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Background and Hypothesis Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). Study Design T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. Results Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. Conclusion Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

Various salt structures, such as diapirs and salt walls, are currently considered as potential locations for the long-term storage of radioactive waste. Yet many scientific questions need to be addressed before safety and integrity of such repositories can be ensured. In particular, the effect of cyclic glacial loading on the long-term stability of a potential nuclear waste repository needs to be investigated.In the first part of this study, we perform a series of simplified 2D thermo-hydro-mechanical model scenarios selected to cover the basic geometrical features of salt diapirs and walls. Our models include internal heterogeneities in the salt and faults in the salt and overburden. We consider various repository design schemes and investigate the effect of the radiogenic heat production on the deformation of the surrounding salt in a thermo-mechanically coupled manner. We explore the sensitivity of the results to variations in the physical rock properties and evaluate the potentially significant effect of the different dominant microphysical deformation mechanisms such as dislocation creep, dynamic recrystallization and pressure solution creep in salt.The second part of this study focuses on the parameterization of the relevant salt rheology that controls the viscoelastic response of the salt structure. We quantify the rock salt rheology in a probabilistic sense by implementing a statistical creep model. Here, we incorporate a priori constraints and observations from the microstructure and determine representative creep law parameters and associated uncertainties.Following this integrated approach, we aim to identify key model parameters and find characteristics of generic salt structures to assist the selection process of suitable salt structures.

ZusammenfassungEin 90-jähriger Mann verstarb durch protrahiertes Verbluten aus einer, mittels Rasierklinge minimal eröffneten, oberflächlichen Beinvene über der Patella und nachfolgender Manipulation. Dabei handelte es sich wahrscheinlich um einen Ast der V. saphena accessoria anterior. Es lag zunächst eine Fehleinschätzung durch den leichenschauhaltenden Arzt vor, der von einer gastrointestinalen Blutung als Todesursache ausging. Diese Einschätzung teilten die Kriminalbeamten aufgrund der Auffindesituation nicht. Begünstigend war eine vorbestehende Varikosis. Die Einnahme von Antikoagulanzien oder eine vorbestehende oder erworbene Gerinnungsstörung konnte nicht nachgewiesen bzw. eruiert werden. Bei Vorlage eines Abschiedsbriefes und Ausschluss fremder Gewalteinwirkungen oder einer Vergiftung kann plausibel von einem ungewöhnlichen suizidalen Ereignis ausgegangen werden. Es wird über die Auffindung sowie die Ergebnisse der Sektion und umfangreicher Zusatzuntersuchungen berichtet.

ZusammenfassungDie CT(Computertomographie)-Koronarangiographie (cCTA) ist bei Patienten mit niedriger und mittlerer Vortestwahrscheinlichkeit für eine koronare Herzkrankheit (KHK) eine sichere Möglichkeit zum nicht-invasiven Ausschluss signifikanter Koronarstenosen und ermöglicht darüber hinaus auch deren funktionelle und morphologische Beurteilung. Der Stellenwert der cCTA wurde durch die 2019 publizierte ESC(European Society of Cardiology)-Leitlinie zu Diagnose und Management des chronischen Koronarsyndroms gestärkt und hat dadurch eine erhebliche Aufwertung erfahren. Die Bestimmung des Agatston-Scores ist eine klinisch etablierte Methodik zur Quantifizierung des Koronarkalks und hat Einfluss auf die Einleitung einer medikamentösen Therapie. Durch Technologien wie die Einführung der EKG-kontrollierten Dosismodulation und der iterativen Bildrekonstruktion kann die cCTA mit hoher Bildqualität und niedriger Strahlendosis durchgeführt werden. Die alleinige anatomische Darstellung von Koronarstenosen wird derzeit um innovative Techniken wie die myokardiale CT-Perfusion oder CT-FFR (fraktionelle Flussreserve) erweitert, jedoch ist der klinische Stellenwert dieser Methoden noch nicht abschließend geklärt. Die cCTA könnte sich zu einem Weichensteller hinsichtlich der Indikationsstellung für eine invasive Koronardiagnostik/-intervention entwickeln.

In view of its heterogeneity, schizophrenia needs new diagnostic tools based on mechanistic biomarkers that would allow early detection. Complex interaction between genetic and environmental risk factors may lead to NMDAR hypofunction, inflammation and redox dysregulation, all converging on oxidative stress. Using computational analysis, the expression of 76 genes linked to these systems, known to be abnormally regulated in schizophrenia, was studied in skin-fibroblasts from early psychosis patients and age-matched controls (N = 30), under additional pro-oxidant challenge to mimic environmental stress. To evaluate the contribution of a genetic risk related to redox dysregulation, we investigated the GAG trinucleotide polymorphism in the key glutathione (GSH) synthesizing enzyme, glutamate-cysteine-ligase-catalytic-subunit (gclc) gene, known to be associated with the disease. Patients and controls showed different gene expression profiles that were modulated by GAG-gclc genotypes in combination with oxidative challenge. In GAG-gclc low-risk genotype patients, a global gene expression dysregulation was observed, especially in the antioxidant system, potentially induced by other risks. Both controls and patients with GAG-gclc high-risk genotype (gclcGAG-HR) showed similar gene expression profiles. However, under oxidative challenge, a boosting of other antioxidant defense, including the master regulator Nrf2 and TRX systems was observed only in gclcGAG-HR controls, suggesting a protective compensation against the genetic GSH dysregulation. Moreover, RAGE (redox/inflammation interaction) and AGMAT (arginine pathway) were increased in the gclcGAG-HR patients, suggesting some additional risk factors interacting with this genotype. Finally, the use of a machine-learning approach allowed discriminating patients and controls with an accuracy up to 100%, paving the way towards early detection of schizophrenia.

Zusammenfassung Hintergrund Die Androgendeprivationstherapie (ADT) mit einem GnRH-Agonisten (Gonadotropin-releasing-Hormon) oder -Antagonisten stellt einen zentralen Bestandteil der Behandlung des Prostatakarzinoms (PCa) dar. Über die Faktoren, welche die Wahl der ADT beeinflussen, ist bis jetzt wenig bekannt. Ziele der Arbeit Faktoren, welche die Wahl der ADT bei Patienten mit hormonsensitivem PCa beeinflussen, werden identifiziert. Vom Urologen zur Identifizierung von Begleiterkrankungen genutzte Informationsquellen sowie deren Prävalenzen werden bestimmt. Methoden Die zweiarmige, prospektive, nicht-interventionelle Studie „ProComD“ wurde von Sept. 2014 bis Juni 2019 an 80 Studienzentren in Deutschland durchgeführt. Patienten mit hormonnaivem PCa und Notwendigkeit einer ADT wurden nach erfolgter Therapieentscheidung in die Studie eingeschlossen. Fragen bezüglich Informationsquelle und Therapieentscheidung wurden vom Arzt direkt im elektronischen Datenerfassungssystem (eCRF) beantwortet. Ergebnisse Es wurden Daten von 413 Patienten ausgewertet (Degarelix n = 268; GnRH-Agonisten n = 145). Ausschlaggebend für die Therapieentscheidung waren für beide Behandlungsgruppen u. a. die Faktoren Komorbiditäten (bei 42 % aller Patienten), Compliance (64 %) und Alter (81 %). Die häufigste konsultierte Informationsquelle bzgl. vorhandener Komorbiditäten ist die Anamnese durch den behandelnden Urologen selbst (68,5 % in beiden Gruppen). Bei Patienten mit kardiovaskulären Vorerkrankungen wurde zusätzlich der Arztbrief (45,8 % Degarelix vs. 38,9 % GnRH-Agonisten) oder der Anamnese-Fragebogen (38,9 % Degarelix vs. 20 % GnRH-Agonisten) herangezogen. Schlussfolgerungen Komorbiditäten zählen neben dem Alter und der Compliance zu den wichtigen Faktoren, die die Wahl der ADT beeinflussen.

The structural complexity of the thalamus, due to its mixed composition of gray and white matter, make it challenging to disjoint and quantify each tissue contribution to the thalamic anatomy. This work promotes the use of partial‐volume‐based over probabilistic‐based tissue segmentation approaches to better capture thalamic gray matter differences between patients at different stages of psychosis (early and chronic) and healthy controls. The study was performed on a cohort of 23 patients with schizophrenia, 41 with early psychosis and 69 age and sex‐matched healthy subjects. Six tissue segmentation approaches were employed to obtain the gray matter concentration/probability images. The statistical tests were applied at three different anatomical scales: whole thalamus, thalamic subregions and voxel‐wise. The results suggest that the partial volume model estimation of gray matter is more sensitive to detect atrophies within the thalamus of patients with psychosis. However all the methods detected gray matter deficit in the pulvinar, particularly in early stages of psychosis. This study demonstrates also that the gray matter decrease varies nonlinearly with age and between nuclei. While a gray matter loss was found in the pulvinar of patients in both stages of psychosis, reduced gray matter in the mediodorsal was only observed in early psychosis subjects. Finally, our analyses point to alterations in a sub‐region comprising the lateral posterior and ventral posterior nuclei. The obtained results reinforce the hypothesis that thalamic gray matter assessment is more reliable when the tissues segmentation method takes into account the partial volume effect., Three partial‐volume‐based and three probabilistic‐based tissue segmentation approaches were employed to assess thalamic gray matter integrity in patients at different stages of psychosis (early and chronic). This study demonstrates also that the gray matter decrease varies nonlinearly with age and between nuclei. The obtained results reinforce the hypothesis that thalamic gray matter assessment is more reliable when the tissues segmentation method takes into account the partial volume effect.

Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies.

The main motivation of paraglider pilots is to stay in the air for as long as possible. Therefore, paraglider pilots are always searching for thermal upwind that allow them to gain altitude. These thermal lifts are difficult to detect. Therefore, sensors and devices that indicate the vertical speed (so-called variometers) are widely used among paraglider pilots. This article presents the design and the implementation of an ultralow-power, self-sustaining, high-precision, wrist-worn variometer with a minimal form factor but infinite lifetime, which can visually and acoustically indicate the vertical velocity. This article demonstrates the benefits of combining multisource energy harvesting (EH) for wearable devices with low power design, exploiting a novel near-threshold ARM Cortex-M4F microcontroller, the Ambiq Apollo2, for the onboard processing. The experimental results show a power consumption of only $17.12~\mu \text{W}$ in sleep mode and $1937.21~\mu \text{W}$ in the worst case scenario when processing the data and outputting an audio feedback. Measurements confirmed that combining both thermal and solar EH makes the designed electronics self-sustaining. Without EH, the system will be operational for up to 372 h in always-on mode (worst case scenario) supplied by a 200-mAh lithium-ion battery.

Extensive salt marsh restoration is expected in the northern Gulf of Mexico over the next several decades, funded in part by settlements from the 2010 Deepwater Horizon oil spill. Understanding the ecological benefits of restored marshes over time is integral to setting appropriate restoration targets and performance criteria and in determining the restoration area needed to achieve desired restoration goals and offset quantified natural resource injuries. We present a method for quantifying anticipated ecological benefits associated with marsh restoration projects, particularly marsh creation or enhancement through the placement of dredged material, in the northern Gulf of Mexico. Using salt marsh vegetation (percent cover, aboveground biomass, and belowground biomass) and indicator faunal species (periwinkle snails and amphipods) as representative marsh community components, we used resource equivalency analysis (REA) to model projected ecological benefits over time and quantified total net project benefits for a hypothetical marsh creation project in Barataria Bay, Louisiana. Sensitivity analysis of the resulting model suggests that the recovery trajectories for each marsh component were the most important drivers of modeled restoration benefits and that model uncertainty was greatest for marsh fauna, which has limited data availability compared to marsh vegetation and high natural variability. Longer-term monitoring at restored restoration sites and/or targeted monitoring of older restoration projects would reduce variability in the recovery trajectories for the marsh community components examined in this case study and improve the reliability of the REA model for projecting benefits associated with salt marsh restoration.

Background: Oxidative stress and glutathione (GSH) metabolism dysregulation has been implicated in the pathophysiology of schizophrenia. GAG-trinucleotide repeat (TNR) polymorphisms in the glutamate-cysteine ligase catalytic gene (GCLC), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia. In addition, GSH may serve as a reserve pool for neuronal glutamate (Glu) through the γ-glutamyl cycle. The aim of this study is to investigate brain [GSH] and its association with GCLC polymorphism, peripheral redox indices and brain Glu. Methods: Magnetic resonance spectroscopy was used to measure [GSH] and [Glu] in the medial prefrontal cortex (mPFC) of 25 early-psychosis patients and 33 controls. GCLC polymorphism was genotyped, glutathione peroxidases (GPx) and glutathione reductase (GR) activities were determined in blood cells. Results: Significantly lower [GSH mPFC ] in GCLC high-risk genotype subjects were revealed as compared to low-risk genotype subjects independent of disease status. In male subjects, [GSH mPFC ] and blood GPx activities correlate positively in controls ( P = .021), but negatively in patients ( P = .039). In GCLC low-risk genotypes, [Glu mPFC ] are lower in patients, while it is not the case for high-risk genotypes. Conclusions: GCLC high-risk genotypes are associated with low [GSH mPFC ], highlighting that GCLC polymorphisms should be considered in pathology studies of cerebral GSH. Low brain GSH levels are related to low peripheral oxidation status in controls but with high oxidation status in patients, pointing to a dysregulated GSH homeostasis in early psychosis patients. GCLC polymorphisms and disease associated correlations between brain GSH and Glu levels may allow patients stratification.

Background CD19. CAR T-cells for the treatment of relapsed and refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL) demonstrated complete responses in 40%-58% of the patients. Recently, others could associate high tumor volume and low CAR T-cell expansion in vivo with poor outcome. We hypothesize, that the expansion and immunphenotype of (CAR) T cells in vivo determine treatment response and depend on patient- and disease associated factors. Materials and Methods Patients with r/r DLBCL (n=34) were treated with either Axi-cel or Tisa-cel at the University Hospitals of Erlangen and Munich (LMU). The CAR T-cell product and peripheral blood were collected on day 0, 4, 7, 14, 30, 60 and 90 post transfusion. CAR T-cells were detected through flow cytometry utilizing a two step-staining with a biotinylated CD19 protein. Effector:Target (E:T) Ratios were estimated as absolute peak expansion of CAR T-cells (/ul) per tumorvolume (cm3). Responder (R, complete or partial remission) were compared to Non-Responder (NR, stable or progressive disease) according to response assessment with PET-CT three months after transfusion. Results CAR T-cell expansion peaked between day 7 and day 14 after transfusion with a greater expansion of CD8+compared to CD8- CAR T-cells on day 14 (59.27% vs 37.42%, p=0.021). The ratio of CD8+ and CD8- CAR T-cells did not differ between R and NR, however R exhibited higher E:T ratios of CD3+ CAR T-cells compared to NR (20.94 vs 12.81, p=0.015) and an increased E:T ratio of CD8+ CAR T-cells correlated with better progression-free survival (p=0.033). Interestingly, high CRP and ferritin levels at baseline were inversely associated with the E:T ratio (p=0.048 and p=0.017). CD3+ CAR T-cells of R showed earlier peak expression of PD-1 than NR (day 7 vs day 21). Further, peak expansion of CD3+ CAR T-cells correlated with higher PD-1 expression in R but not in NR (p=0.003 vs p=0.12). In addition, R revealed an increased relative frequency of effector memory differentiated CD3+ CAR T-cells (CCR7-CD45RA-, p=0.02), whereas CAR T-cells in NR showed an increased relative frequency of a naive phenotype (CCR7+CD45RA+, p=0.001) on day 7 post infusion. Conclusions Flow-based immunomonitoring with longitudinal characterization of CAR T-cells demonstrated a correlation of the E:T ratio with treatment response and survival. Increased inflammatory conditions at baseline correlated with diminished E:T ratios. Notably, in R CAR peak expansion was positively associated with higher PD-1 expression suggestive for superior CAR T-cell activation. In addition, greater memory differentiation was associated with efficacy during the time of peak expansion. Multiparameter analysis with other clinical covariates will show, whether CAR T-cell expansion and immunphenotypes can predict patient outcome. Disclosure Information V. Blumenberg: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Novartis, Gilead Sciences, Janssen, BMS/Celgene. S. Volkl: None. G. Busch: None. S. Baumann: None. M. Winkelmann: None. B. Tast: None. D. Nixdorf: None. G. Hanel: None. L. Frolich: None. C. Schmidt: None. R. Jitschin: None. F. Vettermann: None. W. Kunz: None. D. Mougiakakos: None. M. von Bergwelt: None. V. Bucklein: None. A. Mackensen: None. M. Subklewe: None.

Computed tomography coronary angiography (cCTA) is a safe option for the noninvasive exclusion of significant coronary stenoses in patients with a low or moderate pretest probability for coronary artery disease (CAD). Furthermore, it also allows functional and morphological assessment of coronary stenoses. The European Society of Cardiology (ESC) guidelines on the diagnosis and management of chronic coronary syndrome published in 2019 have strengthened the importance of cCTA in this context and for this reason it has experienced a considerable upgrade. The determination of the Agatston score is a clinically established method for quantifying coronary calcification and influences the initiation of drug treatment. With technologies, such as the introduction of electrocardiography (ECG)-controlled dose modulation and iterative image reconstruction, cCTA can be performed with high image quality and low radiation exposure. Anatomic imaging of coronary stenoses alone is currently being augmented by innovative techniques, such as myocardial CT perfusion imaging or CT-fractional flow reserve (FFR) but the clinical value of these methods merits further investigation. The cCTA could therefore develop into a gatekeeper with respect to the indications for invasive coronary diagnostics and interventions.Die CT(Computertomographie)-Koronarangiographie (cCTA) ist bei Patienten mit niedriger und mittlerer Vortestwahrscheinlichkeit für eine koronare Herzkrankheit (KHK) eine sichere Möglichkeit zum nicht-invasiven Ausschluss signifikanter Koronarstenosen und ermöglicht darüber hinaus auch deren funktionelle und morphologische Beurteilung. Der Stellenwert der cCTA wurde durch die 2019 publizierte ESC(European Society of Cardiology)-Leitlinie zu Diagnose und Management des chronischen Koronarsyndroms gestärkt und hat dadurch eine erhebliche Aufwertung erfahren. Die Bestimmung des Agatston-Scores ist eine klinisch etablierte Methodik zur Quantifizierung des Koronarkalks und hat Einfluss auf die Einleitung einer medikamentösen Therapie. Durch Technologien wie die Einführung der EKG-kontrollierten Dosismodulation und der iterativen Bildrekonstruktion kann die cCTA mit hoher Bildqualität und niedriger Strahlendosis durchgeführt werden. Die alleinige anatomische Darstellung von Koronarstenosen wird derzeit um innovative Techniken wie die myokardiale CT-Perfusion oder CT-FFR (fraktionelle Flussreserve) erweitert, jedoch ist der klinische Stellenwert dieser Methoden noch nicht abschließend geklärt. Die cCTA könnte sich zu einem Weichensteller hinsichtlich der Indikationsstellung für eine invasive Koronardiagnostik/-intervention entwickeln.

Background A high level of insight in first episode psychosis (FEP) is positively correlated to important prognostic factors such as medication adherence and functional outcome but is associated with increased depression level and suicidal behavior. Aims This is the first study questioning the potential moderating role of cannabis use in the relationship between insight and depression one year after a FEP. Method In this prospective observational study, we enrolled 214 FEP patients who had provided informed consent and been referred to a specialized early psychosis program and followed for 36 months. A series of multivariate regression models were used. Baseline insight, medication adherence and cannabis use (level of use on a continuum) were entered as independent variables, while the PANSS (positive and negative), the MADRS and the SOFAS scores after one year were alternately selected as the dependent variable. Results We found a three-way interaction term between cannabis use, insight and medication adherence on depression level one year after the entry into the program. A high level of insight was significantly associated with higher MADRS scores in patients with high cannabis use, while depression decreased in high-insight patients with low cannabis use. Conclusions Cannabis use continuation during the year following a first episode psychosis may play a significant role in the development or the maintenance of post-psychotic depression in patients who present with high level of insight and adherence to medication, stressing the need for specific therapeutic strategies in this subgroup of patients.

Objective To describe spontaneous preterm birth prevention practices self-reported before and after the dissemination of relevant guidelines, and to identify personal and organisational factors associated with adherence. Design A repeated cross-sectional vignette-based survey study. Setting French obstetricians. Population French obstetricians practicing in public or private maternity units. Methods Before and after the dissemination of the 2017 French guidelines on the prevention of spontaneous preterm birth, participants were asked to complete a web-based self-administered questionnaire based on two clinical vignettes. Vignette 1 focused on respondents' attitudes towards strict bed rest, cerclage, and progesterone treatment for women with a short cervix in mid-trimester; vignette 2 focused on attitudes towards strict bed rest and maintenance tocolysis after successful tocolysis for preterm labour. A mixed quantitative and qualitative analysis was conducted. Main outcome measures Non-adherence to guidelines for the prevention of spontaneous preterm birth in responses to each vignette. Results We obtained complete responses from 286 obstetricians before and 282 obstetricians after guideline dissemination, including 145 obstetricians participating in both. After dissemination, 51.4% of obstetricians self-reported non-adherent practices for vignette 1 and 22.3% of obstetricians self-reported non-adherent practices for vignette 2. No improvement was observed after dissemination. The quantitative analysis identified factors associated with non-adherence, including older age and practice in non-university or small hospitals, whereas the qualitative analysis highlighted barriers to implementation, including fear of change, habits, work overload, and lack of time. Conclusions Adherence to guidelines was generally low, with practices unmodified by their dissemination. Improvement is required, especially regarding applicability. Tweetable abstract Adherence to guidelines to prevent spontaneous preterm birth was generally low and remained unmodified after guideline dissemination.

AIM A growing body of evidence suggests that urban living contributes to the development of psychosis. However, the mechanisms underlying this phenomenon remain unclear. This paper aims to explore the best available knowledge on the matter, identify research gaps and outline future prospects for research strategies. METHOD A comprehensive literature survey on the main computerized medical research databases, with a time limit up to August 2017 on the issue of urbanicity and psychosis has been conducted. RESULTS The impact of urbanicity may result from a wide range of factors (from urban material features to stressful impact of social life) leading to "urban stress." The latter may link urban upbringing to the development of psychosis through overlapping neuro- and socio-developmental pathways, possibly unified by dopaminergic hyperactivity in mesocorticolimbic system. However, "urban stress" is poorly defined and research based on patients' experience of the urban environment is scarce. CONCLUSIONS Despite accumulated data, the majority of studies conducted so far failed to explain how specific factors of urban environment combine in patients' daily life to create protective or disruptive milieus. This undermines the translation of a vast epidemiological knowledge into effective therapeutic and urbanistic developments. New studies on urbanicity should therefore be more interdisciplinary, bridging knowledge from different disciplines (psychiatry, epidemiology, human geography, urbanism, etc.) in order to enrich research methods, ensure the development of effective treatment and preventive strategies as well as create urban environments that will contribute to mental well-being.

Various mechanisms involved in schizophrenia pathophysiology, such as dopamine dysregulation, glutamate/NMDA receptor dysfunction, neuroinflammation or redox imbalance, all appear to converge towards an oxidative stress “hub” affecting parvalbumine interneurones (PVI) and their perineuronal nets (PNN) (Lancet Psychiatry. 2015;2:258–70); (Nat Rev Neurosci. 2016;17:125–34). We aim to investigate underlying mechanisms linking oxidative stress with neuroinflammatory and their long-lasting harmful consequences. In a transgenic mouse of redox dysregulation carrying a permanent deficit of glutathione synthesis (gclm−/−), the anterior cingulate cortex presented early in the development increased oxidative stress which was prevented by the antioxidant N-acetylcysteine (Eur J Neurosci. 2000;12:3721–8). This oxidative stress induced microglia activation and redox-sensitive matrix metalloproteinase 9 (MMP9) stimulation, leading to the receptor for advanced glycation end-products (RAGE) shedding into soluble and nuclear forms, and subsequently to nuclear factor-kB (NF-kB) activation and secretion of various cytokines. Blocking MMP9 activation prevented this sequence of alterations and rescued the normal maturation of PVI/PNN, even if performed after an additional insult that exacerbated the long term PVI/PNN impairments. MMP9 inhibition thus appears to be able to interrupt the vicious circle that maintains the long-lasting deleterious effects of the reciprocal interaction between oxidative stress and neuroinflammation, impacting on PVI/PNN integrity. Translation of these experimental findings to first episode patients revealed an increase in plasma soluble RAGE relative to healthy controls. This increase was associated with low prefrontal GABA levels, potentially predicting a central inhibitory/excitatory imbalance linked to RAGE shedding. This study paves the way for mechanistically related biomarkers needed for early intervention and MMP9/RAGE pathway modulation may lead to promising drug targets., SCOPUS: ar.j, info:eu-repo/semantics/published

Memory T cell inflation is a process in which a large number of effector memory T cells accumulates in peripheral tissues. This phenomenon is observed upon certain low level persistent virus infections, but it is most commonly described upon infection with the β-herpesvirus Cytomegalovirus. Due to the induction of this large pool of functional effector CD8 T cells in peripheral tissues, the interest in using CMV-based vaccine vectors for vaccination purposes is rising. However, the exact mechanisms of memory T cell inflation are not yet fully understood. It is clear that repetitive exposure to antigen is a key determinant for memory inflation, and therefore the viral inoculum dose and the subsequent number of viral reactivation events strongly impact on the magnitude of the inflationary T cell pool. In addition, the number of CMV-specific CD8 T cells that is able to sense these reactivation events affects the size of the inflationary T cell pool. In the following, we will discuss factors that either promote or limit T cell inflation from both the virus and host perspective. These factors mostly operate by influencing the amount of available antigen or by affecting the T cell pool that is able to respond to the antigen. Furthermore, we will discuss the recent use of CMV-based vaccines in pre-clinical experimental settings, where these vectors have shown promising results by inducing prolonged effector memory T cell responses to foreign-introduced epitopes and thereby provided protection from subsequent virus or tumour challenges.

Androgen deprivation therapy (ADT) with a GnRH agonist or the GnRH antagonist degarelix is a central component in the treatment of prostate cancer (PCa). Little is currently known regarding the decision criteria. Knowledge of these could improve the success of treatment in the future.To identify factors influencing the treatment decision in patients with hormone-sensitive prostate cancer receiving ADT and to determine the incidence of concomitant disease in both treatment groups.The two-arm, prospective, non-interventional study "ProComD" was conducted from September 2014 to June 2019 at 80 study centers in Germany. After the therapy decision was made, patients with hormone-sensitive prostate cancer needing ADT were included in the study. Data were collected during routine visits.Data from 413 patients were evaluated (degarelix N = 268; GnRH agonists N = 145). Key factors influencing the therapy decision for both treatment options included comorbidities (42% of all patients), compliance (64%), and age (81%). The source of information consulted most frequently regarding existing comorbidities was the patient's medical history conducted by the treating urologist themselves (65% in both groups). For patients with pre-existing cardiovascular diseases, the doctor's letter (45.8% degarelix vs. 38.9% GnRH agonists) or the medical history questionnaire (38.9% degarelix vs. 20% GnRH agonists) was additionally taken into account.Comorbidities along with age and compliance are among the key factors influencing the treatment decisions made by urologists.HINTERGRUND: Die Androgendeprivationstherapie (ADT) mit einem GnRH-Agonisten (Gonadotropin-releasing-Hormon) oder -Antagonisten stellt einen zentralen Bestandteil der Behandlung des Prostatakarzinoms (PCa) dar. Über die Faktoren, welche die Wahl der ADT beeinflussen, ist bis jetzt wenig bekannt.Faktoren, welche die Wahl der ADT bei Patienten mit hormonsensitivem PCa beeinflussen, werden identifiziert. Vom Urologen zur Identifizierung von Begleiterkrankungen genutzte Informationsquellen sowie deren Prävalenzen werden bestimmt.Die zweiarmige, prospektive, nicht-interventionelle Studie „ProComD“ wurde von Sept. 2014 bis Juni 2019 an 80 Studienzentren in Deutschland durchgeführt. Patienten mit hormonnaivem PCa und Notwendigkeit einer ADT wurden nach erfolgter Therapieentscheidung in die Studie eingeschlossen. Fragen bezüglich Informationsquelle und Therapieentscheidung wurden vom Arzt direkt im elektronischen Datenerfassungssystem (eCRF) beantwortet.Es wurden Daten von 413 Patienten ausgewertet (Degarelix n = 268; GnRH-Agonisten n = 145). Ausschlaggebend für die Therapieentscheidung waren für beide Behandlungsgruppen u. a. die Faktoren Komorbiditäten (bei 42 % aller Patienten), Compliance (64 %) und Alter (81 %). Die häufigste konsultierte Informationsquelle bzgl. vorhandener Komorbiditäten ist die Anamnese durch den behandelnden Urologen selbst (68,5 % in beiden Gruppen). Bei Patienten mit kardiovaskulären Vorerkrankungen wurde zusätzlich der Arztbrief (45,8 % Degarelix vs. 38,9 % GnRH-Agonisten) oder der Anamnese-Fragebogen (38,9 % Degarelix vs. 20 % GnRH-Agonisten) herangezogen.Komorbiditäten zählen neben dem Alter und der Compliance zu den wichtigen Faktoren, die die Wahl der ADT beeinflussen.