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

Modeling individual-tree mortality in Pyrenean oak (Quercus pyrenaica Willd.) stands

International audienceTree mortality is an important process in forest ecosystem dynamics and is one of the least understood phenomena, because of the complex interactions between different environmental stresses, minimal understanding of whole-plant mortality processes, and a chronic shortage of data. * A multilevel logistic regression model was developed for predicting the probability of mortality in individual trees with the objective of improving long-term planning in Spanish pyrenean oak forests. The data came from one 10-year re-measurement of the permanent plot network belonging to the Spanish National Forest Inventory distributed throughout north-west Spain. * The probability of mortality decreased with increasing individual diameter at breast height and increasing ratio of the height of subject tree to the dominant height of the sample plot. The resulting mortality model was evaluated using an independent data set from a region close to the study area. * The regeneration of pyrenean oak generally takes place through stump and/or root sprouting; so stand dynamics differ from those of others species. The model developed is expected to improve the accuracy of stand forecasts in northwest Spain

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Balance sheet of15N labelled urea applied to rice in three Australian vertisols differing in soil organic carbon

A glasshouse experiment was conducted to study the balance sheet of15N labelled urea at three rates (zero, 31.48 and 62.97 mmol N pot-1) applied to rice under flooded conditions with two moisture regimes (continuous and alternate flooding) using three Australian vertisols differing in organic carbon level. Walkley-Black organic carbon values for the three soils were 0.65, 2.13 and 3.76 for the low carbon (LC), medium carbon (MC) and high carbon (HC) soils respectively. Rice dry weight and nitrogen uptake was significantly affected by N fertilizer rates, water regimes and soils. Alternate flooding gave much lower dry weight and nitrogen uptake than continuous flooding and the LC soil gave lower dry weight and nitrogen uptake than for the MC and HC soils. Recovery of15N labelled urea fertilizer in the rice plant was low (15.4 to 38.4%) and the15N urea not accounted for in the plant or soil and presumed lost was high (36.2 to 76.0%). Recovery was lower and loss higher under alternate flooding and for the LC soil. There was no effect of fertilizer rate. The results obtained stress the need for careful management to reduce losses of nitrogen fertilizer, particularly for soils low in organic carbon

Reactive indoor air chemistry and health—A workshop summary

International audienc

The use of political risk assessment techniques in Jordanian multinational corporations

This paper describes and explains the use of political risk assessment techniques in Jordanian multinational corporations (MNCs). A multi-method approach to collect data was followed. A self-report questionnaire was delivered by hand to the general managers of all Jordanian MNCs which were identified as operating internationally. Semi-structured interviews were used as a means of elaborating on the findings from the questionnaire. The study identified the extensive use of heuristic political risk assessment techniques (due to their flexibility, simplicity and low cost). Scientific techniques, on the other hand, were used by only a minority of MNCs. As has been the case in earlier studies, flexibility, simplicity and cost considerations were all found to be influential in this regard. However, the study also found that key decision-makers in Jordanian MNCs believe that official data are subject to censorship and are therefore not reliable. This undermines the efficiency of using highly sophisticated scientific techniques. Since there are a number of other countries in the Middle East - and elsewhere - in which these considerations also apply, this finding has important implications for international businesses which operate in these countries, whatever their home country