12 research outputs found

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    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

    Facial Soft Tissue Dynamics before and after Primary Lip Repair

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    OBJECTIVES: (1) To collect three-dimensional, dynamic facial images from two groups of infants: one group born with cleft lip and palate slated to have a primary lip repair and a second, age-matched, noncleft control group. (2) To develop analyses to determine differences in facial movement between infants with cleft lip and/or palate and noncleft control infants and to determine changes in facial movement before and after primary lip repair. DESIGN: Longitudinal, prospective case-control study. SETTING: Facial Animation Laboratory at the University of North Carolina School of Dentistry. PARTICIPANTS: Two groups of infants: one group with unrepaired cleft lip and/or palate slated to have primary lip repair (n = 15) and a second group of age-matched, noncleft controls (n = 15). INTERVENTIONS: Movement testing before and 4 months after primary lip repair in infants with cleft lip and/or palate and at similar time points in noncleft infants. MAIN OUTCOME MEASURES: Seven measures of facial movement. RESULTS: The range of facial movements increased by 17% for all infants during the 4-month period. Compared with the noncleft group (1) infants with unilateral cleft lip and/or palate had 50% less nasolabial movement, and this difference did not change due to the lip repair; and (2) infants with unilateral or bilateral cleft lip and/or palate had 58% and 118% greater lateral upper lip movement, respectively, and 3.67 and 3.56 times greater asymmetry of movement, respectively, before lip repair. The procedure almost entirely removed these problems. CONCLUSIONS: Primary surgical lip repair decreased hypermobility and improved asymmetry of upper lip movement

    Getting Started in Your Academic Career

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