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Reduced hippocampal volume (HV) is an established brain morphological feature of psychiatric conditions. HV is associated with brain connectivity in humans and non-human animals and altered connectivity is associated with risk for psychiatric illness. Associations between HV and connectivity remain poorly characterized in humans, and especially in phases of psychiatric illness that precede disease onset. This study examined associations between HV and hippocampal functional connectivity (FC) during rest in 141 healthy controls and 248 individuals at-risk for psychosis. Significant inverse associations between HV and hippocampal FC with the inferior parietal lobe (IPL) and thalamus were observed. Select associations between hippocampal FC and HV were moderated by diagnostic group. Significant moderation results shifted from implicating the IPL to the temporal pole after excluding participants on antipsychotic medication. Considered together, this work implicates hippocampal FC with the temporoparietal junction, within a specialized subsystem of the default mode network, as sensitive to HV.

BACKGROUND: Social determinants of health (SDoHs) are receiving growing attention and are particularly relevant to persons with schizophrenia-spectrum psychotic disorders (SSPDs), considering their heightened risk of comorbidities, cognitive and functional decline, and early mortality. Yet, we did not find any comprehensive review of multiple SDoHs in SSPD. STUDY DESIGN: We conducted a scoping review of meta-analyses and systematic reviews of nine major SDoHs in SSPD. STUDY RESULTS: Childhood abuse, parental psychopathology, parental communication problems, bullying, and urban settings with lower socioeconomic status were major risk factors for the greater incidence of SSPD and/or worse health. Social network size was inversely associated with overall psychopathology and negative symptoms. Experiences of racial/ethnic discrimination correlated with the prevalence of psychotic symptoms and experiences. Compared to native populations, the risk of psychosis was higher in immigrants, refugees, and asylees. Social fragmentation was associated with an increased prevalence of schizophrenia. Homeless populations had a 30-fold higher prevalence of schizophrenia than the general population. Seriously mentally ill people were 2.7 times more likely to report food insecurity than controls. The prevalence of non-affective psychosis in prisoners was 2.0%-6.5%, compared to 0.3% in the general population. Certain potentially positive factors like family and community resilience remain poorly studied. CONCLUSIONS: SDoHs are associated with higher rates of and worse outcomes in SSPD. Well-designed longitudinal studies are needed to understand SDoHs contribution to health in persons with SSPD, to develop interventions, and to implement changes in clinical care and public health policies that would reduce adverse health impacts of SDoHs. Positive SDoHs deserve greater attention.

Abstract 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.

BACKGROUND AND HYPOTHESIS: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms. STUDY DESIGN: Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms. RESULTS: CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR. CONCLUSIONS: For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

BACKGROUND: The clinical high-risk (CHR) period offers a temporal window into neurobiological deviations preceding psychosis onset, but little attention has been given to regions outside the cerebrum in large-scale studies of CHR. Recently, the North American Prodrome Longitudinal Study (NAPLS)-2 revealed altered functional connectivity of the cerebello-thalamo-cortical circuitry among individuals at CHR; however, cerebellar morphology remains underinvestigated in this at-risk population, despite growing evidence of its involvement in psychosis. STUDY DESIGN: In this multisite study, we analyzed T1-weighted magnetic resonance imaging scans obtained from N = 469 CHR individuals (61% male, ages = 12-36 years) and N = 212 healthy controls (52% male, ages = 12-34 years) from NAPLS-2, with a focus on cerebellar cortex and white matter volumes separately. Symptoms were rated by the Structured Interview for Psychosis-Risk Syndromes (SIPS). The outcome by two-year follow-up was categorized as in-remission, symptomatic, prodromal-progression, or psychotic. General linear models were used for case-control comparisons and tests for volumetric associations with baseline SIPS ratings and clinical outcomes. STUDY RESULTS: Cerebellar cortex and white matter volumes differed between the CHR and healthy control groups at baseline, with sex moderating the difference in cortical volumes, and both sex and age moderating the difference in white matter volumes. Baseline ratings for major psychosis-risk dimensions as well as a clinical outcome at follow-up had tissue-specific associations with cerebellar volumes. CONCLUSIONS: These findings point to clinically relevant deviations in cerebellar cortex and white matter structures among CHR individuals and highlight the importance of considering the complex interplay between sex and age when studying the neuromaturational substrates of psychosis risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Background and hypothesisNegative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness-deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset-were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution.Study designLinear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset (N = 699) and within clinical subgroups.Study resultsNegative symptoms followed a downward curvilinear trend, with marked improvement 0-6 months that subsequently stabilized (6-24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate.ConclusionsContinuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs.

IntroductionPersistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS.MethodCHR participants (N = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS (n = 67) versus those without PNS (n = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables.ResultsThere was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events.ConclusionIn terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence.

BackgroundElevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts.MethodsData on substance use frequency and severity, clinical symptoms, and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage = 19.26 ± 7.84 years) and 1,288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage = 18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed effects models.ResultsControlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use in CHR-P individuals was associated with increased psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social functioning, social anhedonia, and IQ compared to 22qDel carriers, and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at 1 year follow-up.ConclusionIndividuals at genetic and CHR-P have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals.

Abstract Background A quantitative measurement of serum proteome biomarkers that would associate with disease progression endpoints can provide risk stratification for persons with multiple sclerosis (PwMS) and supplement the clinical decision‐making process. Materials and Methods In total, 202 PwMS were enrolled in a longitudinal study with measurements at two time points with an average follow‐up time of 5.4 years. Clinical measures included the Expanded Disability Status Scale, Timed 25‐foot Walk, 9‐Hole Peg, and Symbol Digit Modalities Tests. Subjects underwent magnetic resonance imaging to determine the volumetric measures of the whole brain, gray matter, deep gray matter, and lateral ventricles. Serum samples were analyzed using a custom immunoassay panel on the Olink™ platform, and concentrations of 18 protein biomarkers were measured. Linear mixed‐effects models and adjustment for multiple comparisons were performed. Results Subjects had a significant 55.6% increase in chemokine ligand 20 (9.7 pg/mL vs. 15.1 pg/mL, p

Abstract Background Although age is the biggest known risk factor for dementia, there remains uncertainty about other factors over the life course that contribute to a person’s risk for cognitive decline later in life. Furthermore, the pathological processes leading to dementia are not fully understood. The main goals of Insight 46—a multi-phase longitudinal observational study—are to collect detailed cognitive, neurological, physical, cardiovascular, and sensory data; to combine those data with genetic and life-course information collected from the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort); and thereby contribute to a better understanding of healthy ageing and dementia. Methods/Design Phase 1 of Insight 46 (2015–2018) involved the recruitment of 502 members of the NSHD (median age = 70.7 years; 49% female) and has been described in detail by Lane and Parker et al. 2017. The present paper describes phase 2 (2018–2021) and phase 3 (2021–ongoing). Of the 502 phase 1 study members who were invited to a phase 2 research visit, 413 were willing to return for a clinic visit in London and 29 participated in a remote research assessment due to COVID-19 restrictions. Phase 3 aims to recruit 250 study members who previously participated in both phases 1 and 2 of Insight 46 (providing a third data time point) and 500 additional members of the NSHD who have not previously participated in Insight 46. Discussion The NSHD is the oldest and longest continuously running British birth cohort. Members of the NSHD are now at a critical point in their lives for us to investigate successful ageing and key age-related brain morbidities. Data collected from Insight 46 have the potential to greatly contribute to and impact the field of healthy ageing and dementia by combining unique life course data with longitudinal multiparametric clinical, imaging, and biomarker measurements. Further protocol enhancements are planned, including in-home sleep measurements and the engagement of participants through remote online cognitive testing. Data collected are and will continue to be made available to the scientific community.

AIM: Individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this article was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals. METHODS: From the North American Prodrome Longitudinal Study-3 (NAPLS-3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015 and 2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis. RESULTS: From the 690 CHR participants and 96 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p

Nanomaterials hold immense potential for numerous applications in energy, health care, and environmental sectors, playing an important role in our daily lives. Their utilization spans from improving energy efficiency to enhancing medical diagnostics, and mitigating environmental pollution, thus presenting a multifaceted approach towards achieving sustainability goals. To ensure the sustainable and safe utilization of nanomaterials, a thorough evaluation of potential hazards and risks is essential throughout their lifecycle—from resource extraction and production to use and disposal. In this review, we focus on understanding and addressing potential environmental and health risks associated with nanomaterial utilization. We advocate for a balanced approach with early hazard identification, safe-by-design principles, and life cycle assessments, while emphasizing safe handling and disposal practices, collaboration, and continuous improvement. Our goal is to ensure responsible nanotechnology development, fostering innovation alongside environmental and community well-being, through a holistic approach integrating science, ethics, and proactive risk assessment.

Background: Electroretinographic dysfunction is observed in psychosis, with a-wave and b-wave amplitudes potentially serving as biomarkers. Insulin resistance (IR) and childhood trauma (CT) have also been associated with psychosis-spectrum disorders, particularly schizophrenia. Electroretinographic dysfunction in early-course psychosis (EP) lacks exploration. This case-control exploratory study aimed to understand electroretinographic dysfunction in EP and its relationship with IR and CT. Methods: The study involved healthy controls (n=13) and EP individuals (n=14) and included photopic and scotopic flash-electroretinography (fERG), blood collection for IR assessment, and the Childhood Trauma Questionnaire (CTQ). Data were analyzed using SPSS v.29.0. Case-control differences across fERG conditions were explored using repeated-measures ANCOVA (3 flash conditions X 2 groups) adjusted for gender and age. Sub-analyses included Fisher’s, Mann-Whitney, partial correlations, and logistic and linear regressions. Results: Compared to controls, EP participants showed (1) lower photopic a-wave and b-wave amplitudes, specifically in the left eye and under the P1 condition, (2) greater odds for IR, and (3) higher CTQ scores. IR was associated with a higher CTQ score and a lower P2b amplitude. A higher CTQ score was associated with lower P2b amplitude in the left eye when adjusting for its interacting effect with IR. Conclusion: These findings suggest lower photopic a-wave and b-wave amplitudes, IR, and CT are explanatory markers in EP. CT may dysregulate the hypothalamic-pituitary-adrenal axis, increasing the risk of experiencing later-life psychosis. IR might be a biomarker in psychosis, contributing to electroretinographic dysfunction and neurodegeneration of cone post-synaptic cells. Further investigations are needed.

Introduction Area-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with decreased gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC). Objectives We hypothesize that greater ARI will be associated with reduced right posterior CMFG and rACC GMVs. Methods Data were collected at baseline as part of the North American Prodrome Longitudinal Study. Counties where participants resided during childhood were geographically coded using the US Censuses to area-level factors. ARI was defined as the percentage of residents living in a different house five years ago. Generalized linear mixed models tested associations between ARI and GMVs. Results This study included 29 HC and 64 CHR-P individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG (adjusted β = -0.258; 95% CI = -0.502 – -0.015) and right rACC volumes (adjusted β = -0.318; 95% CI = -0.612 – -0.023). The interaction terms (ARI X diagnostic group) in the prediction of both brain regions were not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs. Conclusions Like urban upbringing, ARI may be an important social environmental characteristic that adversely impacts brain regions related to schizophrenia. Disclosure No significant relationships.

Abstract The spirochete bacterial pathogen Borrelia (Borreliella) burgdorferi (Bbu) affects more than 10% of the world population and causes Lyme disease in about half a million people in the US annually. Therapy for Lyme disease includes antibiotics that target the Bbu ribosome. Here we present the structure of the Bbu 70S ribosome obtained by single particle cryo-electron microscopy at 2.9 Å resolution, revealing a bound hibernation promotion factor protein and two genetically non-annotated ribosomal proteins bS22 and bL38. The ribosomal protein uL30 in Bbu has an N-terminal α-helical extension, partly resembling the mycobacterial bL37 protein, suggesting evolution of bL37 and a shorter uL30 from a longer uL30 protein. Its analogy to proteins uL30m and mL63 in mammalian mitochondrial ribosomes also suggests a plausible evolutionary pathway for expansion of protein content in mammalian mitochondrial ribosomes. Computational binding free energy predictions for antibiotics reflect subtle distinctions in antibiotic-binding sites in the Bbu ribosome. Discovery of these features in the Bbu ribosome may enable better ribosome-targeted antibiotic design for Lyme disease treatment.

Antimony-doped tin oxide nanoparticles (ATO NPs) have emerged as a promising tool in biomedical applications, namely robust photothermal effects upon near-infrared (NIR) light exposure, enabling controlled thermal dynamics to induce spatial cell death. This study investigated the interplay between ATO NPs and macrophages, understanding cellular uptake and cytokine release. ATO NPs demonstrated biocompatibility with no impact on macrophage viability and cytokine secretion. These findings highlight the potential of ATO NPs for inducing targeted cell death in cancer treatments, leveraging their feasibility, unique NIR properties, and safe interactions with immune cells. ATO NPs offer a transformative platform with significant potential for future biomedical applications by combining photothermal capabilities and biocompatibility.

The North American Prodrome Longitudinal Study (NAPLS) is a consortium of nine programs focusing on youth at clinical high risk (CHR) for psychosis. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, University of California at Los Angeles, at San Diego, and at San Francisco, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. There have been two previous endeavors completed by this consortium, known as NAPLS-1 and NAPLS-2. This paper first offers an overview of the methodology of the third phase of the NAPLS consortium, the second five-year prospective study NAPLS-3, which aims to determine mechanisms of the development of psychosis. In addition, we report on the ascertainment and demographics of the 710 CHR participants in NAPLS-3.