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Background: Investigations of causal pathways for psychosis can be guided by the identification of environmental risk factors. A recently developed composite risk tool, the exposome score for schizophrenia (ES-SCZ), which controls for intercorrelations between risk factors, has shown fair to good performance. We tested the transdiagnostic psychosis classifier performance of the ES-SCZ with the Bipolar-Schizophrenia Network for Intermedial Phenotypes data and examined its relationship with clinical-level outcomes., Study Design: We computed the case-control classifier performance for the ES-SCZ from cross-sectional data on 1055 volunteers with psychotic diagnoses (schizophrenia, schizoaffective, bipolar psychosis) and 510 controls. Multivariate regression models were used to control for the correlations between outcomes and to correct for the effects of age, sex, and family socioeconomic status across outcomes. We estimated association for the ES-SCZ with psychosis and mood symptom severity, the 5-factor model of personality, and function across biologically defined biotypes, traditional diagnostic categories, and controls., Study Results: ES-SCZ classifier performance for psychosis was fair to good. ES-SCZ associations with personality factor scores were qualitatively similar between psychosis groups and controls with decreased conscientiousness and agreeableness and increased neuroticism. The patterns of associations between ES-SCZ and symptoms differed across biotypes and diagnoses. Biotype 3 and bipolar disorder had consistent within-group associations where greater exposome score predicted more severe symptoms and worse function., Conclusions: ES-SCZ performance was consistent with previous reports in this transdiagnostic psychosis sample (adjusted odds ratio: 3.331 [2.834, 3.915], P < .001; area under the curve: 0.762 [0.735, 0.789]). Individual differences in ES-SCZ magnitude may be useful for investigating causal pathways between developmentally relevant exposures and symptomatic expression of psychosis., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately., Competing Interests: Competing interests: CX: None. NA-R: None. CAT: B-SNIP Diagnostics, Board of Managers; Kynexis, Scientific Advisory Board and retainer; Merck DSMB; Neuventis, Board, own stock. MSK: B-SNIP Diagnostics, Board of Managers; Advisor to Alkermes. GDP: B-SNIP Diagnostics, Board of Managers. SKK: B-SNIP Diagnostics, Board of Managers. BC: B-SNIP Diagnostics, Board of Managers; Kynexis Corporation, Scientific Advisory Board. JEM: B-SNIP Diagnostics, Board of Managers. DP: None. RL: None. SKH: None. JRB: None. EII: B-SNIP Diagnostics, Board of Managers. CW: None. RD: None. CC: None. CL: None. ESG: B-SNIP Diagnostics, Board of Managers; Consultant: Kynexis Corporation. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. B-SNIP recruitment sites were in Athens GA (the University of Georgia and Augusta University Medical College of Georgia), Baltimore MD (Maryland Psychiatric Research Center), Boston MA (Beth Israel Deaconess Medical Center), Chicago IL (the University of Illinois-Chicago and University of Chicago), Dallas TX (UT Southwestern Medical Center), Detroit MI (Wayne State University), and Hartford CT (Institute of Living). All recruitments, interviews, and laboratory data collections were completed at those locations. The Institutional Review Board at participating institutions approved the projects; all participants provided informed consent prior to involvement., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This scoping review assessed the surgical backlog in Latin America and the Caribbean (LAC) due to COVID-19 and identified mitigation strategies. We searched seven databases for citations from December 2019 to December 2022, focusing on LAC patients with cancelled or postponed procedures. We registered our protocol at Open Science Framework (https://osf.io/x2nd8) and adhered to PRISMA-ScR guidelines. We included 83 citations covering 23 LAC countries and 19 surgical specialities, with Brazil (67%, 56/83) and transplant surgery (24%, 20/83) being the most documented. Surgical backlogs were mainly reported at the hospital (44%, 37/83) and national levels (38%, 32/83). We identified 58 citations that reported a total of 42 strategies to mitigate the backlog, the most cited being establishing prioritisation criteria for surgical cases (41%, 24/58). Our findings highlight challenges across differing healthcare systems in LAC, including disparities in data availability, surgical capacity, and resource allocation. For instance, while countries like Brazil had extensive data on national surgical backlogs, others lacked comprehensive national-level data. Our review can help inform policymakers and healthcare stakeholders to implement targeted interventions to prepare LAC-based surgical systems for future health emergencies., Competing Interests: We would like to declare the following sources of funding which supported the authors during their academic endeavours: Fundação Maria Emília Pedreira Freire de Carvalho (LNC), Fundação Estudar (LNC), Jean-Martin Laberge Pediatric Fellowship Program (AG), Swedish Research Council (grant 2022–00208, MZ), the Swedish Doctors Organization (Svenska Läkaresällskapet, MZ). The funding institutions played no role in the design, collection, analysis, interpretation, writing, or decision to submit the report for publication., (© 2024 The Authors. Published by Elsevier Ltd.)

Recent reports indicate that the Memory Integrated Language Test (MIL) and Making Change Test Abbreviated Index (MCT-AI), two web-based performance validity tests (PVTs), have good sensitivity and specificity when used independently. This study investigated whether using these PVTs together could improve the detection of invalid performance in a mixed neuropsychiatric sample. Participants were 129 adult outpatients who underwent a neuropsychological evaluation and were classified into valid ( n  = 104) or invalid ( n  = 25) performance groups based on several commonly used PVTs. Using cut scores of ≤41 on the MIL and ≥1.05 on the MCT-AI together enhanced classification accuracy, yielding an area under the curve of .84 (95% CI: .75, .93). As compared to using the MIL and MCT-AI independently, the combined use increased the sensitivity from .10-.31 to.70 while maintaining ≥.90 specificity. Findings also indicated that failing either the MIL or MCT-AI was associated with somewhat lower cognitive test scores, but failing both was associated with markedly lower scores. Overall, using the MIL and MCT-AI together may be an effective way to identify invalid test performance during a neuropsychological evaluation. Furthermore, pairing these tests is consistent with current practice guidelines to include multiple PVTs in a neuropsychological test battery.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis., (© 2024. The Author(s).)

Fluorescent organic nanoparticles (NPs) with exceptional brightness hold significant promise for demanding fluorescence bioimaging applications. Although considerable efforts are invested in developing novel organic dyes with enhanced performance, augmenting the brightness of conventional fluorophores is still one of the biggest challenges to overcome. This study presents a supramolecular strategy for constructing ultrabright fluorescent nanoparticles in aqueous media (referred to as "Supra-fluorophores") derived from conventional fluorophores. To achieve this, this course has employed a cylindrical nanoparticle with a hydrophobic microdomain, assembled by a cyclic peptide-diblock copolymer conjugate in water, as a supramolecular scaffold. The noncovalent dispersion of fluorophore moieties within the hydrophobic microdomain of the scaffold effectively mitigates the undesired aggregation-caused quenching and fluorescence quenching by water, resulting in fluorescent NPs with high brightness. This strategy is applicable to a broad spectrum of fluorophore families, covering polyaromatic hydrocarbons, coumarins, boron-dipyrromethenes, cyanines, xanthenes, and squaraines. The resulting fluorescent NPs demonstrate high fluorescence quantum yield (>30%) and brightness per volume (as high as 12 060 m -1 cm -1 nm -3 ). Moreover, high-performance NPs with emission in the NIR region are constructed, showcasing up to 20-fold increase in both brightness and photostability. This Supra-fluorophore strategy offers a versatile and effective method for transforming existing fluorophores into ultrabright fluorescent NPs in aqueous environments, for applications such as bioimaging., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Objective: The Making Change Test (MCT) is a brief, digitized freestanding performance validity test (PVT) designed for tele-neuropsychology (TeleNP). The objective of this study was to report the initial validation of the MCT in a mixed neuropsychiatric sample referred for neuropsychological evaluation using a known-groups design., Method: The sample consisted of 136 adult outpatients who underwent a neuropsychological evaluation. Patients were classified as valid ( n  = 115) or invalid ( n  = 21) based on several established PVTs. Two validity indicators were calculated and assessed, including an Accuracy Response-Score and an Abbreviated Index. The Accuracy Response-Score incorporated both response time and errors. The Abbreviated Index aggregated response time and errors across the most sensitive test items in terms of predicting performance validity status., Results: Correlational analyses indicated that the MCT Accuracy Response-Score and Abbreviated Index were more similar to non-memory-based PVTs than memory-based PVTs. Both the MCT Accuracy Response-Score and Abbreviated Index indicated acceptable classification accuracy (area under the curve of .77). The optimal cut score for the MCT Accuracy Response-Score (≥24) yielded a sensitivity of .38 and specificity of .90. The optimal cut score associated with the Abbreviated Index yielded slightly better operating characteristics, with a sensitivity of .50 and specificity of .90., Conclusions: Initial findings provide support for the criterion and construct validity of the MCT and suggest a promising TeleNP future for this performance validity tool. However, additional support is necessary before the MCT can be used clinically.

Background: Following the launch of the World Health Organization's Strategy to accelerate the elimination of cervical cancer, diagnosis is expected to increase, especially in low- and middle-income countries (LMICs). A well-integrated surgical system is critical to treat cervical cancer. Two major approaches have been employed to build human capacity: task-sharing and training of gynecologic oncologists (GynOncs)., Objectives: This review aimed to explore existing literature on capacity-building for surgical management of early-stage gynecologic cancers., Search Strategy: The search strategy was registered on Open Science Framework (doi 10.17605/OSF.IO/GTRCB) and conducted on OVID Medline, Embase, Global Index Medicus, and Web of Science. Search results were exported and screened in COVIDENCE., Selection Criteria: Studies published in English, Spanish, French, and/or Portuguese conducted in LMIC settings evaluating capacity building, task-sharing, or outcomes following operation by subspecialists compared to specialists were included., Data Collection and Analysis: Results were synthesized using narrative synthesis approach with emergence of key themes by frequency., Main Results: The scoping review identified 18 studies spanning our themes of interest: capacity building, subspecialized versus non-subspecialized care, and task-shifting/-sharing., Conclusions: A multilayered approach is critical to achieve the WHO Strategy to Eliminate Cervical Cancer. Capacity-building and task-sharing programs demonstrate encouraging results to meet this need; nevertheless, a standardized methodology is needed to evaluate these programs, their outcomes, and cost-effectiveness., (© 2023 International Federation of Gynecology and Obstetrics.)

High aspect-ratio nanomaterials have recently emerged as promising drug delivery vehicles due to evidence of strong cellular association and prolonged in vivo circulation times. Cyclic peptide - polymer conjugate nanotubes are excellent candidates due to their elongated morphology, their supramolecular composition and high degree of pliability due to the versatility in manipulating amino acid sequence and polymer type. In this work, we explore the use of a nanotube structure on which a potent anti-cancer drug, camptothecin, is attached alongside hydrophilic or amphiphilic RAFT polymers, which shield the cargo. We show that subtle modifications to the cleavable linker type and polymer architecture have a dramatic influence over the rate of drug release in biological conditions. In vitro studies revealed that multiple cancer cell lines in 2D and 3D models responded effectively to the nanotube treatment, and analogous fluorescently labelled materials revealed key mechanistic information regarding the degree of cellular uptake and intracellular fate. Importantly, the ability to instruct specific drug release profiles indicates a potential for these nanomaterials as vectors which can provide sustained drug concentrations for a maximal therapeutic effect., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Categorical diagnosis, a pillar of the medical model, has not worked well in psychiatry where most diagnoses are still exclusively symptom based. Uncertainty continues about whether categories or dimensions work better for the assessment and treatment of idiopathic psychoses. The Bipolar Schizophrenia Network for Intermediate Phenotypes (B-SNIP) examined multiple cognitive and electrophysiological biomarkers across a large transdiagnostic psychosis data set. None of the variables supported neurobiological distinctiveness for conventional clinical psychosis diagnoses but showed a continuum of severity. Using numerical taxonomy of these data, B-SNIP identified three biological subtypes (Biotypes) agnostic to DSM diagnoses. Biotype-1 is characterized by reduced physiological response to salient stimuli, while Biotype-2 showed accentuated intrinsic (background or ongoing) neural activity and the worst inhibition. Biotype-3 cases are like healthy persons on many laboratory measures. These Biotypes differed in imaging and other electrophysiological measures not included in subgroup creation, illustrating external validation. The Biotypes solution also replicated in an independent sample of psychosis cases. Biotypes are differentiable by clinical characteristics, leading to a feasible algorithm for Biotype estimates. Identifying Biotypes may aid treatment selection and outcome prediction. As an example, preliminary cross-sectional B-SNIP data suggest that Biotype-1 cases may have physiological features that predict a more favorable response to clozapine. While psychosis Biotypes reveal physiological heterogeneity across cases with similar clinical characteristics, data also suggest a dimensional vulnerability for serious psychopathology that cuts across diagnostic boundaries. Both categorical and dimensional diagnostic approaches should be considered within idiopathic psychosis for optimum diagnosis, care, and research., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Fluorescent materials with high brightness play a crucial role in the advancement of various technologies such as bioimaging, photonics, and OLEDs. While significant efforts are dedicated to designing new organic dyes with improved performance, enhancing the brightness of existing dyes holds equal importance. In this study, we present a simple supramolecular strategy to develop ultrabright cyanine-based fluorescent materials by addressing long-standing challenges associated with cyanine dyes, including undesired cis-trans photoisomerization and aggregation-caused quenching. Supra-cyanines are obtained by incorporating cyanine moieties in a cyclic peptide-based supramolecular scaffold, and exhibit high fluorescence quantum yields (up to 50 %) in both solution and in the solid state. These findings offer a versatile approach for constructing highly emissive cyanine-based supramolecular materials., (© 2023 Wiley-VCH GmbH.)

Event-related potentials (ERPs) during oddball tasks and the behavioral performance on the Penn Conditional Exclusion Task (PCET) measure context-appropriate responding: P300 ERPs to oddball targets reflect detection of input changes and context updating in working memory, and PCET performance indexes detection, adherence, and maintenance of mental set changes. More specifically, PCET variables quantify cognitive functions including inductive reasoning (set 1 completion), mental flexibility (perseverative errors), and working memory maintenance (regressive errors). Past research showed that both P300 ERPs and PCET performance are disrupted in psychosis. This study probed the possible neural correlates of 3 PCET abnormalities that occur in participants with psychosis via the overlapping cognitive demands of the two study paradigms. In a two-tiered analysis, psychosis (n = 492) and healthy participants (n = 244) were first divided based on completion of set 1 - which measures subjects' ability to use inductive reasoning to arrive at the correct set. Results showed that participants who failed set 1 produced lower parietal P300, independent of clinical status. In the second tier of analysis, a double dissociation was found among healthy set 1 completers: frontal P300 amplitudes were negatively associated with perseverative errors, and parietal P300 was negatively associated with regressive errors. In contrast, psychosis participants showed global P300 reductions regardless of PCET performance. From this we conclude that in psychosis, overall activations evoked by the oddball task are reduced while the cognitive functions required by PCET are still somewhat supported, showing some level of independence or compensatory physiology in psychosis between neural activities underlying the two tasks., Competing Interests: Declaration of competing interest JS consults to VeraSci; CT functions as the Chair of a Merch DSMB, ad hoc advisor to Astellas and Sunovian, a Clinical Advisory Board member at Kynexis, and Advisor and holds stock at Karuna; MK holds a consulting role for Alkermes and is an editor for Schizophrenia Research (Elsevier); Other authors report no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Clinically defined psychosis diagnoses are neurobiologically heterogeneous. The B-SNIP consortium identified and validated more neurobiologically homogeneous psychosis Biotypes using an extensive battery of neurocognitive and psychophysiological laboratory measures. However, typically the first step in any diagnostic evaluation is the clinical interview. In this project, we evaluated if psychosis Biotypes have clinical characteristics that can support their differentiation in addition to obtaining laboratory testing. Clinical interview data from 1907 individuals with a psychosis Biotype were used to create a diagnostic algorithm. The features were 58 ratings from standard clinical scales. Extremely randomized tree algorithms were used to evaluate sensitivity, specificity, and overall classification success. Biotype classification accuracy peaked at 91 % with the use of 57 items on average. A reduced feature set of 28 items, though, also showed 81 % classification accuracy. Using this reduced item set, we found that only 10-11 items achieved a one-vs-all (Biotype-1 or not, Biotype-2 or not, Biotype-3 or not) area under the sensitivity-specificity curve of .78 to .81. The top clinical characteristics for differentiating psychosis Biotypes, in order of importance, were (i) difficulty in abstract thinking, (ii) multiple indicators of social functioning, (iii) conceptual disorganization, (iv) severity of hallucinations, (v) stereotyped thinking, (vi) suspiciousness, (vii) unusual thought content, (viii) lack of spontaneous speech, and (ix) severity of delusions. These features were remarkably different from those that differentiated DSM psychosis diagnoses. This low-burden adaptive algorithm achieved reasonable classification accuracy and will support Biotype-specific etiological and treatment investigations even in under-resourced clinical and research environments., Competing Interests: Declaration of competing interest Dr. Clementz reports being on the KyNexis SAB. Dr. Tamminga reports serving on the Merck DSmB, being on the Karuna SAB and owning Karuna stock, and being on the KyNexis SAB and owning KyNexis stock. Dr. Gibbons reports serving as an expert witness in cases for the US Department of Justice, receiving expert witness fees from Merck, GlaxoSmithKline, Pfizer, and Wyeth; and founded the company Adaptive Testing Technologies, outside the submitted work. No other authors report any conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Accessibility to surgical services can impact earthquake preparedness and response. We aimed to estimate the population with timely access to surgical care in Guerrero, a Mexican state with high tectonic activity, and identify populations at risk in the event of an earthquake., Methods: We conducted an ecological study using open government data. We extracted data from Guerrero municipalities regarding their earthquake risk, social vulnerability, social inequality, marginalisation, and resilience indices. The latest combines municipalities' resistance to unexpected events and capacity to maintain optimal functionality without immediate federal or international support. Geographical coordinates of active public and private surgical facilities in Guerrero were combined with ancillary spatial data on roads and municipalities' population density to estimate population coverage within 30-min and 1-h driving time to surgical facilities in Redivis. We built an ordered beta regression model for each driving time estimate., Findings: We identified 25 public and 16 private facilities capable of providing surgical care in Guerrero. The population with access to facilities with surgical capacity within 30 min and 1-h driving times were 48.4% and 69.1%, respectively. We found that municipalities with very high levels of earthquake risk, social vulnerability, social inequality, and marginalisation, and very low levels of resilience had decreased coverage. In the multivariable analysis, the resilience index was statistically significant only for the 30-min model, with an effect size of 0.524 (95% CI 0.082, 1.089)., Interpretation: Access to surgical care remains unequally distributed in Guerrero municipalities at the highest risk for earthquakes. Municipalities' resilience was the most significant predictor of higher surgical care coverage in 30-min driving time. Our study provides insights on how surgical system strengthening can enhance earthquake emergency disaster planning., Funding: No funding., Competing Interests: None., (© 2023 Published by Elsevier Ltd.)

Background: Laparoscopic surgery remains limited in low-resource settings. We aimed to examine its use in Mexico and determine associated factors., Methods: By querying open-source databases, we conducted a nationwide retrospective analysis of three common surgical procedures (i.e., cholecystectomies, appendectomies, and inguinal hernia repairs) performed in Mexican public hospitals in 2021. Procedures were classified as laparoscopic based on ICD-9 codes. We extracted patient (e.g., insurance status), clinical (e.g., anaesthesia technique), and geographic data (e.g., region) from procedures performed in hospitals and ambulatories. Multivariable analysis with random forest modelling was performed to identify associated factors and their importance in adopting laparoscopic approach., Findings: We included 97,234 surgical procedures across 676 public hospitals. In total, 16,061 (16.5%) were performed using laparoscopic approaches, which were less common across all procedure categories. The proportion of laparoscopic procedures per 100,000 inhabitants was highest in the northwest (22.2%, 16/72) while the southeast had the lowest (8.3%, 13/155). Significant factors associated with a laparoscopic approach were female sex, number of municipality inhabitants, region, anaesthesia technique, and type of procedure. The number of municipality inhabitants had the highest contribution to the multivariable model., Interpretation: Laparoscopic procedures were more commonly performed in highly populated, urban, and wealthy northern areas. Access to laparoscopic techniques was mostly influenced by the conditions of the settings where procedures are performed, rather than patients' non-modifiable characteristics. These findings call for tailored interventions to sustainably address equitable access to minimally invasive surgery in Mexico., Funding: None., Competing Interests: None., (© 2023 The Author(s).)

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups., Competing Interests: Declaration of Competing Interest Drs. Trotti, Parker, Sabatinelli, Keedy, Gershon, Pearlson, Hill, McDowell, and Clementz reported no potential conflicts of interest. Dr. Keshavan reports serving as an advisor to Alkermes, Takeda, and Vanna Inc. Dr. Tamminga reports the following financial disclosures: American Psychiatric Association – Deputy Editor; Astellas – Ad Hoc Consultant; Autifony – Ad Hoc Consultant; The Brain and Behavior Foundation – Council Member; Eli Lilly Pharmaceuticals – Ad Hoc Consultant; Intra-cellular Therapies (ITI, Inc.) – Advisory Board, drug development; Institute of Medicine – Council Member; National Academy of Medicine – Council Member; Pfizer – Ad Hoc Consultant; Sunovion – Investigator Initiated grant funding., (Copyright © 2023. Published by Elsevier B.V.)

Competing Interests: The authors have nothing to disclose.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R 2  = 0.100, p-value = 2.69e -4 , q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R 2  = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R 2  = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control., Competing Interests: Declaration of competing interest CAT declares an ad hoc consulting relationship with Sunovion, Astellas and Merck and membership on a Merck DSMB; CAT is on the Clinical Advisory Board at Kynexis and Karuna Therapeutics and holds stock in Karuna. MSK has received support from Sunovion and GlaxoSmithKline; MSK is a consultant to Forum Pharmaceuticals. JAS has received support from VeraSci. JRB has served as a consultant to OptumRx. RSEK receives royalties for the BACS, and has consulting relationships with Merck, Karuna, Sunovion, Biogen and Boehringer-Ingelheim. The other authors report no related disclosures., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: Time-resolved, 2D-phase-contrast MRI (2D-CINE-PC-MRI) enables in vivo blood flow analysis. However, accurate vessel contour delineation (VCD) is required to achieve reliable results. We sought to evaluate manual analysis (MA) compared to the performance of a deep learning (DL) application for fully-automated VCD and flow quantification and corrected semi-automated analysis (corSAA)., Methods: We included 97 consecutive patients (age = 52.9 ± 16 years, 41 female) with 2D-CINE-PC-MRI imaging on 1.5T MRI systems at sinotubular junction (STJ), and 28/97 also received 2D-CINE-PC at main pulmonary artery (PA). A cardiovascular radiologist performed MA (reference) and corSAA (built-in tool) in commercial software for all cardiac time frames (median: 20, total contours per analysis: 2358 STJ, 680 PA). DL-analysis automatically performed VCD, followed by net flow (NF) and peak velocity (PV) quantification. Contours were compared using Dice similarity coefficients (DSC). Discrepant cases (> ± 10 mL or > ± 10 cm/s) were reviewed in detail., Results: DL was successfully applied to 97% (121/125) of the 2D-CINE-PC-MRI series (STJ: 95/97, 98%, PA: 26/28, 93%). Compared to MA, mean DSC were 0.91 ± 0.02 (DL), 0.94 ± 0.02 (corSAA) at STJ, and 0.85 ± 0.08 (DL), 0.93 ± 0.02 (corSAA) at PA; this indicated good to excellent DL-performance. Flow quantification revealed similar NF at STJ (p = 0.48) and PA (p > 0.05) between methods while PV assessment was significantly different (STJ: p < 0.001, PA: p = 0.04). A detailed review showed noisy voxels in MA and corSAA impacted PV results. Overall, DL analysis compared to human assessments was accurate in 113/121 (93.4%) cases., Conclusions: Fully-automated DL-analysis of 2D-CINE-PC-MRI provided flow quantification at STJ and PA at expert level in > 93% of cases with results being available instantaneously., Key Points: • Deep learning performed flow quantification on clinical 2D-CINE-PC series at the sinotubular junction and pulmonary artery at the expert level in > 93% of cases. • Location detection and contouring of the vessel boundaries were performed fully-automatic with results being available instantaneously compared to human assessments which approximately takes three minutes per location. • The evaluated tool indicates usability in daily practice., (© 2022. The Author(s).)

Some patients with schizophrenia have severe cognitive impairment and functional deficits that require long-term institutional care. The patterns of brain-behavior alterations in these individuals, and their differences from patients living successfully in the community, remain poorly understood. Previous cognition-based studies for stratifying schizophrenia patients highlight the importance of subcortical structures in the context of illness heterogeneity. In the present study, subcortical volumes from 96 institutionalized patients with long-term schizophrenia were evaluated using cluster analysis to test for heterogeneity. These data were compared to those from two groups of community-dwelling individuals with schizophrenia for comparison purposes, including 68 long-term ill and 126 first-episode individuals. A total of 290 demographically matched healthy participants were included as normative references at a 1:1 ratio for each patient sample. A subtype of institutionalized patients was identified based on their pattern of subcortical alterations. Using a machine learning algorithm developed to discriminate the two groups of institutionalized patients, all three patient samples were found to have similar rates of patients assigned to the two subtypes (approximately 50% each). In institutionalized patients, only the subtype with the identified pattern of subcortical alterations had greater neocortical and cognitive abnormalities than those in the similarity classified community-dwelling patients with long-term illness. Thus, for the subtype of patients with a distinctive pattern of subcortical alterations, when the distinct pattern of subcortical alterations is present and particularly severe, it is associated with cognitive impairments that may contribute to persistent disability and institutionalization., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes., Methods: Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns., Results: Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups., Conclusions: With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.

Cognitive dysfunction is a core feature of psychosis-spectrum illnesses, and the characterization of related genetic mechanisms may provide insights regarding the disease pathophysiology. Substantial efforts have been made to determine the genetic component of cognitive symptoms, without clear success. Illness-related moderators and environmental factors such as medications hinder the detection of genomic association with cognition. Polypharmacy is common in psychotic disorders, and the cumulative effects of medication regimens can confound gene-cognition associations. A review of the relative contributions of important pharmacological and genetic relationships identifies that the effects of medications on cognition in psychotic disorders may be at least, if not more, impactful than individual genes, thus underscoring the importance of accounting for medication exposure in gene-cognition association studies.

Affective and non-affective psychotic disorders are associated with variable levels of impairment in affective processing, but this domain typically has been examined via presentation of static facial images. We compared performance on a dynamic facial expression identification task across six emotions (sad, fear, surprise, disgust, anger, happy) in individuals with psychotic disorders (bipolar with psychotic features [PBD] = 113, schizoaffective [SAD] = 163, schizophrenia [SZ] = 181) and healthy controls (HC; n = 236) derived from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). These same individuals with psychotic disorders were also grouped by B-SNIP-derived Biotype (Biotype 1 [B1] = 115, Biotype 2 [B2] = 132, Biotype 3 [B3] = 158), derived from a cluster analysis applied to a large biomarker panel that did not include the current data. Irrespective of the depicted emotion, groups differed in accuracy of emotion identification (P < 0.0001). The SZ group demonstrated lower accuracy versus HC and PBD groups; the SAD group was less accurate than the HC group (Ps < 0.02). Similar overall group differences were evident in speed of identifying emotional expressions. Controlling for general cognitive ability did not eliminate most group differences on accuracy but eliminated almost all group differences on reaction time for emotion identification. Results from the Biotype groups indicated that B1 and B2 had more severe deficits in emotion recognition than HC and B3, meanwhile B3 did not show significant deficits. In sum, this characterization of facial emotion recognition deficits adds to our emerging understanding of social/emotional deficits across the psychosis spectrum., (Copyright © 2021 Elsevier B.V. All rights reserved.)

An opportunity has opened for research into primary prevention of psychotic disorders, based on progress in endophenotypes, genetics, and genomics. Primary prevention requires reliable prediction of susceptibility before any symptoms are present. We studied a battery of measures where published data supports abnormalities of these measurements prior to appearance of initial psychosis symptoms. These neurobiological and behavioral measurements included cognition, eye movement tracking, Event Related Potentials, and polygenic risk scores. They generated an acceptably precise separation of healthy controls from outpatients with a psychotic disorder. METHODS: The Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) measured this battery in an ancestry-diverse series of consecutively recruited adult outpatients with a psychotic disorder and healthy controls. Participants include all genders, 16 to 50 years of age, 261 with psychotic disorders (Schizophrenia (SZ) 109, Bipolar with psychosis (BPP) 92, Schizoaffective disorder (SAD) 60), 110 healthy controls. Logistic Regression, and an extension of the Linear Mixed Model to include analysis of pairwise interactions between measures (Environmental kernel Relationship Matrices (ERM)) with multiple iterations, were performed to predict case-control status. Each regression analysis was validated with four-fold cross-validation. RESULTS AND CONCLUSIONS: Sensitivity, specificity, and Area Under the Curve of Receiver Operating Characteristic of 85%, 62%, and 86%, respectively, were obtained for both analytic methods. These prediction metrics demonstrate a promising diagnostic distinction based on premorbid risk variables. There were also statistically significant pairwise interactions between measures in the ERM model. The strong prediction metrics of both types of analytic model provide proof-of-principle for biologically-based laboratory tests as a first step toward primary prevention studies. Prospective studies of adolescents at elevated risk, vs. healthy adolescent controls, would be a next step toward development of primary prevention strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cardiometabolic disorders have known inflammatory implications, and peripheral measures of inflammation and cardiometabolic disorders are common in persons with psychotic disorders. Inflammatory signatures are also related to neurobiological and behavioral changes in psychosis. Relationships between systemic inflammation and cardiometabolic genetic risk in persons with psychosis have not been examined. Thirteen peripheral inflammatory markers and genome-wide genotyping were assessed in 122 participants (n ​= ​86 psychosis, n ​= ​36 healthy controls) of European ancestry. Cluster analyses of inflammatory markers classified higher and lower inflammation subgroups. Single-trait genetic risk scores (GRS) were constructed for each participant using previously reported GWAS summary statistics for the following traits: schizophrenia, bipolar disorder, major depressive disorder, coronary artery disease, type-2 diabetes, low-density lipoprotein, high-density lipoprotein, triglycerides, and waist-to-hip ratio. Genetic correlations across traits were quantified. Principal component (PC) analysis of the cardiometabolic GRSs generated six PC loadings used in regression models to examine associations with inflammation markers. Functional module discovery explored biological mechanisms of the inflammation association of cardiometabolic GRS genes. A subgroup of 38% persons with psychotic disorders was characterized with higher inflammation status. These higher inflammation individuals had lower BACS scores ( p  ​= ​0.038) compared to those with lower inflammation. The first PC of the cardiometabolic GRS matrix was related to higher inflammation status in persons with psychotic disorders (OR ​= ​2.037, p  ​= ​0.001). Two of eight modules within the functional interaction network of cardiometabolic GRS genes were enriched for immune processes. Cardiometabolic genetic risk may predispose some individuals with psychosis to elevated inflammation which adversely impacts cognition associated with illness., Competing Interests: CAT declares an ad hoc consulting relationship with Sunovion, Astellas and Merck and membership on a Merck DSMB; CAT is on the Clinical Advisory Board at Kynexis and Karuna Therapeutics and holds stock in Karuna. MSK has received support from Sunovion and GlaxoSmithKline; MSK is a consultant to Forum Pharmaceuticals. JAS has received support from VeraSci. JRB has served as a consultant to OptumRx. The other authors report no related disclosures., (© 2022 The Author(s).)

Background: Cognitive impairment is a core deficit across psychotic disorders, the causes and therapeutics of which remain unclear. Epidemiological observations have suggested associations between cognitive dysfunction in psychotic disorders and cardiovascular risk factors, but an underlying etiology has not been established., Methods: Neuropsychological performance using the Brief Assessment of Cognition in Schizophrenia (BACS) was assessed in 616 individuals of European ancestry (403 psychosis, 213 controls). Polygenic risk scores for coronary artery disease (PRS CAD ) were quantified for each participant across 13 p-value thresholds (P T 0.5-5e -8 ). Cardiovascular and psychotropic medications were categorized for association analyses. Each PRS CAD was examined in relation to the BACS and the optimized P T was confirmed with five-fold cross-validation and independent validation. Functional enrichment analyses were used to identify biological mechanisms linked to PRS CAD -cognition associations. Multiple regression analyses examined PRS CAD under the optimal P T and medication burden in relation to the BACS composite and subtest scores., Results: Higher PRS CAD was associated with lower BACS composite scores (p = 0.001) in the psychosis group, primarily driven by the Verbal Memory subtest (p < 0.001). Genes linked to multiple nervous system related processes and pathways were significantly enriched in PRS CAD . After controlling for PRS CAD , a greater number of cardiovascular medications was also correlated with worse BACS performance in patients with psychotic disorders (p = 0.029)., Conclusions: Higher PRS CAD and taking more cardiovascular medications were both significantly associated with cognitive impairment in psychosis. These findings indicate that cardiovascular factors may increase the risk for cognitive dysfunction and related functional outcomes among individuals with psychotic disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called "B-SNIP1" with 711 psychosis and 274 healthy persons, and the "replication sample" with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r's from .96-.99) and temporally stable (r's from .76-.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%-89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Urban litterfall that is deposited on impervious surface leaches nutrients into stormwater, contributing to downstream eutrophication. Previous studies have focused on the leaching potential of deciduous leaf litter, while other smaller-volume litterfall types-such as blossoms and fruit-may leach significant amounts of nitrogen, phosphorus, and carbon. These additional litterfall types represent an unaccounted-for source of nutrients to urban stormwater. We explored variation in leaching potential of dissolved nutrients and organic carbon across litter types and species by collecting litterfall (blossoms, fruit, leaves) from ten common urban tree species. After 24 h of leaching, we measured total phosphorus (TP), total dissolved nitrogen (TDN), and dissolved organic carbon (DOC) contributions and compared differences across litter types and species. Litter basket estimates then allowed us to quantify annual litterfall inputs. We found that blossoms leached 3-20 times more TDN and 1.5-7 times more TP than leaves of the same species. Furthermore, considering litterfall mass, several species had greater springtime nutrient-leaching potential compared to fall due to high leaching potential in blossoms and lower potential in leaves. We found mixed effects of leaf crushing and leachate solution (stormwater, salinity) on leaching rates. This study highlights the need to consider all litterfall types as well as variation in urban forest communities and conditions when seeking to budget, control, and maintain for potential nutrient sources from the urban forest., Supplementary Information: The online version contains supplementary material available at 10.1007/s11252-022-01217-8., Competing Interests: Conflicts of interestNone., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022.)

Background: Deficits in working memory have been identified as a core cognitive impairment in schizophrenia. Prior work has identified a unique pattern of rapidly decreasing accuracy following intact encoding and updating of a single visuospatial target in patients with schizophrenia. Understanding whether these deficits are related to disruption of working memory stores following retrieval or part of a broader maintenance dysfunction may help elucidate the specific subprocesses underlying working memory deficits in schizophrenia., Methods: Participants were 71 patients with a schizophrenia spectrum disorder and 43 healthy controls who completed a working memory paradigm that parametrically varied maintenance demands from 1000 to 8000 ms., Results: Patients with a schizophrenia spectrum disorder were comparable to healthy controls at delays of 1000 ms. However, when delays were extended to 2000 and 4000 ms, the patient group showed significantly decreased accuracy. Additionally, the patient group showed a greater decline in accuracy following a second delay., Conclusions: These findings suggest that early encoding of one item is intact in patients with a schizophrenia spectrum disorder, but information rapidly decays from working memory stores with extended delays. Accuracy further decreased when information was retrieved from working memory, suggesting that working memory stores may also be susceptible to disruption from internal stimuli. Thus, working memory stores in patients with a schizophrenia spectrum disorder may be vulnerable to both rapid decay and interference., (Copyright © 2021. Published by Elsevier B.V.)

This Review focuses on the establishment and development of self-assemblies governed by the supramolecular interactions between cyclic peptides. The Review first describes the type of cyclic peptides able to assemble into tubular structures to form supramolecular cyclic peptide nanotubes. A range of cyclic peptides have been identified to have such properties, including α-peptides, β-peptides, α,γ-peptides, and peptides based on δ- and ε-amino acids. The Review covers the design and functionalization of these cyclic peptides and expands to a recent advance in the design and application of these materials through their conjugation to polymer chains to generate cyclic peptide-polymer conjugates nanostructures. The Review, then, concentrates on the challenges in characterizing these systems and presents an overview of the various analytical and characterization techniques used to date. This overview concludes with a critical survey of the various applications of the nanomaterials obtained from supramolecular cyclic peptide nanotubes, with a focus on biological and medical applications, ranging from ion channels and membrane insertion to antibacterial materials, anticancer drug delivery, gene delivery, and antiviral applications.

Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features., Methods: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2)., Results: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups., Conclusions: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry., (Copyright © 2020 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objectives: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features., Methods: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance., Results: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P < .01) and predictive (P = .02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P < .01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P < .001), without a significant difference between the two bipolar patient groups., Conclusions: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed-forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups., (© 2019 The Authors. Bipolar Disorders published by Published by John Wiley & Sons Ltd.)

Dopaminergic activity in prefrontal cortex is modulated by the low (Met) and high (Val) activity of the rs4680 Val158Met single nucleotide polymorphism (SNP) in the Catechol-O-Methyltransferase (COMT) gene. While this has been related to working memory maintenance in patients with schizophrenia, the familial pattern, impact across the psychosis spectrum, and the role of this genotype on other aspects of behavior, such as cognitive flexibility, remains unclear. The relationship between COMT Val158Met genotype and both cognitive stability and flexibility were assessed using the Penn Conditional Exclusion Test (PCET) in healthy controls (n = 241), patients with psychotic disorders (n = 542), and their first-degree relatives (n = 613) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Higher rates of perseverative errors (poor flexibility) were associated with the low-activity COMT genotype (Met allele carriers) in probands compared to their first-degree relatives with the same genotype. Probands and first-degree relatives homozygous for the high-activity COMT enzyme (Val/Val) showed elevated rates of regressive errors (poor stability) compared to controls. Conversely, heterozygous relatives had comparable regressive error rates to controls, with probands showing elevated errors in comparison. These findings suggest that impaired suppression of learned response patterns and reduced stability of mental sets may be a familial intermediate cognitive phenotype related to Val COMT allele genotype., Competing Interests: Declaration of competing interest Dr. Tamminga is on the board of IntraCellular Technology and an ad hoc consultant for Takeda, Pierre Fabre, and Atiphony. The other authors have no conflicts of interest at this time. The other authors have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum., Methods: We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability., Results: All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability., Conclusions: We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities., Competing Interests: Declaration of competing interest M.Y. Gotra, S.K. Hill, E.S. Gershon, C.A. Tamminga, E.I. Ivleva, G.D. Pearlson, B.A. Clementz, J.E. McDowell, P.F. Buckley, J.A. Sweeney, and S.K. Keedy report no financial interests or potential conflicts. M.S. Keshavan has served as an adviser for Alkermes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Oxytocin (OT) and arginine vasopressin (AVP) exert sexually dimorphic effects on cognition and emotion processing. Abnormalities in these hormones are observed in schizophrenia and may contribute to multiple established sex differences associated with the disorder. Here we examined sex-dependent hormone associations with resting brain activity and their clinical associations in schizophrenia patients., Methods: OT and AVP serum concentrations were assayed in 35 individuals with schizophrenia (23 men) and 60 controls (24 men) from the Chicago BSNIP study site. Regional cerebral function was assessed with resting state fMRI by measuring the amplitude of low-frequency fluctuations (ALFF) which are believed to reflect intrinsic spontaneous neuronal activity., Results: In female patients, lower OT levels were associated with lower ALFF in frontal and cerebellar cortices (p's < 0.05) and in female controls AVP levels were inversely associated with ALFF in the frontal cortex (p = 0.01). In male patients, lower OT levels were associated with lower ALFF in the posterior cingulate and lower AVP levels were associated with lower ALFF in frontal cortex (p's < 0.05). In male controls, lower OT levels were associated with lower ALFF in frontal cortex and higher ALFF in the thalamus (p's < 0.05). There were some inverse ALFF-behavior associations in patients., Conclusions: Alterations in peripheral hormone levels are associated with resting brain physiology in a sex-dependent manner in schizophrenia. These effects may contribute to sex differences in psychiatric symptom severity and course of illness in schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study evaluated the ability to flexibly shift cognitive set and to consistently maintain a new response preference using the Penn Conditional Exclusion Test (PCET). The relationship of performance errors with catechol-O-methyltransferase (COMT) rs4680 (Val158Met) genotype (Met carriers vs. Val homozygotes) on test performance before and after antipsychotic treatment in 32 first episode psychosis (FEP) patients was examined. After treatment, patients demonstrated a mixture of beneficial and adverse cognitive outcomes that varied in relation to COMT genotype. Met carriers showed decreased perseverative and regressive errors, reflecting improved cognitive flexibility and enhanced stability of behavioral preferences, respectively. In contrast, Val homozygotes exhibited an increase in regressive errors after treatment. These findings suggest that Val homozygotes may be vulnerable to adverse effects of antipsychotic medication on cognitive processes that maintain consistent adaptive response preferences, an ability linked to the striatum in rodent models., (Copyright © 2018 Elsevier B.V. All rights reserved.)