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Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept’s CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept’s PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.Trial registration number: NEON-2 (NCT04920383).

IntroductionDeficits in emotion recognition and processing are characteristic for patients with schizophrenia [SCZ].MethodsWe targeted both emotion recognition and affective sharing, one in static and one in dynamic facial stimuli, during functional magnetic resonance imaging [fMRI] in 22 SCZ patients and 22 matched healthy controls [HC]. Current symptomatology and cognitive deficits were assessed as potential influencing factors.ResultsBehaviorally, patients only showed a prolonged response time in age-discrimination trials. For emotion-processing trials, patients showed a difference in neural response, without an observable behavioral correlate. During emotion and age recognition in static stimuli, a reduced activation of the bilateral anterior cingulate cortex [ACC] and the right anterior insula [AI] emerged. In the affective sharing task, patients showed a reduced activation in the left and right caudate nucleus, right AI and inferior frontal gyrus [IFG], right cerebellum, and left thalamus, key areas of empathy.DiscussionWe conclude that patients have deficits in complex visual information processing regardless of emotional content on a behavioral level and that these deficits coincide with aberrant neural activation patterns in emotion processing networks. The right AI as an integrator of these networks plays a key role in these aberrant neural activation patterns and, thus, is a promising candidate area for neurofeedback approaches.

In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2.

Abstract Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

IntroductionSleep deprivation and electroconvulsive therapy (ECT) effectively ameliorate symptoms in major depressive disorder (MDD). In rodents, both are associated with an enhancement of cerebral adenosine levels, which in turn likely influence adenosinergic receptor expression. The aim of the current study was to investigate cerebral A1 adenosine receptor (A1AR) availability in patients with MDD as a potential mediating factor of antidepressant effects of ECT using [18F]CPFPX and positron emission tomography (PET).MethodsRegional A1AR availability was determined before and after a series of ECT applications (mean number ± SD 10.4 ± 1.2) in 14 subjects (4 males, mean age 49.5 ± 11.8 years). Clinical outcome, measured by neuropsychological testing, and ECT parameters were correlated with changes in A1AR availability.ResultsECT had a strong antidepressive effect (p

Abstract The Immunoscore is a method to quantify the immune cell infiltration within cancers to predict the disease prognosis. Previous immune profiling approaches relied on limited immune markers to establish patients’ tumor immunity. However, immune cells exhibit a higher-level complexity that is typically not obtained by the conventional immunohistochemistry methods. Herein, we present a spatially variant immune infiltration score, termed as SpatialVizScore, to quantify immune cells infiltration within lung tumor samples using multiplex protein imaging data. Imaging mass cytometry (IMC) was used to target 26 markers in tumors to identify stromal, immune, and cancer cell states within 26 human tissues from lung cancer patients. Unsupervised clustering methods dissected the spatial infiltration of cells in tissue using the high-dimensional analysis of 16 immune markers and other cancer and stroma enriched labels to profile alterations in the tumors’ immune infiltration patterns. Spatially resolved maps of distinct tumors determined the spatial proximity and neighborhoods of immune-cancer cell pairs. These SpatialVizScore maps provided a ranking of patients’ tumors consisting of immune inflamed, immune suppressed, and immune cold states, demonstrating the tumor’s immune continuum assigned to three distinct infiltration score ranges. Several inflammatory and suppressive immune markers were used to establish the cell-based scoring schemes at the single-cell and pixel-level, depicting the cellular spectra in diverse lung tissues. Thus, SpatialVizScore is an emerging quantitative method to deeply study tumor immunology in cancer tissues.

BackgroundAnxiety and depressive disorders share common features of mood dysfunctions. This has stimulated interest in transdiagnostic dimensional research as proposed by the Research Domain Criteria (RDoC) approach by the National Institute of Mental Health (NIMH) aiming to improve the understanding of underlying disease mechanisms. The purpose of this study was to investigate the processing of RDoC domains in relation to disease severity in order to identify latent disorder-specific as well as transdiagnostic indicators of disease severity in patients with anxiety and depressive disorders.MethodsWithin the German research network for mental disorders, 895 participants (n = 476 female, n = 602 anxiety disorder, n = 257 depressive disorder) were recruited for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) and included in this cross-sectional study. We performed incremental regression models to investigate the association of four RDoC domains on disease severity in patients with affective disorders: Positive (PVS) and Negative Valance System (NVS), Cognitive Systems (CS) and Social Processes (SP).ResultsThe results confirmed a transdiagnostic relationship for all four domains, as we found significant main effects on disease severity within domain-specific models (PVS: β = −0.35; NVS: β = 0.39; CS: β = −0.12; SP: β = −0.32). We also found three significant interaction effects with main diagnosis showing a disease-specific association.LimitationsThe cross-sectional study design prevents causal conclusions. Further limitations include possible outliers and heteroskedasticity in all regression models which we appropriately controlled for.ConclusionOur key results show that symptom burden in anxiety and depressive disorders is associated with latent RDoC indicators in transdiagnostic and disease-specific ways.

Summary: Protein-protein interaction networks are altered in multi-gene dysregulations in many disorders. Image-based protein multiplexing sheds light on signaling pathways to dissect cell-to-cell heterogeneity, previously masked by the bulk assays. Herein, we present a rapid multiplexed immunofluorescence (RapMIF) method measuring up to 25-plex spatial protein maps from cultures and tissues at subcellular resolution, providing combinatorial 272 pairwise and 1,360 tri-protein signaling states across 33 multiplexed pixel-level clusters. The RapMIF pipeline automated staining, bleaching, and imaging of the biospecimens in a single platform. RapMIF showed that WNT/β-catenin signaling upregulated upon the inhibition of the AKT/mTOR pathway. Subcellular protein images demonstrated translocation patterns, spatial receptor discontinuity, and subcellular signaling clusters in single cells. Signaling networks exhibited spatial redistribution of signaling proteins in drug-responsive cultures. Machine learning analysis predicted the phosphorylated β-catenin expression from interconnected signaling protein images. RapMIF is an ideal signaling discovery approach for precision therapy design.

Acquired resistance is inevitable in non–small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

Summary: Background: Current evidence points towards a high prevalence of psychological distress in refugee populations, contrasting with a scarcity of resources and amplified by linguistic, institutional, financial, and cultural barriers. The objective of the study is to investigate the overall effectiveness and cost-effectiveness of a Stepped Care and Collaborative Model (SCCM) at reducing depressive symptoms in refugees, compared with the overall routine care practices within Germany's mental healthcare system (treatment-as-usual, TAU). Methods: A multicentre, clinician-blinded, randomised, controlled trial was conducted across seven university sites in Germany. Asylum seekers and refugees with relevant depressive symptoms with a Patient Health Questionnaires score of ≥ 5 and a Refugee Health Screener score of ≥ 12. Participants were randomly allocated to one of two treatment arms (SCCM or TAU) for an intervention period of three months between April 2018 and March 2020. In the SCCM, participants were allocated to interventions tailored to their symptom severity, including watchful waiting, peer-to-peer- or smartphone intervention, psychological group therapies or mental health expert treatment. The primary endpoint was defined as the change in depressive symptoms (Patient Health Questionnaire-9, PHQ-9) after 12 weeks. The secondary outcome was the change in Montgomery Åsberg Depression Rating Scale (MADRS) from baseline to post-intervention. Findings: The intention-to-treat sample included 584 participants who were randomized to the SCCM (n= 294) or TAU (n=290). Using a mixed-effects general linear model with time, and the interaction of time by randomisation group as fixed effects and study site as random effect, we found significant effects for time (p < .001) and time by group interaction (p < .05) for intention-to-treat and per-protocol analysis. Estimated marginal means of the PHQ-9 scores after 12 weeks were significantly lower in SCCM than in TAU (for intention-to-treat: PHQ-9 mean difference at T1 1.30, 95% CI 1.12 to 1.48, p < .001; Cohen's d=.23; baseline-adjusted PHQ-9 mean difference at T1 0.57, 95% CI 0.40 to 0.74, p < .001). Cost-effectiveness and net monetary benefit analyses provided evidence of cost-effectiveness for the primary outcome and quality-adjusted life years. Robustness of results were confirmed by sensitivity analyses. Interpretation: The SSCM resulted in a more effective and cost-effective reduction of depressive symptoms compared with TAU. Findings suggest a suitable model to provide mental health services in circumstances where resources are limited, particularly in the context of forced migration and pandemics. Funding: This project is funded by the Innovationsfond and German Ministry of Health [grant number 01VSF16061]. The present trial is registered under Clinical-Trials.gov under the registration number: NCT03109028. https://clinicaltrials.gov/ct2/show/NCT03109028

Abstract Introduction The spine represents the site which is most frequently affected by bone metastases in patients with systemic cancer. Of all local treatment options, combined kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provides both, instantaneous stabilization and immediate pain relief. We here report on the long-term outcomes of the largest cohort treated with Kypho-IORT to date. Methods Between 2009 and 2019 a total of 104 patients underwent Kypho-IORT to vertebral tumors in the thoracic, lumbar, or sacral spine with transpedicular kyphoplasty and intraoperative irradiation with a needle-shaped electronic brachytherapy source at our center. Patients were treated either on trial, within the prospective Kypho-IORT studies (NCT01280032 and NCT02773966), or, after completion of the study, off trial but compliant with the study protocol. Follow-up and imaging with computed tomography (CT) or magnetic resonance imaging was scheduled after 3 and 6 months and then bi-annually. Results A total of 143 vertebrae (89 thoracic spine, 53 lumbar spine, and 1 sacral spine) were treated in 104 patients. The median follow-up was 14.5 months (range 0.4–109). Local progression occurred in 10 patients (10 vertebrae) after a median time of 22.3 months (range 1.5–73) resulting in local control rates of 97.1, 95.9, and 94.2% at 6, 12, and 24 months, respectively. Overall survival was 74.6, 61.7, and 50.3% at 6, 12, and 24 months, respectively. A single serious adverse event was reported. Conclusion In addition to immediate pain reduction and stabilization, Kypho-IORT shows excellent long-term local control with minimal side effects.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington’s disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha‐dihydrotetrabenazine (α‐HTBZ) and beta‐dihydrotetrabenazine (β‐HTBZ), metabolite profile, safety, and tolerability. In the two‐way, cross‐over study, the mean elimination half‐life of deuterated total (α + β)‐HTBZ was doubled compared with nondeuterated total (α + β)‐HTBZ, with a twofold increase in overall mean exposure (area under the concentration‐time curve from zero to infinity (AUC0–inf)) and a marginal increase in mean peak plasma concentration (Cmax). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14C]‐deutetrabenazine relative to [14C]‐tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active‐to‐inactive metabolites, attributes considered to provide significant benefits to patients.

Abstract Background The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases. Methods This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least − 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life. Discussion This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases. Trial registration Registered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).

Summary: The pathogenesis of severe coronavirus disease 2019 (COVID-19) remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (93%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM) and less frequently auto-reactive IgG or IgA. Importantly, these auto-IgMs preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, analytical proteome microarray technology, and lactose dehydrogenase (LDH)-release cytotoxicity assays, we identify high-affinity, complement-fixing, auto-reactive IgM directed against 260 candidate autoantigens, including numerous molecules preferentially expressed on the cellular membranes of pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for therapeutic interventions.

Since May 2020, several COVID-19 outbreaks have occurred in the German meat industry despite various protective measures, and temperature and ventilation conditions were considered as possible high-risk factors. This cross-sectional study examined meat and poultry plants to assess possible risk factors. Companies completed a self-administered questionnaire on the work environment and protective measures taken to prevent SARS-CoV-2 infection. Multivariable logistic regression analysis adjusted for the possibility to distance at least 1.5 meters, break rules, and employment status was performed to identify risk factors associated with COVID-19 cases. Twenty-two meat and poultry plants with 19,072 employees participated. The prevalence of COVID-19 in the seven plants with more than 10 cases was 12.1% and was highest in the deboning and meat cutting area with 16.1%. A subsample analysis where information on maximal ventilation rate per employee was available revealed an association with the ventilation rate (adjusted odds ratio (AOR) 0.996, 95% CI 0.993–0.999). When including temperature as an interaction term in the working area, the association with the ventilation rate did not change. When room temperatures increased, the chance of testing positive for COVID-19 (AOR 0.90 95% CI 0.82–0.99) decreased, and the chance for testing positive for COVID-19for the interaction term (AOR 1.001, 95% CI 1.000–1.003) increased. Employees who work where a minimum distance of less than 1.5 m between workers was the norm had a higher chance of testing positive (AOR 3.61; 95% CI 2.83–4.6). Our results further indicate that climate conditions and low outdoor air flow are factors that can promote the spread of SARS-CoV-2 aerosols. A possible requirement for pandemic mitigation strategies in industrial workplace settings is to increase the ventilation rate.

Adequate emotional control is essential for mental health. Deficiencies in emotion regulation are evident in many psychiatric disorders, including depression. Patients with depression show, for instance, disrupted neural emotion regulation in cognitive regulation regions such as lateral and medial prefrontal cortices. Since depressed individuals tend to attribute positive events to external circumstances and negative events to themselves, modifying this non-self-serving attributional style may represent a promising regulation strategy. Spontaneous causal attributions are generally processed in medial brain structures, particularly the precuneus. However, so far no study has investigated neural correlates of instructed causal attributions (e.g. instructing a person to intentionally relate positive events to the self) and their potential to regulate emotions. The current study therefore aimed to examine how instructed causal attributions of positive and negative events affect the emotional experience of depressed individuals as well as its neural bases. For this purpose pictures of sad and happy faces were presented to 26 patients with a lifetime major depression (MDD) and 26 healthy controls (HC) during fMRI. Participants should respond naturally (“view”) or imagine that the person on the picture was sad/happy because of them (“internal attribution”) or because something else happened (“external attribution”). Trait attributional style and depressive symptoms were assessed with questionnaires to examine potential influential factors on emotion regulation ability.Results revealed that patients compared to controls show a non-self-serving trait attributional style (i.e. more external attributions of positive events and more internal attributions of negative events). Intriguingly, when instructed to apply specific causal attributions during the emotion regulation task, patients and controls were similarly able to regulate positive and negative emotions. Regulating emotions through instructed attributions (internal/external attribution>view) generally engaged the precuneus, which was correlated with patients' trait attributional style (i.e. more precuneus activation during external>view was linked to a general tendency to relate positive events to external sources). Up-regulating happiness through internal (compared to external) attributions recruited the parahippocampal gyrus only in controls. The down-regulation of sadness (external>internal attribution), in contrast, engaged the superior frontal gyrus only in patients. Superior frontal gyrus activation thereby correlated with depression severity, which implies a greater need of cognitive resources for a successful regulation in more severely depressed. Patients and controls did not differ in activation in brain regions related to cognitive emotion regulation or attribution. However, results point to a disturbed processing of positive emotions in depression. Interestingly, increased precuneus resting-state connectivity with emotion regulation brain regions (inferior parietal lobule, middle frontal gyrus) was linked to healthier attributions (i.e. external attributions of negative events) in patients and controls. Adequate neural communication between these regions therefore seem to facilitate an adaptive trait attributional style. Findings of this study emphasize that despite patients' dysfunctional trait attributional style, explicitly applying causal attributions effectively regulates emotions. Future research should examine the efficacy of instructed attributions in reducing negative affect and anhedonia in depressed patients, for instance by means of attribution trainings during psychotherapy. Keywords: Emotion regulation, Depression, Attribution, Positive emotions, Precuneus, fMRI, Resting-state connectivity

Abstract Background In-vivo observations of neural processes during human aggressive behavior are difficult to obtain, limiting the number of studies in this area. To address this gap, the present study implemented a social reactive aggression paradigm in 29 healthy men, employing non-violent provocation in a two-player game to elicit aggressive behavior in fMRI settings. Results Participants responded more aggressively after high provocation reflected in taking more money from their opponents. Comparing aggression trials after high provocation to those after low provocation revealed activations in neural circuits involved in aggression: the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), and the insula. In general, our findings indicate that aggressive behavior activates a complex, widespread brain network, reflecting a cortico-limbic interaction and overlapping with circuits underlying negative emotions and conflicting decision-making. Brain activation during provocation in the OFC was associated with the degree of aggressive behavior in this task. Conclusion Therefore, data suggest there is greater susceptibility for provocation, rather than less inhibition of aggressive tendencies, in individuals with higher aggressive responses. This further supports the hypothesis that reactive aggression can be seen as a consequence of provocation of aggressive emotional responses and parallel evaluative regulatory processes mediated mainly by the insula and prefrontal areas (OFC, mPFC, dlPFC, and ACC) respectively.

As many paths lead to aggression, understanding which situations and which person-specific traits facilitate or impede aggressive behavior is crucial. Provocation is among one of the most frequently reported predictors of aggressive behavior. However, it remains unclear whether the reaction to provocation is universal across different forms of aggression and whether individuals differ in their reactivity to such signals. Using the Taylor Aggression Paradigm (TAP), we investigated the influence of individual and contextual factors on physical and non-physical aggression in healthy men and women. The impact of trait aggression, sex, provocation, and the success of a competition against a fictitious opponent on aggressive behavior was examined in three different versions of the TAP. While equal provocation and punishment modalities were used in the first two versions, monetary deductions in the first and heat stimulus in the second study, the third experiment used non-physical provocation to trigger physical punishment. Trial-by-trial analyses revealed that provocation, independent of its specific nature, is a strong predictor for aggressive behavior, especially in highly aggressive participants. Although women initially showed less aggression than men, sex differences were diminished under prolonged, increasing provocation when provocation and punishment modality were identical. Only when modalities diverged, women, compared with men, were more hesitant to punish their opponent. These results, thus, extend evidence that women show lower levels of aggression under low provocation. However, high levels of provocation have similar effects on males’ and females’ reactive aggressive behavior across different forms of aggression. When competing for money, losing against the fictitious opponent was functioning as an additional provocative signal stimulating aggressive responses. Differences in aggressive responding have to be interpreted in the context of the specific type of provocation and aggression that is investigated since these modalities are shown to interact with individual characteristics.

Individual differences in traits such as impulsivity and processing of risk and reward have been linked to decision making and may underlie divergent decision making strategies. It is, however, unclear whether and how far individual differences in these characteristics jointly influence decision making. Here, we aimed to investigate the roles of skin conductance responses, a psychophysiological marker of risk processing and impulsivity, as assessed by the Barratt Impulsiveness Scale 11 on decision making. Forty-six healthy participants performed a modified version of the Balloon Analog Risk Task (BART), where reward and explosion risk are manipulated separately. Participants are informed about whether they play a high versus low reward and high versus low explosion risk condition. The exact risk and reward contingencies are, however, unknown to participants. Participants were less risk-taking under high, compared to low explosion risk and under high reward, compared to low reward on the modified BART, which served as a validation of the paradigm. Risk-taking was negatively related to skin conductance responses under high explosion risk. This relationship was primarily driven by individuals with relatively high levels of impulsivity. However, impulsivity alone was not found to be related to decision making on the modified BART. These results extend evidence that skin conductance responses may guide decision making in situations, where participants are informed about risk level (high vs. low), which might be differentially moderated by different levels of impulsivity.

BackgroundA disturbed self-image is central to the characteristic symptoms of borderline personality disorder (BPD). Evaluations of self-relevance (SR) are highly important in cognitive and emotional processing of information and adaptive behavior.MethodIn the current study, we used affective statements to investigate if SR is altered in patients with higher scores on Borderline Symptom List (BSL-95). Forthyfemale adults with BPD and 20 healthy participants assessed a set of stimuli consisting of sentences in third-person for relevance to self.ResultsBPD patients exhibited a higher SR for negative contents as compared to healthy controls (p < .001). Furthermore, a significant positive correlation coefficient was found between the increased bias in evaluating the SR of stimuli and borderline symptom severity scores, as measured by BSL-95 questionnaire (r = 0.67, p < .001). This effect persisted after controlling for depressive symptoms by a partial correlation analysis.ConclusionOur results revealed an enhanced SR for negative statements, which was related to the severity of individuals' BPD symptoms. These findings add to the diagnostic information regarding the disturbed organization of self in this clinical population. We suggest the maladaptive evaluation of SR offers an important treatment target for therapeutic approaches to BPD.

Borderline personality disorder (BPD) and major depressive disorder (MDD) are both associated with abnormalities in the regulation of emotion, with BPD being highly comorbid with MDD. Disorder-specific dysfunctions in BPD, however, have hardly been addressed, hence the lack of knowledge pertaining to the specificity of emotion processing deficits and their commonality with MDD. 24 healthy comparison subjects, 21 patients with MDD, and 13 patients with comorbid BPD and MDD (BPD + MDD group) were studied using functional MRI. The subjects were required to perform an emotional interference task that entailed categorizing facial affect while ignoring words that labeled the emotional contents of the external stimuli. Collapsing across emotional face types, we observed that participants with BPD + MDD uniquely displayed a greater involvement of the visual areas and the cerebellum. During emotional conflict processing, on the other hand, the lateral prefrontal cortex (LPFC) appeared to be affected in both patient groups. In comparison to the HC, the MDD group showed differences also in the posterior medial frontal cortex (pMFC) and the inferior parietal lobule (IPL). Thus, our data indicate dysfunctionality in the neural circuitry responsible for emotional conflict control in both disorders. The enhanced visual cortex activation in BPD + MDD suggests the visual system's hyperresponsiveness to faces at an early perceptual level. Not being associated with co-occurring depression, this effect in BPD + MDD appears to represent specific personality traits such as disturbed reactivity toward emotionally expressive facial stimuli.

Aversive odors are highly salient stimuli that serve a protective function. Thus, emotional reactions elicited by negative odors may be hardly influenceable. We aim to elucidate if negative mood induced by negative odors can be modulated automatically by positively valenced stimuli. We included 32 healthy participants (16 men) in an fMRI design combining aversive and neutral olfactory stimuli with positive and neutral auditory stimuli to test the influence of aversive olfactory stimuli on subjective emotional state and brain activation when combined with positive and neutral auditory stimuli. The behavioral results show an interaction of negative olfactory stimuli on ratings of disgust, perceived valence of music, and subjective affective state, while positive auditory stimulation did not show this interaction. On a neuronal level, we observed main effects for auditory and olfactory stimulation, which are largely congruent with previous literature. However, the pairing of both stimuli was associated with attenuated brain activity in a set of brain areas (supplementary motor area, temporal pole, superior frontal gyrus) which overlaps with multisensory processing areas and pave the way for automatic emotion regulation. Our behavioral results and the integrated neural patterns provide evidence of predominance of olfaction in processing of affective rivalry from multiple sensory modalities.

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.