Quantifying the impact of boundary constraint handling methods on differential evolution

Algorithms and the Foundations of Software technolog

“Forward Genetics” as a Method to Maximize Power and Cost-Efficiency in Studies of Human Complex Traits

There is increasing interest in methods to disentangle the relationship between genotype and (endo)phenotypes in human complex traits. We present a population-based method of increasing the power and cost-efficiency of studies by selecting random individuals with a particular genotype and then assessing the accompanying quantitative phenotypes. Using statistical derivations, power- and cost graphs we show that such a “forward genetics” approach can lead to a marked reduction in sample size and costs. This approach is particularly apt for implementing in epidemiological studies for which DNA is already available but the phenotyping costs are high

MRI follow-up of conservatively treated meniscal knee lesions in general practice

Objective: To evaluate meniscal status change on follow-up MRI after 1 year, prognostic factors and association with clinical outcome in patients with conservatively treated knee injury. Methods: We analysed 403 meniscal horns in 101 conservatively treated patients (59 male; mean age 40 years) in general practice who underwent initial knee MRI within 5 weeks of trauma. We performed ordinal logistic regression analysis to analyse prognostic factors for meniscal change on follow-up MRI after 1 year, and we assessed the association with clinical outcome. Results: On follow-up MRI 49 meniscal horns had deteriorated and 18 had improved. Age (odds ratio [OR] 1.3/decade), body weight (OR 1.2/10 kg), total anterior cruciate ligament (ACL) rupture on initial MRI (OR 2.4), location in the posterior horn of the medial meniscus (OR 3.0) and an initial meniscal lesion (OR 0.3) were statistically significant predictors of meniscal MRI appearance change after 1 year, which was not associated with clinical outcome. Conclusion: In conservatively treated patients, meniscal deterioration on follow-up MRI 1 year after trauma is predicted by higher age and body weight, initial total ACL rupture, and location in the medial posterior horn. Change in MRI appearance is not associated with clinical outcome

Predictive factors for new onset or progression of knee osteoarthritis one year after trauma: MRI follow-up in general practice

Objective: To prospectively evaluate prognostic factors for new onset or progression of degenerative change on follow-up MRI one year after knee trauma and the association with clinical outcome. Methods: Within a prospective observational cohort study in general practice, we studied a subgroup of 117 patients with acute knee trauma (mean age 41 years, 43% women). Degenerative change was scored on MRI at baseline and after one year follow-up. Multivariate logistic regression analysis was performed to evaluate prognostic factors for new onset or progressive degenerative change on follow-up MRI. Association between new or progressive degeneration and clinical outcome after one year was assessed. Results: On follow-up MRI 15% of patients with pre-existing knee osteoarthritis showed progression and 26% of patients demonstrated new degenerative change. The only statistically significant prognostic variable in the multivariate analysis was bone marrow oedema on initial MRI (OR 5.29 (95% CI 1.64-17.1), p∈=∈0.005). A significant association between new or progressive degenerative change and clinical outcome was found (p∈=∈0.003). Conclusion: Bone marrow oedema on MRI for acute knee injury is strongly predictive of new onset or progression of degenerative change of the femorotibial joint on follow-up MRI one year after trauma, which is reflected in clinical outcome

Glucocorticoid receptor exon 1_F methylation and the cortisol stress response in health and disease

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level

Словотвір авторських неологізмів у збірці П. Маха "Плеса"

Статья посвящена словообразованию авторських неологизмов, изспользованых в зборнике стихов П. Маха "Озеро". В ней описываются способы словообразования использованых автором неологизмов. Анализируется их речевое распространение.Стаття присвячена словотвору авторських неологізмів, використаних у збірці П. Маха "Плеса". В ній описуються способи словотвору вжитих автором неологізмів. Аналізується їх мовна поширеність.The article is devoted to the word-building of innovations in the creation "Lake" by P. Mach. Word-building of innovations are described in this article. Its language distributions are analised

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD

Independent contribution of polygenic risk for schizophrenia and cannabis use in predicting psychotic-like experiences in young adulthood: Testing gene × environment moderation and mediation

Background. It has not yet been determined if the commonly reported cannabispsychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders.Methods. We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort.Results. PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects.Conclusions. These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis-psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability

Childhood abuse v. neglect and risk for major psychiatric disorders

Background. Childhood maltreatment (CM) is a strong risk factor for psychiatric disorders but serves in its current definitions as an umbrella for various fundamentally different childhood experiences. As first step toward a more refined analysis of the impact of CM, our objective is to revisit the relation of abuse and neglect, major subtypes of CM, with symptoms across disorders.Methods. Three longitudinal studies of major depressive disorder (MDD, N = 1240), bipolar disorder (BD, N = 1339), and schizophrenia (SCZ, N = 577), each including controls (N = 881), were analyzed. Multivariate regression models were used to examine the relation between exposure to abuse, neglect, or their combination to the odds for MDD, BD, SCZ, and symptoms across disorders. Bidirectional Mendelian randomization (MR) was used to probe causality, using genetic instruments of abuse and neglect derived from UK Biobank data (N = 143 473).Results. Abuse was the stronger risk factor for SCZ (OR 3.51, 95% CI 2.17-5.67) and neglect for BD (OR 2.69, 95% CI 2.09-3.46). Combined CM was related to increased risk exceeding additive effects of abuse and neglect for MDD (RERI = 1.4) and BD (RERI = 1.1). Across disorders, abuse was associated with hallucinations (OR 2.16, 95% CI 1.55-3.01) and suicide attempts (OR 2.16, 95% CI 1.55-3.01) whereas neglect was associated with agitation (OR 1.24, 95% CI 1.02-1.51) and reduced need for sleep (OR 1.64, 95% CI 1.08-2.48). MR analyses were consistent with a bidirectional causal effect of abuse with SCZ (IVWforward = 0.13, 95% CI 0.01-0.24).Conclusions. Childhood abuse and neglect are associated with different risks to psychiatric symptoms and disorders. Unraveling the origin of these differences may advance understanding of disease etiology and ultimately facilitate development of improved personalized treatment strategies

Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD