Reproducibility and Visual Inspection of Data

In 2011, Moreau et al. reported in Biological Psychiatry findings concerning patterns of microRNA (miRNA) expression in postmortem samples from prefrontal cortex (Brodmann area 9) from the Stanley Medical Research Institute (SMRI) (Chevy Chase, Maryland). They used advanced statistical techniques and miRNA assays by real-time quantitative polymerase chain reaction (TaqMan probes; Applied Biosystems, Foster City, California) for the canonical sequences in early versions of miRBase (http://www.mirbase.org/). All demographics, sample processing, and data analysis steps were carefully described in their article. The main conclusion was that certain miRNAs were distinguished in comparisons of samples from unaffected control subjects versus samples from subjects with schizophrenia and versus samples from subjects with bipolar disorder. They identified 24 miRNAs in particular with distinctive fold changes [Figure 1 in Moreau et al. (1)]

Clinician Recognition of First Episode Psychosis

Purpose: Psychotic disorders develop during mid-adolescence through early adulthood, with the initial few months a “critical period” offering the greatest promise for recovery. However, the duration of untreated psychosis is typically over a year. This study aimed to identify aspects of care episodes contributing to delays in diagnosis of a first psychotic episode. Methods: Study subjects included 161 adolescents and young adults referred to a first episode psychosis treatment program. We captured the various ways that people who experience a severe mental illness engage in treatment using standardized interviews with patients and informants (e.g., family member) and medical record review. Results: A psychotic disorder diagnosis was not given for 38% of subjects at their initial episode of care. Time to first care episode was virtually the same for subjects that did and did not receive a psychosis diagnosis; 50% within 1 month and 84% within 6 months. Compared to initial care episodes with a psychosis diagnosis, those without a psychosis diagnosis less often involved emergency services (80% vs. 38%, respectively; p value = 1 × 10−7) and more often outpatient primary care (6% vs. 18%; p value = .032) and mental health (32% vs. 49%; p value = .045) services. However, dangerousness indicators were similar (29% vs. 28%; p value = 1). Dangerousness indicators increased to 54% (p value = .002) by the time of eventual diagnosis for those requiring multiple care episodes. Conclusions: Clinicians were important contributors to delays in diagnosis and treatment of psychosis. Interventions targeting outpatient health care providers may be fruitful in reducing the duration of untreated psychosis

Networks of blood proteins in the neuroimmunology of schizophrenia.

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets

Dynamic nuclear polarization and spin-diffusion in non-conducting solids

There has been much renewed interest in dynamic nuclear polarization (DNP), particularly in the context of solid state biomolecular NMR and more recently dissolution DNP techniques for liquids. This paper reviews the role of spin diffusion in polarizing nuclear spins and discusses the role of the spin diffusion barrier, before going on to discuss some recent results.Comment: submitted to Applied Magnetic Resonance. The article should appear in a special issue that is being published in connection with the DNP Symposium help in Nottingham in August 200

Tobacco use and psychosis risk in persons at clinical high risk

Aim: To evaluate the role of tobacco use in the development of psychosis in individuals at clinical high risk. Method: The North American Prodrome Longitudinal Study is a 2-year multi-site prospective case control study of persons at clinical high risk that aims to better understand predictors and mechanisms for the development of psychosis. The cohort consisted of 764 clinical high risk and 279 healthy comparison subjects. Clinical assessments included tobacco and substance use and several risk factors associated with smoking in general population studies. Results: Clinical high risk subjects were more likely to smoke cigarettes than unaffected subjects (light smoking odds ratio [OR] = 3.0, 95% confidence interval [CI] = 1.9-5; heavy smoking OR = 4.8, 95% CI = 1.7-13.7). In both groups, smoking was associated with mood, substance use, stress and perceived discrimination and in clinical high risk subjects with childhood emotional neglect and adaption to school. Clinical high risk subjects reported higher rates of several factors previously associated with smoking, including substance use, anxiety, trauma and perceived discrimination. After controlling for these potential factors, the relationship between clinical high risk state and smoking was no longer significant (light smoking OR = 0.9, 95% CI = 0.4-2.2; heavy smoking OR = 0.3, 95% CI = 0.05-2.3). Moreover, baseline smoking status (hazard ratio [HR] = 1.16, 95% CI = 0.82-1.65) and categorization as ever smoked (HR = 1.3, 95% CI = 0.8-2.1) did not predict time to conversion. Conclusion: Persons at high risk for psychosis are more likely to smoke and have more factors associated with smoking than controls. Smoking status in clinical high risk subjects does not predict conversion. These findings do not support a causal relationship between smoking and psychosis

The Role of microRNA Expression in Cortical Development during Conversion to Psychosis

In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with non-converters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Here we used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N=74). Our cortical thinning classifier included nine microRNAs, p=3.63 × 10-08, R 2 =0.358, permutation-based p=0.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (p<0.05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (p=0.038). Furthermore, miRNAs that predicted conversion status were found to do so in a manner partially mediated by rate of cortical thinning (point estimate=0.078 (95% CIs: 0.003, 0.168), p=0.03). Many of the miRNAs identified here have been previously implicated in brain development, synaptic plasticity, immune function and/or schizophrenia, showing some convergence across studies and methodologies. Altered intracellular signaling within the immune system may interact with cortical maturation in individuals at high risk for schizophrenia promoting disease onset

Polygenic risk score contribution to psychosis prediction in a target population of persons at clinical high risk

Objective: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%225%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. Methods: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. Results: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. Conclusions: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant