Use of computerized dynamic posturography to assess balance in older adults after nighttime awakenings using zolpidem as a reference

<p>Abstract</p> <p>Background</p> <p>Computerized dynamic posturography (CDP) has been used to detect balance and stability impairments in adults of all ages. The goal of the current pilot study was to evaluate balance in healthy older adults after a middle-of-the-night awakening and to assess the ability of CDP to measure effects of bedtime zolpidem administration.</p> <p>Methods</p> <p>Two studies used CDP to evaluate balance in healthy older adults (≥ 65 years) during middle-of-the-night awakenings. The first study used a drug-free, single-period, within-subject, repeated measures study design. Subjects were evaluated during the day, pre-sleep, and 2 hours after bedtime for dynamic standing balance using the NeuroCom EquiTest Sensory Organization Test (SOT). Pairwise comparisons were made using one-way ANOVA. The second study was a single-blind, randomized, placebo-controlled, crossover study evaluating the ability of the SOT to measure medication-induced dynamic standing balance impairments using the commonly prescribed sleep medication, zolpidem 10 mg, as a test medication. Assessments were performed at night before zolpidem administration and then again 2 hours after bedtime. Comparisons were made between the 2 groups using an ANCOVA model.</p> <p>Results</p> <p>Twelve older adults (mean age 68.4 years) were evaluated in the first study. There was no significant difference between pre-sleep and middle-of-the-night assessments for the SOT composite score (<it>P </it>= 0.439). Eleven older adults (mean age 68.9 years) were evaluated in the second study. Zolpidem administration significantly decreased the SOT composite score after a middle-of-the-night awakening compared with placebo (<it>P </it>< 0.001).</p> <p>Conclusion</p> <p>In healthy older adults, getting up in the middle of the night did not have a significant effect on dynamic standing balance; however, bedtime administration of zolpidem 10 mg did lead to significant impairments. Thus, the SOT was able to measure medication-induced dynamic standing balance impairments and may be useful for future studies comparing balance effects of medications.</p

Effects of early life adversity on immune function and cognitive performance: results from the ALSPAC cohort

Background Early life adversity (ELA) is a significant risk factor for mental health disorders. One hypothesised mechanism by which this occurs is via an effect on immune response. In this analysis of epidemiological data, we tested whether ELA was associated with cognitive performance, and if so, whether these effects were influenced by immune function. Methods We investigated the longitudinal relationship between ELA, inflammatory markers, and cognition in data from Avon Longitudinal Study of Parents And Children (ALSPAC; n ~ 5000). ELA was defined in terms of physical/emotional abuse, harsh parenting, or domestic violence before 5 years. Social cognition was measured in terms of theory of mind, and general cognitive ability was measured using IQ. Inflammatory markers included serum C-reactive protein and interleukin-6 levels. Results A significant association was observed between IQ and harsh parenting, whereby children who were physically disciplined had lower IQ scores (accounting for relevant social factors). Both immune markers were associated with variation in cognition, however, neither accounted for the effects of ELA on cognition. Discussion This study highlights the impact of ELA on cognition. In the absence of evidence that these effects are explained by inflammation, other mechanisms by which the effects of ELA are mediated are discussed

Rare copy number variations are associated with poorer cognition in schizophrenia

Background Cognitive impairment in schizophrenia is a major contributor to poor outcomes yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and impact cognition in healthy populations but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia. Methods General cognitive ability was measured using the MATRICS composite z-score in 875 schizophrenia cases, and in a replication sample of 519 schizophrenia cases using WAIS Full-Scale IQ. Using linear regression we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia enriched gene sets (loss of function intolerant or synaptic gene sets) were associated with cognitive impairment. Results 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than non-schizophrenia CNV carriers in discovery (β=-0.66, 95%CI = -1.31 to -0.01) and replication samples (β=-0.91, 95%CI =-1.71 to -0.11), and after meta-analysis (β=-0.76, 95%CI=-1.26 to -0.25, p=0.003). CNVs hitting loss of function intolerant genes were associated with lower cognition (β= -0.15, 95%CI=-0.29 to -0.001, p=0.048). Conclusions In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5-1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss of function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs

Chromosome-length genome assembly and structural variations of the primal Basenji dog (Canis lupus familiaris) genome

Background: Basenjis are considered an ancient dog breed of central African origins that still live and hunt with tribesmen in the African Congo. Nicknamed the barkless dog, Basenjis possess unique phylogeny, geographical origins and traits, making their genome structure of great interest. The increasing number of available canid reference genomes allows us to examine the impact the choice of reference genome makes with regard to reference genome quality and breed relatedness. Results: Here, we report two high quality de novo Basenji genome assemblies: a female, China (CanFam_Bas), and a male, Wags. We conduct pairwise comparisons and report structural variations between assembled genomes of three dog breeds: Basenji (CanFam_Bas), Boxer (CanFam3.1) and German Shepherd Dog (GSD) (CanFam_GSD). CanFam_Bas is superior to CanFam3.1 in terms of genome contiguity and comparable overall to the high quality CanFam_GSD assembly. By aligning short read data from 58 representative dog breeds to three reference genomes, we demonstrate how the choice of reference genome significantly impacts both read mapping and variant detection. Conclusions: The growing number of high-quality canid reference genomes means the choice of reference genome is an increasingly critical decision in subsequent canid variant analyses. The basal position of the Basenji makes it suitable for variant analysis for targeted applications of specific dog breeds. However, we believe more comprehensive analyses across the entire family of canids is more suited to a pangenome approach. Collectively this work highlights the importance the choice of reference genome makes in all variation studies

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707