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The introduction of clinical criteria for the operationalization of psychosis high risk provided a basis for early detection and treatment of vulnerable individuals. However, about two-thirds of people meeting clinical high-risk (CHR) criteria will never develop a psychotic disorder. In the effort to increase prognostic precision, structural and functional neuroimaging have received growing attention as a potentially useful resource in the prediction of psychotic transition in CHR patients. The present review summarizes current research on neuroimaging biomarkers in the CHR state, with a particular focus on their prognostic utility and limitations. Large, multimodal/multicenter studies are warranted to address issues important for clinical applicability such as generalizability and replicability, standardization of clinical definitions and neuroimaging methods, and consideration of contextual factors (e.g., age, comorbidity).

In this paper we make two contributions to the analysis of brain oscillations with CFC techniques. First, we introduce a new bispectral CFC measure which is selective to couplings between three or more brain sources. This measure can be derived from ordinary cross-bispectra by performing a total-antisymmetrization operation on them. Significant coupling values can then be attributed to at least three interacting signals. This selectivity to the number of sources can be helpful to test hypotheses on the number of brain sources involved in the generation of commonly observed brain oscillations, such as the alpha rhythm. In a second step we present the correct empirical distribution for the coupling measure, which is necessary to properly assess the significance of coupling results. More importantly however, this corrected statistic is not limited to our particular measure, but holds for all complex-valued coupling estimators. We illustrate how the very common misassumption of empirical normality of such estimators can lead to a systematic underestimation of p -values, the breakdown of multiple comparison control procedures and in consequence a drastic inflation of the number of false positives., (Copyright © 2020 Bartz, Andreou and Nolte.)

Objectives: Reward system dysfunctions are considered to be a pathophysiological mechanism in schizophrenia. Electrophysiological studies of reward system functions have identified frequency-specific brain networks for the processing of positive (high-beta frequency) and negative (theta frequency) events. Remarkably, midbrain dopaminergic signalling also includes theta and high-beta frequency modes, which have been assumed to reflect tonic and phasic dopamine responses, respectively. The aim of the present study was to identify alterations of oscillatory responses to reward feedback in patients with schizophrenia., Methods: Seventeen patients with schizophrenia and 18 healthy controls performed a gambling task during recording of 64-channel electroencephalography. The theta and high-beta band total power were investigated in response to feedback events depending on feedback valence (loss or gain) and magnitude (5 vs. 25 points)., Results: Both the increase of theta oscillatory activity in response to loss feedback (compared to gain feedback) and the increase of high-beta oscillatory activity in response to gain feedback (compared to loss feedback) were reduced in patients. The difference in high-beta responses to gain versus loss feedback in patients was associated with the severity of negative symptoms., Conclusions: Our findings are consistent with current models of reward system dysfunction in schizophrenia, and indicate deficits in both cortical tonic and subcortical phasic dopamine activity, consistent with the complex dopaminergic abnormalities in schizophrenia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample., Method: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls., Results: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression., Conclusion: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.

Background and Objectives: Individualized Metacognitive Training (MCT+) is a manualized intervention designed to improve delusional severity by reducing delusion-associated cognitive biases such as jumping-to-conclusions. Increased interest in personalized medicine stipulates the identification of patients who are more likely to benefit from specialized interventions. The present study aimed to explore baseline moderators of MCT+ efficacy on delusions and overall positive symptoms in psychosis., Methods: We analyzed data from a randomized rater-blind controlled trial, in which 92 patients with psychotic disorders and current or past delusions were randomly assigned to either MCT+ or CogPack®, a cognitive remediation software. Baseline moderator variables consisted of jumping-to-conclusions, cognitive insight, quality of life, self-esteem, selective attention, and patients' attitudes towards their symptoms. Linear mixed-effects models were applied to investigate specific moderators of MCT+ efficacy., Results: In MCT+ relative to CogPack, presence of a jumping-to-conclusions bias, a lowered decision threshold, and low self-esteem were associated with larger improvements in delusional severity and/or overall positive symptoms over time. Subjective reasoning style and insight, as well as subjective attitudes towards psychosis, did not moderate the treatment efficacy of MCT+ relative to CogPack., Limitations: Participation of both treatment groups in group MCT as a part of standard care, possibly leading to additional effects on delusional severity., Conclusions: Patients with low self-esteem and those who are prone to jumping-to-conclusions seem to particularly benefit from MCT+. Our results can help inform clinical practice as they provide specific criteria for selecting patients for whom MCT+ is most appropriate., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest in relation to the subject of this study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Resting-state EEG microstates are brief (50-100 ms) periods, in which the spatial configuration of scalp global field power remains quasi-stable before rapidly shifting to another configuration. Changes in microstate parameters have been described in patients with psychotic disorders. These changes have also been observed in individuals with a clinical or genetic high risk, suggesting potential usefulness of EEG microstates as a biomarker for psychotic disorders. The present study aimed to investigate the potential of EEG microstates as biomarkers for psychotic disorders and future transition to psychosis in patients at ultra-high-risk (UHR). We used 19-channel clinical EEG recordings and orthogonal contrasts to compare temporal parameters of four normative microstate classes (A-D) between patients with first-episode psychosis (FEP; n = 29), UHR patients with (UHR-T; n = 20) and without (UHR-NT; n = 34) later transition to psychosis, and healthy controls (HC; n = 25). Microstate A was increased in patients (FEP & UHR-T & UHR-NT) compared to HC, suggesting an unspecific state biomarker of general psychopathology. Microstate B displayed a decrease in FEP compared to both UHR patient groups, and thus may represent a state biomarker specific to psychotic illness progression. Microstate D was significantly decreased in UHR-T compared to UHR-NT, suggesting its potential as a selective biomarker of future transition in UHR patients.

Jumping to conclusions (JTC) is the best established cognitive bias in schizophrenia and is increasingly targeted in interventions aimed to improve positive symptoms. To address shortcomings of the standard measure to capture JTC, the beads task, we developed a new variant-the box task-which was subsequently validated in people with elevated psychotic-like experiences. For the first time, the box task was administered in a sample of individuals with manifest schizophrenia. We hypothesized that patients with schizophrenia would display an elevated JTC bias relative to controls., Method: We recruited a large sample of 101 patients with schizophrenia and matched them to an online sample recruited from the general population. In the box task, participants must decide which of two kinds of colored balls are presented more often. Participants are told that the task may end prematurely, and that task performance will be counted as an error if no decision had been made before that point. The primary measure was the number of draws to decision (DTD), where fewer DTD corresponds to greater JTC., Results: In contrast to expectations, participants with schizophrenia showed significantly higher DTD (i.e., reduced JTC). Consistent with our previous findings, patients also displayed a lowered decision threshold compared to controls. Response confidence for the final decision was lower in patients and correlated with self-esteem and positive symptoms. While there was evidence that previous knowledge of the box task lowered DTD, exclusion of participants with experience on the box task did not substantially change results., Discussion: The study fits a growing body of experiments casting doubt on the generalizability of the JTC effect in schizophrenia across different tasks. While the study tentatively supports a liberal acceptance account of psychosis, caution is warranted and we recommend that research should explore and control for potentially important mediators (e.g., task difficulty, stress, test-taking attitudes)., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Theranostic agents should ideally be renally cleared and biodegradable. Here, we report the synthesis, characterization and theranostic applications of fluorescent ultrasmall gold quantum clusters that are stabilized by the milk metalloprotein alpha-lactalbumin. We synthesized three types of these nanoprobes that together display fluorescence across the visible and near-infrared spectra when excited at a single wavelength through optical colour coding. In live tumour-bearing mice, the near-infrared nanoprobe generates contrast for fluorescence, X-ray computed tomography and magnetic resonance imaging, and exhibits long circulation times, low accumulation in the reticuloendothelial system, sustained tumour retention, insignificant toxicity and renal clearance. An intravenously administrated near-infrared nanoprobe with a large Stokes shift facilitated the detection and image-guided resection of breast tumours in vivo using a smartphone with modified optics. Moreover, the partially unfolded structure of alpha-lactalbumin in the nanoprobe helps with the formation of an anti-cancer lipoprotein complex with oleic acid that triggers the inhibition of the MAPK and PI3K-AKT pathways, immunogenic cell death and the recruitment of infiltrating macrophages. The biodegradability and safety profile of the nanoprobes make them suitable for the systemic detection and localized treatment of cancer.

Background: Gluten free (GF) diets are not only restrictive but also costly. The main aim of this study was to evaluate the acceptability, cost and affordability of a Gluten Free Healthy Food Basket (GFHFB) and further examine whether low-income Cypriots diagnosed with celiac disease (CD) experience food stress., Methods: GFΗFBs were constructed for adult women and adult men (±40 years) diagnosed with CD. Feasibility and acceptability was tested through three focus groups. Affordability was defined as the cost of the GFΗFB as a percentage of the Guaranteed Minimum Income (GMI)., Results: The GFΗFB was 33.6 and 47 euros/month more expensive compared to the HB (Healthy Basket) for women and men, respectively. The total budget for GF-manufactured products were 27.81 and 28.5% of the total food budget, for women and men, respectively. For low-income people receiving the GMI, the proportion of income that would need to be spent on the GFHFB ranges from around 42 to 60%., Conclusions: The GFΗFB is costly and not affordable among low-income Cypriots diagnosed with CD; thus, they are likely to suffer from food stress. As such, the risk of reducing their adherence to a GF diet is high and thus compromises their long-term health., (© The Author(s) 2019. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Study drop-out during follow-up and service disengagement frequently occur in patients at clinical high risk for psychosis (CHR-P). However, little is known about their predictors. Therefore, we aimed to analyze the rate and reasons for drop-out and service disengagement in CHR-P patients and investigate their sociodemographic and clinical predictors., Methods: Data from 200 patients of the prospective Früherkennung von Psychosen (FePsy) study were analyzed with competing risks survival models, considering drop-out and transition to psychosis as competing events. To investigate whether symptoms changed immediately before drop-out, t tests were applied., Results: Thirty-six percent of patients dropped out within 5 years. Almost all drop-outs also disengaged from our service. Hence, study drop-out was used as a proxy for service disengagement. Patients with more severe baseline disorganized symptoms and a late inclusion into the study were significantly more likely to disengage. Immediately before disengagement, there was significant improvement in negative symptoms only., Conclusion: A considerable proportion of CHR-P patients disengaged from our clinical study and service. Patients who were included during a later study period with more assessments disengaged more often, which might have been due to more frequent invitations to follow-up assessments and thereby increasing participation burden. Hence, our study provides a cautionary note on high-frequency follow-up assessments. Larger-scale studies evaluating predictors on multiple domains would help to further elucidate drop-out and disengagement.

This retrospective observational study analyses the outcomes of patients undergoing surgery for anal fistula at a single centre in order to assess recurrence and re-operation rates after different surgical techniques. During January 2005 and May 2013, all patients with anal fistula were included. Baseline characteristics, details of presentation, fistula anatomy, type of surgery, post-surgical outcomes and follow-up data were collected. The primary endpoints were long-term closure rate and recurrence rate after 2 years. Secondary endpoints were persistent pain, postoperative complications and continence status. A total of 65 patients were included. From a total amount of 93 operations, 65 were fistulotomies, 13 mucosal advancement flaps, 7 anal fistula plugs and 8 cutting-setons. The mean follow up was 80 months. Healing was achieved in 85%. The highest recurrence rate was seen in anal fistula plug with 42%. On the other hand, no recurrence was observed in the cutting-seton procedures. For all included operation no persistent postoperative pain nor incontinence was observed. In conclusion, despite all existing anal fistula operations up to date, the optimal technique with low recurrence rate and assured safety for the anal sphincter is still lacking. Nonetheless, according to our promising results for the cutting-seton technique, this technique, otherwise considered obsolete, should be further evaluated in a prospective study.

Objectives: We conducted a review and meta-analysis of published data to compare revascularization to deferral strategy for coronary lesions with grey zone fractional flow reserve (FFR)., Background: Optimal treatment for coronary stenoses with FFR values between 0.75 and 0.80, the so-called grey zone, remains a matter of debate., Methods: We included all studies evaluating revascularization versus deferral for lesions with grey zone FFR. The primary outcome was study-defined major adverse cardiac events (MACE). Secondary outcomes were the composite of death or MI and target vessel revascularization (TVR). A total of 2362 patients were included, of whom 1181 underwent revascularization (revascularization group) and 1181 received medical treatment only (deferral group)., Results: After a mean follow-up period of 2.4 years, no difference was found for the primary outcome of the study-defined MACE between the two groups [RR = 1.33 (0.73-2.44), p = 0.35]. In addition, there was no difference for the secondary outcomes of death or MI and TVR between the two groups [RR = 1.39 (0.56-3.47), p = 0.48 and RR = 1.49 (0.89-2.51), p = 0.13, respectively]., Conclusions: In this meta-analysis revascularization of coronary stenoses with grey zone FFR showed no advantage over a deferral strategy in terms of study-defined MACE. Case by case judgment should be implemented to guide treatment in this special subset of patients., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Distortion of nominally planar phthalocyanine macrocycles affects the excited state dynamics in that most of the excited-state energy decays through internal conversion. A click-type annulation reaction on a perfluorophthalocyanine platform appending a seven-membered ring to the β-positions on one or more of the isoindoles distorts the macrocycle and modulates solubility. The distorted derivative enables photoacoustic imaging, photothermal effects, and strong surface-enhanced resonance Raman signals., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Patients diagnosed with glioblastoma have poor prognosis. Conventional treatment strategies such as surgery, chemotherapy, and radiation therapy demonstrated limited clinical success and have considerable side effects on healthy tissues. A central challenge in treating brain tumors is the poor permeability of the blood-brain barrier (BBB) to therapeutics. Recently, various methods based on immunotherapy and nanotechnology have demonstrated potential in addressing these obstacles by enabling precise targeting of brain tumors to minimize adverse effects, while increasing targeted drug delivery across the BBB. In addition to treating the tumors, these approaches may be used in conjunction with imaging modalities, such as magnetic resonance imaging and positron emission tomography to enhance the prognosis procedures. This review aims to provide mechanistic understanding of immune system regulation in the central nervous system and the benefits of nanoparticles in the prognosis of brain tumors. This article is characterized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Cells at the Nanoscale Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2019 Wiley Periodicals, Inc.)

Background: Few studies have followed up patients with a clinical high risk (CHR) for psychosis for more than 2-3 years. We aimed to investigate the rates and baseline predictors for remission from CHR and transition to psychosis over a follow-up period of up to 16 years. Additionally, we examined the clinical and functional long-term outcome of CHR patients who did not transition., Methods: We analyzed the long-term course of CHR patients that had been included in the longitudinal studies "Früherkennung von Psychosen" (FePsy) or "Bruderholz" (BHS). Those patients who had not transitioned to psychosis during the initial follow-up periods (2/5 years), were invited for additional follow-ups., Results: Originally, 255 CHR patients had been included. Of these, 47 had transitioned to psychosis during the initial follow-ups. Thus, 208 were contacted for the long-term follow-up, of which 72 (34.6%) participated. From the original sample of 255, 26%, 31%, 35%, and 38% were estimated to have transitioned after 3, 5, 10, and 16 years, respectively, and 51% had remitted from their high risk status at the latest follow-up. Better psychosocial functioning at baseline was associated with a higher rate of remission. Of the 72 CHR patients re-assessed at long-term follow-up, 60 had not transitioned, but only 28% of those were fully recovered clinically and functionally., Conclusions: Our study shows the need for follow-ups and clinical attention longer than the usual 2-3 years as there are several CHR patients with later transitions and only a minority of CHR those without transition fully recovers., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objectives: Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition. Methods: Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning. Results: Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups. Conclusions: The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.

Grey matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Rationale : The goal of imaging tumors at depth with high sensitivity and specificity represents a significant challenge in the field of biomedical optical imaging. 'Surface enhanced Raman scattering' (SERS) nanoparticles (NPs) have been employed as image contrast agents and can be used to specifically target cells in vivo. By tracking their unique "fingerprint" spectra, it becomes possible to determine their precise location. However, while the detection of SERS NPs is very sensitive and specific, conventional Raman spectroscopy imaging devices are limited in their inability to probe through tissue depths of more than a few millimetres, due to scattering and absorption of photons by biological tissues. Here, we combine the use of "Spatially Offset Raman spectroscopy" (SORS) with that of "surface-enhanced resonance Raman spectroscopy" (SERRS) in a technique known as "surface enhanced spatially offset resonance Raman spectroscopy" (SESO(R)RS) to image deep-seated glioblastoma multiforme (GBM) tumors in vivo in mice through the intact skull. Methods : A SORS imaging system was built in-house. Proof of concept SORS imaging was achieved using a PTFE-skull-tissue phantom. Imaging of GBMs in the RCAS-PDGF/N-tva transgenic mouse model was achieved through the use of gold nanostars functionalized with a resonant Raman reporter to create SERRS nanostars. These were then encapsulated in a thin silica shell and functionalized with a cyclic-RGDyK peptide to yield integrin-targeting SERRS nanostars. Non-invasive in vivo SORS image acquisition of the integrin-targeted nanostars was then performed in living mice under general anesthesia. Conventional non-SORS imaging was used as a direct comparison. Results : Using a low power density laser, GBMs were imaged via SESORRS in mice (n = 5) and confirmed using MRI and histopathology. The results demonstrate that via utilization of the SORS approach, it is possible to acquire clear and distinct Raman spectra from deep-seated GBMs in mice in vivo through the skull. SESORRS images generated using classical least squares outlined the tumors with high precision as confirmed via MRI and histology. Unlike SESORRS, conventional Raman imaging of the same areas did not provide a clear delineation of the tumor. Conclusion : To the best of our knowledge this is the first report of in vivo SESO(R)RS imaging. In a relevant brain tumor mouse model we demonstrate that this technique can overcome the limitations of conventional Raman imaging with regards to penetration depth. This work therefore represents a significant step forward in the potential clinical translation of SERRS nanoparticles for high precision cancer imaging., Competing Interests: Competing Interests: S.R. has several pending patents in the areas of Wavelength Stabilized Lasers, Raman Probes, Raman Concatenation, dual wavelength lasers for fluorescence mitigation and fluid analysis using Raman spectroscopy. M.F.K. has several issued and pending patents in the field of SE(R)RS nanoparticles and instrumentation, and is co-founder of RIO Imaging, Inc., a startup company aiming at translating SERRS nanoparticles into the clinic (which did not contribute financially to this work).

Aim: Ultrahigh risk (UHR) criteria, consisting of brief limited intermittent psychotic symptoms (BLIPS), attenuated psychotic symptoms (APS) and genetic risk and deterioration (GRD) syndrome are the most widely used criteria for assessing the clinical high-risk state for psychosis (CHR-P). The Basel Screening Instrument for Psychosis (BSIP) includes a further risk category, the unspecific risk category (URC). However, little is known about the predictive power of this risk category compared to other risk categories., Methods: Two hundred CHR-P patients were detected as part of the Früherkennung von Psychosen (FePsy) study using the BSIP. Transition to psychosis was assessed in regular intervals for up to 7 years., Results: Patients meeting only the URC criterion (n = 40) had a significantly lower risk of transition to psychosis than the UHR group (including BLIPS, APS and GRD) (HR 0.19 [0.05; 0.80] (P = 0.024). Furthermore, the URC only risk group had a lower transition risk than the APS without BLIPS group (P = 0.015) and a trendwise lower risk than the BLIPS group (P = 0.066). However, despite the lower transition risk in the URC only group, there were still two patients (5%) in this group with a later transition to psychosis., Conclusions: The URC includes patients who have a lower risk of transition than those included by the UHR categories and thereby increases the sensitivity of the BSIP. This offers the possibility of a stratified intervention, with these subjects receiving low intensity follow-up and treatment., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: Research on patients at clinical high risk (CHR) for psychosis has so far mainly focused on those with transition to frank psychosis (CHR-T patients). However, the majority of CHR patients do not transition (CHR-NT patients) and relatively little information is available on their clinical and functional outcome., Methods: We conducted a systematic review on clinical and functional long-term outcome of CHR-NT patients. Studies were included if they had an average follow-up period of at least 24 months and reported on long-term outcome of CHR-NT patients in one or more of the following domains: (non-)remission from CHR, prevalence of clinical symptoms and/or clinical diagnoses (axis I and II), and psychosocial functioning., Results: Ten publications from seven different single or multicenter studies with average follow-up durations of 2-7.5 years could be included. At the last follow-up assessment 28-71% of CHR-NT patients were not remitted from their CHR and 22-82% still had at least one clinical diagnosis. Approximately half of CHR-NT patients presented with poor psychosocial outcome at 2-year and 6-year follow-up., Conclusions: The results suggest that, in the long-term, the majority of CHR-NT patients are not in full clinical remission and seem to suffer from one or more clinical disorders and psychosocial impairments. Since relatively few studies could be identified, further research is required to better understand the trajectories and clinical needs of CHR-NT patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Breast cancer is the most common type of malignant growth in women. Early detection of breast cancer, as well as the identification of possible metastatic spread poses a significant challenge because of the structural and genetic heterogeneity that occurs during the progression of the disease. Currently, mammographies, biopsies and MRI scans are the standard of care techniques used for breast cancer diagnosis, all of which have their individual shortfalls, especially when it comes to discriminating tumors and benign growths. With this in mind, we have developed a non-invasive optoacoustic imaging strategy that targets the acidic environment of breast cancer. A pH low insertion peptide (pHLIP) was conjugated to the dark quencher QC1, yielding a non-fluorescent sonophore with high extinction coefficient in the near infrared that increases signal as a function of increasing amounts of membrane insertion. In an orthotopic murine breast cancer model, pHLIP-targeted optoacoustic imaging allowed us to differentiate between healthy and breast cancer tissues with high signal/noise ratios. In vivo, the sonophore QC1-pHLIP could detect malignancies at higher contrast than its fluorescent analog ICG-pHLIP, which was developed for fluorescence-guided surgical applications. PHLIP-type optoacoustic imaging agents in clinical settings are attractive due to their ability to target breast cancer and a wide variety of other malignant growths for diagnostic purposes. Intuitively, these agents could also be used for visualization during surgery.

Depressive symptoms in subjects at Clinical High Risk for Psychosis (CHR-P) or at first-episode psychosis (FEP) are often treated with antidepressants. Our cross-sectional study investigated whether brain morphology is altered by antidepressant medication. High-resolution T 1 -weighted structural MRI scans of 33 CHR-P and FEP subjects treated with antidepressants, 102 CHR-P and FEP individuals without antidepressant treatment and 55 controls, were automatically segmented using Freesurfer 6.0. Linear mixed-effects modelling was applied to assess the differences in subcortical volume, surface area and cortical thickness in treated, non-treated and healthy subjects, taking into account converted dosages of antidepressants. Increasing antidepressant dose was associated with larger volume of the pallidum and the putamen, and larger surface of the left inferior temporal gyrus. In a pilot subsample of separately studied subjects of known genomic risk loci, we found that in the right postcentral gyrus, the left paracentral lobule and the precentral gyrus antidepressant dose-associated surface increase depended on polygenic schizophrenia-related-risk score. As the reported regions are linked to the symptoms of psychosis, our findings reflect the possible beneficial effects of antidepressant treatment on an emerging psychosis.

Childhood trauma (CT) is a comprehensive concept encompassing experiences of sexual, physical, and emotional abuse, and neglect during childhood and adolescence. Patients with schizophrenia-spectrum psychosis (SSP) display higher rates of CT than healthy controls. Among the potential mediators of this association, insecure attachment has gained attention and empirical validation. The present study aimed to extend existing knowledge on this field by exploring the role of the two attachment dimensions, attachment anxiety and attachment avoidance, in the CT-SSP association. A clinical sample of 63 SSP inpatients was compared to a healthy control group on CT and attachment style measures. Correlations between CT, attachment dimensions and psychopathology were sought. Mediation analyses were also performed to examine whether attachment anxiety and/or attachment avoidance mediated the CT-SSP association. Patients displayed higher rates of CT and insecure attachment than controls. Attachment anxiety and severity of Mother Antipathy were linked to severity of hallucinations. Attachment anxiety was recognized as the sole mediator of the CT-SSP association. Our findings suggest that individuals with severe CT and increased attachment anxiety represent a risk population warranting early clinical attention, regular monitoring and tailored therapeutic interventions aimed at reducing the psychological impact of trauma., (Copyright © 2019. Published by Elsevier B.V.)

Background: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis., Methods: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews., Results: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing., Conclusions: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful., (Copyright © 2019. Published by Elsevier Masson SAS.)

Abnormal gamma-band oscillations (GBO) have been frequently associated with the pathophysiology of schizophrenia. GBO are modulated by glutamate, a neurotransmitter, which is continuously discussed to shape the complex symptom spectrum in schizophrenia. The current study examined the effects of ketamine, a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist, on the auditory-evoked gamma-band response (aeGBR) and psychopathological outcomes in healthy volunteers to investigate neuronal mechanisms of psychotic behavior. In a placebo-controlled, randomized crossover design, the aeGBR power, phase-locking factor (PLF) during a choice reaction task, the Positive and Negative Syndrome Scale (PANSS) and the Altered State of Consciousness (5D-ASC) Rating Scale were assessed in 25 healthy subjects. Ketamine was applied in a subanaesthetic dose. Low-resolution brain electromagnetic tomography was used for EEG source localization. Significant reductions of the aeGBR power and PLF were identified under ketamine administration compared to placebo (p < 0.01). Source-space analysis of aeGBR generators revealed significantly reduced current source density (CSD) within the anterior cingulate cortex during ketamine administration. Ketamine induced an increase in all PANSS (p < 0.001) as well as 5D-ASC scores (p < 0.01) and increased response times (p < 0.001) and error rates (p < 0.01). Only negative symptoms were significantly associated with an aeGBR power decrease (p = 0.033) as revealed by multiple linear regression. These findings argue for a substantial role of the glutamate system in the mediation of dysfunctional gamma band responses and negative symptomatology of schizophrenia and are compatible with the NMDAR hypofunction hypothesis of schizophrenia.

Aim: Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients., Methods: ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models., Results: One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only., Conclusion: Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms., (© 2017 John Wiley & Sons Australia, Ltd.)

Several studies using electroencephalography (EEG) demonstrate that the processing of feedback in patients suffering from borderline personality disorder (BPD) is altered in comparison to healthy controls. Differences occur in the theta (ca. 5 Hz) and high-beta frequency-ranges (ca. 20 Hz) of oscillations in response to negative and positive feedback, respectively. However, alpha (ca. 10 Hz) and low-beta (ca. 15 Hz) oscillations have also been shown to be involved in feedback processing. We hypothesized that additional alterations might occur in these frequency ranges in BPD. Eighteen patients with BPD and twenty-two healthy controls performed a gambling task while 64-channel-EEG was recorded. Induced oscillatory responses to positive (i.e. gain) and negative (i.e. loss) feedback in the alpha and low-beta frequency range were investigated. No significant differences were found in the alpha frequency range. Regarding the low-beta frequency range a significant Group (i.e. BPD vs. healthy controls) × Valence (i.e. gain vs. loss) interaction in the time frame between 600 and 700 milliseconds after feedback was found. This effect showed a significant correlation with symptom severity (assessed with the BSL-23). The results indicate that feedback processing in BPD could be more heavily altered than previously expected, with more severe symptomatology being linked to stronger alterations in oscillatory responses to feedback in the low-beta range.

Recently, surface-enhanced Raman scattering nanoprobes have shown tremendous potential in oncological imaging owing to the high sensitivity and specificity of their fingerprint-like spectra. As current Raman scanners rely on a slow, point-by-point spectrum acquisition, there is an unmet need for faster imaging to cover a clinically relevant area in real-time. Herein, we report the rational design and optimization of fluorescence-Raman bimodal nanoparticles (FRNPs) that synergistically combine the specificity of Raman spectroscopy with the versatility and speed of fluorescence imaging. DNA-enabled molecular engineering allows the rational design of FRNPs with a detection limit as low as 5 × 10 -15  M. FRNPs selectively accumulate in tumor tissue mouse cancer models and enable real-time fluorescence imaging for tumor detection, resection, and subsequent Raman-based verification of clean margins. Furthermore, FRNPs enable highly efficient image-guided photothermal ablation of tumors, widening the scope of the NPs into the therapeutic realm.

Ongoing research is shifting towards a dimensional understanding of borderline personality disorder (BPD). Aim of this study was to identify personality profiles in BPD that are predictive of self-destructive behaviors. Personality traits were assessed (n = 130) according to the five-factor model of personality (i.e., Neuroticism, Extraversion, Openness to Experience, Agreeableness, Conscientiousness) and an additional factor called Risk Preference. Self-destructive behavior parameters such as non-suicidal self-injury (NSSI) and other borderline typical dyscontrolled behaviors (e.g., drug abuse) were assessed by self-report measures. Canonical correlation analyses demonstrated that Neuroticism, Extraversion, and Conscientiousness are predictors of NSSI. Further, Neuroticism, Agreeableness, and Risk Preference were associated with dyscontrolled behaviors. Our results add further support on personality-relevant self-destructive behaviors in BPD. A combined diagnostic assessment could offer clinically meaningful insights about the causes of self-destruction in BPD to expand current therapeutic repertoires.

Ovarian cancer represents the deadliest gynecologic malignancy. Most patients present at an advanced stage (FIGO stage III or IV), when local metastatic spread has already occurred. However, ovarian cancer has a unique pattern of metastatic spread, in that tumor implants are initially contained within the peritoneal cavity. This feature could enable, in principle, the complete resection of tumor implants with curative intent. Many of these metastatic lesions are microscopic, making them hard to identify and treat. Neutralizing such micrometastases is believed to be a major goal towards eliminating tumor recurrence and achieving long-term survival. Raman imaging with surface enhanced resonance Raman scattering nanoprobes can be used to delineate microscopic tumors with high sensitivity, due to their bright and bioorthogonal spectral signatures. Here, we describe the synthesis of two 'flavors' of such nanoprobes: an antibody-functionalized one that targets the folate receptor - overexpressed in many ovarian cancers - and a non-targeted control nanoprobe, with distinct spectra. The nanoprobes are co-administered intraperitoneally to mouse models of metastatic human ovarian adenocarcinoma. All animal studies were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center. The peritoneal cavity of the animals is surgically exposed, washed, and scanned with a Raman microphotospectrometer. Subsequently, the Raman signatures of the two nanoprobes are decoupled using a Classical Least Squares fitting algorithm, and their respective scores divided to provide a ratiometric signal of folate-targeted over untargeted probes. In this way, microscopic metastases are visualized with high specificity. The main benefit of this approach is that the local application into the peritoneal cavity - which can be done conveniently during the surgical procedure - can tag tumors without subjecting the patient to systemic nanoparticle exposure. False positive signals stemming from non-specific binding of the nanoprobes onto visceral surfaces can be eliminated by following a ratiometric approach where targeted and non-targeted nanoprobes with distinct Raman signatures are applied as a mixture. The procedure is currently still limited by the lack of a commercial wide-field Raman imaging camera system, which once available will allow for the application of this technique in the operating theater.

In the past few decades, sex differences have been identified in a number of clinical, cognitive and functional outcomes in patients with schizophrenia spectrum disorders. However, to date, sex differences in higher-order cognitive biases have not been systematically studied. The present study aimed to examine sex differences in jumping-to-conclusions and evidence integration impairment based on data collected in two previous studies in patients with schizophrenia spectrum disorders and healthy controls. For this purpose, data from n = 58 patients and n = 60 healthy controls on the Fish Task (as a measure of jumping to conclusions) and bias against disconfirmatory evidence (BADE; as a measure of evidence integration) task were analyzed. Results indicated a lack of sex differences in jumping-to-conclusions and evidence integration impairment both in patients with schizophrenia spectrum disorders and healthy controls. Although the present study was adequately powered to detect sex differences of a low medium effect size, larger studies are warranted to exclude differences of a smaller magnitude between men and women regarding delusion-associated cognitive biases., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to adapt and validate the Revised Practice Environment Scale of the Nursing Work Index, to be utilized among the Cyprus nurses' population. Validated research scales are valuable tools in the hands of researchers in their attempt to recommend alterations within health care systems, especially during reform periods., Results: Internal consistency reliability of the scale was satisfactory (alpha = 0.94). Exploratory factor analysis produced a five-factor structure solution. Experts in the field provided further guidance. The findings demonstrated that the Cyprus version of the Revised Practice Environment Scale of the Nursing Work Index is a reliable and valid research instrument, however differences with previous studies on the factor structure were observed, mainly due to cultural reasons. As a valid and reliable scale, it can capture the views of nurses concerning their work environment. The Cyprus version of the Revised Practice Environment Scale of the Nursing Work Index can be used by nurse managers and policy makers to introduce changes that may improve the quality of nursing care provided and enhance the patients' satisfaction from the health system as a whole.

Negative symptoms and neurocognitive performance have been reported to be negatively associated in patients with emerging psychosis. However, most previous studies focused on patients with frank psychosis and did not differentiate between subdomains of negative symptoms. Hence, we aimed to elucidate the specific relationship between negative symptoms and cognitive functioning in patients at clinical high risk (CHR) for psychosis. Data from 154 CHR patients collected within the prospective Früherkennung von Psychosen (FePsy) study were analyzed. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and cognitive functioning with an extensive neuropsychological test battery. Regression analyses revealed significant negative associations between negative symptoms and cognitive functioning, particularly in the domains of nonverbal intelligence and verbal fluency. When analyzing each negative symptom domain separately, alogia and asociality/anhedonia were significantly negatively associated with nonverbal intelligence and alogia additionally with verbal fluency. Overall, our results in CHR patients are similar to those reported in patients with frank psychosis. The strong negative association between verbal fluency and negative symptoms may be indicative of an overlap between these constructs. Verbal fluency might have a strong influence on the clinical impression of negative symptoms (particularly alogia) and vice versa., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients with an at-risk mental state (ARMS) for psychosis and patients with attention-deficit/hyperactivity disorder (ADHD) have many overlapping signs and symptoms and hence can be difficult to differentiate clinically. The aim of this study was to investigate whether the differential diagnosis between ARMS and adult ADHD could be improved by neuropsychological testing., Methods: 168 ARMS patients, 123 adult ADHD patients and 109 healthy controls (HC) were recruited via specialized clinics of the University of Basel Psychiatric Hospital. Sustained attention and impulsivity were tested with the Continuous Performance Test, verbal learning and memory with the California Verbal Learning Test, and problem solving abilities with the Tower of Hanoi Task. Group differences in neuropsychological performance were analyzed using generalized linear models. Furthermore, to investigate whether adult ADHD and ARMS can be correctly classified based on the pattern of cognitive deficits, machine learning (i.e. random forests) was applied., Results: Compared to HC, both patient groups showed deficits in attention and impulsivity and verbal learning and memory. However, in adult ADHD patients the deficits were comparatively larger. Accordingly, a machine learning model predicted group membership based on the individual neurocognitive performance profile with good accuracy (AUC = 0.82)., Conclusions: Our results are in line with current meta-analyses reporting that impairments in the domains of attention and verbal learning are of medium effect size in adult ADHD and of small effect size in ARMS patients and suggest that measures of these domains can be exploited to improve the differential diagnosis between adult ADHD and ARMS patients., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Reasoning biases such as the jumping-to-conclusions bias (JTC) are thought to contribute to delusions. Interventions targeting these biases such as metacognitive training (MCT) may improve delusions. So far, it is not clear whether JTC depends on dopaminergic reward areas that constitute the main action locus of antipsychotic drugs, or on additional cortical areas. The present study aimed to investigate fMRI activation and functional connectivity patterns underlying JTC, and their changes following MCT, in patients with delusions., Methods: Participants were 25 healthy individuals and 26 patients with current delusions who were either medication-free or on stable medication without sufficient response. We assessed (1) BOLD activity in the task-positive (TPN), task-negative (TNN), and subcortical reward network (RN); (2) Psychophysiological interactions (PPI) of peak activation areas., Results: Presence of JTC (irrespective of group) was associated with lower RN activity during conclusion events, and with increased effective connectivity between TPN and TNN during draw events. Following MCT, changes were observed in TPN activity and in effective connectivity of inferior parietal cortex (part of the TPN) with all three target networks., Conclusion: JTC is associated not only with reward system areas that constitute the main target of antipsychotic drugs, but also with cortical areas, particularly of the TPN.

We propose a new method for the localization of nonlinear cross-frequency coupling in EEG and MEG data analysis, based on the estimation of bicoherences at the source level. While for the analysis of rhythmic brain activity, source directions are commonly chosen to maximize power, we suggest to maximize bicoherence instead. The resulting nonlinear cost function can be minimized effectively using a gradient approach. We argue, that bicoherence is also a generally useful tool to analyze phase-amplitude coupling (PAC), by deriving formal relations between PAC and bispectra. This is illustrated in simulated and empirical LFP data. The localization method is applied to EEG resting state data, where the most prominent bicoherence signatures originate from the occipital alpha rhythm and the mu rhythm. While the latter is hardly visible using power analysis, we observe clear bicoherence peaks in the high alpha range of sensorymotor areas. We additionally apply our method to resting-state data of subjects with schizophrenia and healthy controls and observe significant bicoherence differences in motor areas which could not be found from analyzing power differences., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Auditory verbal hallucinations (AVH) are a common positive symptom of schizophrenia. Excitatory-to-inhibitory (E/I) imbalance related to disturbed N-methyl-D-aspartate receptor (NMDAR) functioning has been suggested as a possible mechanism underlying altered connectivity and AVH in schizophrenia. The current study examined the effects of ketamine, a NMDAR antagonist, on glutamate-related mechanisms underlying interhemispheric gamma-band connectivity, conscious auditory perception during dichotic listening (DL), and the emergence of auditory verbal distortions and hallucinations (AVD/AVH) in healthy volunteers. In a single-blind, pseudo-randomized, placebo-controlled crossover design, nineteen male, right-handed volunteers were measured using 64 channel electroencephalography (EEG). Psychopathology was assessed with the PANSS interview and the 5D-ASC questionnaire, including a subscale to detect auditory alterations with regard to AVD/AVH (AUA-AVD/AVH). Interhemispheric connectivity analysis was performed using eLORETA source estimation and lagged phase synchronization (LPS) in the gamma-band range (30-100 Hz). Ketamine induced positive symptoms such as hallucinations in a subgroup of healthy subjects. In addition, interhemispheric gamma-band connectivity was found to be altered under ketamine compared to placebo, and subjects with AUA-AVD/AVH under ketamine showed significantly higher interhemispheric gamma-band connectivity than subjects without AUA-AVD/AVH. These findings demonstrate a relationship between NMDAR functioning, interhemispheric connectivity in the gamma-band frequency range between bilateral auditory cortices and the emergence of AVD/AVH in healthy subjects. The result is in accordance with the interhemispheric miscommunication hypothesis of AVH and argues for a possible role of glutamate in AVH in schizophrenia.

Reports linking a 'jumping-to-conclusions' bias to delusions have led to growing interest in the neurobiological correlates of probabilistic reasoning. Several brain areas have been implicated in probabilistic reasoning; however, findings are difficult to integrate into a coherent account. The present study aimed to provide additional evidence by investigating, for the first time, effective connectivity among brain areas involved in different stages of evidence gathering. We investigated evidence gathering in 25 healthy individuals using fMRI and a new paradigm (Box Task) designed such as to minimize the effects of cognitive effort and reward processing. Decisions to collect more evidence ('draws') were contrasted to decisions to reach a final choice ('conclusions') with respect to BOLD activity. Psychophysiological interaction analysis was used to investigate effective connectivity. Conclusion events were associated with extensive brain activations in widely distributed brain areas associated with the task-positive network. In contrast, draw events were characterized by higher activation in areas assumed to be part of the task-negative network. Effective connectivity between the two networks decreased during draws and increased during conclusion events. Our findings indicate that probabilistic reasoning may depend on the balance between the task-positive and task-negative network, and that shifts in connectivity between the two may be crucial for evidence gathering. Thus, abnormal connectivity between the two systems may significantly contribute to the jumping-to-conclusions bias., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Reasoning biases such as jumping-to-conclusions (JTC) and incorrigibility have been suggested to contribute to the generation and maintenance of delusions. However, it is still debated whether these biases represent stable traits of patients with delusions, or are related to state fluctuations of delusion severity. The present study aimed to elucidate this question by combining a cross-sectional with a longitudinal approach. JTC, incorrigibility and delusion severity were assessed in 79 patients with a history of delusions over a 6-month period. To allow for a differentiated look into effects of time vs. symptom changes, patients were divided into patients with (D+) and without (D-) current delusions at baseline. Significant improvement of delusions was noted in D+ at follow-up. JTC did not differ between the two patient groups either at baseline or over time. In contrast, incorrigibility was significantly higher in D+ than D- at baseline; this difference remained stable throughout the 6-month follow-up period. The two biases did not significantly co-vary over time. Our results suggest a dissociation between incorrigibility and JTC as regards their relation to current presence of delusions, and tentatively support theoretical accounts attributing different roles to the two biases in the generation (JTC) and maintenance (incorrigibility) of delusions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Optoacoustic imaging offers the promise of high spatial resolution and, at the same time, penetration depths well beyond the conventional optical imaging technologies, advantages that would be favorable for a variety of clinical applications. However, similar to optical fluorescence imaging, exogenous contrast agents, known as sonophores, need to be developed for molecularly targeted optoacoustic imaging. Despite numerous optoacoustic contrast agents that have been reported, there is a need for more rational design of sonophores. Here, using a library screening approach, we systematically identified and evaluated twelve commercially available near-infrared (690-900 nm) and highly absorbing dyes for multi-spectral optoacoustic tomography (MSOT). In order to achieve more accurate spectral deconvolution and precise data quantification, we sought five practical mathematical methods, namely direct classical least squares based on UV-Vis (UV/Vis-DCLS) or optoacoustic (OA-DCLS) spectra, non-negative LS (NN-LS), independent component analysis (ICA) and principal component analysis (PCA). We found that OA-DCLS is the most suitable method, allowing easy implementation and sufficient accuracy for routine analysis. Here, we demonstrate for the first time that our biocompatible nanoemulsions (NEs), in combination with near-infrared and highly absorbing dyes, enable non-invasive in vivo MSOT detection of tumors. Specifically, we found that NE-IRDye QC1 offers excellent optoacoustic performance and detection compared to related near-infrared NEs. We demonstrate that when loaded with low fluorescent or dark quencher dyes, NEs represent a flexible and new class of exogenous sonophores suitable for non-invasive pre-clinical optoacoustic imaging.

Background: Verbal learning and memory are impaired not only in patients with a first episode of psychosis (FEP) but also-to a lower extent-in those with an at-risk mental state for psychosis (ARMS). However, little is known about the specific nature of these impairments. Hence, we aimed to study learning and memory processes in ARMS and FEP patients by making use of structural equation modelling., Methods: Verbal learning was assessed with the California Verbal Learning Test (CVLT) in 98 FEP patients, 126 ARMS patients and 68 healthy controls (HC) as part of the Basel early detection of psychosis (FePsy) study. The four-factorial CFA model of Donders was used to estimate test performance on latent variables of the CVLT and growth curve analysis was used to model the learning curve. The latter allows disentangling initial recall, which is strongly determined by attentional processes, from the learning rate., Results: The CFA model revealed that ARMS and FEP patients were impaired in Attention Span, Learning Efficiency and Delayed Memory and that FEP patients were additionally impaired in Inaccurate Memory. Additionally, ARMS-NT, but not ARMS-T, performed significantly worse than HC on Learning Efficiency. The growth curve model indicated that FEP patients were impaired in both initial recall and learning rate and that ARMS patients were only impaired in the learning rate., Conclusions: Since impairments were more pronounced in the learning rate than the initial recall, our results suggest that the lower scores in the CVLT reported in previous studies are more strongly driven by impairments in the rate of learning than by attentional processes.

Introduction: Patients diagnosed with schizophrenia display deficits in Theory of Mind (ToM) and Emotion Perception (EP) even before the appearance of full-blown symptomatology., Methods: We evaluated ToM and EP in a male cohort consisting of 25 First Episode Psychosis (FEP) and 16 relapsed schizophrenic patients (CHRON) compared to 12 subjects in Ultra-high Risk (UHR) and 23 healthy controls (CTR). Furthermore, we measured the levels of Cortisol, Insulin like Growth Factor (IGF-1), TNF-a, TNF-b and several interleukins as potential biomarkers., Results: Deficits in EP and ToM were found in FEP, CHRON patients and UHR subjects compared to CTR. The impairments in these two domains seem to follow different patterns in the course of psychosis. EP was more impaired in subjects with a longer history of symptomatology whereas there was no statistically significant difference regarding ToM. On the other hand IL-4 was the only biomarker correlated to ToM and EP scores in two different samples of our study., Conclusion: Social Cognition (SC) domains are impaired in patients with psychosis as well as in UHR subjects compared to healthy controls. There are differences in the progress of ToM and EP deficits in the course of psychosis. Interleukins as IL-4 could correlate to SC.

Schizophrenia is a complex psychiatric disorder with unknown and presumably heterogeneous etiology. While the disorder can have various outcomes, research is predominantly "deficit-oriented" emphasizing the hardship that the disorder inflicts on sufferers as well as their families and society. Beyond symptom reduction, imparting patients with hope and meaning in life is increasingly considered an important treatment target, which may raise self-esteem, and reduce self-stigma and suicidal ideation. The present study compared a psychotherapeutic treatment aimed at improving cognitive insight, individualized metacognitive intervention (MCT+), with an active control in order to elucidate if personal meaning-making and hope can be improved in patients with psychosis across time. A total of 92 patients were randomized to either individualized metacognitive therapy (MCT+) or CogPack (neuropsychological training) and followed up for up to 6 months. The "Subjective Sense in Psychosis Questionnaire" (SUSE) was administered which covers different salutogenetic vs pathogenetic views of the disorder, valence of symptom experiences and the consequences of psychosis. Patients in the MCT+ group showed a significant positive shift in attitudes towards the consequences of their illness over time relative to patients in the active control condition. There was some evidence that MCT+ also enhanced meaning-making. The perceived negative consequences of psychosis were highly correlated with depression and low self-esteem, as well as suicidality. The study shows that a cognitive insight training can improve meaning-making in patients and help them come to terms with their diagnosis.

Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of PTEN loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K-Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA-PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging., (© 2018 Kaittanis et al.)

In constantly changing environments, it is crucial to adaptively respond to threatening events. In particular, painful stimuli are not only processed in terms of their absolute intensity, but also with respect to their context. While contextual pain processing can simply entail the repeated processing of information (i.e., habituation), it can, in a more complex form, be expressed through predictions of magnitude before the delivery of nociceptive information (i.e., adaptive coding). Here, we investigated the brain regions involved in the adaptation to nociceptive electrical stimulation as well as their link to dopaminergic neurotransmission (placebo/haloperidol). The main finding is that haloperidol changed the habituation to the absolute pain intensity over time. More precisely, in the placebo condition, activity in left postcentral gyrus and midcingulate cortex increased linearly with pain intensity only in the beginning of the experiment and subsequently habituated. In contrast, when the dopaminergic system was blocked by haloperidol, a linear increase with pain intensity was present throughout the entire experiment. Finally, there were no adaptive coding effects in any brain regions. Together, our findings provide novel insights into the nature of pain processing by suggesting that dopaminergic neurotransmission plays a specific role for the habituation to painful stimuli over time.

Background: Hyperprolactinemia is a known side effect of antipsychotics. In recent reports it has also been shown in antipsychotic-naïve at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. Prolactin is not only involved in reproduction and lactation, but is also synthesized in response to stress. As stress is thought to play an important role in the onset and relapse of schizophrenia, the aim of this study was to further elucidate the influence of prolactin in emerging psychosis., Methods: The data analysed in this study were collected within the prospective Früherkennung von Psychosen (FePsy) study. Blood sample collection took place under standardized conditions between 8 and 10am after an overnight fast and 30minutes of rest. All patients were antipsychotic-naïve and did not take any prolactin influencing medication., Results: Our sample consisted of 116 antipsychotic-naïve ARMS and 49 FEP patients. Hyperprolactinemia was shown in 32% of ARMS and 35% of FEP patients. After correction for the normal biological variation between the sexes, we still found higher average prolactin levels in female than in male patients (β=0.42; t=2.47; p=0.01) but no difference in prolactin levels between ARMS and FEP patients (β=-0.05; t=-0.30; p=0.76). The survival analysis revealed no significant predictive value for prolactin levels to predict transition to psychosis., Conclusion: Our findings support a possible role of prolactin in emerging psychosis and it could be speculated that stress, which can induce hyperprolactinemia, has a stronger effect on women than on men in emerging psychosis., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: We outline a two-stage heuristic account for the pathogenesis of the positive symptoms of psychosis., Methods: A narrative review on the empirical evidence of the liberal acceptance (LA) account of positive symptoms is presented., Hypothesis: At the heart of our theory is the idea that psychosis is characterized by a lowered decision threshold, which results in the premature acceptance of hypotheses that a nonpsychotic individual would reject. Once the hypothesis is judged as valid, counterevidence is not sought anymore due to a bias against disconfirmatory evidence as well as confirmation biases, consolidating the false hypothesis. As a result of LA, confidence in errors is enhanced relative to controls. Subjective probabilities are initially low for hypotheses in individuals with delusions, and delusional ideas at stage 1 (belief formation) are often fragile. In the course of the second stage (belief maintenance), fleeting delusional ideas evolve into fixed false beliefs, particularly if the delusional idea is congruent with the emotional state and provides "meaning". LA may also contribute to hallucinations through a misattribution of (partially) normal sensory phenomena. Interventions such as metacognitive training that aim to "plant the seeds of doubt" decrease positive symptoms by encouraging individuals to seek more information and to attenuate confidence. The effect of antipsychotic medication is explained by its doubt-inducing properties., Limitations: The model needs to be confirmed by longitudinal designs that allow an examination of causal relationships. Evidence is currently weak for hallucinations., Conclusions: The theory may account for positive symptoms in a subgroup of patients. Future directions are outlined., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)