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

Motivations for organic farming in tourist regions: a case study in Nepal

An increasing number of individuals and businesses involved in the tourism industry have begun activities related to organic farming and organic agro-products not only in Europe and North America but also in developing countries in Asia. Both organic farming and rural tourism are considered important to socially and economically sustainable rural development. The influences on the establishment of or conversion to organic farming have been much discussed in Europe but not in developing countries. This study focuses on Nepal, where small-scale organic farming occurs in tourism areas, and qualitatively reveals the motivations for organic farming and other factors related to its adoption. It was found that the reasons for introducing organic farming practices varied with the timing of their adoption. Additionally, the kinds of organic-related activities adopted varied depending on how the individual adopter first encountered the term "organic farming." However, all individuals involved in organic farming shared some common motivations, such as desires for personal health, quality produce and rural development

Patrimoine et développement durable dans les villes historiques du Maghreb

Le problematiche e le "sfide" della salvaguardia e rivitalizzazione delle città storiche del Maghreb: il quadro istituzionale, il governo lacale e le strategie d'inytervento; i criteri e gli strumenti della salvaguardia; la dimensione sociale; la dimensione economica. Casi studio maghrebini ed europei