Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway

Background There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation. Methods We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls. Results The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465). Conclusions The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise

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

Management and outcomes in critically ill nonagenarian versus octogenarian patients.

BACKGROUND: Intensive care unit (ICU) patients age 90 years or older represent a growing subgroup and place a huge financial burden on health care resources despite the benefit being unclear. This leads to ethical problems. The present investigation assessed the differences in outcome between nonagenarian and octogenarian ICU patients. METHODS: We included 7900 acutely admitted older critically ill patients from two large, multinational studies. The primary outcome was 30-day-mortality, and the secondary outcome was ICU-mortality. Baseline characteristics consisted of frailty assessed by the Clinical Frailty Scale (CFS), ICU-management, and outcomes were compared between octogenarian (80-89.9 years) and nonagenarian (> 90 years) patients. We used multilevel logistic regression to evaluate differences between octogenarians and nonagenarians. RESULTS: The nonagenarians were 10% of the entire cohort. They experienced a higher percentage of frailty (58% vs 42%; p < 0.001), but lower SOFA scores at admission (6 + 5 vs. 7 + 6; p < 0.001). ICU-management strategies were different. Octogenarians required higher rates of organ support and nonagenarians received higher rates of life-sustaining treatment limitations (40% vs. 33%; p < 0.001). ICU mortality was comparable (27% vs. 27%; p = 0.973) but a higher 30-day-mortality (45% vs. 40%; p = 0.029) was seen in the nonagenarians. After multivariable adjustment nonagenarians had no significantly increased risk for 30-day-mortality (aOR 1.25 (95% CI 0.90-1.74; p = 0.19)). CONCLUSION: After adjustment for confounders, nonagenarians demonstrated no higher 30-day mortality than octogenarian patients. In this study, being age 90 years or more is no particular risk factor for an adverse outcome. This should be considered- together with illness severity and pre-existing functional capacity - to effectively guide triage decisions. TRIAL REGISTRATION: NCT03134807 and NCT03370692

Lâminas de irrigação e doses de nitrogênio em pastagem de capim-elefante no período seco do ano no norte de Minas Gerais

Neste trabalho avaliou-se durante o período seco do ano o efeito de quatro doses de nitrogênio (100, 300, 500 e 700 kg.ha-1.ano) e de seis lâminas d'água (0, 20, 40, 80, 100 e 120% da evapotranspiração de referência) sobre o rendimento forrageiro, a densidade de perfilhos, a relação folha/colmo, a altura de plantas e os teores de proteína bruta e fibra em detergente neutro do capim-elefante (Pennisetum purpureum, Schum). O delineamento experimental foi o de blocos casualizados com quatro repetições. Como fonte de adubo nitrogenado utilizou-se ureia, aplicada a lanço. O controle do nível de água e a definição do momento de irrigar foram estabelecidos com base na curva de retenção de água no solo e no teor de água, pelo método gravimétrico de amostras de solo. As lâminas d'água e as doses de nitrogênio aumentaram linearmente a altura das plantas, a produção de matéria seca e a densidade de perfilhos, mas diminuíram os teores de PB. A irrigação teve efeito quadrático no teor FDN, cujo percentual máximo, 69,38%, foi observado quando foi aplicada lâmina d'água de 72,88% da evapotranspiração. A adubação nitrogenada reduziu linearmente o teor de FDN. A menor relação folha/colmo obtida foi de 1,98 quando aplicada lâmina d'água de 65,5% da evapotranspiração com a dose de 300 kg.ha-1.ano de nitrogênio. As lâminas d'água associadas às doses de nitrogênio elevam a produção de MS de 2.539,08 kg/corte para 6.445,72 kg/corte, diminuindo o efeito da estacionalidade de produção do capim-elefante "pioneiro" no norte de Minas Gerais.This work aimed to evaluate the effect of four levels of nitrogen (100, 300, 500 and 700 kg.ha-1.year) and six water depth (0, 20, 40, 80, 100 and 120% of the reference evapotranspiration) on the forrage yield, tillers density, relationship leaf/stem, plants height and crude protein content and neutral detergent fiber of the elephant grass (Pennisetum purpureum, Schum), during the dry period. The experimental design was a random block split plot design with four replications. Broadcast urea was used as source of nitrogen fertilizer. The water level control and the definition of the irrigating moment were established based on the soil-water retention curve and on the water level by the gravimetric method in soil samples. Water depth and nitrogen levels increased linearly the plants height, dry matter production and tillers density, however, they decreased the crude protein content. Irrigation had a quadratic effect irrigation on NDF content, with maximum percentage of 69.38%, when water depth of 72.88% of the evapotranspiration was applied. Nitrogen fertilization decreased linearlly the NDF content. The lowest leaf/stem relation (1.98) was obtained with a combination of 65% evapotranspiration and 300 kg.ha-1.year of nitrogen. Water depth associated to N levels increase dry matter yield from 2539.08 kg/cut to 6445.72 kg/cut, showing a decrease of the seasonality effect of elephant grass "pioneiro" production in northern Minas Gerais

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease