Childhood family income, adolescent violent criminality and substance misuse : a quasi-experimental total population study

Background: Low socioeconomic status in childhood is a well-known predictor of subsequent criminal and substance misuse behaviors but the causal mechanisms are questioned. Aims: To investigate if the associations between childhood family income and subsequent adolescent criminality and substance misuse are explained by unobserved familial risk factors. Method: Swedish population-based quasi-experimental, family-based study following cohorts born 1989-1993 (ntotal=529,428; ncousins=262,816; nsiblings=217,035) from their 15th birthday up until the end of 2009. Results: Children of parents in the lowest income quintile experienced a seven-fold increased hazard rate of being convicted of violent criminality compared to peers in the highest quintile (HR=6.84, 95% CI: 6.28-7.44). This association was entirely accounted for by unobserved familial risk factors (HR=0.99; 95% CI: 0.46-2.13). Similar pattern of effects was found for substance misuse. Conclusions: There are no associations between childhood family income and subsequent violent criminality and substance misuse once unobserved familial risk factors are adjusted for.The Swedish Council for Working Life and Social ResearchThe Swedish Research CouncilThe National Institute of Child Health and Human DevelopmentAccepte

Risk of Subjection to Violence and Perpetration of Violence in Persons With Psychiatric Disorders in Sweden

Importance Key outcomes for persons with psychiatric disorders include subjection to violence and perpetration of violence. The occurrence of these outcomes and their associations with psychiatric disorders need to be clarified. Objective To estimate the associations of a wide range of psychiatric disorders with the risks of subjection to violence and perpetration of violence. Design, Setting, and Participants A total of 250 419 individuals born between January 1, 1973, and December 31, 1993, were identified to have psychiatric disorders using Swedish nationwide registers. Premorbid subjection to violence was measured since birth. The patients were matched by age and sex to individuals in the general population (n = 2504 190) and to their full biological siblings without psychiatric disorders (n = 194 788). The start date for the patients and control groups was defined as the discharge date of the first psychiatric episode. The participants were censored either when they migrated, died, experienced the outcome of interest, or reached the end of the study period on December 31, 2013. Data were analyzed from January 15 to September 14, 2019. Exposures Patients with common psychiatric disorders (eg, schizophrenia, bipolar disorder, depression, and anxiety) were differentiated using a hierarchical approach. Patients with personality disorders and substance use disorders were also included. Main Outcomes and Measures Subjection to violence was defined as an outpatient visit (excluding a primary care visit), inpatient episode, or death associated with any diagnosis of an injury that was purposefully inflicted by other persons. Perpetration of violence was defined as a violent crime conviction. Stratified Cox regression models were fitted to account for the time at risk, a range of sociodemographic factors, a history of violence, and unmeasured familial confounders (via sibling comparisons). Results Among 250 419 patients (55.4% women), the median (interquartile range) age at first diagnosis ranged from 20.0 (17.4-24.0) years for alcohol use disorder to 23.7 (19.9-28.8) years for anxiety disorder. Compared with 2504 190 matched individuals without psychiatric disorders from the general population, patients with psychiatric disorders were more likely to be subjected to violence (7.1 [95% CI, 6.9-7.2] vs 1.0 [95% CI, 0.9-1.0] per 1000 person-years) and to perpetrate violence (7.5 [95% CI, 7.4-7.6] vs 0.7 [95% CI, 0.7-0.7] per 1000 person-years). In the fully adjusted models, patients with psychiatric disorders were 3 to 4 times more likely than their siblings without psychiatric disorders to be either subjected to violence (adjusted hazard ratio [aHR], 3.4 [95% CI, 3.2-3.6]) or to perpetrate violence (aHR, 4.2 [95% CI, 3.9-4.4]). Diagnosis with any of the specific disorders was associated with higher rates of violent outcomes, with the sole exception of schizophrenia, which was not associated with the risk of subjection to violence. Conclusions and Relevance In this study, persons with psychiatric disorders were 3 to 4 times more likely than their siblings without psychiatric disorders to have been subjected to violence or to have perpetrated violence after the onset of their conditions. The risks of both outcomes varied by specific psychiatric diagnosis, history of violence, and familial risks. Clinical interventions may benefit from targeted approaches for the assessment and management of risk of violence in people with psychiatric disorders.Peer reviewe

Associations between individual antipsychotics and the risk of arrests and convictions of violent and other crime : a nationwide within-individual study of 74925 persons

Background Individuals diagnosed with psychiatric disorders who are prescribed antipsycho-tics have lower rates of violence and crime but the differential effects of specific antipsychotics are not known. We investigated associations between 10 specific antipsychotic medications and subsequent risks for a range of criminal outcomes. Method We identified 74 925 individuals who were ever prescribed antipsychotics between 2006 and 2013 using nationwide Swedish registries. We tested for five specific first-generation antipsychotics (levomepromazine, perphenazine, haloperidol, flupentixol, and zuclo-penthixol) and five second-generation antipsychotics (clozapine, olanzapine, quetiapine, ris-peridone, and aripiprazole). The outcomes included violent, drug-related, and any criminal arrests and convictions. We conducted within-individual analyses using fixed-effects Poisson regression models that compared rates of outcomes between periods when each individual was either on or off medication to account for time-stable unmeasured confounders. All models were adjusted for age and concurrent mood stabilizer medications. Results The relative risks of all crime outcomes were substantially reduced [range of adjusted rate ratios (aRRs): 0.50-0.67] during periods when the patients were prescribed antipsychotics v. periods when they were not. We found that clozapine (aRRs: 0.28-0.44), olanzapine (aRRs: 0.46-0.72), and risperidone (aRRs: 0.53-0.64) were associated with lower arrest and conviction risks than other antipsychotics, including quetiapine (aRRs: 0.68-0.84) and haloperidol (aRRs: 0.67-0.77). Long-acting injectables as a combined medication class were associated with lower risks of the outcomes but only risperidone was associated with lower risks of all six outcomes (aRRs: 0.33-0.69). Conclusions There is heterogeneity in the associations between specific antipsychotics and subsequent arrests and convictions for any drug-related and violent crimes.Peer reviewe

Interpreting the role of de novo protein-coding mutations in neuropsychiatric disease

Pedigree, linkage and association studies are consistent with heritable variation for complex disease due to the segregation of genetic factors in families and in the population. In contrast, de novo mutations make only minor contributions to heritability estimates for complex traits. Nonetheless, some de novo variants are known to be important in disease etiology. The identification of risk-conferring de novo variants will contribute to the discovery of etiologically relevant genes and pathways and may help in genetic counseling. There is considerable interest in the role of such mutations in complex neuropsychiatric disease, largely driven by new genotyping and sequencing technologies. An important role for large de novo copy number variations has been established. Recently, whole-exome sequencing has been used to extend the investigation of de novo variation to point mutations in protein-coding regions. Here, we consider several challenges for the interpretation of such mutations in the context of their role in neuropsychiatric disease

Labor epidural analgesia and subsequent risk of offspring autism spectrum disorder and attention-deficit/hyperactivity disorder : A cross-national cohort study of 4.5 million individuals and their siblings

Background A recent study has suggested that labor epidural analgesia may be associated with increased rates of offspring autism spectrum disorder (ASD). Subsequent replication attempts have lacked sufficient power to confidently exclude the possibility of a small effect and the causal nature of this association remains unknown. Objective To investigate the extent to which exposure to labor epidural analgesia is associated with offspring ASD and attention-deficit/hyperactivity disorder (ADHD) following adjustments for unmeasured familial confounding. Study design We identified 4,498,462 singletons and their parents using the Medical Birth Registers in Finland (cohorts born 1987-2005), Norway (1999-2015), and Sweden (1987-2011), linked with population and patient registries. These cohorts were followed from birth until they either had the outcomes of interest, emigrated, died, or reached the end of the follow-up (at mean ages 13.6-16.8 years), whichever occurred first. Cox regression models were used to estimate country-specific associations between labor epidural analgesia recorded at birth and outcomes (e.g., at least one secondary care diagnosis of ASD and ADHD or at least one dispensed prescription of medication used for the treatment of ADHD). The models were adjusted for sex, birth year, birth order, and unmeasured familial confounders via sibling-comparisons. Pooled estimates across all three countries were estimated using inverse variance weighted fixed-effects meta-analysis models. Results A total of 4,498,462 individuals (48.7% female) were included, 1,091,846 (24.3%) of which were exposed to labor epidural analgesia. Of these, 1.2% were diagnosed with ASD and 4.0% with ADHD. On the population level, pooled estimates showed that labor epidural analgesia was associated with increased risk of offspring ASD (adjusted hazard ratio, aHR=1.12; 95% CI: 1.10-1.14, absolute risks: 1.20% vs. 1.07%) and ADHD (aHR=1.20; 1.19-1.21; 3.95% vs. 3.32%). However, when comparing full-siblings who were differentially exposed to labor epidural analgesia, the associations were fully attenuated for both conditions, with narrow confidence intervals (aHRASD=0.98; 0.93-1.03; aHRADHD=0.99; 0.96-1.02). Conclusion In this large cross-national study, we found no support for the hypothesis that exposure to labor epidural analgesia causes either offspring ASD or ADHD.Peer reviewe

A Complete Axiom System for Propositional Interval Temporal Logic with Infinite Time

Interval Temporal Logic (ITL) is an established temporal formalism for reasoning about time periods. For over 25 years, it has been applied in a number of ways and several ITL variants, axiom systems and tools have been investigated. We solve the longstanding open problem of finding a complete axiom system for basic quantifier-free propositional ITL (PITL) with infinite time for analysing nonterminating computational systems. Our completeness proof uses a reduction to completeness for PITL with finite time and conventional propositional linear-time temporal logic. Unlike completeness proofs of equally expressive logics with nonelementary computational complexity, our semantic approach does not use tableaux, subformula closures or explicit deductions involving encodings of omega automata and nontrivial techniques for complementing them. We believe that our result also provides evidence of the naturalness of interval-based reasoning

α-Synuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease

Alpha Synuclein (α-Syn) is a protein implicated in mechanisms of neuronal degeneration in Parkinson's disease (PD). α-Syn is primarily a neuronal protein, however, its expression is found in various tumors including ovarian, colorectal and melanoma tumors. It has been hypothesized that neurodegeneration may share common mechanisms with oncogenesis. We tested whether α-Syn expression affects tumorigenesis of three types of tumors. Specifically, B16 melanoma, E0771 mammary gland adenocarcinoma and D122 Lewis lung carcinoma. For this aim, we utilized transgenic mice expression the human A53T α-Syn form. We found that the in vivo growth of B16 and E0771 but not D122 was enhanced in the A53T α-Syn mice. The effect on tumorigenesis was not detected in age-matched APP/PS1 mice, modeling Alzheimer's disease (AD), suggesting a specific effect for α-Syn- dependent neurodegeneration. Importantly, transgenic α-Syn expression was detected within the three tumor types. We further show uptake of exogenously added, purified α-Syn, by the cultured tumor cells. In accord, with the affected tumorigenesis in the young A53T α-Syn mice, over- expression of α-Syn in cultured B16 and E0771 cells enhanced proliferation, however, had no effect on the proliferation of D122 cells. Based on these results, we suggest that certain forms of α-Syn may selectively accelerate cellular mechanisms leading to cancer

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans