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

Western Pacific international meeting and workshop on Toga Coare : proceedings

A major observational and research program is being undertaken in Darwin, Australia as part of the Tropical Ocean and Global Atmosphere (TOGA) and the National Aeronautics and Space Administration (NASA) Tropical Rainfall Measuring Mission (TRMM). Darwin is situated in northern Australia and experiences a monsoon environment typical of the maritime continent region, together with break and transition periods when continental systems are predominant. The Darwin initiative follows the recent Australian Monsoon Experiment (AMEX) and Equatorial Mesoscale Experiment (EMEX) and represents a continuing effort to gather data on the nature of convection in this strategic tropical location. (Résumé d'auteur

Time signatures of impulsively generated coronal fast wave trains

Impulsively generated short-period fast magneto-acoustic wave trains, guided by solar and stellar coronal loops, are numerically modelled. In the developed stage of the evolution, the wave trains have a characteristic quasi-periodic signature. The quasi-periodicity results from the geometrical dispersion of the guided fast modes, determined by the transverse profile of the loop. A typical feature of the signature is a tadpole wavelet Spectrum: a narrow-spectrum tail precedes a broad-band head. The instantaneous period of the oscillations in the wave train decreases gradually with time. The period and the spectral amplitude evolution are shown to be determined by the steepness of the transverse density profile and the density contrast ratio in the loop. The propagating wave trains recently discovered with the Solar Eclipse Coronal Imaging System (SECIS) instrument are noted to have similar wavelet spectral features, which strengthens the interpretation of SECIS results as guided fast wave trains

Adherence to a Mediterranean diet and cognitive function in the Age-Related Eye Disease Studies 1 & 2

Item does not contain fulltextINTRODUCTION: The objective was to determine whether closer adherence to the alternative Mediterranean Diet (aMED) was associated with altered cognitive function. METHODS: Observational analyses of participants (n = 7,756) enrolled in two randomized trials of nutritional supplements for age-related macular degeneration: Age-Related Eye Disease Study (AREDS) and AREDS2. RESULTS: Odds ratios for cognitive impairment, in aMED tertile 3 (vs 1), were 0.36 (P = .0001) for Modified Mini-Mental State (<80) and 0.56 (P = .001) for composite score in AREDS, and 0.56 for Telephone Interview Cognitive Status-Modified (<30) and 0.48 for composite score (each P < .0001) in AREDS2. Fish intake was associated with higher cognitive function. In AREDS2, rate of cognitive decline over 5 to 10 years was not significantly different by aMED but was significantly slower (P = .019) with higher fish intake. DISCUSSION: Closer Mediterranean diet adherence was associated with lower risk of cognitive impairment but not slower decline in cognitive function. Apolipoprotein E (APOE) haplotype did not influence these relationships

Adherence to the Mediterranean Diet and Progression to Late Age-Related Macular Degeneration in the Age-Related Eye Disease Studies 1 and 2

Item does not contain fulltextPURPOSE: To determine whether closer adherence to a Mediterranean diet (and its individual components) was associated with altered risk of progression to late age-related macular degeneration (AMD) and large drusen. Additional objectives were to assess interactions with AMD genotype. DESIGN: Retrospective analysis of 2 controlled clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS participants (n = 4255) and AREDS2 participants (n = 3611): total of 13n204 eyes (7756 participants). Mean age was 71 years (standard deviation, 6.6); 56.5% were female. METHODS: Color fundus photographs were collected at annual study visits and graded centrally for late AMD. The modified Alternative Mediterranean Diet Index (aMedi) score was calculated for each participant from food frequency questionnaires. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD; progression to large drusen. RESULTS: Over a median follow-up of 10.2 years, of the 13n204 eyes, 34.0% progressed to late AMD. Hazard ratios (HRs) for progression in aMedi tertile 3 versus 1 were 0.78 (95% confidence interval [CI], 0.71-0.85, P &lt; 0.0001) for late AMD, 0.71 (0.63-0.80, P &lt; 0.0001) for GA, and 0.84 (0.75-0.95, P = 0.005) for neovascular AMD. For fish consumption, HRs for late AMD in quartile 4 versus 1 were 0.69 (0.58-0.82, P &lt; 0.0001; AREDS) and 0.92 (0.78-1.07, P = 0.28; AREDS2). In AREDS, both aMedi and its fish component interacted with CFH rs10922109 for late AMD (P = 0.01 and P = 0.0005, respectively); higher aMedi and fish intake were each associated with decreased risk only in participants with protective alleles. In separate analyses (n = 5029 eyes of 3026 AREDS participants), the HR for progression to large drusen in aMedi tertile 3 versus 1 was 0.79 (0.68-0.93, P = 0.004). CONCLUSIONS: Closer adherence to a Mediterranean-type diet was associated with lower risk of progression to late AMD and to large drusen. The signal was greater for GA than neovascular AMD. Fish intake contributed to this protective association. CFH genotype strongly influenced these relationships. These findings may help inform evidence-based dietary recommendations

Natural History of Drusenoid Pigment Epithelial Detachment Associated with Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report No. 17

PURPOSE: To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). DESIGN: Retrospective analysis of a prospective cohort study. PARTICIPANTS: Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. METHODS: Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen >/=433 mum in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan-Meier analyses and multivariable proportional hazard regressions were performed. MAIN OUTCOME MEASURES: Progression rates to late AMD and decrease of >/=3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. RESULTS: Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98-2.82; P /=3 lines of VA loss (HR, 3.08; CI, 2.41-3.93; P < 0.001) with 46% of eyes experiencing vision loss at 5 years (with or without progression to late AMD). ARMS2 risk alleles (1 vs. 0: HR, 2.72, CI, 1.58-4.70; 2 vs. 0: HR, 3.16, CI, 1.60-6.21, P < 0.001) and increasing GRS group (4 vs. 1) (HR, 12.17, CI, 3.66-40.45, P < 0.001) were significantly associated with DPED development in AREDS. There were no significant genetic results in AREDS2. CONCLUSIONS: This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression

A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 x 10(-7)). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 x 10(-4)). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 x 10(-7)) and were more likely to have a first-degree relative with AMD (P = 5.38 x 10(-6)). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 x 10(-11) and P = 3.20 x 10(-9), respectively) and the center subfield (P = 1.24 x 10(-9) and P = 6.68 x 10(-8), respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 x 10(-6)). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD

Multimodal, multitask, multiattention (M3) deep learning detection of reticular pseudodrusen: Toward automated and accessible classification of age-related macular degeneration

OBJECTIVE: Reticular pseudodrusen (RPD), a key feature of age-related macular degeneration (AMD), are poorly detected by human experts on standard color fundus photography (CFP) and typically require advanced imaging modalities such as fundus autofluorescence (FAF). The objective was to develop and evaluate the performance of a novel multimodal, multitask, multiattention (M3) deep learning framework on RPD detection. MATERIALS AND METHODS: A deep learning framework (M3) was developed to detect RPD presence accurately using CFP alone, FAF alone, or both, employing >8000 CFP-FAF image pairs obtained prospectively (Age-Related Eye Disease Study 2). The M3 framework includes multimodal (detection from single or multiple image modalities), multitask (training different tasks simultaneously to improve generalizability), and multiattention (improving ensembled feature representation) operation. Performance on RPD detection was compared with state-of-the-art deep learning models and 13 ophthalmologists; performance on detection of 2 other AMD features (geographic atrophy and pigmentary abnormalities) was also evaluated. RESULTS: For RPD detection, M3 achieved an area under the receiver-operating characteristic curve (AUROC) of 0.832, 0.931, and 0.933 for CFP alone, FAF alone, and both, respectively. M3 performance on CFP was very substantially superior to human retinal specialists (median F1 score = 0.644 vs 0.350). External validation (the Rotterdam Study) demonstrated high accuracy on CFP alone (AUROC, 0.965). The M3 framework also accurately detected geographic atrophy and pigmentary abnormalities (AUROC, 0.909 and 0.912, respectively), demonstrating its generalizability. CONCLUSIONS: This study demonstrates the successful development, robust evaluation, and external validation of a novel deep learning framework that enables accessible, accurate, and automated AMD diagnosis and prognosis