Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease

Background: Education and cognition demonstrate consistent inverse associations with Alzheimer’s disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites reflect the end point of biological processes and are accessible and malleable. Identifying metabolites with etiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms. // Methods: Using data from the largest metabolomics genome-wide association study (N ≈ 24,925) and three independent AD cohorts (N = 4725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization interrogated univariable causal relationships between 1) metabolites and AD; 2) education and cognition; 3) metabolites, education, and cognition; and 4) education, cognition, and AD. Mediating relationships were computed using multivariable Mendelian randomization. // Results: Thirty-four metabolites were genetically associated with AD at p < .05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins demonstrated a protective causal effect (glutamine: 95% confidence interval [CI], 0.70 to 0.92; free cholesterol in extra-large high-density lipoproteins: 95% CI, 0.75 to 0.92). An AD-protective effect was also observed for education (95% CI, 0.61 to 0.85) and cognition (95% CI, 0.60 to 0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice versa, however. No evidence of mediation via any metabolite was found. // Conclusions: Glutamine and free cholesterol in extra-large high-density lipoproteins show protective causal effects on AD. Education and cognition also demonstrate protection, though education’s effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multimodal work and progressing toward effective intervention strategies

Identifying back pain subgroups: developing and applying approaches using individual patient data collected within clinical trials

There is good evidence that therapist delivered interventions have modest beneficial effects for people with low back pain (LBP). Identification of subgroups of people with LBP who may benefit from these different treatment approaches is an important research priority

Brief Report: Testing the Psychometric Properties of the Spence Children’s Anxiety Scale (SCAS) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) in Autism Spectrum Disorder

Anxiety is a prevalent and impairing co-morbidity among individuals with autism spectrum disorder (ASD), yet assessment measures, including screening tools, are seldom validated with autism samples. We explored the psychometric properties of the child and parent reports of the Spence Children’s Anxiety Scale (SCAS) and the Screen for Anxiety Related Disorder-71 (SCARED-71) with 49 males with ASD (10–16 years, 63% co-occurring anxiety). Both measures had excellent internal consistency and fair-good parent–child agreement. The SCAS has a higher proportion of items evaluating observable behaviors. Predictive power of the measures did not differ. Higher cut-points in the parent reports (SCARED only) and lower cut-points in the child reports may enhance prediction in this sample. Choice of measure and cut-points should be considered alongside intended purpose

Finite Element Model of Stress Wave Topology in Unidirectional Graphite/Epoxy: Wave Velocities and Flux Deviations

Until recently, the use of a finite element model (FEM) to simulate stress wave propagation has been limited to solutions where the number of degrees of freedom are kept to a minimum, because of hardware limitations on computer memory and computational speed. With the advent of a numte

The design of a purpose-built exergame for fall prediction and prevention for older people

Background Falls in older people represent a major age-related health challenge facing our society. Novel methods for delivery of falls prevention programs are required to increase effectiveness and adherence to these programs while containing costs. The primary aim of the Information and Communications Technology-based System to Predict and Prevent Falls (iStoppFalls) project was to develop innovative home-based technologies for continuous monitoring and exercise-based prevention of falls in community-dwelling older people. The aim of this paper is to describe the components of the iStoppFalls system. Methods The system comprised of 1) a TV, 2) a PC, 3) the Microsoft Kinect, 4) a wearable sensor and 5) an assessment and training software as the main components. Results The iStoppFalls system implements existing technologies to deliver a tailored home-based exercise and education program aimed at reducing fall risk in older people. A risk assessment tool was designed to identify fall risk factors. The content and progression rules of the iStoppFalls exergames were developed from evidence-based fall prevention interventions targeting muscle strength and balance in older people. Conclusions The iStoppFalls fall prevention program, used in conjunction with the multifactorial fall risk assessment tool, aims to provide a comprehensive and individualised, yet novel fall risk assessment and prevention program that is feasible for widespread use to prevent falls and fall-related injuries. This work provides a new approach to engage older people in home-based exercise programs to complement or provide a potentially motivational alternative to traditional exercise to reduce the risk of falling

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Brief Report: Sensorimotor Gating in Idiopathic Autism and Autism Associated with Fragile X Syndrome

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS−A; n = 17), and idiopathic autism (IA; n = 15). Relative to controls, the FXS+A (p < 0.002) and FXS−A (p < 0.003) groups had impaired PPI. The FXS+A (p < 0.01) and FXS−A (p < 0.03) groups had lower PPI than the IA group. Prolonged startle latency was seen in the IA group. The differing PPI profiles seen in the FXS+A and IA indicates these groups may not share a common neurobiological abnormality of sensorimotor gating

Glutathione pathway gene variation and risk of autism spectrum disorders

Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case–parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary

Reproducibility of Heart Rate Variability Indices in Children with Cystic Fibrosis

Fundamental to the potential utilisation of heart rate variability (HRV) indices as a prognostic tool is the reproducibility of these measures. The purpose of the present study was therefore to investigate the reproducibility of 24-hour derived HRV indices in a clinical paediatric population. Eighteen children (10 boys; 12.4 ± 2.8 years) with mild to moderate Cystic Fibrosis (CF; FVC: 83 ± 12% predicted; FEV1: 80 ± 9% predicted) and eighteen age- and sex-matched controls (10 boys; 12.5 ± 2.7 years) wore a combined ECG and accelerometer for two consecutive days. Standard time and frequency domain indices of HRV were subsequently derived. Reproducibility was assessed by Bland-Altman plots, 95% limits of agreement and intra-class correlation coefficients (ICC). In both groups, there was no systematic difference between days, with the variables demonstrating a symmetrical, homoscedastic distribution around the zero line. The time domain parameters demonstrated a good to excellent reproducibility irrespective of the population considered (ICC: 0.56 to 0.86). In contrast, whilst the frequency domain parameters similarly showed excellent reproducibility in the healthy children (ICC: 0.70 to 0.96), the majority of the frequency domain parameters illustrated a poor to moderate reproducibility in those with CF (ICC: 0.22 to 0.43). The exceptions to this trend were the normalised LF and HF components which were associated with a good to excellent reproducibility. These findings thereby support the utilisation of time and relative frequency domain HRV indices as a prognostic tool in children with CF. Furthermore, the present results highlight the excellent reproducibility of HRV in healthy children, indicating that this may be a useful tool to assess intervention effectiveness in this population