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

Patiromer

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The April 2016 monograph topics are von Willebrand factor (recombinant), daratumumab, elotuzumab, uridine triacetate, and ixazomib. The MUE is on lesinurad

Tree regeneration and future dynamics of the laurel forest on Tenerife, Canary Islands

We studied two sites in the laurel forest of Tenerifeto predict future changes in canopy composition. We used twoprojection methods: Horn’s ‘Markovian Projection’, whichutilizes information on juveniles in the vicinity of canopytrees, and a ‘Stand Projection’, which ignores such informa-tion. We performed these projections both including and ex-cluding a-sexual regeneration. Although all of our projectionspredict a change in species composition, inclusion of a-sexualreproduction decreased the magnitude of successional change.The persistence of Prunus lusitanica and Ilex canariensisappears to be highly dependent on a-sexual regeneration.Both the Markov- and stand projections predict a slightconvergence in species composition between the two siteswhen only sexual regeneration is considered, and also a higherdominance of the shade-tolerant species Laurus azorica. Whena-sexual regeneration is also considered, some divergence isshown, with less projected change in the stand projection thanin the Markov projection. In spite of some differences betweenthe models, general patterns such as an increase of shade-tolerant species (Laurus azorica and Prunus lusitanica) and adecrease of shade-intolerant species (Erica arborea, Ericascoparia and Myrica faya) are consistent