Psychosis risk as a function of age at onset: A comparison between early- and late-onset psychosis in a general population sample

This paper proposes a partial-order semantics for a stochastic process algebra that supports general (non-memoryless) distributions and combines this with an approach to numerically analyse the first passage time of an event. Based on an adaptation of McMillan's complete finite prefix approach tailored to event structures and process algebra, finite representations are obtained for recursive processes. The behaviour between two events is now captured by a partial order that is mapped on a stochastic task graph, a structure amenable to numerical analysis. Our approach is supported by the (new) tool FOREST for generating the complete prefix and the (existing) tool PEPP for analysing the generated task graph. As a case study, the delay of the first resolution in the root contention phase of the IEEE 1394 serial bus protocol is analysed

Precision-medicine findings from the FACE-SZ cohort to develop motivation-enhancing programs in real-world schizophrenia

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes. Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life. Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits. Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p = 0.021), severe nicotine dependence (aOR = 2.906, p < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p = 0.001), positive symptoms (aOR = 1.052, p = 0.006), current major depressive episode (aOR = 2.627, p < 0.001), sleep disorders (aOR = 1.474, p = 0.024) and lower medication adherence (aOR = 0.836, p = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder. Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia. © 2022 Informa UK Limited, trading as Taylor & Francis Group.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

The relationship between genetic liability, childhood maltreatment, and IQ: findings from the EU-GEI multicentric case–control study

This study investigated if the association between childhood maltreatment and cognition among psychosis patients and community controls was partially accounted for by genetic liability for psychosis. Patients with first-episode psychosis (N = 755) and unaffected controls (N = 1219) from the EU-GEI study were assessed for childhood maltreatment, intelligence quotient (IQ), family history of psychosis (FH), and polygenic risk score for schizophrenia (SZ-PRS). Controlling for FH and SZ-PRS did not attenuate the association between childhood maltreatment and IQ in cases or controls. Findings suggest that these expressions of genetic liability cannot account for the lower levels of cognition found among adults maltreated in childhood

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

Agency Conflicts around the World

We construct firm-level indexes for agency conflicts between controlling shareholders and outside investors by estimating a dynamic model of financing decisions. Our estimates for 12,652 firms from 14 countries show that agency conflicts are large and highly variable across firms and countries. Differences in agency conflicts are largely due to differences in firm-level governance, ownership concentration, and other firm characteristics. The origin of law is more relevant for curtailing governance excesses than for guarding the typical firm. Agency costs split about equally between wealth transfers and value losses from policy distortions. Recent governance reforms in Europe have significantly reduced agency costs