Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors. © 2012 The American Society of Human Genetics

The KB paradigm and its application to interactive configuration

The knowledge base paradigm aims to express domain knowledge in a rich formal language, and to use this domain knowledge as a knowledge base to solve various problems and tasks that arise in the domain by applying multiple forms of inference. As such, the paradigm applies a strict separation of concerns between information and problem solving. In this paper, we analyze the principles and feasibility of the knowledge base paradigm in the context of an important class of applications: interactive configuration problems. In interactive configuration problems, a configuration of interrelated objects under constraints is searched, where the system assists the user in reaching an intended configuration. It is widely recognized in industry that good software solutions for these problems are very difficult to develop. We investigate such problems from the perspective of the KB paradigm. We show that multiple functionalities in this domain can be achieved by applying different forms of logical inferences on a formal specification of the configuration domain. We report on a proof of concept of this approach in a real-life application with a banking company. To appear in Theory and Practice of Logic Programming (TPLP).Comment: To appear in Theory and Practice of Logic Programming (TPLP

Frequent pain in older people with and without diabetes - Finnish community based study

Background: The association between pain and diabetes in older people has been largely unexplored. The aim of this survey was to analyze the prevalence and characteristics of pain among Finnish men and women 65 or older with and without diabetes in primary care. Methods: All home-dwelling persons 65 years or older with diabetes (N = 527) and age and gender matched controls (N = 890) were identified from electronic patient records. Frequent pain was regarded as any pain experienced more often than once a week, and it was divided into pain experienced several times a week but not daily and pain experienced daily or continuously. The Numeric Rating Scale (0-10) (NRS) was used to assess the intensity and interference of the pain. Results: The number of subjects who returned the questionnaire was 1084 (76.5%). The prevalence of frequent pain in the preceding week was 50% among women without diabetes and 63% among women with diabetes (adjusted, p = 0.22). In men, the corresponding proportions were 42% without diabetes and 47% with diabetes (adjusted, p = 0.58). In both genders, depressive symptoms and the number of comorbidities were associated with pain experienced more often than once a week and with daily pain. Diabetes was not associated with pain intensity or pain interference in either women or men. Conclusions: Pain in older adults is associated with depressive symptoms and the number of comorbidities more than with diabetes itself.Peer reviewe

A 10-Year Retrospective Study of 490 Hip Fracture Patients: Reoperations, Direct Medical Costs, and Survival

Background and Aims: Reoperations after operative treatment of hip fracture patients may be associated with higher costs and inferior survival. We examined the acute hospital costs, long-term reoperation rates, and survival of patients with a new hip fracture. Materials and Methods: A total of 490 consecutive new hip fracture patients treated at a single center between 31 December 2004 and 6 December 2006 were analyzed retrospectively. Fractures were classified according to Garden and AO. All medical records were checked manually. The costs of reoperations were calculated using the diagnosis-related groups (DRG)-based prices. Survival analysis was performed using the life-table method. The follow-up time was 10 years. Results: In all, 70/490 patients (14.3%) needed reoperations. Of all reoperations, 34.2% were performed during the first month and 72.9% within 1 year after the primary operation. The hemiarthroplasty dislocation rate was 8.5%, and mechanical failures of osteosynthesis occurred in 6.2%. Alcohol abuse was associated with a heightened risk of reoperation. The mean direct costs of primary fracture care were lower than the mean costs of reoperations (euro7500 vs euro9800). The mortality rate at 10 years was 79.8% among non-reoperated patients and 62.9% among reoperated patients. Conclusions: According to our hypothesis, the cost per patient of reoperation in acute care was 31% higher than the corresponding cost of a primary operation. Reoperations increased the overall immediate costs of index fractures by nearly 20%. One-third of all reoperations were performed during the first month and almost 75% within 1 year after the primary operation.Peer reviewe

Towards Utility-Based Prioritization of Requirements in Open Source Environments

Peer reviewe

Negotiating sexuality and masculinity in school sport: An autoethnography

This autoethnography explores challenging and ethically sensitive issues around sexual orientation, sexual identity and masculinity in the context of school sport. Through storytelling, I aim to show how sometimes ambiguous encounters with heterosexism, homophobia and hegemonic masculinity through sport problematise identity development for young same-sex attracted males. By foregrounding personal embodied experience, I respond to an absence of stories of gay and bisexual experiences among males in physical education and school sport, in an effort to reduce a continuing sense of Otherness and difference regarding same-sex attracted males. I rely on the story itself to express the embodied forms of knowing that inhabit the experiences I describe, and resist a finalising interpretation of the story. Instead, I offer personal reflections on particular theoretical and methodological issues which relate to both the form and content of the story

Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia

Background and Hypothesis Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study Methods We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study Results Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6-0.9 DDD/day, and especially at 1.4-Peer reviewe

Dopamine D2 receptor antagonism of antipsychotics and the risk of death due to choking

The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMRchoking) and adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N=59,916). SMRchoking was 20.5 (95% confidence interval (CI)=17.1–23.9). The aHR was 1.74 (95%CI=1.19–2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine 2-antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong dopamine 2-antagonist antipsychotics, particularly when prescribed in high dosages

Genome-wide association study of antisocial personality disorder

The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N = 370, N = 5850 for controls, GWAS; N = 173, N = 3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR) = 2.19 (1.53-3.14), P = 1.9 x 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR = 1.59 (1.37-1.85), P = 1.6 x 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (beta = 0.68, P = 0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder.Peer reviewe