Nabiximols (NBX) suppresses tremor in a rat Harmaline model of essential tremor.

Background: Essential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9-12 Hz in rats, comparable to that of human ET (4-12 Hz).

Purpose: Interestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET.

Characterizing Common and Rare Variations in Nontraditional Glycemic Biomarkers Using Multivariate Approaches on Multiancestry ARIC Study.

Genetic studies of nontraditional glycemic biomarkers, glycated albumin and fructosamine, can shed light on unknown aspects of type 2 diabetes genetics and biology. We performed a multiphenotype genome-wide association study of glycated albumin and fructosamine from 7,395 White and 2,016 Black participants in the Atherosclerosis Risk in Communities (ARIC) study on common variants from genotyped/imputed data. We discovered two genome-wide significant loci, one mapping to a known type 2 diabetes gene (ARAP1/STARD10) and another mapping to a novel region (UGT1A complex of genes), using multiomics gene-mapping strategies in diabetes-relevant tissues.

Adaptive and Innate Immunity Are Key Drivers of Age at Onset of Multiple Sclerosis.

Background And Objectives: Multiple sclerosis (MS) age at onset (AAO) is a clinical predictor of long-term disease outcomes, independent of disease duration. Little is known about the genetic and biological mechanisms underlying age of first symptoms. We conducted a genome-wide association study (GWAS) to investigate associations between individual genetic variation and the MS AAO phenotype.

Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies.

Background And Objectives: Amyloid-related imaging abnormalities (ARIA) were the most common adverse events reported in the phase 3 ENGAGE and EMERGE trials of aducanumab, an anti-amyloid monoclonal antibody. ε4 carrier status has been shown to increase risk of ARIA in prior trials of aducanumab and other anti-amyloid therapies; however, the remainder of the human genome has not been evaluated for ARIA risk factors. Therefore, we sought to determine in a hypothesis-free manner whether genetic variants beyond influence risk of ARIA in aducanumab-treated patients.

Genome-wide study of longitudinal brain imaging measures of multiple sclerosis progression across six clinical trials.

While the genetics of MS risk susceptibility are well-described, and recent progress has been made on the genetics of disease severity, the genetics of disease progression remain elusive. We therefore investigated the genetic determinants of MS progression on longitudinal brain MRI: change in brain volume (BV) and change in T2 lesion volume (T2LV), reflecting progressive tissue loss and increasing disease burden, respectively. We performed genome-wide association studies of change in BV (N = 3401) and change in T2LV (N = 3513) across six randomized clinical trials from Biogen and Roche/Genentech: ADVANCE, ASCEND, DECIDE, OPERA I & II, and ORATORIO.

Characterizing common and rare variations in non-traditional glycemic biomarkers using multivariate approaches on multi-ancestry ARIC study.

Glycated hemoglobin, fasting glucose, glycated albumin, and fructosamine are biomarkers that reflect different aspects of the glycemic process. Genetic studies of these glycemic biomarkers can shed light on unknown aspects of type 2 diabetes genetics and biology. While there exists several GWAS of glycated hemoglobin and fasting glucose, very few GWAS have focused on glycated albumin or fructosamine.

Exploring predictive states via Cantor embeddings and Wasserstein distance.

Predictive states for stochastic processes are a nonparametric and interpretable construct with relevance across a multitude of modeling paradigms. Recent progress on the self-supervised reconstruction of predictive states from time-series data focused on the use of reproducing kernel Hilbert spaces. Here, we examine how Wasserstein distances may be used to detect predictive equivalences in symbolic data.

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression.

Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior.

GARDE: a standards-based clinical decision support platform for identifying population health management cohorts.

Unlabelled: Population health management (PHM) is an important approach to promote wellness and deliver health care to targeted individuals who meet criteria for preventive measures or treatment. A critical component for any PHM program is a data analytics platform that can target those eligible individuals.

Objective: The aim of this study was to design and implement a scalable standards-based clinical decision support (CDS) approach to identify patient cohorts for PHM and maximize opportunities for multi-site dissemination.

A higher burden of multiple sclerosis genetic risk confers an earlier onset.

Background: Age at onset of multiple sclerosis (MS) is an objective, influential predictor of the evolution of MS independent of disease duration.

Objectives: Determine the influence of MS genetic predisposition on age of onset.

Methods: We conducted a comprehensive investigation of MS risk variants and age at onset in 3495 non-Latinx white individuals, including for combinations of alleles and quintiles of an unweighted genetic risk score (GRS) for 198 of 200 autosomal MS risk variants that reside outside the major histocompatibility complex.

Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial.

Background: Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services.

Thermal Efficiency of Quantum Memory Compression.

Quantum coherence allows for reduced-memory simulators of classical processes. Using recent results in single-shot quantum thermodynamics, we derive a minimal work cost rate for quantum simulators that is quasistatically attainable in the limit of asymptotically infinite parallel simulation. Comparing this cost with the classical regime reveals that quantizing classical simulators not only results in memory compression but also in reduced dissipation.

Food restriction induces functional resilience to sleep restriction in rats.

Study Objectives: Sleep restriction (SR) leads to performance decrements across cognitive domains but underlying mechanisms remain largely unknown. The impact of SR on performance in rodents is often assessed using tasks in which food is the reward. Investigating how the drives of hunger and sleep interact to modulate performance may provide insights into mechanisms underlying sleep loss-related performance decrements.

Associations of autozygosity with a broad range of human phenotypes.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.

Heritability analysis of nontraditional glycemic biomarkers in the Atherosclerosis Risk in Communities Study.

Nontraditional glycemic biomarkers, including fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) are potential alternatives or complement to traditional measures of hyperglycemia. Genetic variants are associated with these biomarkers, but the heritability, or extent to which genetics control their variation, is not known. We estimated pedigree-based, SNP-based, and bivariate heritabilities for traditional glycemic biomarkers (fasting glucose, HbA1c), and nontraditional biomarkers (fructosamine, glycated albumin, 1,5-AG) among white participants in the Atherosclerosis Risk in Communities (ARIC) Study (N = 400 first-degree relatives from sibships, N = 5,575 unrelated individuals).

Pharmacological Modulation of Sleep Homeostasis in Rat: Novel Effects of an mGluR2/3 Antagonist.

Increasing vigilance without incurring the negative consequences of extended wakefulness such as daytime sleepiness and cognitive impairment is a major challenge in treating many sleep disorders. The present work compares two closely related mGluR2/3 antagonists LY3020371 and LY341495 with two well-known wake-promoting compounds caffeine and d-amphetamine. Sleep homeostasis properties were explored in male Wistar rats by manipulating levels of wakefulness via (1) physiological sleep restriction (SR), (2) pharmacological action, or (3) a combination of these.

Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study.

Serum 1,5-anhydroglucitol (1,5-AG) is an emerging biomarker used to monitor glycemic control in persons with diabetes. We performed whole-exome sequencing, examining the association between rare, coding genetic variants and 1,5-AG among European ancestry (N = 6,589) and African ancestry (N = 2,309) participants without diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Five variants representing 3 independent signals on chromosome 17 in SLC5A10, a glucose transporter not previously known to transport 1,5-AG, were associated with 1,5-AG levels up to 10.

Disturbances of sleep quality, timing and structure and their relationship with other neuropsychiatric symptoms in Alzheimer's disease and schizophrenia: Insights from studies in patient populations and animal models.

The high prevalence of sleep disturbance in neurodegenerative and psychiatric conditions is often interpreted as evidence for both sleep's sensitivity to and causal involvement in brain pathology. Nevertheless, how and which aspects of sleep contribute to brain function remains largely unknown. This review provides a critical evaluation of clinical and animal literature describing sleep and circadian disturbances in two distinct conditions and animal models thereof: Alzheimer's disease (AD) and schizophrenia.

An ex vivo comparison of cuffed endotracheal tubes and self-sealing baffled endotracheal tubes.

AIMS To compare cuffed silicone endotracheal tubes with self-sealing baffled silicone endotracheal tubes in an ex vivo canine tracheal model, to determine whether the tubes differed in their maintenance of a seal and their effectiveness in removing fluid from the tracheal lumen, and whether the self-sealing endotracheal tubes would release pressure when a closed anaesthetic circuit reached ≥30 cm HO. METHODS Twelve cadaver tracheae were randomly selected to be intubated with either cuffed or self-sealing baffled endotracheal tubes. To test tracheal seal efficacy, the tracheae were positioned vertically, 5 mL of water was instilled proximal to the tube cuff or baffles and they were monitored for leakage at 0, 15, 30, 45, and 60 minutes, recording the total volume leaked.

Diabetic Retinopathy Assessment Variability Among Eye Care Providers in an Urban Teleophthalmology Program.

Background: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability.

Introduction: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program.

Genome-Wide Association Study of Serum Fructosamine and Glycated Albumin in Adults Without Diagnosed Diabetes: Results From the Atherosclerosis Risk in Communities Study.

Fructosamine and glycated albumin are potentially useful alternatives to hemoglobin A (HbA) as diabetes biomarkers. The genetic determinants of fructosamine and glycated albumin, however, are unknown. We performed genome-wide association studies of fructosamine and glycated albumin among 2,104 black and 7,647 white participants without diabetes in the Atherosclerosis Risk in Communities (ARIC) Study and replicated findings in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

Exome Array Analysis of Nuclear Lens Opacity.

Purpose: Nuclear cataract is the most common subtype of age-related cataract, the leading cause of blindness worldwide. It results from advanced nuclear sclerosis, or opacity in the center of the optic lens, and is affected by both genetic and environmental risk factors, including smoking. We sought to understand the genetic factors associated with nuclear sclerosis through interrogation of rare and low frequency coding variants using exome array data.