Evidence of causal effect of major depression on alcohol dependence: findings from the psychiatric genomics consortium

BACKGROUND Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC. METHODS Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals). RESULTS Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation. CONCLUSION This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Enhanced extraction of rare earth elements by novel tuned diglycolamides

International audienceRare earth elements (REE) are essential for our modern economy, in relation to the development of new energy and communication technologies, however their recycling from electronic waste and end-of-life products (such as permanent NdFeB magnets, Ni-MH batteries, etc.) is still not sufficiently developped.1 Although substitution of these materials by less critical ones is growing faster and faster especially in Japan efficient and eco-designed recycling processes will be of great importance in a near middle term. Depending on their technoeconomics efficiency and environmental footprint, hydrometallurgical processes enabling the recovery of separated elements could be of particular interest.Typically these processes include a first pretreatment (crushing, milling, sieving,) followed by an acidic leaching step (with possibly selective precipitation substeps) and a solvent extraction step (SX) in order to separate and purify the REE.2 Recently, diglycolamides (DGAs) appeared as a very interesting group of extractants for the recovery of trivalent lanthanides from nitric acid solutions, particularly in the presence of metal ions commonly found in waste products.3 The TODGA extractant (N,N,N',N'-tetraoctyl diglycolamide) was successfully used for designing a full REE recycling SX process from used permanent magnets.4 Nevertheless its performances have not yet been validated against upscaling tests.Most works concerning the group of DGAs dealt with symmetrical extractants exhibiting different separation efficiencies for REE in nitric acid media. The chain length modification on one side of the DGA (asymmetrical DGAs) can lead to important variation in selectivity during the Eu/Am separation.5 Recently, new dissymmetrical DGAs with very short chains were reported for REE extraction, such as for instance MODGA (N,N'-dimethyl-N,N'dioctyl-diglycolamide),6 however their solubility in industrial diluents is rather limited.The present work describes the organic synthesis of several novel DGAs and their solvent extraction behaviour towards REE in several aqueous acid media which could increase the industrial interest of such SX process. These new ligands displayed a remarkable improvement of REE extraction efficiency compared to reference TODGA in acid media, while presenting a good solubility in industrial aliphatic diluents. Furthermore, the separation factors of REE towards major impurities such as Fe3+ are substantially improved. Figure Distribution ratio of a novel DGA compared to TODGA in an acid solutionNevertheless it will be of primary importance to check whether the REE can be quantitatively de-extracted from the organic phase without any impurity. These promising results will also contribute to the design of an optimized SX process for the separation of REE

Developpement d'un procede pour la separation de l'Americium a partir d'un raffinat PUREX par extraction liquide-liquide

National audienc

Development of a selective americium separation process using TPAEN as a water-soluble stripping agent

International audienceRecycling americium from spent fuels is an important option considered for the future nuclear fuel cycle as americium is the main contributor to the long-term radiotoxicity and heat power of the ultimate waste. The separation of americium alone from a PUREX raffinate can be achieved by co-extracting lanthanide (Ln) and actinide(III) cations in an organic phase containing TODGA diglycolamide extractant, and then strip Am(III) with selectivity towards curium and lanthanides (by analogy with the i-SANEX process for example). The water soluble ligand TPAEN (N,N,N',N'-tetrakis[(6-carboxypyridin-2-yl)methyl]-ethylenediamine) was tested to selectively strip Am from a loaded organic phase. Used in combination with TODGA in the organic phase, TPAEN shows a quite high Cm/Am selectivity (SFCm/Am = 4 at 0.1M HNO3), which allows to selectively strip Am while Cm and Ln remain extracted in the organic phase. The molecule can be used at pH 1 without addition of nitrate salts.Additional batch data were acquired to evaluate the best conditions to develop a liquid-liquid separation flowsheet with this promising TODGA/TPAEN separation system. It was observed that with macro concentrations of lanthanides, an increase of the TPAEN concentration leads to higher Cm/Am selectivity (SFCm/Am up to 5 were measured). It was also demonstrated that TPAEN has a strong complexing capacity allowing the back extraction of Am in macro concentration (1 2 mM) even with low ligand concentrations (around 1.5 equivalent of ligand is enough). TPAEN has a higher affinity for light lanthanides and the selectivity between La and Am might become low depending on the experimental conditions. The influence of parameters such as temperature, pH, ligand and cations concentrations was studied. Kinetics experiments in batch contactors (centrifuges or mixer settlers) were also performed to characterize times necessary to reach equilibrium. This set of experimental work data allowed the elaboration of a thermodynamical model which was implemented in the PAREX simulation code in order propose a flowsheet. The feasibility of this process will be evaluated during spiked tests in centrifugal contactors starting from a surrogate PUREX raffinate spiked with traces amounts of Am and Cm. A final hot test will finally be performed at ITU from a genuine PUREX raffinate.This work is the result of collaborations in the framework of the SACSESS European Project

CMOS-compatible integrated optical hyper-parametric oscillator

Integrated multiple-wavelength laser sources, critical for important applications such as high-precision broadband sensing and spectroscopy, molecular fingerprinting, optical clocks and attosecond physics, have recently been demonstrated in silica and single-crystal microtoroid resonators using parametric gain. However, for applications in telecommunications and optical interconnects, analogous devices compatible with a fully integrated platform do not yet exist. Here, we report a fully integrated, CMOS-compatible, multiple-wavelength source. We achieve optical hyper-parametric oscillation in a high-index silica-glass microring resonator with a differential slope efficiency above threshold of 7.4% for a single oscillating mode, a continuous-wave threshold power as low as 54mW, and a controllable range of frequency spacing from 200GHz to more than 6THz. The low loss, design flexibility and CMOS compatibility of this device will enable the creation of multiple-wavelength sources for telecommunications, computing, sensing, metrology and other areas