Validation of a novel and accurate ApoE4 assay for automated chemistry analyzers

The allele ε4 of the apolipoprotein E gene (APOE ε4) is the major genetic risk factor for non-dominantly inherited Alzheimer's Disease (AD). Current techniques for APOE ε4 carriers identification show good accuracy but have several disadvantages that limit its implementation in a clinical laboratory. These include the need for sample preprocessing, poor automation, low throughput, requirement of additional equipment, and high cost. We followed ISO 13485 guidelines to validate the e4Risk test, a new latex-enhanced immunoturbidimetric blood assay for apolipoprotein E4 (ApoE4) determination in human plasma samples. The test showed high performance in terms of lot to lot variability, precision, interferences, reagents stability, prozone, and detectability. Furthermore, diagnostic accuracy is almost equal (99%) to the gold standard, APOE ε4 genotyping by polymerase chain reaction (PCR). Furthermore, we demonstrated that the e4Risk test can be adapted to any clinical chemistry analyzer, including the high throughput analyzers present in most hospitals and clinical laboratories. The e4Risk test versatility, low cost, and easiness provides an excellent solution for APOE ε4 carriers identification using the same blood sample drawn for biochemical diagnostic work-up of AD patients, which can have important advantages for patient stratification in clinical trials, preventative strategies for AD, and clinical assessment of risk for brain amyloidosis.This research was fully funded by Biocross and did not receive any other specific grant from funding agencies in the public, commercial, or not-for-profit sectors for this research.S

Refined physical parameters for Chariklo's body and rings from stellar occultations observed between 2013 and 2020

Context. The Centaur (10199) Chariklo has the first ring system discovered around a small object. It was first observed using stellar occultation in 2013. Stellar occultations allow sizes and shapes to be determined with kilometre accuracy, and provide the characteristics of the occulting object and its vicinity. Aims. Using stellar occultations observed between 2017 and 2020, our aim is to constrain the physical parameters of Chariklo and its rings. We also determine the structure of the rings, and obtain precise astrometrical positions of Chariklo. Methods. We predicted and organised several observational campaigns of stellar occultations by Chariklo. Occultation light curves were measured from the datasets, from which ingress and egress times, and the ring widths and opacity values were obtained. These measurements, combined with results from previous works, allow us to obtain significant constraints on Chariklo's shape and ring structure. Results. We characterise Chariklo's ring system (C1R and C2R), and obtain radii and pole orientations that are consistent with, but more accurate than, results from previous occultations. We confirm the detection of W-shaped structures within C1R and an evident variation in radial width. The observed width ranges between 4.8 and 9.1 km with a mean value of 6.5 km. One dual observation (visible and red) does not reveal any differences in the C1R opacity profiles, indicating a ring particle size larger than a few microns. The C1R ring eccentricity is found to be smaller than 0.022 (3σ), and its width variations may indicate an eccentricity higher than ~0.005. We fit a tri-axial shape to Chariklo's detections over 11 occultations, and determine that Chariklo is consistent with an ellipsoid with semi-axes of 143.8-1.5+1.4, 135.2-2.8+1.4, and 99.1-2.7+5.4 km. Ultimately, we provided seven astrometric positions at a milliarcsecond accuracy level, based on Gaia EDR3, and use it to improve Chariklo's ephemeris.Fil: Morgado, B.E.. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Sicardy, Bruno. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Braga Ribas, Felipe. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; Brasil. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Universidade Tecnologia Federal do Parana; BrasilFil: Desmars, Josselin. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Gomes Júnior, Altair Ramos. Universidade de Sao Paulo; BrasilFil: Bérard, D.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Leiva, Rodrigo. Universidad de Chile; Chile. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Vieira Martins, Roberto. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Benedetti Rossi, G.. Centre National de la Recherche Scientifique. Observatoire de Paris; Francia. Universidade Federal de Sao Paulo; BrasilFil: Santos Sanz, Pablo. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Camargo, Julio Ignacio Bueno. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Duffard, R.. Universidade Federal do Rio de Janeiro; BrasilFil: Rommel, F.L.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Assafin, M.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Boufleur, R.C.. Universidad Nacional de Córdoba; ArgentinaFil: Colas, F.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Kretlow, Mike. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Beisker, W.. University of North Carolina; Estados UnidosFil: Sfair, Rafael. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Snodgrass, Colin. University of Edinburgh; Reino UnidoFil: Morales, N.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Fernández Valenzuela, E.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Amaral, L.S.. Massachusetts Institute of Technology; Estados UnidosFil: Amarante, A.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Artola, R.A.. Centre National de la Recherche Scientifique. Observatoire de Paris; FranciaFil: Backes, M.. Universidad Nacional de Córdoba; ArgentinaFil: Bath, K. L.. University of North Carolina; Estados UnidosFil: Bouley, S.. University of St. Andrews; Reino UnidoFil: Garcia Lambas, Diego Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; ArgentinaFil: Schneiter, Ernesto Matías. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Ingeniería Económica y Legal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; Argentin

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

Genomic Characterization of Host Factors Related to SARS-CoV-2 Infection in People with Dementia and Control Populations: The GR@ACE/DEGESCO Study

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis

Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease