Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

Walking speed as a predictor of community mobility and quality of life after stroke

Background: Community mobility (CM) is considered a part of community reintegration that enhances Quality of Life (QoL). Achieving an appropriate gait speed is essential in attaining an independent outdoor ambulation and satisfactory CM.

Objective: The aim of this study was to identify whether gait speed is a predictor of CM and QoL in patients with stroke following a multimodal rehabilitation program (MRP).

Methods: This was a baseline control trial with 6-months follow-up in an outpatient rehabilitation setting at a university hospital. Twenty-six stroke survivors completed the MRP (24 sessions, 2 days/wk, 1 hr/session). The MRP consisted of aerobic exercise, task-oriented exercises, balance exercises and stretching. Participants also performed an ambulation program at home. Outcome variables were: walking speed (10-m walking test) and QoL (physical and psychosocial domains of Euroquol and Sickness Impact Profile).

Results: At the end of the intervention, comfortable and fast walking speed increased by an average of 0.16 (SD 0.21) (*p < .05) and 0.40 (SD 0.51) (**p < .001) m/s, respectively. After the intervention, all participants achieved independent outdoor ambulation with an increase of 34.14 of walking minutes/day in the community and a decrease of sitting time of 95.45 minutes/day. Regarding QoL there were increased mean scores on the physical and psychosocial dimensions of Euroquol and the Sickness Impact Profile, respectively (**p < .001).

Conclusions: The results suggest that improved walking speed after the MRP is associated with CM and higher scores in QoL. These findings support the need to implement rehabilitation programs to promote increased speed.     

In the Era of mRNA Vaccines,Is There Any Hope for HIV Functional Cure?

Over 36 million people worldwide are infected with HIV. Antiretroviral therapy (ART) has proven to be highly effective to prevent HIV-1 transmission, clinical progression and death. Despite this success, the number of HIV-1 infected individuals continues increasing and ART should be taken for life. Therefore, there are two main priorities: the development of preventive vaccines to protect from HIV acquisition and achieve an efficient control of HIV infection in the absence of ART (functional cure). In this sense, in the last few years, there has been a broad interest in new and innovative approaches such as mRNA-based vaccines. RNA-based immunogens represent a promising alternative to conventional vaccines because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. Some mRNA-based vaccines platforms against infectious diseases have demonstrated encouraging results in animal models and humans. However, their application is still limited because the instability and inefficient in vivo delivery of mRNA. Immunogens, design, immunogenicity, chemical modifications on the molecule or the vaccine delivery methods are all crucial interventions for improvement. In this review we, will present the current knowledge and challenges in this research field. mRNA vaccines hold great promises as part of a combined strategy, for achieving HIV functional cure.