Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Reflexions Critiques sur la Poesie et sur la Peinture : Vt. Pictura Poesis ...

Todas as edicións, que foron moi frecuentes ata 1733, son anónima

Kritische Betrachtungen über die Poesie und Mahlerey

aus dem Französischen des Herrn Abtes Dü Bos, Eines der Vierziger und beständigen Secretärs der französischen AkademieVorlageform der Veröffentlichungsangabe: Kopenhagen, In der Mummischen Buchhandlun

Réflexions critiques sur la poësie et sur la peinture

Par M. L'Abbé Du Bo

Histoire critique de l'établissement de la Monarchie française dans les Gaules

Port. a dúas tintas: vermella e negr

Les interests de l'Angleterre mal-entendus dans la presente guerre : traduits du livre Anglois intitule, Englands interest mestaken en the present Vvar.

Encabezamiento tomado de B.N. Paris, XLIISign.: *\p4\s, A\p8\s, B\p4\s, C\p8\s, D\p4\s, E\p8\s, F\p4\s, G\p8\s, H\p4\s, I\p8\s, K\p4\s, L\p8\s, M\p4\s, N\p8\s, O\p4\s, P\p8\s, Q\p4\s, R\p8\s, S\p4\s, T\p8\s, V\p4\s, X\p8\s, Y\p4\s, Z\p8\s, 2A\p8\s, 2B\p4\sPort. con grab. xi

Critical reflections on poetry, painting, and music : [with an inquiry into the rise and progress of the theatrical entertainments of the ancients /

Reprint of the 1748 5th ed. rev., cor. and enl. printed for J. Nourse, London.Vol. 2 has title: Critical reflections on poetry and painting.Mode of access: Internet

Histoire critique de l'establissement de la monarchie françoise dans les gaules

Mención de edición precede a mención de parte.Sign.: []\p2\s, *\p2\s, A-Y\p12\s , Z\p4\s, 2A\p2\s.Portada a dos tintas con viñeta xilográfica.Anteportada.Capitales ornadas, cabeceras, viñetas y remates xilográficos.Apostillas marginales