Non-Destructive Testing Inspection for Metal Components Produced Using Wire and Arc Additive Manufacturing

Funding Information: JPO acknowledges funding by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the projects LA/P/0037/2020. This activity has received funding from the European Institute of Innovation and Technology (EIT)—Project Smart WAAM: Microstructural Engineering and Integrated Non-Destructive Testing. This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme. Publisher Copyright: © 2023 by the authors.The wire and arc additive manufacturing (WAAM) process enables the creation and repair of complex structures based on the successive deposition of fed metal in the form of a wire that is fused with an electric arc and then solidifies. The high number of depositions required to create or repair parts increases the likelihood of defect formation. If these are reliably detected during manufacturing, timely correction is possible. However, high temperatures and surface irregularity make inspection difficult. Furthermore, depending on the size, morphology, and location of the defect, the part can be rejected. Recent studies have shown that non-destructive testing (NDT) based on different physical phenomena for the timely, reliable, and customized detection of defects can significantly reduce the rejection rate and allow in-line repair, which consequently reduces waste and rework. This paper presents the latest developments in NDT for WAAM and its limitations and potential.publishersversionpublishe

Salting-out approach is worthy of comparison with ultracentrifugation for extracellular vesicle isolation from tumor and healthy models

The role of extracellular vesicles (EVs) has been completely re-evaluated in the recent decades, and EVs are currently considered to be among the main players in intercellular commu-nication. Beyond their functional aspects, there is strong interest in the development of faster and less expensive isolation protocols that are as reliable for post-isolation characterisations as already-established methods. Therefore, the identification of easy and accessible EV isolation techniques with a low price/performance ratio is of paramount importance. We isolated EVs from a wide spectrum of samples of biological and clinical interest by choosing two isolation techniques, based on their wide use and affordability: ultracentrifugation and salting-out. We collected EVs from human cancer and healthy cell culture media, yeast, bacteria and Drosophila culture media and human fluids (plasma, urine and saliva). The size distribution and concentration of EVs were measured by nanoparticle tracking analysis and dynamic light scattering, and protein depletion was measured by a colori-metric nanoplasmonic assay. Finally, the EVs were characterised by flow cytometry. Our results showed that the salting-out method had a good efficiency in EV separation and was more efficient in protein depletion than ultracentrifugation. Thus, salting-out may represent a good alternative to ultracentrifugation

Hydroxy-propil-β-cyclodextrin inclusion complexes of two biphenylnicotinamide derivatives: Formulation and anti-proliferative activity evaluation in pancreatic cancer cell models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with poor outcomes largely due to its unique microenvironment, which is responsible for the low response to drugs and drug-resistance phenomena. This clinical need led us to explore new therapeutic approaches for systemic PDAC treatment by the utilization of two newly synthesized biphenylnicotinamide derivatives, PTA73 and PTA34, with remarkable antitumor activity in an in vitro PDAC model. Given their poor water solubility, inclusion complexes of PTA34 and PTA73 in Hydroxy-Propil-β-Cyclodextrin (HP-β-CD) were prepared in solution and at the solid state. Complexation studies demonstrated that HP-β-CD is able to form stable host–guest inclusion complexes with PTA34 and PTA73, characterized by a 1:1 apparent formation constant of 503.9 M−1 and 369.2 M−1, respectively (also demonstrated by the Job plot), and by an increase in aqueous solubility of about 150 times (from 1.95 µg/mL to 292.5 µg/mL) and 106 times (from 7.16 µg/mL to 762.5 µg/mL), in the presence of 45% w/v of HP-β-CD, respectively. In vitro studies confirmed the high antitumor activity of the complexed PTA34 and PTA73 towards PDAC cells, the strong G2/M phase arrest followed by induction of apoptosis, and thus their eligibility for PDAC therapy

Combined intravenous and endovascular treatment versus primary mechanical thrombectomy. The Italian Registry of Endovascular Treatment in Acute Stroke

Background: Whether mechanical thrombectomy alone may achieve better or at least equal clinical outcome than mechanical thrombectomy combined with intravenous thrombolysis is a matter of debate. Methods: From the Italian Registry of Endovascular Stroke Treatment, we extracted all cases treated with intravenous thrombolysis followed by mechanical thrombectomy or with primary mechanical thrombectomy for anterior circulation stroke due to proximal vessel occlusion. We included only patients who would have qualified for intravenous thrombolysis. We compared outcomes of the two groups by using multivariate regression analysis and propensity score method. Results: We included 1148 patients, treated with combined intravenous thrombolysis and mechanical thrombectomy therapy (n = 635; 55.3%), or with mechanical thrombectomy alone (n = 513; 44.7%). Demographic and baseline clinical characteristics did not differ between the two groups, except for a shorter onset to groin puncture time (p < 0.05) in the mechanical thrombectomy group. A shift in the 90-day modified Rankin Scale distributions toward a better outcome was found in favor of the combined treatment (adjusted common odds ratio = 1.3; 95% confidence interval: 1.04–1.66). Multivariate analyses on binary outcome show that subjects who underwent combined treatment had higher probability to survive with modified Rankin Scale 0–3 (odds ratio = 1.42; 95% confidence interval: 1.04–1.95) and lower case fatality rate (odds ratio = 0.6; 95% confidence interval: 0.44–0.9). Hemorrhagic transformation did not differ between the two groups. Conclusion: These data seem to indicate that combined intravenous thrombolysis and mechanical thrombectomy could be associated with lower probability of death or severe dependency after three months from stroke due to large vessel occlusion, supporting the current guidelines of treating eligible patients with intravenous thrombolysis before mechanical thrombectomy

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

Background In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.Methods This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.Findings 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.Interpretation The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Benign mammary epithelial cells enhance the transformed phenotype of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Recent research has yielded a wealth of data underscoring the key role of the cancer microenvironment, especially immune and stromal cells, in the progression of cancer and the development of metastases. However, the role of adjacent benign epithelial cells, which provide initial cell-cell contacts with cancer cells, in tumor progression has not been thoroughly examined. In this report we addressed the question whether benign MECs alter the transformed phenotype of human breast cancer cells.</p> <p>Methods</p> <p>We used both <it>in vitro </it>and <it>in vivo </it>co-cultivation approaches, whereby we mixed GFP-tagged MCF-10A cells (G2B-10A), as a model of benign mammary epithelial cells (MECs), and RFP-tagged MDA-MB-231-TIAS cells (R2-T1AS), as a model of breast cancer cells.</p> <p>Results</p> <p>The <it>in vitro </it>studies showed that G2B-10A cells increase the colony formation of R2-T1AS cells in both soft agar and clonogenicity assays. Conditioned media derived from G2B-10A cells enhanced colony formation of R2-T1AS cells, whereas prior paraformaldehyde (PFA) fixation of G2B-10A cells abrogated this enhancement effect. Moreover, two other models of benign MECs, MCF-12A and HuMECs, also enhanced R2-T1AS colony growth in soft agar and clonogenicity assays. These data reveal that factors secreted by benign MECs are responsible for the observed enhancement of the R2-T1AS transformed phenotype. To determine whether G2B-10A cells enhance the tumorigenic growth of co-injected R2-T1AS cells <it>in vivo</it>, we used the nude mouse xenograft assay. Co-injecting R2-T1AS cells with G2B-10A cells ± PFA-fixation, revealed that G2B-10A cells promoted a ~3-fold increase in tumor growth, irrespective of PFA pre-treatment. These results indicate that soluble factors secreted by G2B-10A cells play a less important role in promoting R2-T1AS tumorigenesis <it>in vivo</it>, and that additional components are operative in the nude mouse xenograft assay. Finally, using array analysis, we found that both live and PFA-fixed G2B-10A cells induced R2-T1AS cells to secrete specific cytokines (IL-6 and GM-CSF), suggesting that cell-cell contact activates R2-T1AS cells.</p> <p>Conclusions</p> <p>Taken together, these data shift our understanding of adjacent benign epithelial cells in the cancer process, from passive, noncontributory cells to an active and tumor-promoting vicinal cell population that may have significant effects early, when benign cells outnumber malignant cells.</p

Comparative effectiveness and safety of non-vitamin K antagonists for atrial fibrillation in clinical practice: GLORIA-AF Registry

Background and purpose: Prospectively collected data comparing the safety and effectiveness of individual non-vitamin K antagonists (NOACs) are lacking. Our objective was to directly compare the effectiveness and safety of NOACs in patients with newly diagnosed atrial fibrillation (AF). Methods: In GLORIA-AF, a large, prospective, global registry program, consecutive patients with newly diagnosed AF were followed for 3&nbsp;years. The comparative analyses for (1) dabigatran vs rivaroxaban or apixaban and (2) rivaroxaban vs apixaban were performed on propensity score (PS)-matched patient sets. Proportional hazards regression was used to estimate hazard ratios (HRs) for outcomes of interest. Results: The GLORIA-AF Phase III registry enrolled 21,300 patients between January 2014 and December 2016. Of these, 3839 were prescribed dabigatran, 4015 rivaroxaban and 4505 apixaban, with median ages of 71.0, 71.0, and 73.0&nbsp;years, respectively. In the PS-matched set, the adjusted HRs and 95% confidence intervals (CIs) for dabigatran vs rivaroxaban were, for stroke: 1.27 (0.79–2.03), major bleeding 0.59 (0.40–0.88), myocardial infarction 0.68 (0.40–1.16), and all-cause death 0.86 (0.67–1.10). For the comparison of dabigatran vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 1.16 (0.76–1.78), myocardial infarction 0.84 (0.48–1.46), major bleeding 0.98 (0.63–1.52) and all-cause death 1.01 (0.79–1.29). For the comparison of rivaroxaban vs apixaban, in the PS-matched set, the adjusted HRs were, for stroke 0.78 (0.52–1.19), myocardial infarction 0.96 (0.63–1.45), major bleeding 1.54 (1.14–2.08), and all-cause death 0.97 (0.80–1.19). Conclusions: Patients treated with dabigatran had a 41% lower risk of major bleeding compared with rivaroxaban, but similar risks of stroke, MI, and death. Relative to apixaban, patients treated with dabigatran had similar risks of stroke, major bleeding, MI, and death. Rivaroxaban relative to apixaban had increased risk for major bleeding, but similar risks for stroke, MI, and death. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01468701, NCT01671007. Date of registration: September 2013