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Increased suicide rates in prison are a serious concern. Early identification of inmates at risk is a component of effective suicide prevention. The present study examined two suicide screening instruments in a sample of men in the Berlin, Germany, prison system (n = 289). The Screening for Initial Risk Assessment (SIRAS) identified significantly more high-risk inmates than the Vienna Instrument for Suicidality in Correctional Institutions (VISCI) (66 vs. 24). The results further show that the agreement in the classification was evident only in inmates with suicidal ideation, but was otherwise quite low. This can be explained by the fact that the instruments differ in terms of the risk factors taken into account. Finally, it was found that inmates classified as high risk received more monitoring and psychiatric or psychological support, which supports the construct validity of the instruments. As there were no deaths by suicide in the sample, no statistical information on the predictive validity of the instruments could be provided. Although research in this area is challenging, methodologically sound studies are needed to inform practice.

IntroductionSelf-harming behavior in prisoners is a prevalent phenomenon, with international studies estimating a 4% prevalence rate. However, studies on self-injurious behavior in the German prison system are currently lacking. Therefore, our study aims to conduct an initial assessment.MethodsThe Criminological Service for the Berlin Prison System distributed questionnaires on incidents of self-harm to all Berlin prisons, except for juvenile detention centers. The questionnaires were supplemented with medical data, such as psychiatric diagnoses and medication.Results62 questionnaires were returned, which could be attributed to 52 inmates. Compared to the average population in the Berlin prison system, the study sample exhibited variations in age, gender distribution and nationality. 94% of the inmates received a psychiatric diagnosis. Two-thirds of the male inmates had substance use disorders, while 83% of the female inmates had emotionally unstable personality resp. borderline disorders. Prior to self-harm, 87% of the inmates were administered psychiatric medication.DiscussionOur study found similarities between the study population and international studies in the distribution of certain characteristics. We assume that many of the postulated risk factors can also apply to Berlin prisoners. However, the study is limited by the small number of cases and the absence of a control group.

Selection of patients who may benefit from extracorporeal life support (ECLS) as a bridge to lung transplant (LTx) is crucial. The aim was to assess if validated prognostic scores could help in selecting patients who may benefit from ECLS-bridging predicting their outcomes. Clinical data of patients successfully ECLS-bridged to LTx from 2009 to 2021 were collected from two European centers. For each patient, we calculated Sequential Organ Failure Assessment (SOFA), Simplified Acute Physiology Score III (SAPS III), Acute Physiology and Chronic Health Evaluation II (APACHE II), before placing ECLS support, and then correlated with outcome. Median values of SOFA, SAPS III, and APACHE II were 5 (IQR 3–9), 57 (IQR 47.5–65), and 21 (IQR 15–26). In-hospital, 30 and 90 days mortality were 21%, 14%, and 22%. SOFA, SAPS III, and APACHE II were analyzed as predictors of in-hospital, 30 and 90 days mortality (SOFA C-Index: 0.67, 0.78, 0.72; SAPS III C-index: 0.48, 0.45, 0.51; APACHE II C-Index: 0.49, 0.45, 0.52). For SOFA, the score with the best performance, a value ≥9 was identified to be the optimal cut-off for the prediction of the outcomes of interest. SOFA may be considered an adequate predictor in these patients, helping clinical decision-making. More specific and simplified scores for this population are necessary.

PurposeMultimodal endovascular therapy (EVT) of carotid cavernous fistula (CCF) with different approaches and a variety of available embolization material enable high occlusion rates with good clinical and functional outcome but until now there is still little evidence available. This retrospective single-center study aims to evaluate EVT of CCF with different neuroendovascular techniques regarding occlusion rates, complications and outcomes.Materials and methodsFrom 2001 to 2021 59 patients with CCF were treated at our tertiary university hospital. Patient records and all imaging data including angiograms were reviewed for demographic and epidemiological data, symptoms, fistula type, number of EVTs, complications of EVT, type of embolic materials, occlusion rates and recurrences.ResultsEtiology of the CCF were spontaneous (41/59, 69.5%) post-traumatic (13/59, 22%) and ruptured cavernous aneurysms (5/59, 8.5%). Endovascular therapy was completed in one session in 74.6% (44/59). Transvenous access was most frequent (55.9% 33/59) followed by transarterial catheterization in 33.9% (20/59) and a combination of both (6/59, 10.2%). Exclusively coils were used in 45.8% (27/59), a combination of ethylene vinyl alcohol (EVOH) copolymer (Onyx) and coils in 42.4% (25/59). Complete obliteration was achieved in 96.6% of patients (57/59) with an intraprocedural-related complication rate of 5.1% (3/59) and no mortality.ConclusionEndovascular therapy of CCF has been shown to be safe and effective with high cure rates and low rates of intraprocedural complications and morbidity even in complex scenarios.

Legal requirement in Europe asks for Ecosystem-Based Fisheries Management (EBFM) in European seas, including consideration of trophic interactions and minimization of negative impacts of fishing on food webs and ecosystem functioning. This study presents the first mass-balanced ecosystem model focused on the western Baltic Sea (WBS). Results show that heavy fishing pressure exerted on the WBS has forced top predators such as harbour porpoise and cod to cover their dietary needs by shifting from forage fish to other prey or find food outside of the model area. The model was then developed to explore the dynamics of four future fishery scenarios: (1) business as usual (BAU), (2) maximum sustainable fishing (F = FMSY), (3) half of FMSY, and (4) EBFM with F = 0.5 FMSY for forage fish and F = 0.8 FMSY for other fish. Simulations show that BAU would perpetuate low catches from depleted stocks with a high risk of extinction for harbour porpoise. In contrast, the EBFM scenario would allow the recovery of harbour porpoise, forage fish and cod with increases in catch of herring and cod. EBFM promotes ecosystem resilience to eutrophication and ocean warming, and through the rebuilding of commercial stocks increases by more than three times carbon sequestration compared to BAU. The model provides an interrelated assessment of trophic guilds in the WBS, as required by European law to assess whether European seas are in good environmental status.

BackgroundPrevalence of substance use disorders, especially opioid use disorders, is high in patients admitted into forensic psychiatric settings. Opioid agonist treatment is a safe, well-established, and effective treatment option for patients that suffer from opioid dependence. Surprisingly, data on the availability and practice of opioid agonist treatment (OAT) options in German Forensic Clinics for Dependency Diseases is rare. Furthermore, essential data on the prevalence of critical incidents such as violent behavior, relapse, or escape from the clinic are missing for this particular treatment setting.Materials and methodsWe conducted an observational study on all forensic addiction treatment units in Germany (Sect. 64 of the German Criminal Code). A questionnaire on the availability and practice of OAT was sent to all Forensic Clinics for Dependency Diseases in Germany. Following items were assessed: availability and the total number of patients that received an OAT in 2018, available medication options, specific reasons for start and end of OAT, number of treatments terminated without success, number of successful treatments, and critical incidents such as violent behavior, relapse, escape and reoffending. We compared the forensic clinics that offered OAT with those that did not offer this treatment option. The data were analyzed descriptively. Mean and standard deviation was calculated for metric scaled variables. For categorical variables, absolute and relative frequencies were calculated. The two groups (OAT vs. Non-OAT institutions) were compared concerning the given variables by either using Fishers exact test (categorical variables), t-test (normally distributed metric variables), or Wilcoxon-test (metric variables not normally distributed).ResultsIn total, 15 of 46 Forensic Clinics for Dependency Diseases participated in the study (33%). In total, 2,483 patients were treated in the participating clinics, 18% were relocated into prison due to treatment termination, and 15% were discharged successfully in 2018. 275 critical incidents were reported: violence against a patient (4%), violence against staff (1.6%), escape (4.7%) and reoffending in (0.5%). In seven clinics treating 1,153 patients, an OAT was available. OAT options in forensic clinics were buprenorphine/naloxone, buprenorphine, methadone, and levomethadone. Regarding critical incidents and successful discharge, no differences were detected in the clinics with or without an OAT. In the clinics that offered an OAT, we found a significantly higher rate of treatment termination without success (p < 0.007) in comparison to clinics without an OAT program. Ninety-nine patients received an OAT, and this treatment was ended due to illegal drug abuse (57%), refusal to give a urine drug sample (71%), and cases where the OAT was given away to other patients (85%).ConclusionIn Forensic Clinics for Dependency Diseases in Germany, OAT is not available in every institution, and thus, access is limited. Critical incidents such as violent behavior against staff or patients and escape are not uncommon in these forensic treatment settings. Further studies are needed to enhance the understanding of OAT practice and the risks for patients and staff.

The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4+ T cells are extremely rare in HIV-1 infected patients, making primary CD4+ T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4+ T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4+ T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4+ T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4+ T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4+ T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4+ T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4+ T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4+ T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4+ T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4+ T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4+ T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.

This study investigates how two non-finite forms, infinitives and conversion nouns, are represented in the mind of L1 and L2 speakers and what is their relationship to other members of the corresponding word family. German native speakers and proficient German learners with Czech as L1 participated in four overt priming experiments involving a grammatical judgement task. We investigated the relationship between infinitives (Experiment 1) and conversion nouns (Experiment 2) and formally identical verbal or noun forms. We further focussed on the relationship between conversion nouns and regular nominal derivation forms with two derivational suffixes: -er and -ung (Experiments 3 and 4). Our results show that the two non-finite forms differ in their relations to other members of a word family and do not constitute a special class of non-finites as suggested in previous literature. While German infinitives seem to be closer related to finite verbal forms, conversion nouns behave in the same way as other regular nominal derivatives within the same word family. As for the German L1 and L2 contrast, no significant difference in the mental representation of the examined forms was found. This finding suggests that with respect to the explored phenomena, proficient learners rely on the same linguistic organisation as L1 speakers.

Transcranial magnetic stimulation (TMS) can depolarize cortical neurons through the intact skin and skull. The characteristics of the induced electric field (E-field) have a major impact on specific outcomes of TMS. Using multi-scale computational modeling, we explored whether the stimulation parameters derived from the primary motor cortex (M1) induce comparable macroscopic E-field strengths and subcellular/cellular responses in the dorsolateral prefrontal cortex (DLPFC). To this aim, we calculated the TMS-induced E-field in 16 anatomically realistic head models and simulated the changes in membrane voltage and intracellular calcium levels of morphologically and biophysically realistic human pyramidal cells in the M1 and DLPFC. We found that the conventional intensity selection methods (i.e., motor threshold and fixed intensities) produce variable macroscopic E-fields. Consequently, it was challenging to produce comparable subcellular/cellular responses across cortical regions with distinct folding characteristics. Prospectively, personalized stimulation intensity selection could standardize the E-fields and the subcellular/cellular responses to repetitive TMS across cortical regions and individuals. The suggested computational approach points to the shortcomings of the conventional intensity selection methods used in clinical settings. We propose that multi-scale modeling has the potential to overcome some of these limitations and broaden our understanding of the neuronal mechanisms for TMS.

IntroductionInflammation is a major pathological feature of pulmonary arterial hypertension (PAH), particularly in the context of inflammatory conditions such as systemic sclerosis (SSc). The endothelin system and anti-endothelin A receptor (ETA) autoantibodies have been implicated in the pathogenesis of PAH, and endothelin receptor antagonists are routinely used treatments for PAH. However, immunological functions of the endothelin B receptor (ETB) remain obscure.MethodsSerum levels of anti-ETB receptor autoantibodies were quantified in healthy donors and SSc patients with or without PAH. Age-dependent effects of overexpression of prepro-endothelin-1 or ETB deficiency on pulmonary inflammation and the cardiovascular system were studied in mice. Rescued ETB-deficient mice (ETB-/-) were used to prevent congenital Hirschsprung disease. The effects of pulmonary T-helper type 2 (Th2) inflammation on PAH-associated pathologies were analyzed in ETB-/- mice. Pulmonary vascular hemodynamics were investigated in isolated perfused mouse lungs. Hearts were assessed for right ventricular hypertrophy. Pulmonary inflammation and collagen deposition were assessed via lung microscopy and bronchoalveolar lavage fluid analyses.ResultsAnti-ETB autoantibody levels were elevated in patients with PAH secondary to SSc. Both overexpression of prepro-endothelin-1 and rescued ETB deficiency led to pulmonary hypertension, pulmonary vascular hyperresponsiveness, and right ventricular hypertrophy with accompanying lymphocytic alveolitis. Marked perivascular lymphocytic infiltrates were exclusively found in ETB-/- mice. Following induction of pulmonary Th2 inflammation, PAH-associated pathologies and perivascular collagen deposition were aggravated in ETB-/- mice.ConclusionThis study provides evidence for an anti-inflammatory role of ETB. ETB seems to have protective effects on Th2-evoked pathologies of the cardiovascular system. Anti-ETB autoantibodies may modulate ETB-mediated immune homeostasis.

Healthy aging is accompanied by multi-faceted changes. Especially within the brain, healthy aging exerts substantial impetus on core parts of cognitive and motivational networks. Rewards comprise basic needs, such as food, sleep, and social contact. Thus, a functionally intact reward system remains indispensable for elderly people to cope with everyday life and adapt to their changing environment. Research shows that reward system function is better preserved in the elderly than most cognitive functions. To investigate the compensatory mechanisms providing reward system stability in aging, we employed a well-established reward paradigm (Monetary Incentive Delay Task) in groups of young and old participants while undergoing EEG measurement. As a new approach, we applied EEG connectivity analyses to assess cortical reward-related network connectivity. At the behavioral level, our results confirm that the function of the reward system is preserved in old age. The mechanisms identified for maintaining reward system function in old age do not fit into previously described models of cognitive aging. Overall, older adults exhibit lower reward-related connectivity modulation, higher reliance on posterior and right-lateralized brain areas than younger adults, and connectivity modulation in the opposite direction than younger adults, with usually greater connectivity during non-reward compared to reward conditions. We believe that the reward system has unique compensatory mechanisms distinct from other cognitive functions, probably due to its etymologically very early origin. In summary, this study provides important new insights into cortical reward network connectivity in healthy aging.

Objectives: The intracellular NLRP3 inflammasome is an important regulator of sterile inflammation. Recent data suggest that inflammasome particles can be released into circulation. The effects of exercise on circulating extracellular apoptosis-associated speck-like protein (ASC) particles and their effects on endothelial cells are not known.Methods: We established a flow cytometric method to quantitate extracellular ASC specks in human serum. ASC specks were quantitated in 52 marathon runners 24–72 h before, immediately after, and again 24–58 h after the run. For mechanistic characterization, NLRP3 inflammasome particles were isolated from a stable mutant NLRP3 (p.D303N)-YFP HEK cell line and used to treat primary human coronary artery endothelial cells.Results: Athletes showed a significant increase in serum concentration of circulating ASC specks immediately after the marathon (+52% compared with the baseline, p < 0.05) and a decrease during the follow-up after 24–58 h (12% reduction compared with immediately after the run, p < 0.01). Confocal microscopy revealed that human endothelial cells can internalize extracellular NLRP3 inflammasome particles. After internalization, endothelial cells showed an inflammatory response with a higher expression of the cell adhesion molecule ICAM1 (6.9-fold, p < 0.05) and increased adhesion of monocytes (1.5-fold, p < 0.05).Conclusion: These findings identify extracellular inflammasome particles as novel systemic mediators of cell–cell communication that are transiently increased after acute extensive exercise with a high mechanical muscular load.

IntroductionProtective loop-ileostomy is one of the most common interventions in abdominal surgery to provide an alternative intestinal outlet until sufficient healing of a distal anastomosis has occurred. However, closure of a loop-ileostomy is also associated with complications. Thus, knowledge of the optimal time interval between primary and secondary surgery is crucial.MethodsData from 409 patients were retrospectively analyzed regarding complications and risk factors in closure-associated morbidity and mortality. A modified Clavien-Dindo classification of surgical complications was used to evaluate the severity of complications.ResultsA total of 96 (23.5%) patients suffered from postoperative complications after the closure of the loop-ileostomy. Early closure within 150 days from enterostomy (n = 229) was associated with less complications (p < 0.001**). Looking at the severity of complications, there were significantly more (p = 0.014*) mild postoperative complications in the late closure group (>150 days). Dysfunctional digestive problems—either (sub-) ileus (p = 0.004*), diarrhea or stool incontinence (p = 0.003*)—were the most frequent complications associated with late closure. Finally, we could validate in a multivariate analysis that “time to closure” (p = 0.002*) is independently associated with the development of complications after closure of a protective loop-ileostomy.ConclusionLate closure (>150 days) of a loop-ileostomy is an independent risk factor in post-closure complications in a multivariate analysis. Nevertheless, circumstances of disease and therapy need to be considered when scheduling the closure procedure.

Precise genome editing in combination with viral delivery systems provides a valuable tool for neuroscience research. Traditionally, the role of genes in neuronal circuits has been addressed by overexpression or knock-out/knock-down systems. However, those techniques do not manipulate the endogenous loci and therefore have limitations. Those constraints include that many genes exhibit extensive alternative splicing, which can be regulated by neuronal activity. This complexity cannot be easily reproduced by overexpression of one protein variant. The CRISPR activation and interference/inhibition systems (CRISPRa/i) directed to promoter sequences can modulate the expression of selected target genes in a highly specific manner. This strategy could be particularly useful for the overexpression of large proteins and for alternatively spliced genes, e.g., for studying large ion channels known to be affected in ion channelopathies in a variety of neurological diseases. Here, we demonstrate the feasibility of a newly developed CRISPRa/i toolbox to manipulate the promoter activity of the Cacna1h gene. Impaired, function of the low-voltage-activated T-Type calcium channel CaV3.2 is involved in genetic/mutational as well as acquired/transcriptional channelopathies that emerge with epileptic seizures. We show CRISPR-induced activation and inhibition of the Cacna1h locus in NS20Y cells and primary cortical neurons, as well as activation in mouse organotypic slice cultures. In future applications, the system offers the intriguing perspective to study functional effects of gain-of-function or loss-of-function variations in the Cacna1h gene in more detail. A better understanding of CaV3.2 channelopathies might result in a major advancement in the pharmacotherapy of CaV3.2 channelopathy diseases.

The study explores the degree to which readers can use their previous linguistic knowledge, which goes beyond the immediate evidence in the input, to create mental representations of new words and how the employment of this knowledge may reduce the fuzziness of the new representations. Using self-paced reading, initial representations of novel identical forms with different grammatical functions were compared in native German speakers and advanced L2 German learners with L1 Czech. The results reveal that although both groups can employ general knowledge about German grammar when establishing new representations, the L1 native speakers outperform the L2 learners: Their new representations have more precise structure and are better differentiated from related representations with respect to their grammatical information. Modeling consequences of these findings are discussed in the context of the Ontogenesis Model of the L2 Lexical Representation and the Fuzzy Lexical Representation Hypothesis.

Background: Extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is highly abandoned due to high morbidity and mortality rates and impaired quality of life (QoL). However, there are still rare indications for this intervention. The aim of this longitudinal prospective study was to monitor QoL and lung function in patients undergoing EPP and compare the outcomes with extended pleurectomy/decortication [(E)PD].Methods: Between June 2013 and June 2017, 42 patients underwent induction chemotherapy followed by either EPP (n = 7) or (E)PD (n = 35). All patients filled out the EORTC QLC-C15-PAL, –LC13, and SF-36 self-rating questionnaires pre-operatively, 6 weeks and 4 months after the operation. Additionally, lung function was measured pre-operatively and 4 months post-operatively.Results: We observed no significant differences in all QoL categories (general global health, pain, and dyspnea) between both surgical procedures, over the whole observation period. Moreover, a general tendency toward restoration of the pre-operative QoL status was documented at 4 months after the both operations. Forced expiratory volume in 1 s (FEV1) showed a significant decrease after surgery in both the groups [EPP group p = 0.06 and (E)PD group p < 0.001]; also, the forced volume vital capacity (FVC) significantly decreased (EPP group p = 0.046 P/D group

We propose the fuzzy lexical representations (FLRs) hypothesis that regards fuzziness as a core property of nonnative (L2) lexical representations (LRs). Fuzziness refers to imprecise encoding at different levels of LRs and interacts with input frequency during lexical processing and learning in adult L2 speakers. The FLR hypothesis primarily focuses on the encoding of spoken L2 words. We discuss the causes of fuzzy encoding of phonological form and meaning as well as fuzzy form-meaning mappings and the consequences of fuzzy encoding for word storage and retrieval. A central factor contributing to the fuzziness of L2 LRs is the fact that the L2 lexicon is acquired when the L1 lexicon is already in place. There are two immediate consequences of such sequential learning. First, L2 phonological categorization difficulties lead to fuzzy phonological form encoding. Second, the acquisition of L2 word forms subsequently to their meanings, which had already been acquired together with the L1 word forms, leads to weak L2 form-meaning mappings. The FLR hypothesis accounts for a range of phenomena observed in L2 lexical processing, including lexical confusions, slow lexical access, retrieval of incorrect lexical entries, weak lexical competition, reliance on sublexical rather than lexical heuristics in word recognition, the precedence of word form over meaning, and the prominence of detailed, even if imprecisely encoded, information about LRs in episodic memory. The main claim of the FLR hypothesis – that the quality of lexical encoding is a product of a complex interplay between fuzziness and input frequency – can contribute to increasing the efficiency of the existing models of LRs and lexical access.

The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).

Research has established that Spontaneous Focusing on Numerosity (SFON) and symbolic number skills (e.g., counting out loud, counting objects, linking small magnitudes and numbers) are predictors of mathematical achievement in primary school. However, little is known about the relationship between SFON and symbolic number skills, or whether one of these factors is more influential on a child’s subsequent mathematical achievement. This study investigated the effect of SFON and symbolic number skills on mathematical achievement at the end of Grade 1 by controlling for first language, gender, working memory and nonverbal IQ. Participants were N = 1,279 first graders. SFON, symbolic number skills and control variables (first language, gender, working memory, and nonverbal IQ) were measured at the beginning of Grade 1. SFON was assessed with a verbally-based task. Data on mathematical achievement was collected at the end of Grade 1. Descriptive statistics demonstrated that the children’s SFON was relatively low at the beginning of Grade 1. Structural equation modeling was used to examine the relationship between SFON, symbolic number skills and mathematical achievement at the end of Grade 1. The results revealed a weakly significant correlation between SFON and symbolic number skills. SFON and symbolic number skills were significant predictors of mathematical achievement at the end of Grade 1. However, the effect of symbolic number skills on mathematical achievement was greater than the effect of SFON. It is therefore concluded that numerical skills are more important than SFON for predicting mathematical achievement over the course of first grade.

Thymic epithelial cells (TECs) are essential in supporting the development of mature T cells from hematopoietic progenitor cells and facilitate their lineage-commitment, proliferation, T-cell receptor repertoire selection and maturation. While animal model systems have greatly aided in elucidating the contribution of stromal cells to these intricate processes, human tissue has been more difficult to study, partly due to a lack of suitable surface markers comprehensively defining human TECs. Here, we conducted a flow cytometry based surface marker screen to reliably identify and quantify human TECs and delineate medullary from cortical subsets. These findings were validated by transcriptomic and histologic means. The combination of EpCAM, podoplanin (pdpn), CD49f and CD200 comprehensively identified human TECs and not only allowed their reliable distinction in medullary and cortical subsets but also their detailed quantitation. Transcriptomic profiling of each subset in comparison to fibroblasts and endothelial cells confirmed the identity of the different stromal cell subsets sorted according to the proposed strategy. Our dataset not only demonstrated transcriptional similarities between TEC and cells of mesenchymal origin but furthermore revealed a subset-specific distribution of a specific set of extracellular matrix-related genes in TECs. This indicates that TECs significantly contribute to the distinct compartmentalization – and thus function – of the human thymus. We applied the strategy to quantify TEC subsets in 31 immunologically healthy children, which revealed sex-specific differences of TEC composition early in life. As the distribution of mature CD4- or CD8-single-positive thymocytes was correspondingly altered, the composition of the thymic epithelial compartment may directly impact on the CD4-CD8-lineage choice of thymocytes. We prove that the plain, reliable strategy proposed here to comprehensively identify human TEC subpopulations by flow cytometry based on surface marker expression is suitable to determine their frequency and phenotype in health and disease and allows sorting of live cells for downstream analysis. Its use reaches from a reliable diagnostic tool for thymic biopsies to improved phenotypic characterization of thymic grafts intended for therapeutic use.

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.

Malignant pleural mesothelioma (MPM) is a rare and fatal disease of the pleural lining. Up to 80% of the MPM cases are linked to asbestos exposure. Even though its use has been banned in the industrialized countries, the cases continue to increase. MPM is a lethal cancer, with very little survival improvements in the last years, mirroring very limited therapeutic advances. Platinum-based chemotherapy in combination with pemetrexed and surgery are the standard of care, but prognosis is still unacceptably poor with median overall survival of approximately 12 months. The genomic landscape of MPM has been widely characterized showing a low mutational burden and the impairment of tumor suppressor genes. Among them, BAP1 and BLM are present as a germline inactivation in a small subset of patients and increases predisposition to tumorigenesis. Other studies have demonstrated a high frequency of mutations in DNA repair genes. Many therapy approaches targeting these alterations have emerged and are under evaluation in the clinic. High-throughput technologies have allowed the detection of more complex molecular events, like chromotripsis and revealed different transcriptional programs for each histological subtype. Transcriptional analysis has also paved the way to the study of tumor-infiltrating cells, thus shedding lights on the crosstalk between tumor cells and the microenvironment. The tumor microenvironment of MPM is indeed crucial for the pathogenesis and outcome of this disease; it is characterized by an inflammatory response to asbestos exposure, involving a variety of chemokines and suppressive immune cells such as M2-like macrophages and regulatory T cells. Another important feature of MPM is the dysregulation of microRNA expression, being frequently linked to cancer development and drug resistance. This review will give a detailed overview of all the above mentioned features of MPM in order to improve the understanding of this disease and the development of new therapeutic strategies.

Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by low bone density, bone fragility and recurrent fractures. The characterization of its heterogeneous genetic basis has allowed the identification of novel players in bone development. In 2016, we described the first X-linked recessive form of OI caused by hemizygous MBTPS2 missense variants resulting in moderate to severe phenotypes. MBTPS2 encodes site-2 protease (S2P), which activates transcription factors involved in bone (OASIS) and cartilage development (BBF2H7), ER stress response (ATF6) and lipid metabolism (SREBP) via regulated intramembrane proteolysis. In times of ER stress or sterol deficiency, the aforementioned transcription factors are sequentially cleaved by site-1 protease (S1P) and S2P. Their N-terminal fragments shuttle to the nucleus to activate gene transcription. Intriguingly, missense mutations at other positions of MBTPS2 cause the dermatological spectrum condition Ichthyosis Follicularis, Atrichia and Photophobia (IFAP) and Keratosis Follicularis Spinulosa Decalvans (KFSD) without clinical overlap with OI despite the proximity of some of the pathogenic variants. To understand how single amino acid substitutions in S2P can lead to non-overlapping phenotypes, we aimed to compare the molecular features of MBTPS2-OI and MBTPS2-IFAP/KFSD, with the ultimate goal to unravel the pathomechanisms underlying MBTPS2-OI. RNA-sequencing-based transcriptome profiling of primary skin fibroblasts from healthy controls (n = 4), MBTPS2-OI (n = 3), and MBTPS2-IFAP/KFSD (n = 2) patients was performed to identify genes that are differentially expressed in MBTPS2-OI and MBTPS2-IFAP/KFSD individuals compared to controls. We observed that SREBP-dependent genes are more downregulated in OI than in IFAP/KFSD. This is coupled to alterations in the relative abundance of fatty acids in MBTPS2-OI fibroblasts in vitro, while no consistent alterations in the sterol profile were observed. Few OASIS-dependent genes are suppressed in MBTPS2-OI, while BBF2H7- and ATF6-dependent genes are comparable between OI and IFAP/KFSD patients and control fibroblasts. Importantly, we identified genes involved in cartilage physiology that are differentially expressed in MBTPS2-OI but not in MBTPS2-IFAP/KFSD fibroblasts. In conclusion, our data provide clues to how pathogenic MBTPS2 mutations cause skeletal deformities via altered fatty acid metabolism or cartilage development that may affect bone development, mineralization and endochondral ossification.

We present new mineralogical and geochemical data from modern sediments in the Chew Bahir basin and catchment, Ethiopia. Our goal is to better understand the role of modern sedimentary processes in chemical proxy formation in the Chew Bahir paleolake, a newly investigated paleoclimatic archive, to provide environmental context for human evolution and dispersal. Modern sediment outside the currently dry playa lake floor have higher SiO2 and Al2O3 (50–70 wt.%) content compared to mudflat samples. On average, mudflat sediment samples are enriched in elements such as Mg, Ca, Ce, Nd, and Na, indicating possible enrichment during chemical weathering (e.g., clay formation). Thermodynamic modeling of evaporating water in upstream Lake Chamo is shown to produce an authigenic mineral assemblage of calcite, analcime, and Mg-enriched authigenic illitic clay minerals, consistent with the prevalence of environments of enhanced evaporative concentration in the Chew Bahir basin. A comparison with samples from the sediment cores of Chew Bahir based on whole-rock MgO/Al2O3, Ba/Sr and authigenic clay mineral δ18O values shows the following: modern sediments deposited in the saline mudflats of the Chew Bahir dried out lake bed resemble paleosediments deposited during dry periods, such as during times of the Last Glacial Maximum and Younger Dryas stadial. Sediments from modern detrital upstream sources are more similar to sediments deposited during wetter periods, such as the early Holocene African Humid Period.

Motor proficiency reflects the ability to perform precise and coordinated movements in different contexts. Previous research suggests that different profiles of motor proficiency may be associated with different cognitive functioning characteristics thus suggesting an interaction between cognitive and motor processes. The current study investigated this interaction in the general population of healthy adults with different profiles of motor proficiency by focusing on error-related cognitive control and behavioral adaptation mechanisms. In addition, the impact of these processes was assessed in terms of trait anxiety and worries. Forty healthy adults were divided into high and low motor proficiency groups based on an assessment of their motor skills. Using electroencephalography during a flanker task, error-related negativity (ERN) was measured as the neural indicator of cognitive control. Post-error slowing (PES) was measured to represent behavioral adaptation. Participants also completed an anxiety assessment questionnaire. Participants in the high motor proficiency group achieved better task accuracy and showed relatively enhanced cognitive control through increased ERN. Contrastingly, individuals in the lower motor proficiency group achieved poorer accuracy whilst showing some evidence of compensation through increased PES. Trait anxiety reflecting general worries was found to be correlated with motor functioning, but the study could not provide evidence that this was related to cognitive or behavioral control mechanisms. The interaction between cognitive and motor processes observed in this study is unique for healthy and sub-clinical populations and provides a baseline for the interpretation of similar investigations in individuals with motor disorders.

The liver is the central hub for processing and maintaining homeostatic levels of dietary nutrients especially essential amino acids such as tryptophan (Trp). Trp is required not only to sustain protein synthesis but also as a precursor for the production of NAD, neurotransmitters and immunosuppressive metabolites. In light of these roles of Trp and its metabolic products, maintaining homeostatic levels of Trp is essential for health and well-being. The liver regulates global Trp supply by the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2), which degrades Trp down the kynurenine pathway (KP). In the current study, we show that isolated primary hepatocytes when exposed to hypoxic environments, extensively rewire their Trp metabolism by reducing constitutive Tdo2 expression and differentially regulating other Trp pathway enzymes and transporters. Mathematical modelling of Trp metabolism in liver cells under hypoxia predicted decreased flux through the KP while metabolic flux through the tryptamine branch significantly increased. In line, the model also revealed an increased accumulation of tryptamines under hypoxia, at the expense of kynurenines. Metabolic measurements in hypoxic hepatocytes confirmed the predicted reduction in KP metabolites as well as accumulation of tryptamine. Tdo2 expression in cultured primary hepatocytes was reduced upon hypoxia inducible factor (HIF) stabilisation by dimethyloxalylglycine (DMOG), demonstrating that HIFs are involved in the hypoxic downregulation of hepatic Tdo2. DMOG abrogated hepatic luciferase signals in Tdo2 reporter mice, indicating that HIF stability also recapitulates hypoxic rewiring of Trp metabolism in vivo. Also in WT mice HIF stabilization drove homeostatic Trp metabolism away from the KP towards enhanced tryptamine production, leading to enhanced levels of tryptamine in liver, serum and brain. As tryptamines are the most potent hallucinogens known, the observed upregulation of tryptamine in response to hypoxic exposure of hepatocytes may be involved in the generation of hallucinations occurring at high altitude. KP metabolites are known to activate the aryl hydrocarbon receptor (AHR). The AHR-activating properties of tryptamines may explain why immunosuppressive AHR activity is maintained under hypoxia despite downregulation of the KP. In summary our results identify hypoxia as an important factor controlling Trp metabolism in the liver with possible implications for immunosuppressive AHR activation and mental disturbances.

BackgroundThe conventional dose rate of radiation therapy is 0.01–0.05 Gy per second. According to preclinical studies, an increased dose rate may offer similar anti-tumoral effect while dramatically improving normal tissue protection. This study aims at evaluating the early toxicities for patients irradiated with high dose rate pulsed proton therapy (PT).Materials and MethodsA single institution retrospective chart review was performed for patients treated with high dose rate (10 Gy per second) pulsed proton therapy, from September 2016 to April 2020. This included both benign and malignant tumors with ≥3 months follow-up, evaluated for acute (≤2 months) and subacute (>2 months) toxicity after the completion of PT.ResultsThere were 127 patients identified, with a median follow up of 14.8 months (3–42.9 months). The median age was 55 years (1.6–89). The cohort most commonly consisted of benign disease (55.1%), cranial targets (95.1%), and were treated with surgery prior to PT (56.7%). There was a median total PT dose of 56 Gy (30–74 Gy), dose per fraction of 2 Gy (1–3 Gy), and CTV size of 47.6 ml (5.6–2,106.1 ml). Maximum acute grade ≥2 toxicity were observed in 49 (38.6%) patients, of which 8 (6.3%) experienced grade 3 toxicity. No acute grade 4 or 5 toxicity was observed. Maximum subacute grade 2, 3, and 4 toxicity were discovered in 25 (19.7%), 12 (9.4%), and 1 (0.8%) patient(s), respectively.ConclusionIn this cohort, utilizing high dose rate proton therapy (10 Gy per second) did not result in a major decrease in acute and subacute toxicity. Longer follow-up and comparative studies with conventional dose rate are required to evaluate whether this approach offers a toxicity benefit.

ObjectivesAdding bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF), to platinum-based chemotherapy/pemetrexed in 1st line treatment of advanced malignant pleural mesothelioma (MPM), significantly improved overall survival. However, increased high grade bleeding after operation was reported in patients with colorectal cancer who previously received bevacizumab. In the present analysis, we assessed for the first time the impact of adding bevacizumab to induction chemotherapy prior to surgery for mesothelioma patients.MethodsTwo hundred twenty-seven MPM patients, intended to be treated with induction chemotherapy followed by surgery at the University Hospital of Zurich between 2002 and December 2018, were included in the present analysis. After propensity score matching for gender, histology and age (1:3 ratio), data from 88 patients were analyzed. Sixty-six patients underwent induction chemotherapy (with cis-/carboplatin and pemetrexed: control group) alone and 22 patients underwent induction chemotherapy with the addition of bevacizumab (bevacizumab group) prior macroscopic complete resection (MCR). Perioperative and long-term outcome variables were analyzed.ResultsPatients undergoing combination treatment with bevacizumab had a significantly better response than with chemotherapy alone as assessed by modified RECIST (p=0.046). Intraoperative complications in the bevacizumab group (one patient), or in the control group (three patients) were not related to intraoperative bleeding. Postoperative transfusion of blood products occurred in a larger amount in the control group than in the bevacizumab group (p=0.047). Overall survival was not statistically different between both groups.ConclusionThese initial data demonstrate that MCR can be performed safely after triple induction chemotherapy with bevacizumab without increased intra- and postoperative bleeding complications. Response rates were significantly improved by the addition of bevacizumab.

Social acceptance is vital to students’ development. Being rejected by classmates can result in negative socio-emotional and academic outcomes. Finding relevant factors to be able to effectively support student social acceptance is especially challenging in inclusive classrooms because of the high heterogeneity of the student group. There is evidence that social acceptance is determined by the social behavior of students. In addition, current research suggests that affect-motivation dispositions, such as teacher attitudes, are related to teaching practices, which in turn are associated with student outcomes. This longitudinal study examines, on an individual level, the relationship between social behavior and the social acceptance of students. On a classroom level, the extent to which a teacher’s attitudes toward the inclusion of students with special educational needs affects their classroom management (i.e., implementation of clear rules and successful time management) is analyzed. In addition, the effect of teacher attitudes toward inclusion and classroom management on social acceptance in the classroom is investigated. The social acceptance of a sample of 580 students in 34 inclusive classrooms was assessed at the beginning and the end of the school year. In addition, student social behavior was rated by peers at the beginning of the school year. Teachers (n = 34) were asked about their attitudes toward inclusion at the beginning of the school year. One mathematics lesson in each classroom was videotaped to assess the teachers’ classroom management practices. Multilevel structural equation models revealed a positive relationship between student social behavior and their social acceptance in the peer group. Contrary to expectations, teachers’ attitudes toward inclusion did not predict their classroom management practices (i.e., implementation of clear rules and successful time management). As hypothesized, teachers’ classroom management predicted the level of social acceptance in the classroom, whereas teachers’ attitudes toward the inclusion of students with special educational needs did not. The study results are discussed in light of previous findings and implications for teacher education are described.

BackgroundAmong people living in detention, substance use is highly prevalent, including opioid dependence. Opioid agonist treatment (OAT) has been established as an evidence-based, first-line treatment for opioid dependence. Despite high prevalence of opioid dependence, conclusive data regarding its prevalence and the OAT practice in German prisons is scarce; rather, the existing data widely diverges concerning the rates of people in detention receiving OAT.Materials and MethodsWe conducted a cross-sectional survey of all detention facilities in Berlin. On the date of data collection, a full census of the routine records was completed based on the medical documentation system. For each opioid dependent individual, we extracted sociodemographic data (i.e., age, sex, and non-/German nationality, whether people experienced language-related communication barriers), information about OAT, comorbidities (HIV, hepatitis C, schizophrenia), and the detention center, as well as the anticipated imprisonment duration and sentence type. The data was first analyzed descriptively and secondly in an evaluative-analytical manner by analyzing factors that influence the access to OAT of people living in detention.ResultsAmong the 4,038 people in detention in the Berlin custodial setting under investigation, we identified a 16% prevalence of opioid dependence. Of the opioid-dependent individuals, 42% received OAT; 31% were treated with methadone, 55% were treated with levomethadone, and 14% were treated with buprenorphine. Access to OAT seemed mainly dependent upon initial receipt of OAT at the time of imprisonment, detention duration, the prisons in which individuals were detained, German nationality, and sex. The overall prevalence of HIV was 4–8%, hepatitis C was 31–42%, and schizophrenia was 5%.ConclusionsThe prevalence of opioid dependence and access to OAT remains a major health issue in the custodial setting. OAT implementation must be especially intensified among male, non-German, opioid-dependent individuals with a short detention period. Treatment itself must be diversified regarding the substances used for OAT, and institutional treatment differences suggest the need for a consistent treatment approach and the standardized implementation of treatment guidelines within local prison’s standard operating procedures. Testing for infectious diseases should be intensified among opioid-dependent people living in detention to address scarcely known infection statuses and high infection rates.

Inflammatory bowel disease is associated with intestinal dysbiosis and with elevated antibody production toward microbial epitopes. The underlying processes linking the gut microbiota with inflammation are still unclear. Considering the constant induction of antibodies by gut microbial glycans, the aim of this study was to address whether the repertoire of carbohydrate-specific antibodies is altered in Crohn’s disease or ulcerative colitis. IgG and IgM reactivities to oligosaccharides representative of mucosal glycans were tested in blood serum from 20 healthy control subjects, 17 ulcerative colitis patients, and 23 Crohn’s disease patients using glycan arrays. An increased IgG and IgM reactivity toward fucosylated oligosaccharides was detected in Crohn’s disease but not in ulcerative colitis. To address the antibody reactivity to the gut microbiota, IgG binding to members of a complex intestinal microbiota was measured and observed to be increased in sera of patients with Crohn’s disease. Based on the elevated reactivity to fucosylated oligosaccharides, gut bacteria were tested for recognition by the fucose-binding Aleuria aurantia lectin. Bacteroides stercoris was detected in IgG- and lectin-positive fractions and reactivity of A. aurantia lectin was demonstrated for additional Bacteroides species. IgG reactivity to these Bacteroides species was significantly increased in inflammatory bowel disease patients, indicating that the increased reactivity to fucosylated oligosaccharides detected in Crohn’s disease may be induced by fucose-carrying intestinal bacteria. Enhanced antibody response to fucosylated epitopes may have systemic effects by altering the binding of circulating antibodies to endogenous glycoproteins.

Catabolism of the essential amino acid tryptophan is a key metabolic pathway contributing to the immunosuppressive tumor microenvironment and therefore a viable drug target for cancer immunotherapy. In addition to the rate-limiting enzyme indoleamine-2,3-dioxygenase-1 (IDO1), tryptophan catabolism via tryptophan-2,3-dioxygenase (TDO2) is a feature of many tumors, particularly malignant gliomas. The pathways regulating TDO2 in tumors are poorly understood; using unbiased promoter and gene expression analyses, we identify a distinct CCAAT/enhancer-binding protein β (C/EBPβ) binding site in the promoter of TDO2 essential for driving constitutive TDO2 expression in glioblastoma cells. Using The Cancer Genome Atlas (TCGA) data, we find that C/EBPβ expression is correlated with TDO2, and both are enriched in malignant glioma of the mesenchymal subtype and associated with poor patient outcome. We determine that TDO2 expression is sustained mainly by the LAP isoform of CEBPB and interleukin-1β, which activates TDO2 via C/EBPβ in a mitogen-activated protein kinase (MAPK) kinase-dependent fashion. In summary, we provide evidence for a novel regulatory and therapeutically targetable pathway of immunosuppressive tryptophan degradation in a subtype of glioblastoma with a particularly poor prognosis.

One of the hypotheses about mental representation of conversion (i.e., zero-derivation) claims that converted forms are a product of a costly mental process that converts a word’s category into another one when needed, i.e., depending on the syntactic context in which the word appears. The empirical evidence for the claim is based primarily on self-paced reading experiments by Stolterfoht et al. (2010) in which they explored the assumed conversion of German verbs into adjectives in two syntactic contexts with past participles. In our priming study, we show that the effects that had been attributed to the conversion process are in fact frequency effects. In addition, based on our data we argue that past participles do not undergo any change in word class in either of the two syntactic contexts, which is consistent with, e.g., traditional German grammars. The same pattern of frequency effects was observed for German native speakers and advanced L2 German learners.

Transgenic Cre-recombinase expressing mouse lines are widely used to express fluorescent proteins and opto-/chemogenetic actuators, making them a cornerstone of modern neuroscience. The investigation of interneurons in particular has benefitted from the ability to genetically target specific cell types. However, the specificity of some Cre driver lines has been called into question. Here, we show that nonspecific expression in a subset of hippocampal neurons can have substantial nonspecific functional effects in a somatostatin-Cre (SST-Cre) mouse line. Nonspecific targeting of CA3 pyramidal cells caused large optogenetically evoked excitatory currents in remote brain regions. Similar, but less severe patterns of nonspecific expression were observed in a widely used SST-IRES-Cre line, when crossed with a reporter mouse line. Viral transduction on the other hand yielded more specific expression but still resulted in nonspecific expression in a minority of pyramidal layer cells. These results suggest that a careful analysis of specificity is mandatory before the use of Cre driver lines for opto- or chemogenetic manipulation approaches.

Reading digital texts is a common practice in today's education. Prior studies showed that the coherence of a text can influence text comprehensibility with low degrees of coherence causing attention failures (mind wandering) and, consequently, negatively impacts reading comprehension. In addition, working memory capacity (WMC) and prior knowledge of the subject have been suggested to be related to both reading comprehension and mind wandering. However, results remain controversial as the interaction of these three factors has not yet been explored. Ninety participants either studying law or a different subject read either a coherent or incoherent version of the same unfamiliar hypertext about the copyright law. While reading, they reported self-caught mind wandering with task-embedded thought probes. After reading the hypertext, participants were tested on their text comprehension. Supporting prior findings, mind wandering did occur more frequently when participants read difficult rather than easy texts regardless of their undergraduate course. Moreover, this was modulated by WMC in that participants with lower WMC exhibited more frequent mind wandering than high WMC participants solely when reading low coherent texts. In addition, high WMC participants outperformed low WMC participants on all measures of text comprehension. With a low WMC it seems difficult to inhibit irrelevant information and access related information from working memory, especially when text complexity is high. Interestingly, the present results also indicate that prior knowledge benefits later text comprehension despite not affecting reader's attention. These findings provide insights into processing attention during reading online texts.

IntroductionOver the past few years, the share of foreign national prisoners in the European and American justice systems has increased at a disproportionately high rate, yet studies on mental health issues among this diverse group are rare. Recent research suggests a range of factors leading to mental health vulnerability in foreign national prisoners, including language barriers, isolation, cultural misunderstanding, and legal standing. Relevant findings of topic-related studies indicate that under-referral to mental health services due to missed or misinterpreted symptoms is a major risk for foreign national prisoners.AimsWe aimed to investigate the disparities regarding the percentage of foreign national patients who were treated in high-security hospitals compared to the psychiatric ward of prison hospitals—after adjusting for diagnosis, age, marital status, and substance abuse. We hypothesized that foreign national patients were underrepresented in compulsory, high-security mental health care. We also aimed to explore citizenship-related institutional disparities concerning diagnoses and self-harmful behavior.MethodFrom 2010 to 2015, data collected from high-security hospitals in the federal state of Baden-Wurttemberg and the psychiatric ward of a Berlin prison hospital was evaluated by comparing nationality, diagnosis, and self-harm using Fisher’s exact test and χ²-test. The odds ratios for citizenship-related differences in diagnosis and institution of treatment were evaluated by using logistic regression.ResultsMentally ill foreign national patients were significantly less likely to be treated in high-security hospitals rather than prison hospital psychiatry (adjusted for diagnosis, age at admission, marital status, and substance abuse; adjusted OR = 0.5). Foreign nationals and Germans in prison hospital psychiatry showed no significant disparities in diagnosis; however, in high-security hospitals, foreign nationals were more likely to have been diagnosed with schizophrenia/psychotic or neurotic/stress-related disorders and were less likely to have been diagnosed with personality disorders than German patients. Additionally, foreign nationals were more likely to commit self-harm than Germans in prison hospital psychiatry, but significant citizenship-related differences could not be verified in high-security hospital patients.ConclusionTreatment conditions of foreign national patients in prison psychiatry must be improved. To achieve this, the psychiatric assessment and (mental) health-related aspects of these patients should be further investigated.

Abnormal circulation in solid tumors results in hypoxia, which modulates both tumor intrinsic malignant properties as well as anti-tumor immune responses. Given the importance of hypoxia in glioblastoma (GBM) biology and particularly in shaping anti-tumor immunity, we analyzed which immunomodulatory genes are differentially regulated in response to hypoxia in GBM cells. Gene expression analyses identified the immunosuppressive enzyme tryptophan-2,3-dioxygenase (TDO2) as the second most downregulated gene in GBM cells cultured under hypoxic conditions. TDO2 catalyses the oxidation of tryptophan to N-formyl kynurenine, which is the first and rate-limiting step of Trp degradation along the kynurenine pathway (KP). In multiple GBM cell lines hypoxia reduced TDO2 expression both at mRNA and protein levels. The downregulation of TDO2 through hypoxia was reversible as re-oxygenation rescued TDO2 expression. Computational modeling of tryptophan metabolism predicted reduced flux through the KP and lower intracellular concentrations of kynurenine and its downstream metabolite 3-hydroxyanthranilic acid under hypoxia. Metabolic measurements confirmed the predicted changes, thus demonstrating the ability of the mathematical model to infer intracellular tryptophan metabolite concentrations. Moreover, we identified hypoxia inducible factor 1α (HIF1α) to regulate TDO2 expression under hypoxic conditions, as the HIF1α-stabilizing agents dimethyloxalylglycine (DMOG) and cobalt chloride reduced TDO2 expression. Knockdown of HIF1α restored the expression of TDO2 upon cobalt chloride treatment, confirming that HIF1α controls TDO2 expression. To investigate the immunoregulatory effects of this novel mechanism of TDO2 regulation, we co-cultured isolated T cells with TDO2-expressing GBM cells under normoxic and hypoxic conditions. Under normoxia TDO2-expressing GBM cells suppressed T cell proliferation, while hypoxia restored the proliferation of the T cells, likely due to the reduction in kynurenine levels produced by the GBM cells. Taken together, our data suggest that the regulation of TDO2 expression by HIF1α may be involved in modulating anti-tumor immunity in GBM.

Introduction: Chronic recreational methamphetamine use causes dopaminergic neurotoxicity, which has been linked to impairments in executive functioning. Within this functional domain, response selection and the resolution of associated conflicts have repeatedly been demonstrated to be strongly modulated by dopamine. Yet, it has never been investigated whether chronic methamphetamine use leads to general impairments in response selection (i.e., irrespective of consumption-associated behavior) after substance use is discontinued.Materials and Methods: We tested n = 24 abstinent methamphetamine users (on average 2.7 years of abstinence) and n = 24 individually matched controls in a cross-sectional design with a flanker task.Results: Compared to healthy controls, former methamphetamine consumers had significantly slower reaction times, but did not show differences in the size of the flanker or Gratton effect, or post-error slowing. Complementary Bayesian analyses further substantiated this lack of effects despite prior consumption for an average of 7.2 years.Discussion: The ability to select a correct response from a subset of conflicting alternatives, as well as the selective attention required for this seem to be largely preserved in case of prolonged abstinence. Likewise, the ability to take previous contextual information into account during response selection and to process errors seem to be largely preserved as well. Complementing previously published finding of worse inhibition/interference control in abstinent consumers, our results suggest that not all executive domains are (equally) impaired by methamphetamine, possibly because different cognitive processes require different levels of dopamine activity.

Violent behavior in correctional facilities is common and differs substantially in type, target, implication, and trigger. Research on frequency and characteristics of violent behavior in correctional facilities and psychiatric hospitals is limited. Results from recent research suggest that comorbidity of severe mental disorder, personality disorder, and diagnosis of substance abuse is related to a higher risk of violent behavior. In the Berlin prison hospital, a database was created to collect data from all violent incidences (n=210) between 1997 and 2006 and between 2010 and 2016. In a retrospective, case-control study, we analyzed specific socioeconomic data and psychiatric diagnosis and compared the group of prisoners with violent behavior with randomly selected prisoners of the same department without violent behavior (n = 210). Diagnosis of schizophrenia, non-German nationality, no use of an interpreter, no children, and no previous sentence remained significantly associated with the dependent variable violent behavior. There were no significant differences regarding age and legal statuses. Practical implications for clinical work are discussed.

Introduction: Therapy options for patients with oligoprogressive malignant pleural mesothelioma (MPM) are limited. Stereotactic Body Radiotherapy (SBRT) may be a promising therapeutic option, as it delivers a localized ablative dose of radiation and therefore balances efficacy and treatment related toxicities. The intent of this retrospective analysis was to evaluate the feasibility of SBRT for limited pleural recurrences.Methods and Materials: This retrospective single-institution study is based on the 21 consecutive patients treated with hypofractionated radiotherapy for oligoprogressive MPM. Clinical and radiological data was collected at regular follow-up visits including toxicity, local control and survival.Results: At primary diagnosis, 57% of the patients presented with stage III disease. Initial treatment of MPM consisted of induction chemotherapy (n = 12) prior to a macroscopic complete resection (n = 18). Three patients received additional intracavitary chemotherapy and another three patients were treated with chemotherapy alone without another treatment at the time of first diagnosis. A total of 50 lesions in recurrent MPM were treated with SBRT. The median number of radiotherapy fractions was 5 (range 3–20) with a median dose per fraction of 5 Gy (range 2.5–12.5 Gy). The median total treatment dose was 30 Gy (20–50 Gy) with a median prescription isodose line (IDL) of 65% (65–100%). Median follow-up of all patients from diagnosis was 28 months (range 7–152 months). Analyzing all lesions separately, the 12-months-local control from SBRT was 73.5%. The median progression free survival (PFS) after SBRT was 6 months (range 0–21 months) and the median OS from first first SBRT was 29 months (range 0–61 months). Only one patients experienced above Grade 3 toxicities.Conclusion: This analysis demonstrates the feasibility of a SBRT approach for oligorecurrent MPM. SBRT was well-tolerated even after multiple repetitions and local control was high with a promising median OS.

Purpose: Evidence from preclinical studies and trials in healthy volunteers suggests that exercise may modulate the levels of tryptophan (TRP) metabolites along the kynurenine (KYN) pathway. As KYN and downstream KYN metabolites are known to promote cancer progression by inhibiting anti-tumor immune responses and by promoting the motility of cancer cells, we investigated if resistance exercise can also control the levels of KYN pathway metabolites in breast cancer patients undergoing radiotherapy (NCT01468766).Patients and Methods: Chemotherapy-naïve breast cancer patients (n = 96) were either randomized to an exercise/intervention group (IG) or a control group (CG). The IG participated in a 12-week supervised progressive resistance exercise program twice a week, whereas the CG received a supervised relaxation program. Serum levels of TRP and KYN as well as urine levels of kynurenic acid (KYNA) and neurotoxic quinolinic acid (QUINA) were assessed before (t0), after radiotherapy, and mid-term of the exercise intervention (t1) and after the exercise intervention (t2). Additionally, 24 healthy women (HIG) participated in the exercise program to investigate potential differences in its effects on KYN metabolites in comparison to the breast cancer patients.Results: At baseline (t0) the breast cancer patients showed a significantly elevated serum KYN/TRP ratio and urine QUINA/KYNA ratio, as well as increased urine QUINA levels in comparison to the healthy women. In response to exercise the healthy women and the breast cancer patients differed significantly in the levels of urine QUINA and the QUINA/KYNA ratio. Most importantly, serum KYN levels and the KYN/TRP ratio were significantly reduced in exercising patients (IG) compared to non-exercising patients (CG) both at t1 and t2.Conclusion: Resistance exercise may represent a potent non-pharmacological avenue to counteract an activation of the KYN pathway in breast cancer patients undergoing radiotherapy.

Background: Although there is evidence that individuals who suffer from severe mental disorders are at higher risk for aggressive behavior, only a minority eventually become violent. In 2017, Fazel et al. developed a risk calculator (Oxford Mental Illness and Violence tool, OxMIV) to identify the risk of violent crime in patients with mental disorders. For the first time, we tested the predictive validity of the OxMIV in the department of psychiatry at the prison hospital in Berlin, Germany, and presented findings from our internal validation.Materials and Methods: We designed a cohort study with 474 patients aged 16–65 years old who met the inclusion criteria of schizophrenia-spectrum or bipolar disorder and classified the patients into two groups: a violent group with 191 patients and a nonviolent group with 283 patients. Violence was defined as the aggressive behavior of a patient with the necessity of special observation. We obtained all the required information retrospectively through patient files, applied the OxMIV tool on each subject, and compared the results of both groups. Sensitivity, specificity, and positive/negative predictive values were determined. We used logistic regression including variable selection and internal validation to identify relevant predictors of aggressive behavior in our cohort.Results: The OxMIV score was significantly higher in the violent group [median 4.21%; Interquartile range (IQR) 8.51%] compared to the nonviolent group (median 1.77%; IQR 2.01%; p < 0.0001). For the risk of violent behavior, using the 5% cutoff for “increased risk,” the sensitivity was 44%, and the specificity was 89%, with a positive predictive value of 72% and a negative predictive value of 70%. Applying logistic regression, four items were statistically significant in predicting violent behavior: previous violent crime (adjusted odds ratio 5.29 [95% CI 3.10–9.05], p < 0.0001), previous drug abuse (1.80 [1.08–3.02], p = 0.025), and previous alcohol abuse (1.89 [1.21–2.95], p = 0.005). The item recent antidepressant treatment (0.28 [0.17–0.47]. p < 0.0001) had a statistically significant risk reduction effect.Conclusions: In our opinion, the risk assessment tool OxMIV succeeded in predicting violent behavior in imprisoned psychiatric patients. As a result, it may be applicable for identification of patients with special needs in a prison environment and, thus, improving prison safety.

As in many countries, the numbers of older prisoners are rising in Germany, but scientific information on this group is scarce. For the current study, a survey was used that included all prison suicides in Germany between the years of 2000 and 2013. Suicide rates of the elderly prisoners exceeded the suicide rates of the general population and the same age group. We observed a continuous decrease in the suicide rate of elderly prisoners. When compared to the younger suicide victims in prison, significantly more elderly suicide victims were: female, of German nationality, remand prisoners, or serving a life sentence. In Germany, elderly prisoners are a vulnerable subpopulation of the prison population. Higher suicide rates than in the same age group in the general population indicate unmet needs regarding mental disorders and their specific treatment.

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer with a poor survival rate. Treatment options are limited at best and drug resistance is common. Thus, there is an urgent need to identify novel therapeutic targets in this disease in order to improve patient outcomes and survival times. MST1R (RON) is a trans-membrane receptor tyrosine kinase (RTK), which is part of the c-MET proto-oncogene family. The only ligand recognized to bind MST1R (RON) is Macrophage Stimulating 1 (MST1), also known as Macrophage Stimulating Protein (MSP) or Hepatocyte Growth Factor-Like Protein (HGFL). In this study, we demonstrate that the MST1-MST1R (RON) signaling axis is active in MPM. Targeting this pathway with a small molecule inhibitor, LCRF-0004, resulted in decreased proliferation with a concomitant increase in apoptosis. Cell cycle progression was also affected. Recombinant MST1 treatment was unable to overcome the effect of LCRF-0004 in terms of either proliferation or apoptosis. Subsequently, the effect of an additional small molecular inhibitor, BMS-777607 (which targets MST1R (RON), MET, Tyro3, and Axl) also resulted in a decreased proliferative capacity of MPM cells. In a cohort of MPM patient samples, high positivity for total MST1R by IHC was an independent predictor of favorable prognosis. Additionally, elevated expression levels of MST1 also correlated with better survival. This study also determined the efficacy of LCRF-0004 and BMS-777607 in xenograft MPM models. Both LCRF-0004 and BMS-777607 demonstrated significant anti-tumor efficacy in vitro, however BMS-777607 was far superior to LCRF-0004. The in vivo and in vitro data generated by this study indicates that a multi-TKI, targeting the MST1R/MET/TAM signaling pathways, may provide a more effective therapeutic strategy for the treatment of MPM as opposed to targeting MST1R alone.