Evaluierung von quervernetztem nicht-isomerisierten carboxyterminalen Telopeptid desKollagens Typ I (alpha-CTX) als neuen Marker desKnochenstoffwechsels bei Patienten mit lokalisiertem,metastasiertem und hormonrefraktärem Prostatakarzinom

Das Skelett ist ein sehr häufig von Metastasen befallenes Organ und stellt beim Prostatakarzinom den primären Ort für ihr Auftreten dar. Die Mehrzahl der an Krebs erkrankten Patienten verstirbt nicht am Primärtumor selbst, sondern häufiger an den Folgen der Metastasierung. Die metastatische Osteopathie beeinflusst, aufgrund stark erhöhter Morbidität bei deutlich reduzierter Lebensqualität, entscheidend den Krankheitsverlauf der Patienten. Neben den zahlreichen Folgen der Knochenmetastasierung für die Prostatakarzinompatienten, wie Schmerzen, pathologischen Frakturen mit zum Teil einhergehender Querschnittssymptomatik und karzinomassoziierter Hyperkalzämie, stellt die Diagnostik und Therapie nicht nur eine große Herausforderung an den Urologen, sondern wegen des oft langen Krankheitsverlaufs, auch an die finanziellen Ressourcen unseres Gesundheitssystems. Eine frühzeitige Diagnostik und zeitnah einsetzende therapeutische Interventionen sind in der Behandlung von Knochenmetastasen zwar äußerst wünschenswert, jedoch anhand der derzeit verfügbaren diagnostischen Mittel nur beschränkt möglich. Zum Nachweis kleinster metastatischer Knochenabsiedlungen reicht die Sensitivität der etablierten radiologischen und szintigraphischen Verfahren nicht aus. Die humoral induzierte Tumorosteopathie ist morphologisch stumm und manifestiert sich oft erst im Spätstadium durch eine zufällig entdeckte Hyperkalzämie. Zum Zeitpunkt der Diagnosestellung ist sie oftmals schon weit fortgeschritten und bietet für eine dann einsetzende pharmakologische Therapie ungünstige Voraussetzungen. Die Entdeckung neuer spezifischer Biomarker des Knochenmetabolismus hat daher die Frage nach ihrer Nutzbarkeit hinsichtlich der Frühdiagnose von Knochenmetastasen aufgeworfen und sie in jüngster Zeit ins Zentrum onkologischer Forschung gestellt. Hierbei ist nicht nur der diagnostische Aspekt von Interesse, sondern gleichwohl die Aussagekraft der Parameter für die anschließende antiosteolytische Behandlung. Zusammenfassend lassen sich aus den hier vorliegenden Ergebnissen folgende Aussagen treffen: Urin-Alpha-CTX (quervernetztes nicht-isomerisiertes carboxyterminales Telopeptid des Kollagens Typ I, alpha-CTX) zeigte bei hormonrefraktären Prostatakarzinom-Patienten (HRPCA) mit Knochenmetastasen den größten Anstieg im Vergleich zu Patienten ohne Knochenmetastasen. Dieser Parameter scheint somit nützliche Zusatzinformationen zu liefern, um die Ausdehnung des Tumors hinsichtlich möglicher ossärer Fernmetastasen zu bewerten. Weiterhin zeigte der Urin-Marker keine Beeinflussung durch die chemotherapeutische Docetaxel-Therapie bei Patienten ohne Knochenmetastasen (-BM), jedoch konnte in der HRPCA-Gruppe mit Knochenmetastasen (+BM) unter kombinierter Docetaxel/Zoledronsäure-Behandlung eine signifikante Abnahme der Alpha-CTX-Levels beobachtet werden. Die Ergebnisse unterstreichen die Wertigkeit und Spezifität dieses neuen Urinmarkers zum Monitoring einer „bone targeting“-Therapie. Alpha-CTX war zugleich der einzige Marker, dessen Verlauf sich als unabhängig vom Primärtumor der Prostata erwies. Ein signifikanter Anstieg des Parameters konnte erst bei Patienten mit metastatischen Absiedlungen in Lymphknoten (N1M0) beobachtet werden. Das lässt darauf schließen, dass Alpha-CTX für die Erkennung von Patienten mit lokal fortgeschrittenem Prostatakarzinom, die bereits ein hohes Risiko für versteckte ossäre Mikrometastasen haben, einen sinnvollen Stellenwert einnehmen könnte. Trotzdem muss vor Etablierung dieses neuen Biomarkers in der klinischen Praxis im Rahmen von Longitudinaluntersuchungen geklärt werden, inwieweit die erhöhten Alpha-CTX-Levels bei N1M0-Patienten, welche eine Hochrisikogruppe darstellen, auf bereits vorhandene, aber durch die Bildgebung nicht detektierbare Knochenabsiedlungen hinweisen. Überdies bleibt es zukünftigen Untersuchungen vorbehalten zu klären, ob bildgebende Verfahren, insbesondere die Szintigraphie, durch den Einsatz von ossären Biomarkern zur frühzeitigen Detektion einer Knochenmetastasierung bei Patienten mit malignen Neoplasien ersetzt werden können. Ein paralleles Monitoring von Biomarkern und röntgenologischen Techniken an einem großen Pool von Prostatakarzinompatienten wäre notwendig, um das vielversprechende Potential von Alpha-CTX sowie anderer Knochenstoffwechselparameter weiter zu untermauern

ECoG Beta Suppression and Modulation During Finger Extension and Flexion

Neural oscillations originate predominantly from interacting cortical neurons and consequently reflect aspects of cortical information processing. However, their functional role is not yet fully understood and their interpretation is debatable. Amplitude modulations (AMs) in alpha (8–12 Hz), beta (13–30 Hz), and high gamma (70–150 Hz) band in invasive electrocorticogram (ECoG) and non-invasive electroencephalogram (EEG) signals change with behavior. Alpha and beta band AMs are typically suppressed (desynchronized) during motor behavior, while high gamma AMs highly correlate with the behavior. These two phenomena are successfully used for functional brain mapping and brain-computer interface (BCI) applications. Recent research found movement-phase related AMs (MPA) also in high beta/low gamma (24–40 Hz) EEG rhythms. These MPAs were found by separating the suppressed AMs into sustained and dynamic components. Sustained AM components are those with frequencies that are lower than the motor behavior. Dynamic components those with frequencies higher than the behavior. In this paper, we study ECoG beta/low gamma band (12–30 Hz/30–42 Hz) AM during repetitive finger movements addressing the question whether or not MPAs can be found in ECoG beta band. Indeed, MPA in the 12–18 Hz and 18–24 Hz band were found. This additional information may lead to further improvements in ECoG-based prediction and reconstruction of motor behavior by combining high gamma AM and beta band MPA

A Population Based Regional Dynamic Microsimulation of Germany: The MikroSim Model

Microsimulation models are widely used to evaluate the potential effects of different policies on social indicators. Most microsimulation models in use operate on a national level, disregarding regional variations. We describe the construction of a national microsimulation model for Germany, accounting for local variations in each of the more than 10,000 communities in Germany. The database used and the mechanisms implementing the population dynamics are described. Finally, the further development of the database and microsimulation programs are outlined, which will contribute towards a research lab that will be made available to the wider scientific community

Age-Related Changes of Peak Width Skeletonized Mean Diffusivity (PSMD) Across the Adult Lifespan: A Multi-Cohort Study

Parameters of water diffusion in white matter derived from diffusion-weighted imaging (DWI), such as fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, and RD), and more recently, peak width of skeletonized mean diffusivity (PSMD), have been proposed as potential markers of normal and pathological brain ageing. However, their relative evolution over the entire adult lifespan in healthy individuals remains partly unknown during early and late adulthood, and particularly for the PSMD index. Here, we gathered and analyzed cross-sectional diffusion tensor imaging (DTI) data from 10 population-based cohort studies in order to establish the time course of white matter water diffusion phenotypes from post-adolescence to late adulthood. DTI data were obtained from a total of 20,005 individuals aged 18.1 to 92.6 years and analyzed with the same pipeline for computing skeletonized DTI metrics from DTI maps. For each individual, MD, AD, RD, and FA mean values were computed over their FA volume skeleton, PSMD being calculated as the 90% peak width of the MD values distribution across the FA skeleton. Mean values of each DTI metric were found to strongly vary across cohorts, most likely due to major differences in DWI acquisition protocols as well as pre-processing and DTI model fitting. However, age effects on each DTI metric were found to be highly consistent across cohorts. RD, MD, and AD variations with age exhibited the same U-shape pattern, first slowly decreasing during post-adolescence until the age of 30, 40, and 50 years, respectively, then progressively increasing until late life. FA showed a reverse profile, initially increasing then continuously decreasing, slowly until the 70s, then sharply declining thereafter. By contrast, PSMD constantly increased, first slowly until the 60s, then more sharply. These results demonstrate that, in the general population, age affects PSMD in a manner different from that of other DTI metrics. The constant increase in PSMD throughout the entire adult life, including during post-adolescence, indicates that PSMD could be an early marker of the ageing process

New constraint on cosmological variation of the proton-to-electron mass ratio from Q0528-250

Molecular hydrogen transitions in quasar spectra can be used to constrain variation in the proton-to-electron mass ratio, $\mu\equiv m_p/m_e$, at high redshifts ($z\gtrsim 2$). We present here an analysis of a new spectrum of the quasar Q0528$-$250, obtained on VLT/UVES (the Ultraviolet and Visual Echelle Spectrograph, on the Very Large Telescope), and analyse the well-known H$_2$ absorber at $z=2.811$ in this spectrum. For the first time we detect HD (deuterated molecular hydrogen) in this system with a column density of $\log_{10}(N/\mathrm{cm^{-2}})=13.27 \pm 0.07$; HD is sensitive to variation in $\mu$, and so we include it in our analysis. Using 76 H$_2$ and 7 HD transitions we constrain variation in $\mu$ from the current laboratory value to be $\Delta\mu/\mu = (0.3\pm 3.2_\mathrm{stat} \pm 1.9_\mathrm{sys})\times 10^{-6}$, which is consistent with no cosmological variation in $\mu$, as well as with previous results from other H$_2$/HD absorbers. The main sources of systematic uncertainty relate to accurate wavelength calibration of the spectra and the re-dispersion of multiple telescope exposures onto the one pixel grid.Comment: 30 pages, 6 figures + 14 supplementary figures. Accepted for publication for MNRA

Premature termination, satisfaction with care, and shared decision-making during home treatment compared to inpatient treatment: A quasi-experimental trial

Abstract Background Inpatient equivalent home treatment (IEHT), implemented in Germany since 2018, is a specific form of home treatment. Between 2021 and 2022, IEHT was compared to inpatient psychiatric treatment in a 12-months follow-up quasi-experimental study with two propensity score matched cohorts in 10 psychiatric centers in Germany. This article reports results on the treatment during the acute episode and focuses on involvement in decision-making, patient satisfaction, and drop-out rates. Methods A total of 200 service users receiving IEHT were compared with 200 matched statistical “twins” in standard inpatient treatment. Premature termination of treatment as well as reasons for this was assessed using routine data and a questionnaire. In addition, we measured patient satisfaction with care with a specific scale. For the evaluation of patient involvement in treatment decisions, we used the 9-item Shared Decision Making Questionnaire (SDM-Q-9). Results Patients were comparable in both groups with regard to sociodemographic and clinical characteristics. Mean length-of-stay was 37 days for IEHT and 28 days for inpatient treatment. In both groups, a similar proportion of participants stopped treatment prematurely. At the end of the acute episode, patient involvement in decision-making (SDM-Q-9) as well as treatment satisfaction scores were significantly higher for IEHT patients compared to inpatients. Conclusions Compared to inpatient care, IEHT treatment for acute psychiatric episodes was associated with higher treatment satisfaction and more involvement in clinical decisions

Risk governance in organizations

Dieses Buch dokumentiert 10 Jahre Risk-Governance-Forschung an der Universität Siegen. In 50 Beiträgen reflektieren Forscher und Praktiker Risk Governance vor dem Hintergrund ihrer eigenen Forschungen und/oder Erfahrungen und geben jeweils einen Entwicklungsimpuls für die Zukunft der Risk Governance. Das Buch zeigt die große Bandbreite und Tiefe des Forschungsgebietes auf und diskutiert Grundannahmen, Implementierungsfragen, die Rolle der Risk Governance als Transformationsmotor, ihre Wirkung in den verschiedenen betrieblichen Funktionen, Entwicklungsperspektiven und den Beitrag der Risk Governance zu einer nachhaltigen Ausrichtung von Unternehmen.This book documents 10 years of risk governance research at the University of Siegen. In 50 contributions, researchers and practitioners reflect on risk governance against the background of their own research and/or experience and provide a development impetus for the future of risk governance. The book shows the wide range and depth of the research field and discusses basic assumptions, implementation issues, the role of risk governance as transformation engine, its impact in the various operational functions, development perspectives, and the contribution of risk governance to a sustainable orientation of companies

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.Etude de cohorte sur la santé des étudiantsStopping cognitive decline and dementia by fighting covert cerebral small vessel diseaseStudy on Environmental and GenomeWide predictors of early structural brain Alterations in Young student

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22824 adults

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging