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Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome.We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302.From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease.Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work.Alana Foundation.For the Portuguese translation of the abstract see Supplementary Materials section.

Problem gambling (PG) is associated with significant personal and societal loss. These losses may be exacerbated when a person with intellectual and developmental disabilities (IDD), who may not fully appreciate the inherent risks, engages in such behavior. Literature on this particular population is scarce, leaving the scientific community and treatment providers at a loss as to best practices. The present paper reviews three cases that illustrate common challenges faced by people with IDD and PG. Suggestions for effective prevention and treatment efforts are offered. Future directions include development of measures and instruments, with the eventual goal of effective prevention and treatment for this unique population.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

Objective This study evaluated the utility of Patient-Reported Outcomes Measure Information System Depression Scale (PROMIS-8a) compared with selected "Legacy" depression scales, including the Montgomery-Asberg Depression Rating Scale (MADRS), Geriatric Depression Scale (GDS), and GDS-Short Form (GDS-SF). Additionally, the measures' properties were assessed across levels of cognitive functioning. Methods This cross-sectional analysis was extracted from a prospective cohort study. PROMIS-8a and Legacy depression measures were administered to individuals aged at least 70 years grouped by cognitive status based on the Saint Louis University Mental Status Examination. McNemar tests were run to determine if measures categorized the absence or presence of depression differently and item analysis evaluated classification discrepancies. Results Sample mean age was 78, and most participants were women (71%), white (79%), with at least a high school education (89%). The percentage of individuals with at least mild depression was similar across measures (20.7% PROMIS-8a, 19.0% MADRS, 17.9% GDS, 13.9% GDS-SF). PROMIS-8a total score correlated moderately with MADRS (r = 0.56, df = 295, p Conclusion Although all measures identified a similar percent of depressed individuals, the classification differed by measure. Item analysis showed that PROMIS-8a was more likely to identify feelings of dysphoria while the MADRS and GDS were more likely to identify physiologic aspects of depression. Given the brevity and ease of administration of the PROMIS-8a, it appears to be a useful depression screen for community-dwelling older adults.

We explore the process of initiating motion through a granular medium by measuring the force required to push a flat circular plate upward from underneath the medium. In contrast with previous measurements of the drag and penetration forces, which were conducted during steady state motion, the initiation force has a robust dependence on the diameter of the grains in the medium. We attribute this dependence to the requirement for local dilation of the grains around the circumference of the plate, as evidenced by an observed linear dependence of the initiation force on the plate diameter.

Asenapine (Saphris(®)) is an atypical antipsychotic drug which has been approved by the US Food and Drug Administration for the treatment of schizophrenia in adults, as well as the treatment of acute manic or mixed episodes of bipolar I in both adult and pediatric populations. Asenapine is a tetracyclic drug with antidopaminergic and antiserotonergic activity with a unique sublingual route of administration. In this review, we examine and summarize the available literature on the safety, efficacy, and tolerability of asenapine in the treatment of bipolar disorder (BD). Data from randomized, double-blind trials comparing asenapine to placebo or olanzapine in the treatment of acute manic or mixed episodes showed asenapine to be an effective monotherapy treatment in clinical settings; asenapine outperformed placebo and showed noninferior performance to olanzapine based on improvement in the Young Mania Rating Scale scores. There are limited data available on the use of asenapine in the treatment of depressive symptoms of BD, or in the maintenance phase of BD. The available data are inconclusive, suggesting the need for more robust data from prospective trials in these clinical domains. The most commonly reported adverse effect associated with use of asenapine is somnolence. However, the somnolence associated with asenapine use did not cause significant rates of discontinuation. While asenapine was associated with weight gain when compared to placebo, it appeared to be modest when compared to other atypical antipsychotics, and its propensity to cause increases in hemoglobin A1c or serum lipid levels appeared to be similarly modest. Asenapine does not appear to cause any clinically significant QTc prolongation. The most commonly reported extra-pyramidal symptom associated with asenapine was akathisia. Overall, asenapine appears to be a relatively well-tolerated atypical antipsychotic, effective in the treatment of acute manic and mixed episodes of BD.

One of the oldest and most intriguing problems in the handling of materials is how a collection of solid grains packs together. While granular packing is normally determined by how grains are poured or shaken, we find that a systematic and controllable increase in packing is induced by simply raising and lowering the temperature, e.g., without the input of mechanical energy. The results demonstrate that thermal processing provides a largely unexplored mechanism of grain dynamics, as well as an important practical consideration in the handling and storage of granular materials., 7 pages, 1 figure

We have measured the flux of grains from a hole in the bottom of a shaken container of grains. We find that the peak velocity of the vibration, vmax, controls the flux, i.e., the flux is nearly independent of the frequency and acceleration amplitude for a given value of vmax. The flux decreases with increasing peak velocity and then becomes almost constant for the largest values of vmax. The data at low peak velocity can be quantitatively described by a simple model, but the crossover to nearly constant flux at larger peak velocity suggests a regime in which the granular density near the container bottom is independent of the energy input to the system., 14 pages, 4 figures. to appear in Physical Review E