IFIH1 loss-of-function predisposes to inflammatory and SARS-CoV-2-related infectious diseases (preprint)

The IFIH1 gene, encoding melanoma differentiation-associated protein 5 (MDA5), is an indispensable innate immune regulator involved in the early detection of viral infections. Previous studies described MDA5 dysregulation linking it to weakened immunological responses, and increased susceptibility to microbial infections and autoimmune disorders. Monoallelic gain-of-function of the IFIH1 gene has been associated with multisystem disorders, namely Aicardi-Goutieres and Singleton-Merten syndromes, while biallelic loss of this gene causes immunodeficiency. In this study, nine patients suffering from different cases of recurrent infections, inflammatory diseases, severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C) were identified with putative loss-of-function IFIH1 variants by whole exome sequencing. All patients revealed signs of lymphopenia and an increase in inflammatory markers, including CRP, amyloid A, ferritin, and IL-6. One patient with a pathogenic homozygous variant c.2807+1G>A was the most severe case showing immunodeficiency and glomerulonephritis. The c.1641+1G>C variant was identified in the heterozygous state in patients suffering from periodic fever, COVID-19, or MIS-C, while the c.2016delA variant was identified in two patients with inflammatory bowel disease or MIS-C. Expression analysis showed that PBMCs of one patient with a c.2016delA variant had a significant decrease in ISG15, IFNA and IFNG transcript levels, compared to normal PBMCs, upon stimulation with poly(I:C), suggesting that MDA5 receptor truncation disrupts the immune response. Our findings accentuate the implication of rare monogenic IFIH1 loss-of-function variants in altering the immune response, and severely predisposing patients to inflammatory and infectious diseases, including SARS-CoV-2 related disorders.

Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients (preprint)

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 {+/-} SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediated and bacterial infection-susceptibility genes, when compared to control, mildly affected, or asymptomatic COVID-19 patients (N = 25), or to general populations representing Asia and the Middle East. Genetic variants tended to associate with mortality, intensive care admission, and ventilation support. Our findings confirm the association of interferon pathway genes with severe COVID-19 and highlight the importance of extending genetic studies to diverse populations given implications for pan-ethnic therapeutic and genetic screening options.

Investment certainty in ESG investing due to COVID-19: evidence from India

This article analyses the impact of COVID-19 on the volatility of ESG investing in India. Furthermore, it assesses the investment certainty in ESG related activities in India after detecting the first case of disease. A generalised autoregressive conditional heteroscedasticity model has been applied to the S&P BSE 100 ESG Index returns. The results show that after COVID-19, the risk related to the market price of the S&P BSE 100 ESG Index has increased, and the certainty of investment decreased. Further, the result of the GARCH (1, 1) model estimation indicates the presence of a large degree of persistency in the S&P BSE 100 ESG index. In addition, after reporting the first case of COVID-19, unconditional variance has been increased by 211.98%.

Genomic and phenotypic characterization of Multisystem Inflammatory Syndrome in Children (MIS-C): a prospective multicenter study from the Middle East (preprint)

Importance: Clinical, genetic and laboratory characteristics of patients with multisystem inflammatory syndrome in children (MISC) in the Middle East have not yet been documented. Objective: To uncover rare genetic variants contributing to MISC in patients of primarily Arab and Asian origin. Design, Setting, and Participants: A prospective multicenter cohort study was conducted between September 2020 and August 2021 in the United Arab Emirates and Jordan. Forty-five patients meeting the case definition of MISC, and a matched control group of twenty-five healthy children with a confirmed severe acute respiratory syndrome coronavirus 2 (SARSCoV2) infection status, were recruited. Whole Exome Sequencing (WES) in all 70 participants was performed to identify rare likely deleterious variants in patients with MISC and to correlate genetic findings with the clinical course of illness. Exposures: SARSCoV2. Main Outcomes and Measures: Fever, organ system complications, laboratory biomarkers, WES findings, treatments, and clinical outcomes. Mann Whitney U test was used to assess the association between genetic variations and MISC attributes. Fishers exact test was used to compute the genetic burden in MISC relative to controls. Results: In 45 MISC patients (23 boys [51.1%]; average age, 7 years [range, 2-14 years]), key inflammatory markers were significantly dysregulated in all patients. Mucocutaneous and gastrointestinal manifestations were reported in 80% (95% CI 66% to 89%) while cardiac and neurological findings were reported in 49% (95% CI 35% to 63%) and 31% (95% CI 19.5% to 45.6%) of patients, respectively. Rare, likely deleterious heterozygous variants in immune related genes including TLR3, TLR6, IFNAR2, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%, 95% CI 29% to 56.7%), of whom seven had more than one variant. There was significant enrichment of genetic variants in patients relative to the control group (29 versus 3, P

SARS-CoV-2 (COVID-19) pandemic: a critical review on novel coronavirus pathogenesis, clinical diagnosis and treatment

The 2019-nCoV is officially called SARS-CoV-2 and the disease is named COVID-19. The Novel coronavirus (SARS-CoV-2) caused pneumonia in Wuhan, China in December 2019 is a highly contagious disease. The World Health Organization (WHO) has declared it as a global public health emergency. This is the third serious Coronavirus outbreak in less than 20 years, following SARS in 2002-2003 and MERS in 2012. Currently, the research on novel coronavirus is still in the primary stage. It is currently believed that this deadly Coronavirus strain originated from wild animals at the Huanan market in Wuhan by Bats, snakes and pangolins have been cited as potential carriers. On the basis of current published evidence, we systematically summarize the epidemiology, clinical characteristics, diagnosis, treatment and prevention of COVID-19. This review in the hope of helping the public effectively recognize and deal with the novel coronavirus (SARS-CoV-2) and providing a reference for future studies.