Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.The nine Bradford Hill (BH) viewpoints (sometimes referred to as criteria) are commonly used to assess causality within epidemiology. However, causal thinking has since developed, with three of the most prominent approaches implicitly or explicitly building on the potential outcomes framework directed acyclic graphs (DAGs), sufficient-component cause models (SCC models, also referred to as 'causal pies') and the grading of recommendations, assessment, development and evaluation (GRADE) methodology. This paper explores how these approaches relate to BH's viewpoints and considers implications for improving causal assessment.  https://www.selleckchem.com/products/4u8c.html  We mapped the three approaches above against each BH viewpoint. We found overlap across the approaches and BH viewpoints, underscoring BH viewpoints' enduring importance. Mapping the approaches helped elucidate the theoretical underpinning of each viewpoint and articulate the conditions when the viewpoint would be relevant. Our comparisons identified commonality on four viewpoints strength of association (including analysis of plausible confounding); temporality; plausibility (encoded by DAGs or SCC models to articulate mediation and interaction, respectively); and experiments (including implications of study design on exchangeability). Consistency may be more usefully operationalised by considering an effect size's transportability to a different population or unexplained inconsistency in effect sizes (statistical heterogeneity). Because specificity rarely occurs, falsification exposures or outcomes (i.e., negative controls) may be more useful. The presence of a dose-response relationship may be less than widely perceived as it can easily arise from confounding. We found limited utility for coherence and analogy. This study highlights a need for greater clarity on BH viewpoints to improve causal assessment.
  Multiple sclerosis (MS) is accompanied by an increased risk of epileptic seizures, but data with a detailed description of the competing causes are lacking.
 
  We aimed to describe a cohort of patients with both MS and epileptic seizures in a retrospective, population-based study.
 
  We included 59 out of 2285 MS patients who had at least one epileptic seizure. Out of them, 22 had seizures before the diagnosis of MS, whereas epileptic seizures occurred after MS diagnosis in 37 patients, resulting in a total prevalence of epileptic seizures in MS of 2.6%. Competing causes could be found in 50.8% (30/59) of all patients, with 40.9% (9/22) compared to 56.8% (21/37) of the MS patients with seizures before vs after MS diagnosis. The main alternative causes were traumatic brain injury and cerebral ischemia accounting for more than 30% of the patients, with no difference between the subgroups. 33.3% and 55.6% of MS patients with seizures before/after MS diagnosis had documented pathological EEG alterations.
 
  A remarkable percentage of MS patients with epileptic seizures do have alternative competing causes at the time of the first seizure. A detailed diagnostic setup including patient history, EEG and MRI is recommended in the evaluation and choice for the best treatment.
 A remarkable percentage of MS patients with epileptic seizures do have alternative competing causes at the time of the first seizure. A detailed diagnostic setup including patient history, EEG and MRI is recommended in the evaluation and choice for the best treatment.The present study aimed to develop and validate a novel reversed-phase high-performance liquid chromatography method for simultaneous estimation of Diacerein (DIA) and Rhein (Rh, alkaline degradation product and active metabolite) in the presence of various coformers used to prepare eutectic oral formulation. Chromatographic separations were achieved on a Phenomenex Gemini C18 column (250 mm × 4.6 mm, 5 μm) placed in the thermostated column oven at 40°C. The mobile phase, comprising of acetonitrile and 10 mM ammonium acetate (pH 3.0), was eluted through the gradient system with 0.8 mL/min flow rate at 254 nm detection and analytical run time of 14 min. Additionally, the method was validated for specificity, linearity, precision, accuracy, selectivity, limit of quantitation, limit of detection and robustness as per International Conference on Harmonization guideline. The developed method was applied for the comparison of drug release profiles of pure DIA and from prepared eutectic formulations for the quantitation of DIA and Rh in the multicomponent adducts.