Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Macrosocial determinants of population health in the context of globalization

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55738/1/florey_globalization_2007.pd

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

Impaired pulmonary status in cystic fibrosis adults with two mutated MBL-2 alleles

Mannose-binding lectin has recently been identified as a modifier of severity in cystic fibrosis, although studies have produced differing results and the mechanism of action remains unclear. The current authors have studied large cohorts of adults (n=298) and children (n=260) to explore this apparent relationship further. Adults with two structural mutations, but not heterozygotes, had significantly reduced lung function and oxygen saturations, more frequent hospital admissions and raised systemic inflammatory markers. This was not related to increased rates of infection with Pseudomonas aeruginosa, and there was no increased susceptibility to Burkholderia cepacia. None of these findings was mirrored in the paediatric cohort. In conclusion, severe mannose-binding lectin deficiency appears to be detrimental to cystic fibrosis adults, although heterozygotes are not affected. It is suggested that this is not related to impaired complement-mediated bacterial killing, and a link with the host inflammatory response is hypothesised. If mannose-binding lectin replacement is developed as a new approach to treatment for this disease, the present study would suggest that the small group of severely deficient patients with two structural mutations may be the group to benefit

Impaired pulmonary status in cystic fibrosis adults with two mutated MBL-2 alleles

Mannose-binding lectin has recently been identified as a modifier of severity in cystic fibrosis, although studies have produced differing results and the mechanism of action remains unclear. The current authors have studied large cohorts of adults (n=298) and children (n=260) to explore this apparent relationship further. Adults with two structural mutations, but not heterozygotes, had significantly reduced lung function and oxygen saturations, more frequent hospital admissions and raised systemic inflammatory markers. This was not related to increased rates of infection with Pseudomonas aeruginosa, and there was no increased susceptibility to Burkholderia cepacia. None of these findings was mirrored in the paediatric cohort. In conclusion, severe mannose-binding lectin deficiency appears to be detrimental to cystic fibrosis adults, although heterozygotes are not affected. It is suggested that this is not related to impaired complement-mediated bacterial killing, and a link with the host inflammatory response is hypothesised. If mannose-binding lectin replacement is developed as a new approach to treatment for this disease, the present study would suggest that the small group of severely deficient patients with two structural mutations may be the group to benefit