RESUMO
BACKGROUND: Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear. METHODS: We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome. RESULTS: Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection. CONCLUSIONS: The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.
RESUMO
BACKGROUND: Ovarian reserve is the number of oocytes remaining in the ovary and is one of the most important aspects of a woman's reproductive potential. Research on the association between thyroid dysfunction and ovarian reserve has yielded controversial results. In our study, we aimed to investigate the relationship between thyroid-stimulating hormone (TSH) levels and ovarian reserve markers. METHODS: From 1443 women seeking infertility care, the data of 1396 women aged between 20-45 years old who had a body mass index between 18-30 kg/m2 were recruited for this retrospective study. The anti-Müllerian hormone (AMH) and TSH relationship was analyzed with generalized linear and polynomial regression. RESULTS: Median age, follicle-stimulating hormone (FSH), AMH, and TSH levels were 36.79 years, 9.55 IU/L, 3.57 pmol/L, and 1.80 mIU/L, respectively. Differences between TSH groups were statistically significant in terms of AMH level, antral follicle count (AFC), and age (p = 0.007 and p = 0.038, respectively). A generalized linear regression model could not explain age-matched TSH levels concerning AMH levels (p > 0.05). TSH levels were utilized in polynomial regression models of AMH, and the 2nd degree was found to have the best fit. The inflection point of the model was 2.88 mIU/L. CONCLUSIONS: Our study shows a correlation between TSH and AMH values in a population of infertile women. Our results are as follows: a TSH value of 2.88 mIU/L yields the highest AMH result. It was also found that AMH and AFC were positively correlated, while AMH and FSH were negatively correlated.
