Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomisation approach

Background: Executive function consists of several cognitive control processes that are able to regulate lower level processes. Poorer performance in tasks designed to test executive function is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as with smoking and alcohol consumption. Despite these well-documented associations, whether they reflect causal relationships, and if so in what direction, remains unclear. We aimed to establish whether there is a causal relationship between a latent factor for performance on multiple executive function tasks - which we refer to as common executive function (cEF) - and liability to schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD), and the directionality of any relationship observed. Methods: We used a two-sample bidirectional Mendelian randomisation (MR) approach using genome-wide association study (GWAS) summary data from large cohorts (N=17,310 to 848,460) to examine whether causal relationships exist, and if so in which direction. Results: We found evidence of a causal effect of increased cEF on reduced schizophrenia liability (IVW: OR=0.10; 95% CI 0.05 to 0.19; p-value=3.43x10-12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23x10-05), decreased drinks per week (IVW: β=-0.06; 95% CI -0.10 to -0.02; p-value=0.003), and reduced CUD liability (IVW: OR=0.27; 95% CI 0.12 to 0.61; p-value=1.58x10-03). We also found evidence of a causal effect of increased schizophrenia liability on decreased cEF (IVW: β=-0.04; 95% CI -0.04 to -0.03; p-value=3.25x10-27), as well as smoking initiation on decreased cEF (IVW: β=-0.06; 95%CI -0.09 to -0.03; p-value=6.11x10-05). Conclusion: Our results indicate a potential bidirectional causal relationship between a latent factor measure of executive function (cEF) and schizophrenia liability, a possible causal effect of increased cEF on reduced MDD liability, CUD liability, and alcohol consumption, and a possible causal effect of smoking initiation on decreased cEF. These results suggest that executive function should be considered as a potential risk factor for some mental health and substance use outcomes, and may also be impacted by mental health (particularly schizophrenia). Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that executive function may be a promising intervention target. These results may therefore inform the prioritisation of experimental medicine studies (e.g., of executive function interventions), for both mental health and substance use outcomes, to improve the likelihood of successful translation.

Causal Association Between Heart Failure and Alzheimer’s Disease: A Two-Sample Bidirectional Mendelian Randomization Study

Background: Traditional observational studies have demonstrated an association between heart failure and Alzheimer’s disease. The strengths of observational studies lie in their speed of implementation, cost, and applicability to rare diseases. However, observational studies have several limitations, such as uncontrollable confounders. Therefore, we employed Mendelian randomization of genetic variants to evaluate the causal relationships existing between AD and HF, which can avoid these limitations.Materials and Methods: A two-sample bidirectional MR analysis was employed. All datasets were results from the UK’s Medical Research Council Integrative Epidemiology Unit genome-wide association study database, and we conducted a series of control steps to select the most suitable single-nucleotide polymorphisms for MR analysis, for which five primary methods are offered. We reversed the functions of exposure and outcomes to explore the causal direction of HF and AD. Sensitivity analysis was used to conduct several tests to avoid heterogeneity and pleiotropic bias in the MR results.Results: Our MR studies did not support a meaningful causal relationship between AD on HF (MR-Egger, p = 0.634 > 0.05; weighted median (WM), p = 0.337 > 0.05; inverse variance weighted (IVW), p = 0.471 > 0.05; simple mode, p = 0.454 > 0.05; weighted mode, p = 0.401 > 0.05). At the same time, we did not find a significant causal relationship between HF and AD with four of the methods (MR-Egger, p = 0.195 > 0.05; IVW, p = 0.0879 > 0.05; simple mode, p = 0.170 > 0.05; weighted mode, p = 0.110 > 0.05), but the WM method indicated a significant effect of HF on AD (p = 0.025 < 0.05). Because the statistical powers of IVW and MR-Egger are more than that of WM, we think that there is no causal effect of HF on AD. Sensitivity analysis and horizontal pleiotropy were not detected in the MR analysis.Conclusion: Our results did not provide significant evidence indicating any causal relationships between HF and AD in the European population. Therefore, more large-scale datasets or datasets related to similar factors are expected for further MR analysis.

Modelling the balance of care: Impact of an evidence-informed policy on a mental health ecosystem

Major efforts worldwide have been made to provide balanced Mental Health (MH) care. Any integrated MH ecosystem includes hospital and community-based care, highlighting the role of outpatient care in reducing relapses and readmissions. This study aimed (i) to identify potential expert-based causal relationships between inpatient and outpatient care variables, (ii) to assess them by using statistical procedures, and finally (iii) to assess the potential impact of a specific policy enhancing the MH care balance on real ecosystem performance. Causal relationships (Bayesian network) between inpatient and outpatient care variables were defined by expert knowledge and confirmed by using multivariate linear regression (generalized least squares). Based on the Bayesian network and regression results, a decision support system that combines data envelopment analysis, Monte Carlo simulation and fuzzy inference was used to assess the potential impact of the designed policy. As expected, there were strong statistical relationships between outpatient and inpatient care variables, which preliminarily confirmed their potential and a priori causal nature. The global impact of the proposed policy on the ecosystem was positive in terms of efficiency assessment, stability and entropy. To the best of our knowledge, this is the first study that formalized expert-based causal relationships between inpatient and outpatient care variables. These relationships, structured by a Bayesian network, can be used for designing evidence-informed policies trying to balance MH care provision. By integrating causal models and statistical analysis, decision support systems are useful tools to support evidence-informed planning and decision making, as they allow us to predict the potential impact of specific policies on the ecosystem prior to its real application, reducing the risk and considering the population’s needs and scientific findings.

Causal effects of motor control on gait kinematics after orthopedic surgery in cerebral palsy: a machine-learning approach

Background Altered motor control is common in cerebral palsy (CP). Understanding how altered motor control effects movement and treatment outcomes is important, but challenging due to complex interactions between impairments. While regression can be used to examine associations between impairments and gait, causal modeling provides a mathematical framework to specify assumed causal relationships, identify covariates that may introduce bias, and test model plausibility. The goal of this research was to quantify the causal effects of altered motor control and other impairments on gait, before and after single-event multi-level orthopedic surgery (SEMLS). Methods We evaluated the impact of SEMLS on change in Gait Deviation Index (GDI) between gait analyses. We constructed our causal model with a Directed Acyclic Graph that included the assumed causal relationships between SEMLS, change in GDI, baseline GDI (GDIpre), baseline neurologic and orthopedic impairments (Imppre), age, and surgical history. We identified the adjustment set to evaluate the causal effect of SEMLS on change in GDI and the impact of Imppre on change in GDI and GDIpre. We used Bayesian Additive Regression Trees (BART) and accumulated local effects to assess relative effects. Results We prospectively recruited a cohort of children with bilateral CP undergoing SEMLS (N=54, 35 males, age: 10.5+/-3.1 years) and identified a control cohort with bilateral CP who did not undergo SEMLS (N=55, 30 males, age: 10.0+/-3.4 years). There was a small positive causal effect of SEMLS on change in GDI (1.68 GDI points). Altered motor control (i.e., dynamic and static motor control) and strength had strong effects on GDIpre, but minimal effects on change in GDI. Spasticity and orthopedic impairments had minimal effects on GDIpre or change in GDI. Conclusions Altered motor control and other baseline impairments did have a strong effect on GDIpre, indicating that these impairments do have a causal effect on a child's gait pattern but minimal effect on expected changes in GDI after SEMLS. Heterogeneity in outcomes suggests there are other factors contributing to changes in gait. Identifying these factors and employing causal methods to examine the complex relationships between impairments and movement will be required to advance our understanding and care of children with CP.

Shared brain and genetic architectures between mental health and physical activity

Physical activity is correlated with, and effectively treats various forms of psychopathology. However, whether biological correlates of physical activity and psychopathology are shared remains unclear. Here, we examined the extent to which the neural and genetic architecture of physical activity and mental health are shared. Using data from the UK Biobank (N=6,389), canonical correlation analysis was applied to estimate associations between the amplitude and connectivity strength of sub-networks of three major neurocognitive networks (default mode, DMN; salience, SN; central executive networks, CEN) with accelerometer-derived measures of physical activity and self-reported mental health. We estimated the genetic correlation between mental health and physical activity measures, as well as putative causal relationships by applying linkage disequilibrium score regression, genomic structural equational modeling, and latent causal variable analysis to genome-wide association summary statistics (GWAS N=91,105-500,199). Physical activity and mental health were associated with connectivity strength and amplitude of the DMN, SN, and CEN (all r>0.13, all p<0.048). These neural correlates exhibited highly similar loading patterns across mental health and physical activity models even when accounting for their shared variance. This suggests a largely shared brain network architecture between mental health and physical activity. Mental health and physical activity were also genetically correlated (|rg|=0.085-0.121), but we found no evidence for causal relationships between them. Collectively, our findings provide empirical evidence that mental health and physical activity have shared brain and genetic architectures and suggest potential candidate sub-networks for future studies on brain mechanisms underlying beneficial effects of physical activity on mental health.

Ekolingwistyka w dobie antropocenu: w stronę integracji i konsiliencji

Celem artykułu jest ukazanie głównych wyzwań antropocenu dla językoznawstwa oraz wynikający z nich kierunek rozwoju ekolingwistyki w stronę konsiliencji, rozumianej jako idea systematycznego poszukiwania zależności przyczynowych między zjawiskami z różnych dziedzin wiedzy. Integracyjny model ekolingwistyki, który jest budowany od niespełna dekady, zostanie przedstawiony w powiązaniu z najtrudniejszymi problemami poznawczymi „epoki człowieka”, do których zalicza się przełamywanie antropocentryzmu oraz problematyzowanie pojęcia natury. Odpowiedzią ekolingwistów jest sformułowanie zasady nielokalności języka oraz jego znaturalizowany ogląd w hipotezie rozszerzonej ekologii. Z tymi nowymi ideami wiążą się nadzieje na to, że ekolingwistyka nie będzie traktowana jako tematyczny dział językoznawstwa, a stanie się awangardą w takim myśleniu o języku, które dotrzyma kroku trudnym wyzwaniom antropocenu. Ecolinguistics in the Anthropocene Era: Towards Integration and Consilience Summary: The aim of the paper is to present the main challenges that the Anthropocene presents to linguistics, and discuss the subsequent development of ecolinguistics towards consilience, understood as the idea of a systematic search for causal relationships between phenomena from various fields of science. The integrative model of ecolinguistics, which has been built for less than a decade, will be presented in relation to the most difficult cognitive problems of the Human Era, such as the overcoming of anthropocentrism and the addressing of the concept of nature. The solution proposed by ecolinguists is the principle of the non-locality of language and the nature-oriented view of language that follows the Extended Ecology Hypothesis. These new ideas will, hopefully, lead to considering ecolinguistics not so much as a thematic branch of linguistics, but as the avant-garde in such thinking about language that will keep pace with the challenges of the Anthropocene.

Design of a roll crusher for sunflower stems and substantiation of the rational modes of its operation

This paper reports a study of the technological process of grinding plant residues of sunflower and the causal relationships of factors that form the system of quality indicators. The necessary prerequisites for determining rational modes and parameters of the roll crusher have been devised. A prototype of the roll crusher was designed and fabricated, in which the cutting knives are arranged along the entire width of the grip in a staggered manner, with the possibility to change the angle of inclination to the axis of drum rotation in the range of 5...20°. It was established that in the case of the right-side arrangement of the cutting edge of knives, the highest total level of the percentage of crushed stems in the range of 101‒150 mm with an additional load weighing 800 kg exceeded by 1.58 times the corresponding indicators of the roll with an additional load of 600 kg. The largest overall value of the percentage of crushed stems in the range of 0‒200 mm when additionally loading the roll with 800 kg was 1.13 times higher than the corresponding indicators of the roll with an additional load of 600 kg. In the range of 0‒200 mm, with an additional load on the roll of 600 kg, at the left-side arrangement of the cutting edge of the knives of the roll, higher total percentage of crushed stems was observed compared to the right-side arrangement. At a speed of 7.45 km/h, 13.6 km/h, the cumulative value of the percentage of crushed stems exceeded the corresponding indicators at the right-side arrangement of knives by 1.09 times, at the speed of 18.6 km/h – by 1.04 times, at the speed of 22 km/h – by 1.04 times, respectively. It has been noted that at the left-side arrangement of the cutting edge of the knives of the roll, the percentage of crushed stems in the range of 51‒100 mm, with an additional load of 600 kg, exceeded the corresponding indicators with an additional load of 800 kg. At the speed of 10.08 km/h, it was exceeded by 1.9 times; at the speed of 13.6 km/h – by 1.44 times; at the speed of 18.6 km/h – by 1.96 times; at the speed of 22 km/h – by 1.99 times, respectively