Objective To determine the effects of cognitive training on cognitive abilities and everyday function over 10 years. Design, Setting, and Participants Ten-year follow-up of a randomized, controlled single-blind trial with 3 intervention groups and a no-contact control group. A volunteer sample of 2832 persons (mean baseline age, 73.6 years; 26% African American) living independently in 6 US cities. Interventions Ten-session training for memory, reasoning, or speed-of-processing.; 4-session booster training at 11 and at 35 months after training. Measurements Objectively measured cognitive abilities and self-reported and performance-based measures of everyday function. Results Participants in each intervention group reported less difficulty with instrumental activities of daily living (IADL) (memory: effect size, 0.48 [99% CI, 0.12-0.84]; reasoning: effect size, 0.38 [99% CI, 0.02-0.74]; speed-of-processing: effect size, 0.36 [99% CI, 0.01-0.72]). At mean age of 82 years, about 60% of trained participants compared to 50% of controls (p<.05) were at or above their baseline level of self-reported IADL function at 10 years. The reasoning and speed-of-processing interventions maintained their effects on their targeted cognitive abilities at 10 years (reasoning: effect size, 0.23 [99% CI, 0.09-0.38]; speed-of-processing: effect size, 0.66 [99% CI, 0.43-0.88]). Memory training effects were no longer maintained for memory performance. Booster training produced additional and durable improvement for the reasoning intervention for reasoning performance (effect size, 0.21 [99% CI, 0.01-0.41]) and the speed-of-processing intervention for speed-of-processing performance (effect size, 0.62 [99% CI, 0.31-0.93]). Conclusions Each ACTIVE cognitive intervention resulted in less decline in self-reported IADL compared with the control group. Reasoning and speed, but not memory, training resulted in improved targeted cognitive abilities for 10 years.

Low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, but considerable between-study heterogeneity, which was related to study and subject characteristics, suggests that effects are driven by differences between cohorts (e.g. in underlying health status).

A diverse antibody repertoire is essential for an effective adaptive immune response to novel molecular surfaces. Although past studies have observed common patterns of V-segment use, as well as variation in V-segment use between individuals, the relative contributions to variance from genetics, disease, age, and environment have remained unclear. Using high-throughput sequence analysis of monozygotic twins, we show that variation in naive V H and D H segment use is strongly determined by an individual's germ-line genetic background. The inherited segment-use profiles are resilient to differential environmental exposure, disease processes, and chronic lymphocyte depletion therapy. Signatures of the inherited profiles were observed in class switched germ-line use of each individual. However, despite heritable segment use, the rearranged complementarity-determining region-H3 repertoires remained highly specific to the individual. As it has been previously demonstrated that certain V-segments exhibit biased representation in autoimmunity, lymphoma, and viral infection, we anticipate our findings may provide a unique mechanism for stratifying individual risk profiles in specific diseases.heritable variation | next generation sequencing | V-gene S pecific biases in the antibody repertoire have been found in many diseases, from viral infections to cancers to autoimmune disorders (1-15). Although it is possible that heritable variation in the composition of the antibody repertoire could alter inherent risk to specific diseases, the diversity of the antibody repertoire has hindered direct characterization of heritable influences.Early twin studies provided some evidence of genetic variation affecting reactive titers from the antibody repertoire. Multiple studies observed both total Ig and antigen-specific titers to be more correlated in monozygotic twins than dizygotic twins or unrelated individuals (16)(17)(18). In some cases of monozygotic twins discordant for autoimmune diseases, the healthy twin often shared high autoantibody reactive titers with their affected twin (16,19,20).Early sequencing studies were able to identify some systematic biases in the antibody repertoire with limited sampling depth. The first sequencing studies to characterize V(D)J diversification mechanisms identified the gene segment recombination process, but also implied a repertoire too diverse to exhaustively interrogate by traditional sequencing technologies (21). Complete characterization of V-segment loci established ∼50 V H , 40 V κ , and 30 V λ segments in an individual, with a number of allelic variants for the majority of segments (22)(23)(24). Evaluation of use across individuals revealed biased V-gene representation that preceded selection (25)(26)(27). Quantitative PCR of V-gene families showed family use largely stable over time, with fluctuations in use correlated to antigen-specific responses (28). In the T-cell receptor (TCR) repertoire, TCRB-V use was more highly correlated in healthy monozygotic twins than unrelated individua...

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Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a pseudoU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%-85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice.

Objective The authors examined the relationship between cannabis use and the course of illness in schizophrenia over 10 years following first psychiatric hospitalization. Method We assessed 229 patients with a schizophrenia-spectrum disorder five times: during the first admission, and 6 months, 2 years, 4 years, and 10 years later. Ratings of cannabis use and psychiatric symptoms (psychotic, negative, disorganized, and depressive) were made at each assessment. Results The lifetime rate of cannabis use was 66.2%, and survival analysis revealed that this usage was associated with an earlier onset of psychosis. The rates of current use ranged from 10% to 18% across assessments. Cannabis status was moderately stable, with concordance between waves ranging rtet = 0.48 – 0.78. Mixed-effects logistic regression revealed that changes in cannabis use were associated with changes in psychotic symptoms over time even after gender, age, socio-economic status, other drug use, antipsychotic medication use, and other symptoms were controlled. Structural equation modeling indicated that the association with psychotic symptoms was bi-directional. Conclusions Cannabis use is associated with an adverse course of psychotic symptoms in schizophrenia, and vice versa, even after taking into account other clinical, substance, and demographic variables. The specificity of this relationship suggests that clinical interventions to reduce cannabis use may be best targeted at individuals with prominent psychotic symptoms.

Next-generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost-effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two-stage design. Two-stage designs include a broad-based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow-up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype—suggesting high false-negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well-cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling.