Filamentation of a relativistic proton bunch in plasma.

We show in experiments that a long, underdense, relativistic proton bunch propagating in plasma undergoes the oblique instability, which we observe as filamentation. We determine a threshold value for the ratio between the bunch transverse size and plasma skin depth for the instability to occur. At the threshold, the outcome of the experiment alternates between filamentation and self-modulation instability (evidenced by longitudinal modulation into microbunches). Time-resolved images of the bunch density distribution reveal that filamentation grows to an observable level late along the bunch, confirming the spatiotemporal nature of the instability. We provide a rough estimate of the amplitude of the magnetic field generated in the plasma by the instability and show that the associated magnetic energy increases with plasma density.

Hosing of a Long Relativistic Particle Bunch in Plasma.

Experimental results show that hosing of a long particle bunch in plasma can be induced by wakefields driven by a short, misaligned preceding bunch. Hosing develops in the plane of misalignment, self-modulation in the perpendicular plane, at frequencies close to the plasma electron frequency, and are reproducible. Development of hosing depends on misalignment direction, its growth on misalignment extent and on proton bunch charge. Results have the main characteristics of a theoretical model, are relevant to other plasma-based accelerators and represent the first characterization of hosing.

Factors Associated With Reasons for Living Among Suicidal Adolescents.

OBJECTIVE: The objective of this study was to identify baseline demographic and clinical factors associated with higher scores on the Reasons for Living Inventory for Adolescents (RFL-A) at baseline and over follow-up. METHOD: Using data from a pilot clinical trial of a brief intervention for suicidal youth transitioning from inpatient to outpatient, we identified univariate associations of baseline characteristics with RFL-A and used regression to identify the most parsimonious subset of these variables. Finally, we examined to what extent changes in these characteristics over time were related to changes in RFL-A. RESULTS: Univariate analyses found that better external functional emotion regulation and social support were associated with higher RFL-A scores; more self-reported depression, internal dysfunctional emotion regulation, sleep disturbance, anxiety, and distress tolerance were associated with lower RFL-A scores. Multiple linear regression identified internal dysfunctional emotion regulation and external functional emotion regulation as the most parsimonious set of characteristics associated with RFL-A. Improvement in internal emotion regulation, sleep, and depression were related to improvements in RFL-A over time. CONCLUSION: Our findings indicate that emotion regulation-specifically maladaptive internal strategies and use of external resources-is strongly associated with RFL-A. Improvements in internal emotion regulation (r = 0.57), sleep (r = -0.45), and depression (r = -0.34) were related to increases in RFL-A.HIGHLIGHTSIn the literature, greater reasons for living are associated with lower risk for future suicidal ideation and suicide attempts.The most salient correlate of concurrent and future lower RFL-A was dysfunctional internal emotion regulation. Improved sleep and decreases in depression were correlated with increases in RFL-A.

In vitro fertilization: an unexpected finding in a cohort of patients with biliary atresia.

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

Blood lactate in mild and moderate ARDS secondary to SARS COV 2.

BACKGROUND AND OBJECTIVES: Elevated blood lactate levels are associated with poor outcome in several critical conditions. Patients with SARS-CoV-2 rarely develop hyperlactatemia. The purpose of this study is to evaluate the trend of lactatemia in patients affected by mild/moderate SARS-Co V-2-ARDS and if it affected prognosis. METHODS: We analyzed blood lactate levels in thirty-eight patients with severe SARS-CoV-2 infection admitted to COVID Care Unit of Santa Maria delle Grazie Hospital, Pozzuoli. RESULTS: Twenty patients survived and were discharged at home and 18 patients died. Despite severe hypoxia that affected all patients enrolled, T0 lactate was within normal values. All survivors showed a significant increase in lactate concentration the day prior to clinical improvement. In not-survivors levels of lactate did not increase significantly. CONCLUSION: In our study, patients who survive SARS CoV-2 ARDS have a fleeting increase in lactate, which precedes clinical improvement by one day.

Modelling parametric uncertainty in large-scale stratigraphic simulations.

We combine forward stratigraphic models with a suite of uncertainty quantification and stochastic model calibration algorithms for the characterization of sedimentary successions in large scale systems. The analysis focuses on the information value provided by a probabilistic approach in the modelling of large-scale sedimentary basins. Stratigraphic forward models (SFMs) require a large number of input parameters usually affected by uncertainty. Thus, model calibration requires considerable time both in terms of human and computational resources, an issue currently limiting the applications of SFMs. Our work tackles this issue through the combination of sensitivity analysis, model reduction techniques and machine learning-based optimization algorithms. We first employ a two-step parameter screening procedure to identify relevant parameters and their assumed probability distributions. After selecting a restricted set of important parameters these are calibrated against available information, i.e., the depth of interpreted stratigraphic surfaces. Because of the large costs associated with SFM simulations, probability distributions of model parameters and outputs are obtained through a data driven reduced complexity model. Our study demonstrates the numerical approaches by considering a portion of the Porcupine Basin, Ireland. Results of the analysis are postprocessed to assess (i) the uncertainty and practical identifiability of model parameters given a set of observations, (ii) spatial distribution of lithologies. We analyse here the occurrences of sand bodies pinching against the continental slope, these systems likely resulting from gravity driven processes in deep sea environment.

In vitro fertilization: an unexpected finding in a cohort of patients with biliary atresia

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

Quantitative and qualitative features of acute phase-adverse events following SARS-CoV-2 vaccination in a large sample of people with multiple sclerosis.

INTRODUCTION: Few data are available on adverse events (AE) associated to vaccines in persons with multiple sclerosis (pwMS). AIMS: to study the incidence of acute phase AE (AP-AE) related to SARS-CoV-2 mRNA vaccines in pwMS compared to a control group, and to analyze the association between AP-AE and disease modifying treatments (DMT). METHODS: This was a cross-sectional study on 438 PwMS and 481 age- and sex-matched subjects not affected by dysimmune diseases that underwent two doses of SARS-CoV-2 mRNA BNT162b2 vaccine (Pfizer/BioNtech). RESULTS: Two hundred and twenty five (51.4%) pwMS complained of ≥1 AP-AE after the first dose, 269 (61.4%) after the second dose. A logistic regression analysis revealed that only pwMS on Fingolimod and Ocrelizumab did not show a higher risk of developing AP-AE. The likelihood to present with ≥1 AP-AE, after correcting for age and sex, was significantly higher in pwMS than controls. CONCLUSIONS: This study reports qualitative and quantitative features of AP-AE associated with the first and second doses of SARS-CoV-2 vaccine in a large sample of pwMS. The only risk factor identified for developing AP-AE is female gender. AntiCD-20 monoclonal antibodies and S1P inhibitors are associated with a lower risk of AP-AE occurrence.

Controlled Growth of the Self-Modulation of a Relativistic Proton Bunch in Plasma.

A long, narrow, relativistic charged particle bunch propagating in plasma is subject to the self-modulation (SM) instability. We show that SM of a proton bunch can be seeded by the wakefields driven by a preceding electron bunch. SM timing reproducibility and control are at the level of a small fraction of the modulation period. With this seeding method, we independently control the amplitude of the seed wakefields with the charge of the electron bunch and the growth rate of SM with the charge of the proton bunch. Seeding leads to larger growth of the wakefields than in the instability case.

Lipid nano-vesicles for thyroid hormone encapsulation: A comparison between different fabrication technologies, drug loading, and an in vitro delivery to human tendon stem/progenitor cells in 2D and 3D culture.

Phosphatidylcholine (PC) vesicles loaded with Triiodothyronine (T3) were fabricated using different manufacturing methods: thin layer hydration plus sonication (TF-UF), supercritical liposome formation (SC), and microfluidic technology (MF). Vesicles obtained by MF had the lowest mean diameter (88.61 ± 44.48 nm) with a Zeta Potential of -20.1 ± 5.90 mV and loading of 10 mg/g (encapsulation efficiency: 57%). In contrast, SC vesicles showed extremely low encapsulation efficiency (<10%) probably due to T3 solubility in ethanol/carbon dioxide mixture; despite TF-UF vesicles exhibiting good size (167.7 ± 90 nm; Zp -8.50 ± 0.60 mV) and loading (10 mg/g), poor mass recovery was obtained (50% loss). MF vesicles had low cytotoxicity, and they were well enough internalized by both HeLa and human tendon stem/progenitor cells (hTSPCs). Their biological activity was also monitored in both 2D and 3D cultures of hTSPCs supplemented with therapeutical concentrations of PC/T3 nano-liposomes. 2D culture showed almost similar constitutive gene expression compared to control culture supplemented with free-T3. On the contrary, when hTPSCs 3D culture was assembled, it showed a more evident homogeneous distribution of FITC labeled vesicles within the high-density structure and a significant upregulation of cell constitutive genes, such as type I Collagen (4.8-fold; p < 0.0001) at day 7, compared to the control, suggesting that T3/PC formulation has increased T3 cytosolic concentration, thus improving cells metabolic activity. The study supported MF technology for nano-carriers fabrication and opens perspectives on the activity of PC/T3 nano-vesicles as innovative formulations for TPSCs stimulation in ECM secretion.

Myogenic commitment of human stem cells by myoblasts Co-culture: a static vs. a dynamic approach.

An in-vitro model of human bone marrow mesenchymal stem cells (hBM-MSCs) myogenic commitment by synergic effect of a differentiation media coupled with human primary skeletal myoblasts (hSkMs) co-culture was developed adopting both conventional static co-seeding and perfused culture systems. Static co-seeding provided a notable outcome in terms of gene expression with a significant increase of Desmin (141-fold) and Myosin heavy chain II (MYH2, 32-fold) at day 21, clearly detected also by semi-quantitative immunofluorescence. Under perfusion conditions, myogenic induction ability of hSkMs on hBM-MSCs was exerted by paracrine effect with an excellent gene overexpression and immunofluorescence detection of MYH2 protein; furthermore, due to the dynamic cell culture in separate wells, western blot data were acquired confirming a successful cell commitment at day 14. A significant increase of anti-inflammatory cytokine gene expression, including IL-10 and IL-4 (15-fold and 11-fold, respectively) at day 14, with respect to the pro-inflammatory cytokines IL-12A (7-fold at day 21) and IL-1ß (1.4-fold at day 7) was also detected during dynamic culture, confirming the immunomodulatory activity of hBM-MSCs along with commitment events. The present study opens interesting perspectives on the use of dynamic culture based on perfusion as a versatile tool to study myogenic events and paracrine cross-talk compared to the simple co-seeding static culture.

Non-invasive CPAP in mild and moderate ARDS secondary to SARS-CoV-2.

BACKGROUND: During the COVID-19 outbreak, a very high number of infected patients developed pneumonia and many of them complicated with acute respiratory distress syndrome. The optimal management of respiratory failure and the role of lung ultrasound imaging in the evaluation of efficacy of treatment are unknown. METHODS: In March 2020 we treated 18 patients with mild and moderate ARDS secondary to SARS-CoV-2 with non-invasive continuous positive airway pressure therapy (NI-CPAP). All patients underwent lung ultrasound imaging to verify the entity of lung recruitment after NI-CPAP initiation. RESULTS: After one hour of treatment we observed a significant improvement in PaO2/FiO2 ratio in 10 patients. Notably, only 50 % of them reached an effective improvement in lung aeration detectable with lung ultrasound. In the other 50 % or patients the improvement in PaO2/FiO2 might be related to blood redistribution and reverse of hypoxic vasoconstriction. CONCLUSION: NI- CPAP is a valid therapeutic option in mild and moderate ARDS secondary SARS-CoV-2. Lung recruitment detected by means of lung ultrasound is a relevant but not the exclusive mechanism that underlies the therapeutic efficacy of NI-CPAP in this clinical setting.

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience.

OBJECTIVE: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2)-related pneumonia, referred to as COVID-19 (Coronavirus Disease 19), is a public health emergency as it carries high morbidity, mortality, and has no approved specific pharmacological treatments. In this case series, we aimed to report preliminary data obtained with anti-complement C5 therapy with eculizumab in COVID-19 patients admitted to intensive care unit (ICU) of ASL Napoli 2 Nord. PATIENTS AND METHODS: This is a case series of patients with a confirmed diagnosis of SARS-CoV2 infection and severe pneumonia or ARDS who were treated with up to 4 infusions of eculizumab as an off-label agent. Patients were also treated with anticoagulant therapy with Enoxaparin 4000 IU/day via subcutaneous injection, antiviral therapy with Lopinavir 800 mg/day + Ritonavir 200 mg/day, hydroxychloroquine 400 mg/day, ceftriaxone 2 g/day IV, vitamine C 6 g/day for 4 days, and were on Non-Invasive Ventilation (NIV). RESULTS: We treated four COVID-19 patients admitted to the intensive care unit because of severe pneumonia or ARDS. All patients successfully recovered after treatment with eculizumab. Eculizumab induced a drop in inflammatory markers. Mean C Reactive Protein levels dropped from 14.6 mg/dl to 3.5 mg/dl and the mean duration of the disease was 12.8 days. CONCLUSIONS: Eculizumab has the potential to be a key player in treatment of severe cases of COVID-19. Our results support eculizumab use as an off-label treatment of COVID-19, pending confirmation from the ongoing SOLID-C19 trial.

Heavy metal bioaccumulation in honey bee matrix, an indicator to assess the contamination level in terrestrial environments.

The most significant risk factor for organisms living in an environment contaminated by heavy metals is the metal bioavailability. Therefore, an efficient ecotoxicological approach to metal contamination is the measure of bioaccumulation level in target organisms. In this work, we characterized the heavy metal bioaccumulation in honey bees, Apis mellifera ligustica, collected at 35 sites from Umbria (Central Italy). The comparison of our data with selected Italian investigations revealed metal bioaccumulation in honey bee matrix of the same order of magnitude, with Cd showing a higher variability. To generalize the results, we developed a Honeybee Contamination Index (HCI) based on metal bioaccumulation in honey bees. An application of the HCI to the present dataset revealed cases of low (sixteen sites), intermediate (eighteen sites), and high (one site) metal contaminations. The comparison of HCI values from the Umbrian dataset with values calculated for other Italian and European metadata showed that most of the Umbrian sites fell in the portion of low and intermediate contamination conditions. HCI represented a reliable tool that provided a piece of concise information on metal contamination in terrestrial environments. Parallel to this effort, we have determined, the metal concentrations in the airborne particulate matter (PM10) at three regional background-monitoring stations in Umbria. These stations are representative of the average air quality of the areas of the investigated apiaries. A comparative analysis of metal enrichment factors in PM10, and honey bees suggested that the contamination in the bees was related to the PM10 values only to a minor extent. On the other side, a clear enrichment of metals such as Cd, Mn, Zn, and Cu in the honey bees appeared to depend on very local conditions and was probably related to the use of pesticides and fertilizers, and the resuspension of the locally contaminated soils and agriculture residues.

A bioavailability study on microbeads and nanoliposomes fabricated by dense carbon dioxide technologies using human-primary monocytes and flow cytometry assay.

Supercritical Emulsion Extraction (SEE) and Supercritical assisted Liposome formation (SuperLip), use dense gases such as carbon dioxide (dCO2) to fabricate advanced micro/nanocarriers. SEE uses dCO2 to extract solvent from the oily phase of an emulsion and obtain biopolymer microbead; For this study, poly-Lactic Acid (PLA) microbeads of 1 ±â€¯0.2 µm in mean size loaded at 1 µg/mgPLA with Rhodamine B (ROD) were prepared by SEE; the beads showed a solvent residue lower than 10 ppm and encapsulated the fluorochrome with an efficiency of 90%. SuperLip uses dCO2 to enhance lipid/ethanol/water mixing and to promote the ethanol extraction from liposome suspension. In this case, phosphatidyl-choline (PC) vesicles with a mean size of 0.2 ±â€¯0.05 µm and loaded with Fluorescein Iso-ThioCyanate (FITC) at 8 µg/mgPC were prepared; small unilamellar structure was observed for all the vesicles with FITC encapsulation efficiency of 80%. Ethanol residue of 50 ppm was measured in all the liposome suspensions. The bioavailability of microbeads and nanoliposomes was assessed through incubation with human monocytes previously isolated from healthy donors' blood. A specifically optimized protocol that allowed their quenching on the cell surface was developed to monitor by flow cytometer assay only the cell population that effectively internalized the carriers. When microbeads were tested, the percentage of alive internalizing monocytes was of about 30%. An internalization of 96.1 ±â€¯21% was, instead, obtained at dosage of 0.1 mg/mL for nanoliposomes. In this last case, monocytes showed a vitality of almost 100% after vesicles internalization at all the concentrations studied; on the other hand, cell apoptosis progressively increased in a dose/response manner, after polymer microbeads phagocytosis. The proposed data suggested that dCO2 technologies can be reliably used to fabricate intracellular carriers.

Role of the TAp63 Isoform in Recurrent Nasal Polyps.

The pathogenic molecular mechanisms underlying the insurgence of nasal polyps has not been completely defined. In some patients, these lesions can have a recurrence after surgery removal, and the difference between recurrent and not recurrent patients is still unclear. To molecularly characterize and distinguish between these two classes, a cohort of patients affected by nasal polyposis was analysed. In all patients we analysed the p63 isoform expression using fresh tissues taken after surgery. Moreover, confocal immunofluorescence analysis of fixed sections was performed. The results show high ΔNp63 expression in samples from the nasal polyps of patients compared to the normal epithelia. Analysis of the expression level of the TAp63 isoform shows differential expression between the patients with recurrence compared to those not recurring. The data, considered as the ΔN/TAp63 ratio, really discriminate the two groups. In fact, even though ΔNp63 is expressed in non-recurrent patients, the resulting ratio ΔN/TAp63 is significantly lower in these patients. This clearly indicates that the status of TAp63 expression, represented by the ΔN/TAp63 ratio, could be considered a prognostic marker of low recurrence probability. In these samples we also investigated the expression of OTX2 transcription factor, known to be a selective activator of TAp63, detecting a significant correlation. Database analysis of HNSCC patients showed increased survival for the patients presenting OTX2 amplification and/or overexpression. These results, together with the fact that TAp63 can be selectively upregulated by HDAC inhibitors, open the possibility to consider local treatment of recurrent nasal polyps with these molecules.

Long-term outcomes of transmesenteric portal vein recanalization for the treatment of chronic portal vein thrombosis after pediatric liver transplantation.

Portal vein thrombosis (PVT) may occur at any time following liver transplantation. We describe our experience with portal vein recanalization in cases of thrombosis after liver transplantation. Twenty-eight children (5%) out of 566 liver transplant recipients underwent portal vein recanalization using a transmesenteric approach. All children received left hepatic segments, developed PVT, and had symptoms or signs of portal hypertension. Portal vein recanalization was performed via the transmesenteric route in all cases. Twenty-two (78.6%) patients underwent successful recanalization and stent placement. They received oral anticoagulants after the procedure, and clinical symptoms subsided. Symptoms recurred due to portal vein restenosis/thrombosis in seven patients. On an intention-to-treat basis, the success rate of the proposed treatment was 60.7%. Only 17 out of 28 children with posttransplant chronic PVT retained stent patency (primary + assisted) at the end of the study period. In cases of portal vein obstruction, the transmesenteric approach via minilaparotomy is technically feasible with good clinical and hemodynamic results. It is an alternative procedure to reestablish the portal flow to the liver graft that can be performed in selected cases and a therapeutic addition to other treatment strategies currently used to treat chronic PVT.