Developmental changes in word recognition threshold from two to five years of age in children with different middle ear status

The aims were to: (1) provide word recognition thresholds (WRTs) at 31, 43, and 61 months of age; (2) investigate developmental changes over time; (3) investigate the relationship between OME and WRT, and (4) investigate the relationship between WRT and hearing thresholds. Around 1000 children were tested longitudinally as part of the ALSPAC study, using an adaptive measure of word recognition in quiet. Mean WRTs were 28, 23, and 23 dB (A) at 31, 43, and 61 months, respectively. Normal auditory development is associated with a mean improvement in WRT of 5 dB between age 31 and 61 months. There was a mean increase in WRT of 5 dB and 15 dB when OME was present in one and two ears, respectively. Thus, both unilateral and bilateral OME results in a detrimental effect on hearing ability for speech. Additionally, early and ‘persistent’ OME is associated with greater disability. However by 61 months, previous OME status was not significant. To our knowledge, this is the largest longitudinal study reporting WRT in preschool children with different middle ear status

Alcohol use and cognitive functioning in young adults : improving causal inference

Background and Aims: There have been few longitudinal studies of association between alcohol use and cognitive functioning in young people. We aimed to examine whether alcohol use is a causal risk factor for deficient cognitive functioning in young adults. Design: Linear regression was used to examine the relationship between longitudinal latent class patterns of binge drinking and subsequent cognitive functioning. Two-sample Mendelian randomisation (MR) tested evidence for the causal relationship between alcohol use and cognitive functioning. Setting: South West England. Participants: The observational study included 3,155 adolescents and their parents (fully adjusted models) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Genetic instruments for alcohol use were based on almost 1,000,000 individuals from the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN). Genome-wide association studies for cognitive outcomes were based on 2,500 individuals from ALSPAC. Measurements: Binge drinking was assessed at approximately 16, 17, 18, 21, and 23 years. Cognitive functioning comprised working memory, response inhibition, and emotion recognition assessed at 24 years of age. Ninety-nine independent genome-wide significant SNPs associated with ‘number of drinks per week’ were used as the genetic instrument for alcohol consumption. Potential confounders were included in the observational analyses. Findings: Four binge drinking classes were identified: ‘low-risk’ (41%), ‘early-onset monthly’ (19%), ‘adult frequent’ (23%), and ‘early-onset frequent’ (17%). The association between early-onset frequent binge drinking and cognitive functioning: working memory (b=0.09, 95%CI=-0.10 to 0.28), response inhibition (b=0.70, 95%CI=-10.55 to 11.95), and emotion recognition (b=0.01, 95%CI=-0.01 to 0.02) in comparison to low-risk drinkers were inconclusive as to whether a difference was present. Two-sample MR analyses similarly provided little evidence that alcohol use is associated with deficits in working memory using the inverse variance weight (b=0.29, 95%CI=-0.42 to 0.99), response inhibition (b=-0.32, 95%CI=-1.04 to 0.39), and emotion recognition (b=0.03, 95%CI=-0.55 to 0.61). Conclusions: Binge drinking in adolescence and early adulthood may not be causally related to deficiencies in working memory, response inhibition, or emotion recognition in youths

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