Clinical Use of Aided Cortical Auditory Evoked Potentials as a Measure of Physiological Detection or Physiological Discrimination

The clinical usefulness of aided cortical auditory evoked potentials (CAEPs) remains unclear despite several decades of research. One major contributor to this ambiguity is the wide range of variability across published studies and across individuals within a given study; some results demonstrate expected amplification effects, while others demonstrate limited or no amplification effects. Recent evidence indicates that some of the variability in amplification effects may be explained by distinguishing between experiments that focused on physiological detection of a stimulus versus those that differentiate responses to two audible signals, or physiological discrimination. Herein, we ask if either of these approaches is clinically feasible given the inherent challenges with aided CAEPs. N1 and P2 waves were elicited from 12 noise-masked normal-hearing individuals using hearing-aid-processed 1000-Hz pure tones. Stimulus levels were varied to study the effect of hearing-aid-signal/hearing-aid-noise audibility relative to the noise-masked thresholds. Results demonstrate that clinical use of aided CAEPs may be justified when determining whether audible stimuli are physiologically detectable relative to inaudible signals. However, differentiating aided CAEPs elicited from two suprathreshold stimuli (i.e., physiological discrimination) is problematic and should not be used for clinical decision making until a better understanding of the interaction between hearing-aid-processed stimuli and CAEPs can be established

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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 hospitalization2–4 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

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

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

Cortical Entrainment to Speech: Effects of Attention, Intelligibility, and Regularity

A neural response can be recorded from the scalp that follows ongoing fluctuations in speech energy. This response has been labelled cortical “entrainment”, and while a number of theoretical proposals have been offered regarding the functional role of cortical entrainment in speech perception, the degree to which cortical entrainment reflects peripheral vs. central representations of speech, and acoustic vs. linguistic processes remains unclear. First, we show that the entrainment response reflects differential attentional weights applied across auditory frequency channels, suggesting the entrainment response follows fluctuations in speech within peripheral frequency channels. Second, we show that the strength of the entrainment response to natural fluctuations in speech energy does not depend on whether or not the speech is intelligible, suggesting that the response reflects primarily acoustic rather than linguistic processes. Third, we show that with unnaturally periodic speech stimuli, an entrainment response follows changes in hierarchically-organized levels of linguistic information, independent of acoustic energy, suggesting that under certain conditions, the entrainment response reflects linguistic processes. However, we observe the same entrainment response to hierarchically-organized levels of musical information, suggesting that the cortical processes underlying this entrainment response are not necessarily specific to speech. Together, these results suggest that cortical entrainment can reflect both peripheral and central processes, and that these processes may not be unique to speech