Novel genes and sex differences in COVID-19 severity

[EN] Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.S

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Identidad étnica y conductas sociales en adolescentes indígenas Mapuche sancionados por la Ley de Responsabilidad Penal Adolescente en regiones del sur de Chile

We examined the relationship between ethnic identity and social behaviors in 60 indigenous juvenile offenders self-identified as mapuche. Ethnic identity is obtained with IEM scale, social behaviors with CACSA, self-reported and sentenced offenses with EDA and FER-R. The objective was to evaluate the association between the degree of ethnic identity development with presence of antisocial and prosocial behavior. The results indicate that ethnic identity development was related to lesser presence of antisocial behaviors, though no relationship between ethnic identity and prosocial behaviors. The possible relevance of ethnic identity as a protective factor in mapuche youth offenders in specific and in general to adolescents of other indigenous people, becoming a possible focus of intervention to dismiss these behaviors is discussed.Se analiza la relación entre identidad étnica y conductas sociales en 60 adolescentes indígenas infractores de ley autoidentificados como Mapuche. La identidad étnica se obtiene con la Escala IEM, conductas sociales con CACSA, delitos autoreportados con EDA y judicializados con Ficha FER-R. El objetivo fue evaluar la asociación entre grado de desarrollo de identidad étnica con presencia de conductas antisociales y prosociales. Los resultados indican que a mayor desarrollo de identidad étnica menor presencia de conductas antisociales, no observándose relación entre identidad étnica y conductas prosociales. Se discute la relevancia de la identidad étnica como factor protector específico en adolescentes infractores Mapuche y en adolescentes de otros pueblos indígenas en general, convirtiéndose en posible foco de intervención para desestimar estas conductas

Identidad étnica y conductas sociales en adolescentes indígenas Mapuche sancionados por la Ley de Responsabilidad Penal Adolescente en regiones del sur de Chile

We examined the relationship between ethnic identity and social behaviors in 60 indigenous juvenile offenders self-identified as mapuche. Ethnic identity is obtained with IEM scale, social behaviors with CACSA, self-reported and sentenced offenses with EDA and FER-R. The objective was to evaluate the association between the degree of ethnic identity development with presence of antisocial and prosocial behavior. The results indicate that ethnic identity development was related to lesser presence of antisocial behaviors, though no relationship between ethnic identity and prosocial behaviors. The possible relevance of ethnic identity as a protective factor in mapuche youth offenders in specific and in general to adolescents of other indigenous people, becoming a possible focus of intervention to dismiss these behaviors is discussed.Se analiza la relación entre identidad étnica y conductas sociales en 60 adolescentes indígenas infractores de ley autoidentificados como Mapuche. La identidad étnica se obtiene con la Escala IEM, conductas sociales con CACSA, delitos autoreportados con EDA y judicializados con Ficha FER-R. El objetivo fue evaluar la asociación entre grado de desarrollo de identidad étnica con presencia de conductas antisociales y prosociales. Los resultados indican que a mayor desarrollo de identidad étnica menor presencia de conductas antisociales, no observándose relación entre identidad étnica y conductas prosociales. Se discute la relevancia de la identidad étnica como factor protector específico en adolescentes infractores Mapuche y en adolescentes de otros pueblos indígenas en general, convirtiéndose en posible foco de intervención para desestimar estas conductas

Wear Dry Behavior of the Al-6061-Al2O3 Composite Synthesized by Mechanical Alloying

The present research deals with the comparative wear behavior of a mechanically milled Al-6061 alloy and the same alloy reinforced with 5 wt.% of Al2O3 nanoparticles (Al-6061-Al2O3) under different dry sliding conditions. For this purpose, an aluminum-silicon-based material was synthesized by high-energy mechanical alloying, cold consolidated, and sintered under pressureless and vacuum conditions. The mechanical behavior was evaluated by sliding wear and microhardness tests. The structural characterization was carried out by X-ray diffraction and scanning electron microscopy. Results showed a clear wear resistance improvement in the aluminum matrix composite (Al-6061-Al2O3) in comparison with the Al-6061 alloy since nanoparticles act as a third hard body against wear. This behavior is attributed to the significant increment in hardness on the reinforced material, whose strengthening mechanisms mainly lie in a nanometric size and homogeneous dispersion of particles offering an effective load transfer from the matrix to the reinforcement. Discussion of the wear performance was in terms of a protective thin film oxide formation, where protective behavior decreases as a function of the sliding speed

Novel genes and sex differences in COVID-19 severity.

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

International audienceLife-threatening ‘breakthrough’ cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population