Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

Introdução: A obesidade/sobrepeso pode interferir na aquisição das habilidades motoras do lactente, o qual, na tentativa de buscar mecanismos de adaptações tem o seu desenvolvimento motor alterado. Objetivos: Verificar se o peso elevado para a idade interfere no desenvolvimento motor da criança de zero a dois anos de idade e, se há diferença do desenvolvimento entre meninos e meninas. Materiais e Métodos: Participaram do estudo 43 lactentes de zero a dois anos, divididos em dois grupos: Grupo com peso elevado para a idade (GE) e Grupo de comparação (GC). Todos foram avaliados por meio da “Escala Motora Infantil de Alberta”. A análise dos dados foi realizada por meio de estatística descritiva, com frequências relativas e absolutas, média e desvio padrão. Para verificar a normalidade das variáveis aleatórias utilizou-se o teste Kolmogorov-Smirnov, e considerando a normalidade dos dados, foi aplicado o teste t-Student para amostras independentes. Em todos os casos, considerou-se um nível de significância de 5% (p<0,05). Resultados: Verificou-se diferença estatisticamente significativa entre o GE e o GC para as seguintes variáveis: Índice de Massa Corpórea (p=0,000), peso para a idade (p=0,002), e déficit no desenvolvimento motor observado nas crianças com peso elevado (p=0,039). Não houve diferença estatisticamente significativa para o desenvolvimento motor entre meninos e meninas em ambos os grupos. Conclusão: Os resultados confirmam que o peso elevado, entre zero a dois anos de idade, pode interferir negativamente no desenvolvimento motor. Assim, é necessário monitorar o desenvolvimento dessas crianças, orientar e intervir precocemente para minimizar e prevenir as possíveis alterações.

Following the thermodynamic formulation of multifractal measure that was shown to be capable of detecting large fluctuations at an early stage, here we propose a new index which permits us to distinguish events like financial crisis in real time . We calculate the partition function from where we obtain thermodynamic quantities analogous to free energy and specific heat. The index is defined as the normalized energy variation and it can be used to study the behavior of stochastic time series, such as financial market daily data. Famous financial market crashes - Black Thursday (1929), Black Monday (1987) and Subprime crisis (2008) - are identified with clear and robust results. The method is also applied to the market fluctuations of 2011. From these results it appears as if the apparent crisis of 2011 is of a different nature from the other three. We also show that the analysis has forecasting capabilities.Comment: 8 pages, 6 figure

Background Early Onset Alzheimer Disease (EOAD, age at onset [AAO] < = 65) is a severe form of AD, often occurring when patients are still caring for children or adults. Despite this, most genetic studies of EOAD have focused on autosomal dominant forms, and there is little understanding of similarities and differences between early and late onset forms of AD (LOAD, [AAO]>65). To address this, we present a genome‐wide association study of non‐Mendelian EOAD and compare it to LOAD GWAS. Methods Primary single‐variant analyses were performed using two additive logistic regression for case‐control models (full: SNPs, PCs, sex and APOE‐ɛ4 dosage as covariates; reduced: SNPs and PCs); secondary models included PCs+sex and PCs+APOE. Models were applied on data derived from the Alzheimer Disease Genetics Consortium (ADGC), composed by unrelated individuals. Samples varied from 1293‐1459 cases and 8894‐9366 controls for EOAD, and 8795‐9508 cases and 9702‐10273 controls for LOAD, depending on the considered model. The SNP heritability (h2) and genetic correlation (rg) were estimated using LD score regression. Gene‐based and pathway analysis (gene sets from Msigdb‐v7.0) were performed using FUMA/MAGMA‐v1.6. Results We identified two novel loci associated with EOAD: Chromosome 4 (full model: chr4:102027610, P = 2.98×10−08, near PPP3CA gene) and Chromosome 12 (PCs+sex model: rs117001070, P = 2.11×10−08, intergenic between LINC02444 and LINC02882). We additionally confirmed BIN1 and APOE in the EOAD subset. Several known genes also showed a significant association with LOAD. Heritability analyses showed higher h2 values for EOAD (h2 = 0.29, 0.29, 0.29 and 0.27) than LOAD (h2 = 0.19, 0.16, 0.19, and 0.15), for full, reduced, PCs+sex and PCs+APOE models respectively. Genetic correlation showed moderate but incomplete genetic correlation between EOAD and LOAD. Other than APOE (p = 3.89×10−12), gene‐based tests showed nominal association for EOAD C8orf44‐SGK3 (p = 9.95×10−06), SGK3 (p = 2.01×10−05) and HIST1H2AC (p = 3.04×10−05), and plausible pathways such as HDL remodeling (p = 5.50×10−05) and positive regulation of cholesterol efflux (p = 9.79×10−05). These pathways were nominally associated with LOAD (p = 0.04 and p = 4.05×10−03). Conclusions We identified two novel loci associated to EOAD not previously reported by LOAD studies. Heritability and genetic correlation results suggest that the genetic etiology of EOAD has an incomplete genetic overlap with LOAD.

BackgroundEarly‐onset (≤65 years old) Alzheimer Disease (EOAD), which accounts for approximately 10% of all AD cases, is sometimes equated with dominantly inherited forms of AD (i.e., caused by known mutations in APP, PSEN1 or PSEN2). However, 90% of EOAD cases remain unexplained by these variants. This project aims to identify novel EOAD‐associated variants through a large‐scale, multi‐ethnic genome‐wide association (GWA) study.MethodWe have leveraged the Alzheimer Disease Genetics Consortium (ADGC) GWAS dataset that is aligned to GRCh38 and imputed with the TOPMed imputation server. This includes 39 studies from non‐Hispanic Whites (NHW; CA = 3,202; CO = 5,782), 17 from African American (CA = 139; CO = 253), six from Asian (CA = 133; CO = 474), and seven from Hispanic (CA = 199; CO = 59) cohorts. Only the younger (≤65yo) and older participants (>80yo) were included for analysis as cases and controls, respectively. The genetic background was confirmed using PCA. We are performing single‐variant analysis to identify variants that confer a higher risk for EOAD.ResultOur preliminary single‐variant association analysis (using sex, PC1‐PC10 as covariates) emerging from the largest NHW cohort (CA = 3,202; CO = 5,782) have revealed nine different loci that were associated with EOAD at a suggestive P‐value<1×10−6. The strongest signal from our analysis was in the APOE region. Additionally, we identified three novel genome‐wide significant (P‐value <5×10−8) loci of interest at HLA‐DRB9 (rs9268852, P‐value = 2.9×10−9, OR = 1.22); FAM86B3P (rs73199790, P‐value = 3×10−11, OR = 1.32); and MSMB (rs2075895, P‐value = 2.83×10−16, OR = 1.26); while also confirming the previously identified loci at MS4A4A (rs7108663, P‐value = 1.13×10−10, OR = 0.80) and CR1 (rs6656401, P‐value = 2.54×10−12, OR = 1.32). We will perform qualitative associations on the other three ethnicities to confirm the transferability of these signals.ConclusionOur single‐variant analysis has identified three novel loci associated with EOAD. This study is the largest genetic screening for risk and protective variants in EOAD and will be instrumental to identifying novel variants and pathways implicated in unexplained EOAD. Our future analysis includes gene‐based association and pathway analyses per ethnicity to identify variants that confer a higher risk for EOAD, followed by transethnic analysis to validate the comprehensive nature of these risk factors. Additionally, we have also generated GWAS data from the Knight‐ADRC participants, which will be merged with the ADGC datasets for our future analysis.

Agradeço primeiramente a Deus, por sempre me dar conforto e esperança nos momentos em que mais precisei. Por sempre ouvir minhas preces e por ser um importante guia que impulsiona a minha vida. Agradeço por me trazer até aqui. Agradeço carinhosamente meus pais Osvaldir Lucio da Fonseca e Sônia Aparecida Borges Fonseca, por apoiarem incondicionalmente os meus projetos de vida. Agradeço pelo amor, dedicação e zelo para com a nossa família. Agradeço principalmente por serem exemplos de caráter, honestidade e integridade. A eles todo o meu amor, respeito e gratidão. Aos meus dois amados irmãos Eber Lucio da Fonseca e Franciele Borges Fonseca, por serem presenças constantes e queridas em minha vida. Agradecimentoà minha cunhada Cristina Silva eà Yasmin Vitória Fonseca, minha querida sobrinha. Aos meus queridos sogros Plínio Teixeira da Silva e Maria das Graças P. da Silva, por serem pessoas maravilhosas e por me tratarem como a um filho. Agradeçoàs minhas duas cunhadas/irmãs Adriana Almeida P. da Silva eÂngela P. da Silva (eterna Man) pelo apoio e pelas risadas despendidas gratuitamente. Especial agradecimentoà Andréa Almeida P. da Silva, amor da minha vida, por me apoiar em todos os momentos, incondicionalmente. Razão do meu viver, luz da minha vida! Agradeço também ao nosso cãozinho Malik, por continuar ao meu lado, sempre vigilante, principalmente nas solitárias madrugadas de estudo. Agradeçoà minha orientadora Airlane Pereira Alencar, por sempre me apoiar e contribuir para o meu crescimento científico, intelectual e profissional. Por sempre estar aberta ao diálogo e por sempre estar disposta a ouvir as minhas ideias. Por sempre poder contar com a sua ajuda. Agradeço pelo privilégio de ter sido seu orientado.

Introduction: In Brazil, interventions during labor and childbirth are harmful and, for the most part, unnecessary. In addition, there is a high prevalence of abuse and disrespect for women and babies during this period. Objective: To describe the prevalence of maternal and neonatal harm and harm-free care in a Brazilian maternity setting. Methods: Pilot application of the Portuguese version of Maternal Safety Thermometer (MST) by a cross-sectional study in a public setting. Data collection was made at two timepoints. Results: 140 women were included. Over 84% of women had a postpartum sutured wound, resulting from a caesarean section, an episiotomy, or a perineal trauma. Puerperal infection, especially on a caesarean wound, was the most frequent physical harm. Women’s perception of safety, including being left alone in labour, and feeling their safety concerns were not taken seriously, decreased from 80.6% to 43.3% in the second timepoint. Using the MST helped to improve the quality of medical records since critical information about a patient’s health status was not properly recorded, or even absent. Conclusion: MST is a concise tool and includes indicators related to harm-free care in a short time range. However, this study suggests that the MST can underestimate harm if it is used alone to assess harm-free care in maternities with excessive levels of intervention, and poor reporting of harms (i.e., blood loss), as in most Brazilian settings.

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