Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and 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. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Low viscosity ionic liquids based on organic salts of the dicyanamide anion

New families of salts viz. quaternary ammonium, N-alkyl-N-methylpyrrolidinium or 1-alkyl-3-methylimidazolium dicyanamides, Cat+N(CN)2&minus;, are low melting compounds, most being liquid at rt, water-miscible and have low (for ionic liquids) viscosity at rt, e.g.&eta; = 21 cP for 1-ethyl-3-methylimidazolium dicyanamide.<br /

Physical trends and structural features in organic salts of the thiocyanate anion

A new series of ionic liquids based on the thiocyanate anion has been prepared. Incorporation of this anion with an imidazolium, tetraalkylammonium or pyrrolidinium cation produces ionic liquids with advantageously low melting points and good thermal stability. The low temperature phase behaviour of the salts has been investigated using differential scanning calorimetry and multiple solid phases have been observed. The electrochemical windows of representative imidazolium and pyrrolidinium species have been investigated by cyclic voltammetry and determined to be 2.4 and 3.5 V, respectively. In addition, the solid-state structure of N,N-dimethylpyrrolidinium thiocyanate has been determined by X-ray crystallography. This is the first reported structure of a pyrrolidinium thiocyanate species and shows a layered structure with linear thiocyanate groups having bond lengths comparable to those observed in similar SCN&minus;-containing species.<br /

Teenage Children of Teenage Mothers: Psychological, Behavioural and Health Outcomes from an Australian Prospective Longitudinal Study

In many industrialised countries teenage pregnancy and teenage parenthood have in recent years been identified as social and public health problems that need to be tackled. A number of studies have looked at various outcomes for teenage mothers and their offspring, and many report a strong association with poverty for the mother both before and after having a child. Few studies, however, adequately control for socioeconomic circumstances when examining health and related outcomes. Most studies have focused on perinatal outcomes in the offspring with few looking at later health and development. In Australia, where the rate of teenage pregnancy is relatively high compared to other comparable countries, teenage pregnancy is a not prominent policy concern. As such, Australia offers the opportunity to study the outcomes of teenage parenthood in a country where there may be less stigma than in countries that portray teenage parenthood as a major health and/or social problem. This paper reports findings from the Mater-University Study of Pregnancy (MUSP) and its outcomes, a prospective study of women, and their offspring, who received antenatal care at a major public hospital (Mater Misericordiae Hospital) in South Brisbane, Australia, between 1981 and 1984. We have examined the associations of maternal age ( 18 years (n = 4800)) at first antenatal visit with offspring psychological, behavioural and health characteristics when the offspring the teenage children of teenage mothers were aged 14 years. Multiple logistic regression was used to determine the effect of maternal and family characteristics on associations between maternal age and childhood outcomes at age 14. Results show that the 14 year old offspring of mothers who were aged 18 years and younger compared to those who were offspring of older mothers were more likely to have disturbed psychological behaviour, poorer school performance, poorer reading ability, were more likely to have been in contact with the criminal justice system and were more likely to smoke regularly and to consume alcohol. However, maternal age was not associated with health outcomes in their offspring at age 14 years. Indicators of low socioeconomic position and maternal depression were also associated with poorer psychological, cognitive and behavioural outcomes among 14 year olds. In addition children from poorer socioeconomic backgrounds and whose mothers were depressed were more likely to have self- reported poor health, asthma, to have been admitted to hospital twice or more since birth and to be bed-wetters at age 14. The associations between maternal age and psychological distress, school performance, and smoking and alcohol use were all largely explained by socioeconomic factors, maternal depression, family structure and maternal smoking. These findings confirm that not all teenage mothers and their offspring have adverse outcomes, and that many if not the majority have good outcomes

Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counter-intuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfv\'en waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, $\alpha=2$ as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed $>$600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: pre-flare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that $\alpha = 1.63 \pm 0.03$. This is below the critical threshold, suggesting that Alfv\'en waves are an important driver of coronal heating.Comment: 1,002 authors, 14 pages, 4 figures, 3 tables, published by The Astrophysical Journal on 2023-05-09, volume 948, page 7