Biomarkers in the cerebrospinal fluid of patients with psychotic disorders compared to healthy controls: a systematic review and meta-analysis.

Psychotic disorders are severe mental disorders with poorly understood etiology. Biomarkers in the cerebrospinal fluid (CSF) could provide etiological clues and diagnostic tools for psychosis; however, an unbiased overview of CSF alterations in individuals with psychotic disorders is lacking. The objective of this study was to summarize all quantifiable findings in CSF from individuals with psychotic disorders compared to healthy controls (HC). Studies published before January 25th, 2023 were identified searching PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO. Screening, full-text review, data extraction, and risk of bias assessments were performed by two independent reviewers following PRISMA guidelines. Findings in patients and healthy controls were compared and summarized using random-effects analyses and assessment of publication bias, subgroup and sensitivity analyses were performed. 145 studies, covering 197 biomarkers, were included, of which 163 biomarkers have not previously been investigated in meta-analyses. All studies showed some degree of bias. 55 biomarkers measured in CSF were associated with psychosis and of these were 15 biomarkers measured in ≥2 studies. Patients showed increased levels of noradrenaline (standardized mean difference/SMD, 0.53; 95% confidence interval/CI, 0.16 to 0.90) and its metabolite 3-methoxy-4-hydroxyphenylglycol (SMD, 0.30; 95% CI: 0.05 to 0.55), the serotonin metabolite 5-hydroxyindoleacetic acid (SMD, 0.11; 95% CI: 0.01 to 0.21), the pro-inflammatory neurotransmitter kynurenic acid (SMD, 1.58; 95% CI: 0.34 to 2.81), its precursor kynurenine (SMD,0.99; 95% CI: 0.60 to 1.38), the cytokines interleukin-6 (SMD, 0.58; 95% CI: 0.39 to 0.77) and interleukin-8 (SMD, 0.43; 95% CI: 0.24 to 0.62), the endocannabinoid anandamide (SMD, 0.78; 95% CI: 0.53 to 1.02), albumin ratio (SMD, 0.40; 95% CI: 0.08 to 0.72), total protein (SMD, 0.29; 95% CI: 0.16 to 0.43), immunoglobulin ratio (SMD, 0.45; 95% CI: 0.06 to 0.85) and glucose (SMD, 0.48; 95% CI: 0.01 to 0.94). Neurotensin (SMD, -0.67; 95% CI: -0.89 to -0.46) and γ-aminobutyric acid (SMD, -0.29; 95% CI: -0.50 to -0.09) were decreased. Most biomarkers showed no significant differences, including the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid. These findings suggest that dysregulation of the immune and adrenergic system as well as blood-brain barrier dysfunction are implicated in the pathophysiology of psychotic disorders.

CRISPR-screen identifies ZIP9 and dysregulated Zn2+ homeostasis as a cause of cancer-associated changes in glycosylation.

INTRODUCTION: In epithelial cancers, truncated O-glycans, such as the Thomson-nouveau antigen (Tn) and its sialylated form (STn), are upregulated on the cell surface and associated with poor prognosis and immunological escape. Recent studies have shown that these carbohydrate epitopes facilitate cancer development and can be targeted therapeutically; however, the mechanism underpinning their expression remains unclear. METHODS: To identify genes directly influencing the expression of cancer-associated O-glycans, we conducted an unbiased, positive-selection, whole-genome CRISPR knockout-screen using monoclonal antibodies against Tn and STn. RESULTS AND CONCLUSIONS: We show that knockout of the Zn2+-transporter SLC39A9 (ZIP9), alongside the well-described targets C1GALT1 (C1GalT1) and its molecular chaperone, C1GALT1C1 (COSMC), results in surface-expression of cancer-associated O-glycans. No other gene perturbations were found to reliably induce O-glycan truncation. We furthermore show that ZIP9 knockout affects N-linked glycosylation, resulting in upregulation of oligo-mannose, hybrid-type, and α2,6-sialylated structures as well as downregulation of tri- and tetra-antennary structures. Finally, we demonstrate that accumulation of Zn2+ in the secretory pathway coincides with cell-surface presentation of truncated O-glycans in cancer tissue, and that over-expression of COSMC mitigates such changes. Collectively, the findings show that dysregulation of ZIP9 and Zn2+ induces cancer-like glycosylation on the cell surface by affecting the glycosylation machinery.

Mapping of truncated O-glycans in cancers of epithelial and non-epithelial origin.

BACKGROUND: Novel immunotherapies targeting cancer-associated truncated O-glycans Tn (GalNAcα-Ser/Thr) and STn (Neu5Acα2-6GalNacα-Ser/Thr) are promising strategies for cancer treatment. However, no comprehensive, antibody-based mapping of truncated O-glycans in tumours exist to guide drug development. METHODS: We used monoclonal antibodies to map the expression of truncated O-glycans in >700 tissue cores representing healthy and tumour tissues originating from breast, colon, lung, pancreas, skin, CNS and mesenchymal tissue. Patient-derived xenografts were used to evaluate Tn expression upon tumour engraftment. RESULTS: The Tn-antigen was highly expressed in breast (57%, n = 64), colorectal (51%, n = 140) and pancreatic (53%, n = 108) tumours, while STn was mainly observed in colorectal (80%, n = 140) and pancreatic (56%, n = 108) tumours. We observed no truncated O-glycans in mesenchymal tumours (n = 32) and low expression of Tn (5%, n = 87) and STn (1%, n = 75) in CNS tumours. No Tn-antigen was found in normal tissue (n = 124) while STn was occasionally observed in healthy gastrointestinal tissue. Surface expression of Tn-antigen was identified across several cancers. Tn and STn expression decreased with tumour grade, but not with cancer stage. Numerous xenografts maintained Tn expression. CONCLUSIONS: Surface expression of truncated O-glycans is limited to cancers of epithelial origin, making Tn and STn attractive immunological targets in the treatment of human carcinomas.

Psychiatric Admissions, Referrals, and Suicidal Behavior Before and During the COVID-19 Pandemic in Denmark: A Time-Trend Study.

OBJECTIVE: To assess the patterns in psychiatric admissions, referrals, and suicidal behavior before and during the COVID-19 pandemic. METHODS: This study utilized health records from hospitals and Emergency Medical Services (EMS) covering 46% of the Danish population (n = 2,693,924). In a time-trend study, we compared the number of psychiatric in-patients, referrals to mental health services and suicidal behavior in years prior to the COVID-19 pandemic to levels during the first lockdown (March 11 - May 17, 2020), inter-lockdown period (May 18 - December 15, 2020), and second lockdown (December 16, 2020 - February 28, 2021). RESULTS: During the pandemic, the rate of psychiatric in-patients declined compared to pre-pandemic levels (RR = 0.95, 95% CI = 0.94 - 0.96, p < 0.01), with the largest decrease of 19% observed three weeks into the first lockdown. Referrals to mental health services were not significantly different (RR = 1.01, 95% CI = 0.92 - 1.10, p = 0.91) during the pandemic; neither was suicidal behavior among hospital contacts (RR = 1.04, 95% CI = 0.94 - 1.14, p = 0.48) nor EMS contacts (RR = 1.08, 95% CI = 1.00 - 1.18, p = 0.06). Similar trends were observed across nearly all age groups, sexes, and types of mental disorders examined. In the age group <18, an increase in the rate of psychiatric in-patients (RR = 1.11, 95% CI = 1.07 - 1.15, p < 0.01) was observed during the pandemic; however, this did not exceed the pre-pandemic, upwards trend in psychiatric hospitalizations in the age group <18 (p = 0.78). CONCLUSION: The COVID-19 pandemic has been associated with a decrease in psychiatric hospitalizations, while no significant change was observed in referrals to mental health services and suicidal behavior. Psychiatric hospitalizations among children and adolescents increased during the pandemic; however, this appears to be a continuation of a pre-pandemic trend.

Hip-fracture osteosynthesis training: exploring learning curves and setting proficiency standards.

Background and purpose - Orthopedic surgeons must be able to perform internal fixation of proximal femoral fractures early in their career, but inexperienced trainees prolong surgery and cause increased reoperation rates. Simulation-based virtual reality (VR) training has been proposed to overcome the initial steep part of the learning curve but it is unknown how much simulation training is necessary before trainees can progress to supervised surgery on patients. We determined characteristics of learning curves for novices and experts and a pass/fail mastery-learning standard for junior trainees was established. Methods - 38 first-year residents and 8 consultants specialized in orthopedic trauma surgery performed cannulated screws, Hansson pins, and sliding hip screw on the Swemac TraumaVision VR simulator. A previously validated test was used. The participants repeated the procedures until they reached their learning plateau. Results - The novices and the experts reached their learning plateau after an average of 169 minutes (95% CI 152-87) and 143 minutes (CI 109-177), respectively. Highest achieved scores were 92% (CI 91-93) for novices and 96% (CI 94-97) for experts. Plateau score, defined as the average of the 4 last scores, was 85% (CI 82-87) and 92% (CI 89-96) for the novices and the experts, respectively. Interpretation - Training time to reach plateau varied widely and it is paramount that simulation-based training continues to a predefined standard instead of ending after a fixed number of attempts or amount of time. A score of 92% comparable to the experts' plateau score could be used as a mastery learning pass/fail standard.

Associations Between Mental Disorders in Donors and Matched Recipients of Hematopoietic Stem Cell Transplants: A Population-Based Cohort Study.

Background: Immunological mechanisms have been implicated in the development of mental disorders, and interestingly, case reports have suggested that hematopoietic stem cell transplantation (HSCT) can both transmit and cure psychotic disorders by replacing immune progenitor cells. Methods: Using Danish registers, we followed patients who received HSCT from donors with a psychiatric diagnosis or psychotropic medication use. We assessed risk of incident mental disorders or psychotropic medication use compared with recipients with unaffected donors. We identified 464 donor-recipient pairs (51.3% male recipients). All donor-recipient pairs were related. Results: Receiving HSCT from a donor with a psychiatric history was not significantly associated with incident psychiatric diagnoses (hazard rate ratio [HRR] 2.79, 95% CI, 0.83-9.39; p = .098) or incident use of psychotropics (HRR 1.43, 95% CI, 0.91-2.24; p = .118). Subgroup analysis showed an increased risk of antipsychotic use, which remained significant after adjusting for confounders (HRR 4.73, 95% CI, 1.26-17.78; p = .021); however, this was based on a small number of cases. For depression and antidepressant use, data were available to perform a meta-analysis of our and one additional study, which showed no significant difference (HRR 1.24, 95%, CI 0.66-2.35). Conclusions: Receiving HSCT from a donor with a psychiatric history did not affect risk of mental disorders. An increased risk of antipsychotic use was observed only in subgroup analyses; however, the exploratory nature of the study, the limited sample size, and family relationship between donors and recipients do not allow for causal conclusions, and external replication studies are warranted.

Immunological disturbances have been implicated in the development of mental disorders, and prior case reports have suggested that stem cell transplants can both cause and cure psychotic disorders. Using data on stem cell transplants in Denmark, we did not find evidence of a risk of transmitting mental disorders through transplantation. However, risk of antipsychotic use was elevated in recipients who had donors with antipsychotic use.