posidonieti di località limitrofe non colpite dal fenomeno; - Confrontare la struttura trofica della comunità bentonica associata a matte di Posidonia oceanica in località invase e non invase da alghe aliene del genere Caulerpa della Sicilia meridionale; - Valutare gli effetti dell’invasione di Caulerpa racemosa var. cylindracea sulla struttura e sulla funzione di popolamenti macrobentonici sessili di fondo duro dell’infralitorale

Effect of β2-adrenergic receptor stimulation on lung fluid in stable heart failure patients

Introduction: The purpose of this study was to determine 1) if stable heart-failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) versus healthy control subjects, and 2) the effect of acute β2AR agonist inhalation on lung fluid balance. Methods: Twenty-two stable HFrEF patients and 18 age- and sex-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary conductance (DmCO), pulmonary capillary blood volume (Vc) (via rebreathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 min of administration of nebulized albuterol. EVLW was derived as Vtis – Vc. Results: Pre-albuterol, Vtis and EVLW were greater in HFrEF vs. control (998 ± 200 vs. 884 ± 123 ml, P = 0.041; 943 ± 202 vs. 802 ± 133 ml, P = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF (−4.6 ± 7.8%, P = 0.010; −4.6 ± 8.8%, P = 0.018) and control (−2.8 ± 4.9%, P = 0.029; −3.0 ± 5.7%, P = 0.045). There was an inverse relationship between pre-albuterol values and the pre- to post-albuterol change for EVLW (r2 = −0.264, P = 0.015) and DmCO (r2 = −0.343, P = 0.004) in HFrEF only. Conclusion: Lung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of the β2ARs may cause fluid removal in HFrEF, especially in patients who exhibit greater evidence for increased lung water at baseline

Time course of risk factors associated with mortality of 1260 critically ill patients with COVID-19 admitted to 24 Italian intensive care units

94noopenPurpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19). Methods: In this retrospective–prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome. Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55–69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 122 [89–175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO2/FiO2, driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil–lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO2/FiO2, respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values. Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid–base derangement, coagulation impairment, or systemic inflammation were associated with patient survival.openZanella A.; Florio G.; Antonelli M.; Bellani G.; Berselli A.; Bove T.; Cabrini L.; Carlesso E.; Castelli G.P.; Cecconi M.; Citerio G.; Coloretti I.; Corti D.; Dalla Corte F.; De Robertis E.; Foti G.; Fumagalli R.; Girardis M.; Giudici R.; Guiotto L.; Langer T.; Mirabella L.; Pasero D.; Protti A.; Ranieri M.V.; Rona R.; Scudeller L.; Severgnini P.; Spadaro S.; Stocchetti N.; Vigano M.; Pesenti A.; Grasselli G.; Aspesi M.; Baccanelli F.; Bassi F.; Bet A.; Biagioni E.; Biondo A.; Bonenti C.; Bottino N.; Brazzi L.; Buquicchio I.; Busani S.; Calini A.; Calligaro P.; Cantatore L.P.; Carelli S.; Carsetti A.; Cavallini S.; Cimicchi G.; Coppadoro A.; Dall'Ara L.; Di Gravio V.; Erba M.; Evasi G.; Facchini A.; Fanelli V.; Feliciotti G.; Fusarini C.F.; Ferraro G.; Gagliardi G.; Garberi R.; Gay H.; Giacche L.; Grieco D.; Guzzardella A.; Longhini F.; Manzan A.; Maraggia D.; Milani A.; Mischi A.; Montalto C.; Mormina S.; Noseda V.; Paleari C.; Pedeferri M.; Pezzi A.; Pizzilli G.; Pozzi M.; Properzi P.; Rauseo M.; Russotto V.; Saccarelli L.; Servillo G.; Spano S.; Tagliabue P.; Tonetti T.; Tullo L.; Vetrugno L.; Vivona L.; Volta C.A.; Zambelli V.; Zanoni A.Zanella, A.; Florio, G.; Antonelli, M.; Bellani, G.; Berselli, A.; Bove, T.; Cabrini, L.; Carlesso, E.; Castelli, G. P.; Cecconi, M.; Citerio, G.; Coloretti, I.; Corti, D.; Dalla Corte, F.; De Robertis, E.; Foti, G.; Fumagalli, R.; Girardis, M.; Giudici, R.; Guiotto, L.; Langer, T.; Mirabella, L.; Pasero, D.; Protti, A.; Ranieri, M. V.; Rona, R.; Scudeller, L.; Severgnini, P.; Spadaro, S.; Stocchetti, N.; Vigano, M.; Pesenti, A.; Grasselli, G.; Aspesi, M.; Baccanelli, F.; Bassi, F.; Bet, A.; Biagioni, E.; Biondo, A.; Bonenti, C.; Bottino, N.; Brazzi, L.; Buquicchio, I.; Busani, S.; Calini, A.; Calligaro, P.; Cantatore, L. P.; Carelli, S.; Carsetti, A.; Cavallini, S.; Cimicchi, G.; Coppadoro, A.; Dall'Ara, L.; Di Gravio, V.; Erba, M.; Evasi, G.; Facchini, A.; Fanelli, V.; Feliciotti, G.; Fusarini, C. F.; Ferraro, G.; Gagliardi, G.; Garberi, R.; Gay, H.; Giacche, L.; Grieco, D.; Guzzardella, A.; Longhini, F.; Manzan, A.; Maraggia, D.; Milani, A.; Mischi, A.; Montalto, C.; Mormina, S.; Noseda, V.; Paleari, C.; Pedeferri, M.; Pezzi, A.; Pizzilli, G.; Pozzi, M.; Properzi, P.; Rauseo, M.; Russotto, V.; Saccarelli, L.; Servillo, G.; Spano, S.; Tagliabue, P.; Tonetti, T.; Tullo, L.; Vetrugno, L.; Vivona, L.; Volta, C. A.; Zambelli, V.; Zanoni, A

Uncoupling the functions of CALM in VAMP sorting and clathrin-coated pit formation.

CALM (clathrin assembly lymphoid myeloid leukemia protein) is a cargo-selective adaptor for the post-Golgi R-SNAREs VAMPs 2, 3, and 8, and it also regulates the size of clathrin-coated pits and vesicles at the plasma membrane. The present study has two objectives: to determine whether CALM can sort additional VAMPs, and to investigate whether VAMP sorting contributes to CALM-dependent vesicle size regulation. Using a flow cytometry-based endocytosis efficiency assay, we demonstrate that CALM is also able to sort VAMPs 4 and 7, even though they have sorting signals for other clathrin adaptors. CALM homologues are present in nearly every eukaryote, suggesting that the CALM family may have evolved as adaptors for retrieving all post-Golgi VAMPs from the plasma membrane. Using a knockdown/rescue system, we show that wild-type CALM restores normal VAMP sorting in CALM-depleted cells, but that two non-VAMP-binding mutants do not. However, when we assayed the effect of CALM depletion on coated pit morphology, using a fluorescence microscopy-based assay, we found that the two mutants were as effective as wild-type CALM. Thus, we can uncouple the sorting function of CALM from its structural role

Subtle Alterations in PCNA-Partner Interactions Severely Impair DNA Replication and Repair

Dynamic switching of PCNA-partner interactions is essential for normal DNA replication and repair in yeast