MTOR gene variants are associated with severe COVID-19 outcomes: A multicenter study.

BACKGROUND: The worst outcomes linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been attributed to the cytokine storm, which contributes significantly to the immunopathogenesis of the disease. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. The individual genetic background might play a role in the exacerbated immune response. OBJECTIVE: In this study, we aimed to investigate the association between MTOR genetic variants and COVID-19 outcomes. METHODS: This study enrolled groups of individuals with severe (n = 285) and mild (n = 207) COVID-19 from Brazilian states. The MTOR variants, rs1057079 and rs2536, were genotyped. A logistic regression analysis and Kaplan-Meier survival curves were performed. We applied a genotyping risk score to estimate the cumulative contribution of the risk alleles. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were also measured. RESULTS: The T allele of the MTOR rs1057079 variant was associated with a higher likelihood of developing the most severe form of COVID-19. In addition, higher levels of IL-6 and COVID-19 death was linked to the T allele of the rs2536 variant. These variants exhibited a cumulative risk when inherited collectively. CONCLUSIONS: These results show a potential pathogenetic role of MTOR gene variants and may be useful for predicting severe outcomes following COVID-19 infection, resulting in a more effective allocation of health resources.

Nuclear score evaluation in follicular-patterned thyroid lesions using optical and digital environments.

INTRODUCTION: The subjective evaluation of nuclear features in follicular-patterned lesions of the thyroid is a reason for diagnosis discordance. The assessment of nuclear features also varies whether the observation is performed optically or digitally. Our objective was to study the concordance among pathologists regarding the nuclear score (NS) evaluation in a series of follicular-patterned lesions, using optical versus three digital scanning protocols. METHODS: Three pathologists evaluated the NS in a 3mm2 area randomly selected from 20 hematoxylin-eosin slides representative of the respective 20 follicular-patterned thyroid lesions. The NS evaluation was performed using optical and three different scanning protocols in two scanners: P1000_20x, P1000_40x and DP200_20x. Kappa statistic (κ) and intraclass correlation coefficient (ICC) were obtained for intra- and interpathologist concordance. RESULTS: We recorded a good agreement among pathologists in the optical evaluation of the NS (ICC of 0.73). The concordance between optical versus digital observation had an almost perfect agreement for P1000_20x [κ = 0.85 (0.67-1.02); p < 0.0001] and a substantial agreement for both P1000_40x [κ = 0.69 (0.43-0.95) p = 0.002] and DP200_20x [κ = 0.77 (0.57-0.97); p = 0.001]. The P1000_20x protocol had the best intrapathologist concordance with the optical method, classified as almost perfect agreement for pathologists A (80%) and B (85%), and substantial agreement for pathologist C (70%). CONCLUSION: Digital observation of the WSI is valid for the NS evaluation in follicular-patterned thyroid lesions, with good agreement among pathologists and between optical and scanning protocols. Performance studies and validation procedures cannot be avoided in this setting to prevent diagnostic discordance due to the scanning process.

Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19.

CONTEXT: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. OBJECTIVE: Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. METHODS: Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. RESULTS: In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 subgroups: Thr/Thr (n = 79), Thr/Ala (n = 119), and Ala/Ala (n = 23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. CONCLUSION: Here we provide evidence for a protective role played by Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.