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

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Desenvolvimento do tomateiro e modificações nas propriedades químicas do solo em função da aplicação de resíduos orgânicos, sob cultivo protegido Development of tomato and changes in soil properties with organic materials application in greenhouse

O experimento foi conduzido de fevereiro a agosto de 1997 no município de Piracicaba (SP), a fim de avaliar os efeitos de doses e resíduos orgânicos no desenvolvimento do tomateiro (Lycopersicon esculentum Mill) cultivado em estufa e nos atributos químicos de um solo Podzólico vermelho-amarelo abrupto, A moderado, textura arenosa/média. O delineamento experimental foi de blocos casualizados em esquema fatorial 3 x 4, sendo usados três resíduos orgânicos [composto de lodo de cervejaria e cavaco de eucalipto (CLC), composto de lixo (CL) e cama de frango (CF)] e quatro doses equivalentes a 0; 100; 150 e 200 kg ha-1 de N, com quatro repetições. A produção de frutos de tomate não aumentou com a adição dos materiais orgânicos. A aplicação de CF reduziu o pH e o teor de Mg no solo. As doses do CLC elevaram o conteúdo de matéria orgânica, o teor de cálcio trocável e a capacidade de troca de cátions do solo. O CL, por sua vez, não alterou as propriedades químicas do solo.<br>An experiment was carried out between February and August/97 to evaluate the effects of different organic wastes on the growth of tomato (Lycopersicon esculentum Mill) plants and on the chemical properties of an Ultisol soil. The experimental design was of complete randomized blocks with four replicates and treatments disposed in a factorial 3x4: three organic wastes [malt residue and eucalyptus chip compost (CLC), urban solid waste compost (CL) and chicken litter (CF)] and four rates equivalent to 0; 100; 150 and 200 kg ha-1 of N. The fruit yield did not increase with organic waste additions. CF application decreased the pH and exchange Mg of soil. CLC addition increased the organic matter; exchange Ca and cation exchange capacity of soil. However, CL did not change the soil chemical properties

Viabilidade da irrigação do meloeiro com águas salinas em diferentes fases fenológicas Feasibility of irrigation of musk melon with salinity water in different phenological stages

Com o objetivo de estudar os efeitos da aplicação de águas de irrigação de diferentes salinidades no rendimento do melão irrigado por gotejamento e de associar a produção obtida com o custo da água utilizada, desenvolveu-se este trabalho em Mossoró-RN. Águas de diferentes salinidades (S1=0,6, S2=1,9, S3=3,2 e S4=4,5dS m-1), utilizadas de forma incremental em três estádios de desenvolvimento ou sem variar durante o ciclo da cultura, formaram dez tratamentos arranjados em blocos inteiramente casualizados com quatro repetições. O uso de águas salinas por longos períodos afetou a produção de melão. Substituições tardias na salinidade da água tenderam a não exercer efeito significativo sobre a produção do meloeiro. O tratamento irrigado com a água de menor salinidade durante todo ciclo apresentou, simultaneamente, o maior custo com água de irrigação e o maior lucro na produção de melão.<br>This study was carried out in Mossoró, RN, Brazil, to evaluate the effects of different irrigation water salinity levels on yield of drip irrigated melon, and to relate yield with the cost of water. The waters of different salinities (S1=0.6, S2=1.9, S3=3.2 e S4=4.5dS m-1) were used both in incremental way in three different phenological stages and without replacement during the crop cycle totalizing ten treatments arranged in a completely randomized block design with four repetitions. The use of saline waters without substitutions affected melon production. The treatments irrigated with low salinity water presented simultaneously the higher cost of irrigation water and higher profits of melon cultivation

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

Genetic 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

Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow

Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 108/kg with a median of 2.7 × 108/kg. The PB cell dose ranged from 0.02 to 77 × 10 8/kg with a median of 9.3 × 108/kg. The median dose for patients receiving BM (2.7 × 108/kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology

Marrow versus peripheral blood for geno-identical allogeneic stem cell transplantation in acute myelocytic leukemia: Influence of dose and stem cell source shows better outcome with rich marrow

PubMed ID: 12829583Several studies have compared bone marrow (BM) and peripheral blood (PB) as stem cell sources in patients receiving allografts, but the cell doses infused have not been considered, especially for BM. Using the ALWP/EBMT registry, we retrospectively studied 881 adult patients with acute myelocytic leukemia (AML), who received a non-T-depleted allogeneic BM (n = 515) or mobilized PB (n = 366) standard transplant, in first remission (CR1), from an HLA-identical sibling, over a 5-year period from January 1994. The BM cell dose ranged from 0.17 to 29 × 10 8 /kg with a median of 2.7 × 10 8 /kg. The PB cell dose ranged from 0.02 to 77 × 10 8 /kg with a median of 9.3 × 10 8 /kg. The median dose for patients receiving BM (2.7 × 10 8 /kg) gave the greatest discrimination. In multivariate analyses, high-dose BM compared to PB was associated with lower transplant-related mortality (RR = 0.61; 95% CI, 0.39-0.98; P = .04), better leukemia-free survival (RR = 0.65; 95% CI, 0.46-0.91; P = .013), and better overall survival (RR = 0.64; 95% CI, 0.44-0. 92; P = .016). The present study in patients with AML receiving allografts in first remission indicates a better outcome with BM as compared to PB, when the dose of BM infused is rich. © 2003 by The American Society of Hematology