Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs.Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.Molecular Epidemiolog

Mortalidade por neoplasias no Brasil (1980/1983/1985): agrupamento dos Estados, comportamento e tendências Mortality from neoplasms in Brazil (1980/1983/1985): grouping by State, behaviors and tendencies

Examinou-se a mortalidade por neoplasias no Brasil, utilizando-se dados oficiais do Ministério da Saúde, abrangendo 26 Unidades da Federação e 13 diferentes localizações neoplásicas, para os anos de 1980, 1983 e 1985. As Análises de Agrupamento e de Componentes Principais revelaram comportamento heterogêneo entre regiões do país, com relação às 13 variáveis estudadas, sendo que os principais elementos discriminantes foram as neoplasias malignas da traquéia/brônquio/pulmão, seguidas das do estômago, esôfago, cólon e pâncreas. Análises complementares evidenciaram tendência de crescimento das taxas de mortalidade para as neoplasias malignas da próstata (17,74%), da traquéia/brônquio/pulmão(15,22%), da mama (11,32%), do pâncreas (10,23%), do cólon (8,08%), do colo uterino (6,45%) e da laringe (6,36%). Houve redução da mortalidade por neoplasias benignas/carcinoma "in situ"/ outras (27,37%), por neoplasias malignas no reto sigmóide/ânus (7,67%), do estômago (5,31%), de outro local do útero não especificado (2,56%), por leucemia (0,70%) e por neoplasias malignas do esôfago (0,44%). As neoplasias malignas do estômago foram a principal causa de morte por câncer no Brasil, representando 21,30% do total médio, seguidas das neoplasias malignas da traquéia/brônquio/pulmão(17,49% do total médio). Destacam-se os altos índices de mortalidade por neoplasias malignas do esôfago no Estado do Rio Grande do Sul.<br>Mortality caused by neoplasms in Brazil was examined by means of official Ministry of Health data covering 26 of the Federal Units and 13 different tumoral sites and referring to the years 1980,1983 and 1985. Both cluster analyses and those of principal components have shown heterogenous behaviour as between the different regions of the country in relation to the 13 variants studied. The main discriminatory elements are the trachea/bronchus/lung malign neoplasms followed by those of stomach, pancreas, colon and larynx. Complementary analyses have demonstrated a tendency to an increase in the mortality rate due to prostate malign neoplasms (17.74%), followed by those of trachea/bronchus/lung (15.22%), breast (11.32%), pancreas (10.23%), colon (8.08%), uterine colon (6.45%) and larynx (6.36). There has been a decrease of the mortality due to benign neoplasms/carcinoma "in situ "/others (27.37%), malign rectus neoplasms of the sigmoide/anus (7.67%), stomach (5.31%), of other non-specific locations in the uterus (2.56%), of leukaemia (0.70%) and malign neoplasms of the oesophagus (0.44%). Maling neoplasms of the stomach have been the main cause of cancer mortality in Brazil accounting for 21.27% of the mean total, followed by of the malign neoplasms trachea/bronchus/lung (17.52% of the general average). The mortality rates by esophageal malign neoplasms in Rio Grande do Sul is stressed

Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study

Background: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments. Methods: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407). Findings: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5–42·3) from diagnosis and 16·2 months (6·6–31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1–17·3) versus 20·7 months (17·9–23·4); hazard ratio (HR) 1·39 (1·17–1·65; p=0·0002) and 14·0 months (9·8–17·2) versus 20·7 months (17·9–23·4; HR 1·55 [1·16–2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7–15·0) versus 17·6 months (14·8–21·5; HR 1·38 [1·12–1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4–16·6) versus 17·6 months (14·8–21·5; HR 1·44 [1·02–2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with &lt;10% blasts, CMML-0, or lower-risk CPSS). Interpretation: These data suggest hypomethylating agents as the preferred therapy for patients with higher-risk chronic myelomonocytic leukaemia and those with myeloproliferative CMML. Our findings also suggest that CPSS is a valuable tool to identify patients who are most likely to benefit from hypomethylating agents. Further evidence from prospective cohorts would be desirable. Funding: The Austrian Group for Medical Tumor Therapy. © 2021 Elsevier Lt

In vitro

The in vitro antimicrobial and in vivo heavy metal abatement properties of aqueous extracts of Garcinia kola Heckel (bitter cola) were investigated using opportunistic pathogens and Wistar rats as experimental models. A marked inhibitory activity against Aspergillus niger, Aspergillus flavus and Candida albicans was recorded at 100 mg/ml of the crude relative to ketoconozole and fluconazole drugs. Similarly, different concentrations (25 mg/ml, 50 mg/ml and 100 mg/ml) of the crude extracts of bitter cola inhibited species of Escherichia coli and Pseudomonas aeruginosa almost as effectively as the control drug of streptomycine used. Chronic lead acetate poisoned wistar rats in groups B, C, D, E exposed to G. kola supplemented feed and water ad libitum showed variable decrease in the serum alkaline phosphatase level while aspartate and alanine aminotransferases level reduces in C and D groups compared to the negative control group. The kidney biomarkers; serum creatinine and urea concentrations were not significantly different at P â¤Â 0.05 for rat groups C, D, E when compared with the positive and negative control groups respectively. Mild infiltration and cell distortion were observed in the liver and kidney sections of the rats exposed to uncoated bitter cola supplemented feed while suggesting an overriding effect from the nut coats. The study reaffirms the medicinal potential of coated and uncoated bitter cola to act as abatement of lead toxicity and alternative antimicrobial. Furthermore, G. kola could be a double-edged drug for the spontaneous amelioration of lead toxicity and secondary infections due to lead poisoning. Keywords: Garcinia kola, Antimicrobial, Lead abatement, Histopathology, Opportunistic pathogen

A passagem pelo sistema de ensino em três gerações: classe e gênero na segmentação do sistema de ensino The passage of three generations through the schooling system: class and gender in the segmentation of the schooling system

Este artigo analisa os investimentos educativos diferenciados, realizados por três gerações de famílias inseridas em um grupo socialmente privilegiado. A análise centra-se na discussão de como, de uma geração a outra, a passagem pelo sistema de ensino esteve na base dos processos de diferenciação social entre os indivíduos. O material empírico trabalhado foi obtido no quadro de uma pesquisa de doutorado, na qual identifiquei a escola de nível secundário e as trajetórias sócio-profissionais de oitenta e duas mulheres, ex-alunas de três escolas católicas de São Paulo. Discute se modificações estruturais, de longa duração, tais como a expansão do acesso ao ensino, o investimento crescente das meninas nos caminhos da escolarização e a conotação sexual dos percursos escolares. Por meio da comparação sistemática da passagem pelo sistema de ensino e de ingresso no ensino superior é possível verificar a maneira pela qual a ordem social foi transposta para o universo escolar definindo os horizontes possíveis para cada um.<br>This paper analyses the different educational investments made by three generations of families included in a socially privileged group. It discusses how, from one generation to the other, passing through the education system was the basis of the social differentiation processes among individuals. The empirical material studied was obtained as part of a doctoral research, which identified the secondary school level and socio-professional trajectories of eighty-two women who had studied in three Catholic schools. It focuses on the structural long-duration changes, such as the expanding access to education, the increased investment in girls' schooling paths and the survival of the sexual connotation of school courses. By systematically comparing the passage through the education system and the enrollment in higher education, it shows how the social order was transferred into the school environment and how it defines the possible horizons for each person

O impacto dos efeitos da ocupação sobre a saúde de trabalhadores: II - Mortalidade The impact of occupation on worker's health: II - Mortality

Foi realizada revisão bibliográfica analítica com o objetivo de quantificar o impacto dos efeitos da ocupação sobre a mortalidade de trabalhadores em suas implicações sobre o setor saúde. As repercussões sobre a mortalidade de trabalhadores são medidas através das mortes diretamente relacionadas com o trabalho (acidentes do trabalho fatais e intoxicações fatais) e das indiretamente relacionadas. Partindo das grandes causas de morte entre adultos - doenças cardiovasculares, câncer e mortes violentas - e explorando as informações obtidas em estudos epidemiológicos realizados em outros países, estimou-se a força da contribuição da ocupação sobre a mortalidade. O peso e a complexidade das repercussões sobre o setor saúde pressupõem um desempenho mais ativo na definição de políticas e responsabilidades, e na organização de ações destinadas a identificar, reduzir ou eliminar a participação dos riscos ocupacionais nas grandes causas de doença e morte.<br>An attempt to estimate the impact of occupation on worker's health was made as part of the rationale for the progressive integration of Occupational Health into the Health Sector. In this second study, based on a critical review of the literature, the repercussions on mortality are discussed on this basis analysis of the Brazilian data on deaths directly related to occupation (fatal occupational accidents and acute poisonings), as well as on those indirectly so related. The analysis of the major causes of adult deaths - cardiovascular diseases, cancer and violent deaths - compared with the proportion of "work-relatedness" according to several epidemiologic studies carried out in developed countries, make possible an estimation of the influence of the contribution of occupation on mortality. The size of this contribution is the main argument for an active involvement of the health sector in Occupational Health issues, because of the heavy toll in terms of adult morbidity and mortality exacted on industrialized societies