Facilitating relaxation and stress reduction in healthy participants through a virtual reality intervention: study protocol for a non-inferiority randomized controlled trial.

BACKGROUND: Repeated or chronic stress is considered a major source of disease, in terms of both somatic and mental illnesses. The prevention of stress-related disease by interventions for relaxation has thus increased societal relevance. In this randomized controlled non-inferiority trial, we will compare a newly developed virtual reality (VR) environment for relaxation to an active control group applying a freely chosen relaxation method. To test if our VR environment supports relaxation in a situation of acute stress, a standardized stress induction protocol will precede the relaxation phase. METHODS: One hundred healthy participants will be recruited from the University of Siegen and randomly assigned to the VR or the active control group that will be free to choose their own relaxation strategy. The multi-sensory VR includes visual, acoustic, and haptic features to induce a strong feeling of presence. The laboratory testing will comprise a baseline measurement, a stress induction, a relaxation intervention, and a recovery measurement. The primary outcomes are self-reported stress and relaxation measured with a visual analog scale (VAS) at pre- and post-baseline, at the start, middle, and end of the stress induction, at pre- and post-relaxation, at pre- and post-recovery, and in the evening of testing. Secondary outcomes are the physiological parameters, namely heart rate and heart rate variability, tonic skin conductance level as well as the number of non-specific skin conductance responses, systolic and diastolic blood pressure and respiratory rate recorded during the four experimental phases as well as state mood, and state rumination assessed at four time points (pre- and post-stress, post-relaxation, and in the evening of testing). Finally, post-event processing will be assessed after relaxation and in the evening of testing. Repeated measures ANOVAs will be performed to test for statistical effects of group, time, and group × time interaction. DISCUSSION: The newly developed, multi-sensory VR offers an intervention for relaxation without prior training. Its immersive character might increase efficacy compared to other relaxation methods, especially in situations of acute stress. Future directions could be the development of a mobile version of the VR to enhance accessibility for users. To achieve a transfer of training effects to real life, VR components should successively be eliminated until relaxation is practiced without guidance by the VR. TRIAL REGISTRATION: ISRCTN Registry ISRCTN11162338 . Retrospectively registered on January 22, 2021.

A Novel Approach to the Holistic 3D Characterization of Weld Seams-Paving the Way for Deep Learning-Based Process Monitoring.

In an industrial environment, the quality assurance of weld seams requires extensive efforts. The most commonly used methods for that are expensive and time-consuming destructive tests, since quality assurance procedures are difficult to integrate into production processes. Beyond that, available test methods allow only the assessment of a very limited set of characteristics. They are either suitable for determining selected geometric features or for locating and evaluating internal seam defects. The presented work describes an evaluation methodology based on microfocus X-ray computed tomography scans (µCT scans) which enable the 3D characterization of weld seams, including internal defects such as cracks and pores. A 3D representation of the weld contour, i.e., the complete geometry of the joint area in the component with all quality-relevant geometric criteria, is an unprecedented novelty. Both the dimensions of the weld seam and internal defects can be revealed, quantified with a resolution down to a few micrometers and precisely assigned to the welded component. On the basis of the methodology developed within the framework of this study, the results of the scans performed on the alloy AA 2219 can be transferred to other aluminum alloys. In this way, the data evaluation framework can be used to obtain extensive reference data for the calibration and validation of inline process monitoring systems employing Deep Learning-based data processing in the scope of subsequent work.

Conformationally constrained kappa receptor agonists: stereoselective synthesis and pharmacological evaluation of 6,8-diazabicyclo[3.2.2]nonane derivatives.

Three sets of stereoisomeric bicyclic kappa agonists with defined orientation of the pharmacophoric elements pyrrolidine and dichlorophenylacetamide were stereoselectively prepared and pharmacologically evaluated. Stereoselective reduction, reductive amination, and Mitsunobu inversions were the key steps for the establishment of the desired stereochemistry. The kappa affinity decreased in the following order depending on the N-substituent: CO(2)CH(3) > benzyl > COCH(2)CH(3). Bicyclic derivatives with (1S,2R,5R)-configuration showed the highest kappa receptor affinity, which led to dihedral angles of 97 degrees and 45 degrees for the N(pyrrolidine)-C-C-N(phenylacetamide) structural element. The most potent kappa agonist of this series was (+)-methyl (1S,2R,5R)-8-[2-(3,4-dichlorophenyl)acetyl]-2-(pyrrolidin-1-yl)-6,8-diazabicyclo[3.2.2]nonane-6-carboxylate (ent-23, WMS-0121) with an K(i) value of 1.0 nM. ent-23 revealed high selectivity against the other classical opioid receptors and related receptor systems. In the [(35)S]GTPgammaS-binding assay at human kappa-opioid receptors, ent-23 was proved to be a full agonist with the same EC(50) value (87 nM) as the prototypical full agonist U-69,593 (EC(50) = 80 nM).

Structure-affinity-relationship study of bicyclic sigma receptor ligands.

It was postulated that N(6)-allyl bicyclic derivatives 1 bind with N-8 at the proton donor site of the sigma(1) receptor and that a substituent in 2-position of the bicyclic framework 1 results in unfavorable steric interactions with the sigma(1) receptor protein. In order to support this hypothesis both enantiomers of 6-allyl-8-(4-methoxybenzyl)-6,8-diazabi-cyclo[3.2.2]non-2-ene (2/ent-2) and 6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane 3/ent-3 were synthesized stereoselectively. The (S,S)-configured enantiomers 2 and 3 are the eutomers with eudismic ratios of 31 and 4.8, respectively. Therefore, these enantiomers are used in the sigma(1) pharmacophore model. The N(6)-allyl derivative 2 with a double bond in the three carbon bridge adopts the orientation 2c with N-8 interacting with the sigma(1) receptor proton donor site (Fig. 2) resulting in slightly reduced steric interactions of the small double bond in 2/3-position. The almost C(2)-symmetric benzyl derivative 3 can adopt both orientations 2c and 2d at the sigma (1) receptor (N-8 or N-6 interacts with the sigma (1) receptor proton donor site) resulting in subnanomolar sigma(1) receptor affinity (K(i) = 0.91 nM).

Synthesis of bicyclic sigma receptor ligands with cytotoxic activity.

All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high sigma1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 muM the four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of sigma1 and sigma2 receptors.