Plasma synthetic jet actuators for biological indirect treatment: the role of the charged particles

Plasma Synthetic Jet Actuators (PSJA) have demonstrated their ability to produce a flow from the surface where the Dielectric Barrier Discharge (DBD) is ignited. This ionic wind is due to the Electro Hydro Dynamic (EHD) interaction. These fluid-dynamic actuators enhance the delivery of reactive species towards the target to be treated. The long-life charged particles are generated within the plasma region and then carried on by the induced flow. The disinfection efficacy of PSJA used to indirectly treat different pathogens was demonstrated. In particular, the inactivation effect of free charges advected by the ionic wind has been investigated. An assessment of the various factors that may affect the production and the effect of the free charges are analysed. It was observed that humidity rate weakly influences the charge deposition. Besides, the most notable effect is an increase of the deposition time for higher humidity rate. In addition, a higher applied electric field produces higher charge deposition rates. Moreover, different geometries and dielectric materials have been considered. Linear actuators have proven to be more effective in charge delivery with respect to annular actuators. The EHD interaction was measured also for a streamer corona discharge utilised for cancer cells treatment

Calcolo delle perdite AC in cavi superconduttori di tipo Cable in Conduit

ITER, International Thermonuclear Experimental Reactor, è un progetto internazionale che ha lo scopo di realizzare un reattore sperimentale, per dimostrare la fattibilità tecnica e scientifica della generazione di energia tramite fusione termonucleare controllata. La reazione di fusione è prevista in un tokamak, progettato per produrre 500 MW di potenza termica. Il plasma caldo, necessario alla reazione, deve essere confinato tramite l'uso di intensi campi magnetici. Questi campi, le cui linee di forza sono in direzione polidale e toroidale, sono generati da magneti superconduttori. Il cuore tecnologico dei magneti è costituito dai cavi superconduttori, in cui scorre la corrente necessaria a creare il campo magnetico. In questa tesi sono stati analizzati due cavi, uno per i magneti del campo toroidale e l’altro per il magnete del solenoide centrale, con lo scopo di calcolare le perdite in presenza di un campo magnetico variabile nel tempo e confrontare i dati sperimentali con i valori analitici. L’ambiente in cui sono stati testati, rappresentato dalla facility SULTAN, è stato riprodotto nel codice THELMA. Inoltre, è stata avviata e condotta una collaborazione, tuttora in corso, con un gruppo di ricerca del CEA, Commissione per l’Energia Atomica e le Energie Alternative, con sede a Cadarache, in Francia. Questo gruppo ha elaborato un ulteriore modello per il calcolo delle perdite AC, chiamato M-PAS, Multizone Partial Shielding. Lo scopo della collaborazione è quello di verificare che si ottengano dei risultati coincidenti nei due diversi modelli, analizzando un cavo rettilineo, del tipo CICC, sottoposto all'azione di un campo esterno uniforme nello spazio ma variabile nel tempo, con diverse condizioni al contorno. L’obbiettivo che questa tesi si propone, ovvero il calcolo dell’energia dissipata durante il normale funzionamento dei cavi superconduttori, risulta fondamentale per dimensionare il sistema di raffreddamento dei cavi

Simulation of urea-induced protein unfolding: A lesson from bovine β-lactoglobulin

To investigate the molecular mechanisms involved in the very initial stages of protein unfolding, we carried out one long (1μs) simulation of bovine β-lactoglobulin (BLG) together with three (500 ns) supporting MD runs, in which the unfolding conditions were produced by adding the osmolyte urea to the simulated systems and/or by increasing the thermal energy raising the temperature from 300 to 350 K. BLG was chosen, since it is a well-characterized model protein, for which structural and folding properties have been widely investigated by X-ray and NMR. MD trajectories were analyzed not only in terms of standard progress variables, such as backbone H-bonds, gyration radius width, secondary structure elements, but also through the scrutiny of interactions and dynamical behavior of specific key residues previously pointed out and investigated by NMR and belonging to a well known hydrophobic cluster. MD trajectories simulated in different unfolding conditions suggest that urea destabilizes BLG structure weakening protein::protein hydrophobic interactions and the hydrogen bond network. The early unfolding events, better observed at higher temperature, affect both secondary and tertiary structure of the protein. © 2011 Elsevier Inc. All rights reserved

Human iPS-Derived Astroglia from a Stable Neural Precursor State Show Improved Functionality Compared with Conventional Astrocytic Models

Summary: In vivo studies of human brain cellular function face challenging ethical and practical difficulties. Animal models are typically used but display distinct cellular differences. One specific example is astrocytes, recently recognized for contribution to neurological diseases and a link to the genetic risk factor apolipoprotein E (APOE). Current astrocytic in vitro models are questioned for lack of biological characterization. Here, we report human induced pluripotent stem cell (hiPSC)-derived astroglia (NES-Astro) developed under defined conditions through long-term neuroepithelial-like stem (ltNES) cells. We characterized NES-Astro and astrocytic models from primary sources, astrocytoma (CCF-STTG1), and hiPSCs through transcriptomics, proteomics, glutamate uptake, inflammatory competence, calcium signaling response, and APOE secretion. Finally, we assess modulation of astrocyte biology using APOE-annotated compounds, confirming hits of the cholesterol biosynthesis pathway in adult and hiPSC-derived astrocytes. Our data show large diversity among astrocytic models and emphasize a cellular context when studying astrocyte biology. : Human studies can typically not be used to understand cellular functions of the brain. Astrocytes, important for neuronal circuit regulation and support, lack cellular model characterization and biological translation. Falk, Herland, and colleagues report striking differences in astrocyte models. A pilot screen of Alzheimer's disease-related drugs demonstrates dependence between compound hit finding and astrocytic model biology. Keywords: astrocytes, induced pluripotent stem cells, cell differentiation, glutamate plasma membrane transport proteins, neuroinflammation, calcium signaling, apolipoproteins E, high-throughput screening assays, neurodegenerative diseases, drug discover

Development of a new generic analytical modeling of AC coupling losses in cable-in-conduit conductors

Coupling losses induced in CICCs when subject to a time-varying magnetic field are a major issue commonly encountered in large fusion tokamaks (e.g. JT-60SA, ITER, DEMO). The knowledge of these losses is crucial to determine the stability of CICCs but is yet difficult to achieve analytically (thus in a short computation time) given the specific and complex architecture of these conductors although numerical solutions such as THELMA and JACKPOT already exists. In an attempt to ease the resolution of this problem, we have previously presented a theoretical generic study of a group of elements twisted together (representing a cabling stage of a CICC) and derived the analytical expression of its coupling losses. We have now extended this study to a two cabling stage conductor by establishing an analytical model to calculate its coupling losses as function of its effective features. In a second part, we compare our results to these of THELMA and JACKPOT on geometries representing ITER CS and JT-60SA TF conductors. Finally, we have set up a specific algorithm to reconstruct strand trajectories from X-ray images and have extracted the effective geometrical parameters of a JT-60SA TF conductor

Predictors of hypogammaglobulinemia in ANCA-associated vasculitis after a rituximab-based induction : a multicentre study

OBJECTIVES: Rituximab has become the cornerstone of induction treatment in ANCA-associated vasculitis (AAV). B cell depletion may increase the risk of hypogammaglobulinemia, potentially leading to severe infections. This study aims to assess factors associated with hypogammaglobulinemia in AAV patients treated with rituximab.METHODS: This retrospective cohort study included AAV patients treated with rituximab induction in 14 European centers. Severe adverse events (SAEs) were defined as episodes requiring hospitalization or intravenous antibiotics, malignancies, or death. Linear and logistic regression were used to identify predictors of IgG levels and of the risk of hypogammaglobulinemia, defined as IgG ≤7 g/l at 6 months.RESULTS: The study included 227 patients. IgG levels at 6 months were lower than baseline (p< 0.001). Patients requiring intravenous antibiotics during the first 6 months had lower IgG levels at 6 months (p= 0.004). Age (β [95%CI]: -0.23 [-0.38;-0.08] per 10 years, p= 0.003), oral glucocorticoid dose at induction (β [95%CI]:-0.37[-0.51;-0.24] per sqrt-transformed mg prednisone, p< 0.001) and concomitant use of intravenous glucocorticoid pulses (β [95%CI]:-0.88[-1.73;-0.02], p= 0.044) were associated with IgG levels at 6 months. Hypogammaglobulinemia was identified in 97 (42.7%) patients. In multivariable logistic regression, factors associated with the risk of hypogammaglobulinemia were age (OR [95%CI]: 1.46 [1.15; 1.86] per 10 years, p= 0.002) and oral glucocorticoid dose at induction (OR [95%CI]: 1.52[1.23; 1.89] per 10 mg prednisone, p< 0.001).CONCLUSIONS: In AAV patients treated with rituximab, hypogammaglobulinemia at 6 months after induction is common, and lower IgG levels are associated with serious infections. The risk of hypogammaglobulinemia in these patients increases with age and higher glucocorticoid doses

Reducing salt intake by urine chloride self-measurement in non-compliant patients with chronic kidney disease followed in nephrology clinics: a randomized trial

Adherence to low salt diets and control of hypertension remain unmet clinical needs in chronic kidney disease (CKD) patients

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

A multi-country analysis of COVID-19 hospitalizations by vaccination status

Background: Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease&nbsp;that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes. Methods: Here, we use data from an international consortium to study this&nbsp;question and assess whether differences between these groups are&nbsp;context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed. Findings: While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed. Conclusions: These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history. Funding: This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill&nbsp;&amp; Melinda Gates&nbsp;Foundation (OPP1209135); and the philanthropic support of the donors&nbsp;to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics