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Thomas Wagener untersuchte die Wechseslwirkung von Einsamkeit und psychischen Erkrankungen in einer Psychiatrie. Hierzu befragte er 15 Patient:innen, mit 10 von ihnen führte er längere Interviews, wobei davon vier verschriftlicht und veröffentlicht wurden. Die nicht verschriftlichten Interviews dienten als ein Erfahrungsbericht, der den abgedruckten Interviews vorangestellt wurde. Ein besonderes Augenmerk lag auf den sozialen Interaktionen zwischen den Patient:innen und der sie umgebenen Gesellschaft, wie Familie, Freunde und Bekannte. Auch wurde die Rolle der modernen Psychiatrie und ihr Bezug zum gesellschaftlichen Umfeld ausgeleuchtet. Abschließend erfolgte eine Schlußfolgerung des Verfassers, in dem verschiedene Aussagen der Interviewten nocheinmal gegenüber gestellt wurden.

Introduction: Many patients do not benefit from immunotherapies targeting immune checkpoints such as PD(L)-1 due to a variety of resistance mechanisms. The AhR pathway is downstream of the Trp-IDO/TDO-Kyn axis. High levels of immune-suppressive AhR-activating ligands, such as kynurenine derived from IDO1/TDO2-expressing tumors, have been implicated as a potential resistance mechanism and are associated with poor responses to PD-1 therapies. Compared with inhibition of IDO1/TDO2 alone, direct AhR inhibition can block the activation of this transcription factor and may better counteract immune suppression. BAY2416964 is a novel, oral AhR inhibitor currently in a Phase I clinical trial in patients with solid tumors. Preclinically, BAY2416964 can block the activation of AhR by kynurenine and relieve its immune-suppressive effects, thereby restoring anti-tumor T-cell activity, reducing the level of inhibitory myeloid-derived suppressor cells and regulatory T cells, and improving the effectiveness of PD-1 blockade. We have analyzed PK and biomarker data from the ongoing monotherapy dose-escalation study to explore a potential optimal dose and schedule for effective AhR inhibition. Methods: PK data were intensely sampled from patients in 10 different groups with different dosing regimens (once and twice daily) and various food-intake scenarios. AhR downstream target gene expression after ex vivo kynurenic acid stimulation of patients’ peripheral blood mononuclear cells (PBMCs) was assessed. A population PK (popPK) model was developed and calibrated to characterize the PK of BAY2416964 across treatment groups. This model accounts for the non-linear relationship between dose and bioavailability as well as the effect of food intake. Results: The preliminary popPK model identified a non-linear relationship between the BAY2416964 dose and its (relative) bioavailability which was dependent on the respective food condition. The popPK model was able to describe the clinical BAY2416964 plasma exposures from all dose groups, including the effect of food intake. Ex vivo analysis of PBMCs showed inhibition of kynurenic acid-induced AhR downstream gene expression (such as CYP1A1, CYP1B1), suggesting effective in vivo target engagement in the doses tested. Conclusion: This modeling-based PK analysis along with target engagement in peripheral blood informed the posology to be tested in the dose-expansion part of the ongoing clinical trial. Citation Format: Kyriakos Papadopoulos, Michael Cecchini, Juanita S. Lopez, Dirk Jäger, Ki Young Chung, Michael Platten, Florian Prinz, Yuko Ishii, David Schaer, Ilona Gutcher, Gabriele Leder, Radost Pencheva, Thomas Wagener, Christian Scheerans, Carsten Zieschang, Andrea Wagner, Spyros Stamatelos, Ecaterina Dumbrava. Preliminary analysis of pharmacokinetic (PK) and target engagement biomarkers from a first in human phase 1 study of immunomodulatory aryl hydrocarbon receptor (AhR) inhibitor BAY2416964 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT276.

The present study examines a US Department of Defense (DOD) foreign language program using linear and logistic regression to model foreign language proficiency growth over three time intervals. The analysis demonstrates growth from start to finish for a program involving domestic immersion and study abroad and tests the ability of aptitude and achievement measures to predict that growth for a group of 80 students. The findings suggest that a measure of foreign language aptitude and a measure of quantitative aptitude differentiate learning outcomes for the intensive domestic immersion portion of the program while measures of quantitative aptitude and native language verbal aptitude differentiate later-stage learners on the study abroad portion of the program.

Ground motion intensity measures such as the peak ground acceleration (PGA) and the pseudo-spectral acceleration (PSA) at two sites due to the same seismic event are correlated. The spatial correlation needs to be considered when modeling ground-motion fields for seismic loss assessments, since it can have a significant influence on the statistical moments and probability distribution of aggregated seismic loss of a building portfolio. Empirical models of spatial correlation of ground motion intensity measures exist only for a few seismic regions in the world such as Japan, Taiwan and California, since for this purpose a dense observation network of earthquake ground motion is required. The Istanbul Earthquake Rapid Response and Early Warning System (IERREWS) provides one such dense array with station spacing of typically 2 km in the urban area of Istanbul. Based on the records of eight small to moderate ( M w 3.5– M w 5.1) events, which occurred since 2003 in the Marmara region, we establish a model of intra-event spatial correlation for PGA and PSA up to the natural period of 1.0 s. The results indicate that the correlation coefficients of PGA and short-period PSA decay rapidly with increasing interstation distance, resulting in correlation lengths of approximately 3–4 km, while correlation lengths at longer natural periods (above 0.5 s) exceed 6 km. Finally, we implement the correlation model in a Monte Carlo simulation to evaluate economic loss in Istanbul's district Zeytinburnu due to a M w 7.2 scenario earthquake.

0049-3848/$ see front matter © 2007 Elsevier Ltd. All rights reserv doi:10.1016/j.thromres.2007.12.012 patients had been immobile within 30days before DVT diagnosis [3]. In a prospective observational study with 189 patients conducted from 2001 to 2003 in a coronary care unit pulmonary embolism was significantly associated with immobilization (RR, 5.4; 95% CI, 2.0 to 14.4) [4]. In surgical patients immobility is part of postoperative and/or posttraumatic recovery. In medical patients immobility may be more complex. The surgical situation is mirrored only if there is a severe acute illness that first confines a previously healthy patient to his or her bed and is later followed by complete recovery. More often, though, the degree of immobility in medical patients varies due to comorbidity or the chronicity of the disease. Some authors use the expression “bedridden”, but it is not clearly stated whether their patients stayed in bed for 24h a day or what level of mobility they had. Even in the three large studies on DVT prophylaxis in medical patients (Medenox, Prevent, Artemis) the publications do not give a precise definition of immobility [5–7]. In a subgroup analysis of the Medenox trial immobility is defined “as an

Background. Darbepoetin alfa is a unique molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its � 3-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEpo), darbepoetin alfa maintains effective haemoglobin control at extended dose intervals compared with rHuEpo. This study assessed the efficacy and safety of unit doses of darbepoetin alfa for the treatment of renal anaemia. Methods. In this multicentre, prospective, open-label study, 1502 dialysis subjects maintained on stable rHuEpo treatment were switched to darbepoetin alfa at extended dose intervals by the same route of administration as previous rHuEpo therapy [intravenous (i.v.), n ¼ 900 or subcutaneous (s.c.), n ¼ 602]. Subjects receiving rHuEpo two (n ¼ 408, 27%) or three times (n ¼ 884, 59%) a week were switched to darbepoetin alfa once a week, and those receiving rHuEpo once a week (n ¼ 210, 14%) were switched to darbepoetin alfa once every 2 weeks. The unit doses of darbepoetin alfa (10–150mg) were titrated to maintain haemoglobin concentrations of 10–13 g/dl for 24 weeks. Results. Haemoglobin concentrations were maintained effectively in subjects regardless of whether they received darbepoetin alfa once a week or once every 2 weeks. The overall mean change in haemoglobin from baseline to the evaluation period (weeks 21–24) was þ0.10 g/dl [95% confidence interval (CI) 0.04± 0.17]. The mean haemoglobin concentration increased by 0.19 g/dl (95% CI 0.11±0.27) in subjects receiving i.v. darbepoetin alfa, and was unchanged (� 0.02 g/dl; 95% CI � 0.12 to 0.07) in patients treated with s.c. darbepoetin alfa. Subjects with baseline haemoglobin

Quantum mechanical calculations at the HF, MP2, DFT (B3LYP), and CCSD(T) levels of theory using quasi-relativistic effective core potentials for the metal and valence basis sets of DZP quality are reported for the transition metal complexes [M(P)(NH2)3] (1, 2), [M(PS)(NH2)3] (3, 4), [M(P)(NH2)3(NH3)] (5, 6), [M(P)(N3N)] (7, 8; N3N = [(HNCH2CH2)3N]3-), and [(M(PS)(NH2)3(NH3)] (9, 10) with M = Mo, W. The B3LYP-optimized geometries of 1−10 are in good agreement with experiment. Bond dissociation energies for the LnMP−S bonds calculated at B3LYP are 8−10 kcal/mol higher than the CCSD(T) values. The LnMP−S and M−NH3 bonds of 9 and 10 are predicted to be stronger than the respective bonds of 3−6. 31P NMR chemical shifts and the anisotropic components have been calculated using the IGLO and GIAO approaches. The results are in accord with experimental data. The bonding situation of the complexes has been analyzed with the help of the NBO partitioning scheme. The phosphido complexes LnMP have metal⋮P triple bonds,...

Quantum mechanical ab initio calculations are reported for the Cu and Cu+ complexes with acetylene and ethylene and for the dicopper-substituted ethylenes C2H2Cu2 and di- and tetracopper-substituted ethanes C2H4Cu2 and C2H2Cu4. The geometries were optimized at the MP2 level of theory while the bond energies are predicted at CCSD(T) using relativistic effective core potentials with valence basis sets of TZ + P quality for copper. The calculated copper-acetylene and copper-ethylene complexes have C2v symmetry, which is in agreement with experimental evidence. The metal-ligand bond energies of the charged species Cu+ (C2H2) (De = 40.6 kcal mol−1) and Cu+(C2H4) (De = 43.9 kcal mol−1) are significantly higher than predicted in most previous studies. The neutral complexes Cu(C2H2) and Cu(C2H4) are much more weakly bonded. There are four energy minima with C2v symmetry on the C2H2Cu2 potential energy surface which have rather strong CuC bonds. The geminal isomer of dicopper-substituted ethylene is 2.8 kcal mol−1 lower in energy than the trans form and 6.4 kcal mol−1 more stable than the cis form. The global minimum structure is an end-on bonded Cu2 complex with acetylene, which is 5.9 kcal mol−1 lower in energy than 1,1-dicopperethylene. Strong CuC bonds are also predicted for the dicopper- and tetracopper-substituted ethanes. Two energy minima are found on the C2H4Cu2 potential energy surface. The anti form of C2H4Cu2 is 4.5 kcal mol−1 lower in energy than the gauche form. There are also two energy minima on the C2H2Cu4 potential energy surface. The gauche form of tetracopperethane is calculated as only 0.3 kcal mol−1 more stable than the anti form. It is suggested that the deformed structure 5d of C2H2Cu4 with two copper atoms bridging the carbon atoms may be used as a model for the interactions between acetylene adsorbed on a copper(III) surface. The nature of the CuC bonding was analysed using the NBO partitioning scheme and the topological analysis of the electronic charge distribution. The charged complexes Cu+(C2H2) and Cu+ (C2H4) have a T-shaped rather than a cyclic electronic structure. They are held together mainly by Coulombic interactions. The neutral complexes Cu(C2H2) and Cu(C2H4) show cyclic electronic structures. The weak CuC bonds of the neutral complexes Cu(C2H2) and Cu(C2H4) are caused by dispersion forces. The rather strong CuC bonds of the copper-substituted ethylenes and ethanes are strongly polarized towards the carbon end. Relativistic effects yield clearly shorter CuC and CuCu bonds.

Retroviral insertion mutagenesis has been used extensively in vivo but not in vitro to induce and identify critical mutations during oncogenic progression and differentiation. We have developed a tissue culture system using the human, growth factor-dependent, hematopoietic precursor cell line TF-1 that permits the use of retroviral vectors to induce a large (up to 28-fold) increase in the mutation frequency to growth factor independence and thus the isolation of many mutants. The mutation frequency, as expected, is directly proportional to the number of retroviral insertions (2.2 x 10(-7) mutants per insertion). The mutant phenotypes can be subdivided into mutants that release growth factors and those that do not ("autonomous" mutants). The majority of growth factor-producing mutants release an unidentified ligand. A subset of the autonomous mutants shows alterations in expression of the alpha subunit of either the GM-CSF or the IL-3 receptor. One mutant expresses neither GM-CSF nor IL-3 alpha receptor chains, thus showing coordinate regulation of the alpha receptor subunits.