Mesenchymal stromal cells induce regulatory T cells via epigenetic conversion of human conventional CD4 T cells in vitro.

Regulatory T cells (Treg) play a critical role in immune tolerance. The scarcity of Treg therapy clinical trials in humans has been largely due to the difficulty in obtaining sufficient Treg numbers. We performed a preclinical investigation on the potential of mesenchymal stromal cells (MSCs) to expand Treg in vitro to support future clinical trials. Human peripheral blood mononuclear cells from healthy donors were cocultured with allogeneic bone marrow-derived MSCs expanded under xenogeneic-free conditions. Our data show an increase in the counts and frequency of CD4+ CD25high Foxp3+ CD127low Treg cells (4- and 6-fold, respectively) after a 14-day coculture. However, natural Treg do not proliferate in coculture with MSCs. When purified conventional CD4 T cells (Tcon) are cocultured with MSCs, only cells that acquire a Treg-like phenotype proliferate. These MSC-induced Treg-like cells also resemble Treg functionally, since they suppress autologous Tcon proliferation. Importantly, the DNA methylation profile of MSC-induced Treg-like cells more closely resembles that of natural Treg than of Tcon, indicating that this population is stable. The expression of PD-1 is higher in Treg-like cells than in Tcon, whereas the frequency of PDL-1 increases in MSCs after coculture. TGF-β levels are also significantly increased MSC cocultures. Overall, our data suggest that Treg enrichment by MSCs results from Tcon conversion into Treg-like cells, rather than to expansion of natural Treg, possibly through mechanisms involving TGF-β and/or PD-1/PDL-1 expression. This MSC-induced Treg population closely resembles natural Treg in terms of phenotype, suppressive ability, and methylation profile

MAGIC: A European program to push the insertion of maskless lithography

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Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it?

Background and purpose: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. Methods: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. Results: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3–100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3–50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2–4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4–3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1–2.7, p = 0.012), compared to patients treated with other DMTs. Conclusions: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff

Nanopatterning of magnetic disks by single-step Ar+ Ion projection

Large-area Ar+ projection has been used to generate planar magnetic nanostructures on a 1¿-format hard disk in a single step (see Figure). The recording pattern was transferred to a Co/Pt multilayer without resist processes or any other contact to the delicate media surface. It is conceivable that magnetic nanostructures can be replicated from a single stencil mask on large quantities of disks for future high-density recording

Transcranial Magnetic Stimulation in the Differential Diagnosis of Unilateral Peripheral Facial Nerve Palsy

(1) Background: This study aims to assess the diagnostic accuracy of parameters based on a combination of transcranial magnetic stimulation (TMS) and electrical stimulation (ES) in the differentiation between idiopathic and secondary facial palsy in a large cohort of patients. (2) Methods: Patients with unilateral facial palsy ≤7 days after symptom onset were included. Compound muscle action potential (CMAP) amplitudes were measured after stimulation of both facial nerves at (A) the internal acoustic meatus using TMS, CMAP-TMS, and (B) at the stylomastoid foramen using electrical stimulation, CMAP-ES. To express the degree of nerve dysfunction in the facial canal specifically, the amplitude reduction of the CMAP-TMS in relation to CMAP-ES was calculated and expressed as a percentage (amplitude reduction over the facial canal, ARFC). Receiver Operating Characteristic (ROC) curves were constructed to assess the diagnostic accuracy of ARFC as a marker to discriminate between patients with idiopathic and secondary facial palsy. (3) Results: Data from 498 patient records were analyzed. Idiopathic facial palsy was diagnosed in 424 patients, and secondary facial palsy in 74 patients. The area under the ROC curve for ARFC was 0.398. (4) Conclusions: The overall diagnostic accuracy of this method to differentiate secondary from idiopathic facial palsy is low

Preoperative MRI is helpful but not sufficient to detect associated lesions in patients with chronic ankle instability

Purpose The aim of this study was to determine the reliability and validity of preoperative magnetic resonance imaging (MRI) scans for the detection of additional pathologies in patients with chronic ankle instability (CAI) compared to arthroscopic findings. Methods Preoperative MRI images of 30 patients were evaluated regarding articular and periarticular comorbidities and compared to intraoperative findings. The reliability of MRI was determined by calculating specificity, sensitivity, as well as positive and negative predictive values. The accuracy of the classification of cartilage lesions by Outerbridge and Berndt and Harty rating scales was determined by calculating the area under the receiver operating curve (AUC). Results In total, 72 additional pathologies were found arthroscopically compared to 73 lesions gathered from MRI images. Sensitivity ranged from 89% for peroneal tendinopathy to 28% for additional ligamentous lesions. Specificity ranged from 100% for anterolateral impingement, loose bodies and peroneal tendinopathy to 38% for additional ligamentous lesions. For cartilage lesions, sensitivity was at 91% and specificity was at 55% for the Outerbridge grading scale. For the Berndt and Harty classification system, sensitivity was at 91% and specificity was at 28%. Correlation of additional pathologies ranged from weak (r s = 0.48; p = 0.02) to moderate results (r s = 0.67; p < 0.001). Conclusion CAI is associated with a high incidence of additional pathologies. In some cases, MRI delivers insufficient results, which may lead to misinterpretation of present comorbidities. MRI is a helpful tool for preoperative evaluation, but arthroscopy remains gold standard in the diagnosis of associated lesions in patients with CAI. Level of evidence III.(VLID)359027

Multipath Curved Planar Reformations of Peripheral CT Angiography : Diagnostic Accuracy and Time Efficiency

Objectives To compare diagnostic performance and time efficiency between 3D multipath curved planar reformations (mpCPRs) and axial images of CT angiography for the pre-interventional assessment of peripheral arterial disease (PAD), with digital subtraction angiography as the standard of reference. Methods Forty patients (10 females, mean age 72 years), referred to CTA prior to endovascular treatment of PAD, were prospectively included and underwent peripheral CT angiography. A semiautomated toolbox was used to render mpCPRs. Twenty-one arterial segments were defined in each leg; for each segment, the presence of stenosis > 70% was assessed on mpCPRs and axial images by two readers, independently, with digital subtraction angiography as gold standard. Results Both readers reached lower sensitivity (Reader 1: 91 vs. 94%, p = 0.08; Reader 2: 89 vs. 93%, p = 0.03) but significantly higher specificity (Reader 1: 94 vs. 89%, p < 0.01; Reader 2: 96 vs. 95%, p = 0.01) with mpCPRs than with axial images. Reader 1 achieved significantly higher accuracy with mpCPRs (93 vs. 91%, p = 0.02), and Reader 2 had similar overall accuracy in both evaluations (94 vs. 94%, p = 0.96). Both readers read mpCPRs significantly faster than axial images (Reader 1: 5′45″ based on mpCPRs vs. 7′40″ based on axial images; Reader 2: 4′41″ based on mpCPRs vs. 6′57″ based on axial images; p < 0.01). Conclusions mpCPRs are a promising 3D reformation technique that facilitates a fast assessment of PAD with high diagnostic accuracy.(VLID)357824

Charged particle multi-beam lithography evaluations for sub-16nm hp mask node fabrication and wafer direct write

A detailed evaluation study has been performed with respect to the suitability of projection electron and ion multi-beam lithography for the fabrication of leading-edge complex masks. The study includes recent results as obtained with electron and ion multi-beam proof-of-concept systems with 200× reduction projection optics where patterns are generated on substrates using a programmable aperture plate system (APS) with integrated CMOS electronics, generating several thousands of well defined beams in parallel. A comparison of electron and ion projection multi-beam writing is provided, in particular with respect to the suitability to expose non-chemically amplified resist (non-CAR) materials. The extendibility of projection multi-beam technologies for 16nm hp, 11nm hp and 8nm hp mask nodes is discussed as well as for wafer direct write for 22nm hp and below