Parâmetros e tendências genéticas para características produtivas de bovinos da raça nelore

The Midwest region has excelled as a beef producer and producing efficiently has been the goal of livestock farmers. This study aimed to estimate the genetic parameters and trends for weights at 240(W240) and 420(W420) days of age in Nellore cattle, reared in Goias state, Brazil. A total of 48,580 data for W240 and 28,685 for W420 were used. Genetic parameters were obtained by univariate analysis. The model included the fixed effects of contemporary group (birth season-dry and wet-, year of birth, sex and farm) and covariate age of cow. Direct and maternal effects were used as random effect for W240 and the direct effect for W420. The genetic trends were obtained by regression analysis of the genetic value of the animal on the year of birth. The results of direct heritability were 0.15 ± 0.02 for W240 and 0.24 ± 0.00 for W420. The annual genetic gain was 0.311 kg for W240 and 0.511 kg for 420 days of age (W420). The results indicate the possibility of obtaining higher genetic gains through selection; however, the selection is being more efficient at W420.Keywords: genetic gain; heritability; weight.A região Centro-Oeste tem se destacado como produtora de carne bovina e, para tanto, produzir com eficiência tem sido a meta dos produtores. Nesse sentido, objetivou-se estimar parâmetros e tendências genéticas para pesos aos 240 (P240) e 420 (P420) dias de idade em bovinos da raça Nelore, criados na região de Goiás, Brasil. Utilizaram-se 48.580 dados para P240 e 28.685 para P420. Os parâmetros genéticos foram obtidos por análises univariadas em que o modelo continha os efeitos fixos de grupo de contemporâneos (estação de nascimento - águas e seca -, ano de nascimento, sexo e fazenda) e a covariável idade da vaca. Como efeito aleatório, utilizou-se o efeito aditivo direto e materno para P240 e apenas direto para P420. As tendências genéticas foram obtidas por meio da análise de regressão do valor genético do animal sobre ano de nascimento. Os resultados obtidos de herdabilidade direta foram 0,15 ± 0,02 para P240 e 0,24 ± 0,00 para P420. O ganho genético anual foi de 0,274 kg para P240 e de 0,506 kg P420. Os resultados indicam a possibilidade de se obterem maiores ganhos genéticos por meio da seleção, que está sendo mais eficiente sobre o P420

Parâmetros e tendências genéticas para peso ao sobreano de animais Nelore criados no estado do Paraná, Brasil

Environmental effects and genetic parameters were estimated for weights at 365 and 550 days for Nellore cattle raised in the Parana State. Least Squared Means methodology, was used to estimate environmental effects. The model included as fixed effects year and month of birth calf, sex and age of dam at calving as a covariate and error as random effects. The variance components were estimated using an animal model considered as fixed effects contemporary group and age of dam. As random effect were composite of direct and maternal genetic additive effects and permanent environment. The genetic trends for direct and maternal effects were estimated by the regression of annual breeding value means on the animals’ year of birth. The heritability were 0.24±0.03 and 0.35±0.05 for direct genetic effect and 0.08±0.03 and 0.03±0.04 for maternal heritability for weights at 365 and 550 days, respectively. The genetic trends of the direct and maternal effects were 0.506 kg/year and -0.184 kg/year for weights at 365 days; and 0.712 kg/year and 0.187 kg/year for weights at 550 days. The results indicate the existence of adequate genetic variability to enable successful selection of breeding stock and realization of genetic gain.Objetivou-se avaliar os efeitos de meio e estimar os parâmetros e tendência genética para peso aos 365 e 550 dias de animais da raça Nelore criados no estado do Paraná. Utilizou-se do método dos quadrados mínimos, incluindo os efeitos fixos de ano, mês de nascimento, sexo e a co-variável idade da vaca ao parto (linear e quadrática). Os parâmetros genéticos foram estimados utilizando-se um modelo animal que continha os efeitos aleatórios genéticos direto e materno, de ambiente permanente e o erro; além do efeito fixo de grupo contemporâneo e da co-variável idade da vaca ao parto. A tendência genética foi obtida por meio de análise de regressão linear do valor genético do animal sobre o ano de nascimento. As herdabilidades diretas foram 0,24±0,03 e 0,35±0,05; as herdabilidades maternas foram 0,08±0,03 e 0,03±0,04, para peso aos 365 e 550 dias, respectivamente. As tendências genéticas direta e materna foram 0,506 kg/ano e -0,184 kg/ano para P365; e 0,712 kg/ano e 0,187 kg/ano para P550. Os resultados indicam a existência de variabilidade genética o que possibilitam ganhos através de seleção

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Comunicação, Saúde e Pluralidade: novos olhares e abordagens em pauta

Propomos um passeio acadêmico por 11 textos de pesquisadores afinados com a temática Health Communication na versão brasileira, mostrando a riqueza de assuntos, metodologias e enfoques que os estudos dessa área permitem na academia. Trata-se de uma visão multidisciplinar, às vezes com a Comunicação no foco principal, por outras a Saúde no estetoscópio dos pesquisadores.O livro Comunicação, Saúde e Pluralidade: novos olhares e abordagens em pauta compõe a Coleção Comunicação & Inovação, que, entre outros volumes, pretende discutir reflexões sobre processos e produtos comunicacionais cujos aspectos de inovação sejam marcantes nas interfaces com diversos conceitos e abordagensUniversidade Municipal de São Caetano do Su

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in Covid-19.

Host-mediated lung inflammation is present,1 and drives mortality,2 in critical illness caused by Covid-19. Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development.3 Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study(GWAS) in 2244 critically ill Covid-19 patients from 208 UK intensive care units (ICUs). We identify and replicate novel genome-wide significant associations, on chr12q24.13 (rs10735079, p=1.65 [Formula: see text] 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), on chr19p13.2 (rs2109069, p=2.3 [Formula: see text] 10-12) near the gene encoding tyrosine kinase 2 (TYK2), on chr19p13.3 (rs2109069, p=3.98 [Formula: see text] 10-12) within the gene encoding dipeptidyl peptidase 9 (DPP9), and on chr21q22.1 (rs2236757, p=4.99 [Formula: see text] 10-8) in the interferon receptor gene IFNAR2. We identify potential targets for repurposing of licensed medications: using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease; transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice