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Abstract Background Intranasal (i.n.) drug application is a widely known and low-invasive route of administration that may be able to achieve rapid symptom control in terminally ill patients. According to the German S3 guideline “Palliative care for patients with incurable cancer”, benzodiazepines, such as midazolam, are recommended for the treatment of terminal agitation. To the best of our knowledge there is no evidence for i.n. midazolam in terminally ill patients. We aim to assess the use of i.n. midazolam as an alternative to subcutaneous administration of the drug. Methods In this monocentric, randomised, controlled, open-label investigator initiated trial, n = 60 patients treated at the palliative care unit of a University Hospital will be treated with 5 mg midazolam i.n. versus 5 mg subcutaneous (s.c.) midazolam in the control arm when terminal agitation occurs (randomly assigned 1:1). The estimated recruitment period is 18 months. Treatment efficacy is defined as an improvement on the Richmond Agitation Sedation Scale (Palliative Version) (RASS-PAL) and a study specific numeric rating scale (NRS) before and after drug administration. Furthermore, plasma concentration determinations of midazolam will be conducted at t1 = 0 min, t2 = 5 min, and t3 = 20 min using liquid chromatography/mass spectrometry (LC-MS). The primary objective is to demonstrate non-inferiority of midazolam i.n. in comparison to midazolam s.c. for the treatment of agitation in terminally ill patients. Discussion Midazolam i.n. is expected to achieve at least equivalent reduction of terminal agitation compared to s.c. administration. In addition, plasma concentrations of midazolam i.n. are not expected to be lower than those of midazolam s.c. and the dynamics of the plasma concentration with an earlier increase could be beneficial. Trial registration German Clinical Trials Registry DRKS00026775, registered 07.07.2022, Eudra CT No.: 2021-004789-36.

Perturbation of thyroid hormone (T4) synthesis is known to cause numerous developmental, metabolic, and cognitive disorders in humans. Due to species differences in sensitivity to chemical exposures, there is a need for human-based in vitro approaches that recapitulate thyroid cellular architecture and T4 production when screening. To address these limitations, primary human thyrocytes, isolated from healthy adult donor tissues and cryopreserved at passage one (p’1) were characterized for cellular composition, 3D follicular architecture, and thyroglobulin (TG)/T4 expression and inhibition by prototype thyroid disrupting chemicals (TDC). Flow analysis of the post-thaw cell suspension showed >80% EpCAM-positive cells with 10%–50% CD90-positive cells. When seeded onto 96-well Matrigel® -coated plates and treated with bovine thyroid stimulating hormone (TSH), thyrocytes formed 3D microtissues during the initial 4–5 days of culture. The microtissues exhibited a stable morphology and size over a 14-day culture period. TG and T4 production were highest in microtissues when the proportion of CD90-positive cells, seeding density and thyroid stimulating hormone concentrations were between 10%–30%, 6K–12K cells per well, and 0.03–1 mIU/mL, respectively. At maximal TG and T4 production levels, average microtissue diameters ranged between 50 and 200 µm. The T4 IC50 values for two prototype TPO inhibitors, 6-propyl-2-thiouracil and methimazole, were ~0.7 µM and ~0.5 µM, respectively, in microtissue cultures treated between days 9 and 14. Overall, p’1 cryopreserved primary human thyrocytes in 3D microtissue culture represent a promising new model system to prioritize potential TDC acting directly on the thyroid as part of a weight-of-evidence hazard characterization. [ABSTRACT FROM AUTHOR]

The transitional nuclei Xe132 and Xe133 are investigated after multinucleon-transfer (MNT) and fusion-evaporation reactions. Both nuclei are populated (i) in Xe136+Pb208 MNT reactions employing the high-resolution Advanced GAmma Tracking Array (AGATA) coupled to the magnetic spectrometer PRISMA, (ii) in the Xe136+Pt198 MNT reaction employing the GAMMASPHERE spectrometer in combination with the gas-detector array CHICO, and (iii) as an evaporation residue after a Te130(α,xn)Xe134-xn fusion-evaporation reaction employing the HORUS γ-ray array at the University of Cologne. The high-spin level schemes are considerably extended above the Jπ=(7-) and (10+) isomers in Xe132 and above the 11/2- isomer in Xe133. The results are compared to the high-spin systematics of the Z=54 as well as the N=78 and N=79 chains. Furthermore, evidence is found for a long-lived (T1/2â‰1μs) isomer in Xe133 which closes a gap along the N=79 isotones. Shell-model calculations employing the SN100PN and PQM130 effective interactions reproduce the experimental findings and provide guidance to the interpretation of the observed high-spin features.

The transitional nuclei Xe132 and Xe133 are investigated after multinucleon-transfer (MNT) and fusion-evaporation reactions. Both nuclei are populated (i) in Xe136+Pb208 MNT reactions employing the high-resolution Advanced GAmma Tracking Array (AGATA) coupled to the magnetic spectrometer PRISMA, (ii) in the Xe136+Pt198 MNT reaction employing the GAMMASPHERE spectrometer in combination with the gas-detector array CHICO, and (iii) as an evaporation residue after a Te130(α,xn)Xe134-xn fusion-evaporation reaction employing the HORUS γ-ray array at the University of Cologne. The high-spin level schemes are considerably extended above the Jπ=(7-) and (10+) isomers in Xe132 and above the 11/2- isomer in Xe133. The results are compared to the high-spin systematics of the Z=54 as well as the N=78 and N=79 chains. Furthermore, evidence is found for a long-lived (T1/2â‰1μs) isomer in Xe133 which closes a gap along the N=79 isotones. Shell-model calculations employing the SN100PN and PQM130 effective interactions reproduce the experimental findings and provide guidance to the interpretation of the observed high-spin features.

As part of the Synergetic Utilisation of CO2$_2$ storage Coupled with geothermal EnErgy Deployment project, investigating CO2$_2$ reinjection with different seismic methods, both passive and active seismic surveys have been conducted at the geothermal power plant at Hellisheiði, Iceland. During the 2021 survey, two geophone lines recorded noise for a week. We process the passive‐source data with seismic interferometry to image the subsurface structure around the CarbFix2 reinjection reservoir. To improve image quality, we perform an illumination analysis to select only noise panels dominated by body‐wave energy. The results show that most noise panels are dominated by air‐wave energy arriving from the direction of the power plant. We use panels with a near‐vertical incidence to create a zero‐offset image and a larger selection of body‐wave‐dominated panels to create virtual common‐shot gathers. We process the gathers with a simple reflection seismology processing workflow to obtain stacked images. The zero‐offset images show a relatively lower signal‐to‐noise ratio and only horizontal reflectors. The stacked images show slightly dipping reflectors and possibly lateral amplitude variations around the expected injection region. This could indicate a region of interest for future research into the reinjection reservoir. [ABSTRACT FROM AUTHOR]

Infusion of endothelial progenitor cells (EPCs), but not of mature endothelial cells (ECs), promotes neovascularization after ischemia. We performed a gene expression profiling of EPCs and ECs to identify genes, which might be important for the neovascularization capacity of EPCs. Intriguingly, the protease cathepsin L (CathL) was highly expressed in EPCs as opposed to ECs and is essential for matrix degradation and invasion by EPCs in vitro. CathL deficient mice showed impaired functional recovery after hind limb ischemia supporting the concept for an important role of CathL in postnatal neovascularization. Infused CathL deficient progenitor cells failed to home to sites of ischemia and to augment neovascularization. In contrast, over expression of CathL in mature ECs significantly enhanced their invasive activity and induced their neovascularization capacity in vivo. Taken together, CathL plays a crucial role for the integration of circulating EPCs into the ischemic tissue and is required for neovascularization mediated by EPCs.

Proton and deuteron production has been observed in S+S and S+Pb collisions at 200 A·GeV and in Pb+Pb reactions at 158 A·GeV at the CERN SPS accelerator. For Pb+Pb triton production was also measured. The p and d spectra as well as the p and t spectra were observed in similar rapidity ranges and over similar ranges of transverse momenta per nucleon, making it possible to interpret the cross sections of the composite particles in terms of coalescence mechanisms. Volumes of homogeneity were extracted and compared to pion-pair HBT interferometry results. Special attention is given to the dependence on transverse mass, centrality and rapidity.