CYP19A1 mediates severe SARS-CoV-2 disease outcome in males.

Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment.

Sustained weight loss with semaglutide once weekly in patients without type 2 diabetes and post-bariatric treatment failure.

About 20%-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) following bariatric surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with semaglutide in patients without type 2 diabetes (T2D) with post-bariatric treatment failure over a 12 months period. Post-bariatric patients without T2D with WR or IWL (n = 29) were included in the analysis. The primary endpoint was weight loss 12 months after initiation of adjunct treatment. Secondary endpoints included change in body mass index, HbA1c, lipid profile, high sensitive C-reactive protein and liver enzymes. Total weight loss during semaglutide treatment added up to 14.7% ± 8.9% (mean ± SD, p < .001) after 12 months. Categorical weight loss was >5% in 89.7% of patients, >10% in 62.1% of patients, >15% in 34.5% of patients, >20% in 24.1% of patients and > 25% in 17.2% of patients. Adjunct treatment with semaglutide resulted in sustained weight loss regardless of sex, WR or IWL and type of surgery. Among patients with prediabetes (n = 6), 12 months treatment led to normoglycemia in all patients (p < .05). Treatment options to manage post-bariatric treatment failure are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients over a 12 months follow-up period.

Low-Grade Hepatic Steatosis Is Associated with Long-term Remission of Type 2 Diabetes Independent of Type of Bariatric-Metabolic Surgery.

BACKGROUND: Bariatric-metabolic surgery (BS) decreases the grade of steatosis, hepatic inflammation, and fibrosis in patients with severe obesity and non-alcoholic fatty liver disease (NAFLD). Mechanisms include substantial weight loss, but also simultaneous effects on glucose homeostasis. Therefore, we aimed to investigate the association between NAFLD and remission of type 2 diabetes (T2D) up to 8 years following different types of BS. METHODS: In a retrospective cohort study including 107 patients with obesity and T2D at baseline, the association between biopsy-proven NAFLD defined as steatosis in > 5% of hepatocytes at the time of surgery and T2D remission up to 8 years following different surgical procedures was investigated. Univariate regression analysis was used to examine the association between NAFLD and remission of T2D. RESULTS: Long-term remission of T2D was present in 56% of patients (n = 60). The presence of low-grade liver steatosis (grade 1) was associated with remission of T2D. Patients with a liver steatosis score ≥ 2 showed higher HbA1c levels at baseline. There were no significant differences in preoperative presence of lobular inflammation, hepatocyte ballooning, or fibrosis between patients who achieved T2D remission compared with those with no remission. Type of surgery did not affect remission of T2D. CONCLUSION: Our results suggest that the presence of low-grade liver steatosis is associated with remission of T2D following sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). Therefore, BS should be considered at an early NAFLD stage in patients with T2D.

The Potential of Semaglutide Once-Weekly in Patients Without Type 2 Diabetes with Weight Regain or Insufficient Weight Loss After Bariatric Surgery-a Retrospective Analysis.

PURPOSE: About 20-25% of patients experience weight regain (WR) or insufficient weight loss (IWL) after bariatric metabolic surgery (BS). Therefore, we aimed to retrospectively assess the effectiveness of adjunct treatment with the GLP-1 receptor agonist semaglutide in non-diabetic patients with WR or IWL after BS. MATERIALS AND METHODS: Post-bariatric patients without type 2 diabetes (T2D) with WR or IWL (n = 44) were included in the analysis. The primary endpoint was weight loss 3 and 6 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP, and liver enzymes. RESULTS: Patients started semaglutide 64.7 ± 47.6 months (mean ± SD) after BS. At initiation of semaglutide, WR after post-bariatric weight nadir was 12.3 ± 14.4% (mean ± SD). Total weight loss during semaglutide treatment was - 6.0 ± 4.3% (mean ± SD, p < 0.001) after 3 months (3.2 months, IQR 3.0-3.5, n = 38) and - 10.3 ± 5.5% (mean ± SD, p < 0.001) after 6 months (5.8 months, IQR 5.8-6.4, n = 20). At 3 months, categorical weight loss was > 5% in 61% of patients, > 10% in 16% of patients, and > 15% in 2% of patients. Triglycerides (OR = 0.99; p < 0.05), ALT (OR = 0.87; p = 0.05), and AST (OR = 0.89; p < 0.05) at baseline were negatively associated with weight loss of at least 5% at 3 months' follow-up (p < 0.05). CONCLUSION: Treatment options to manage post-bariatric excess weight (regain) are scarce. Our results imply a clear benefit of adjunct treatment with semaglutide in post-bariatric patients. However, these results need to be confirmed in a prospective randomized controlled trial to close the gap between lifestyle intervention and revision surgery in patients with IWL or WR after BS.

NET Release of Long-Term Surviving Neutrophils.

BACKGROUND: Neutrophil extracellular traps (NETs)-as double-edged swords of innate immunity-are involved in numerous processes such as infection, inflammation and tissue repair. Research on neutrophil granulocytes is limited because of their short lifetime of only a few hours. Several attempts have been made to prolong the half-life of neutrophils using cytokines and bacterial products and have shown promising results. These long-term surviving neutrophils are reported to maintain phagocytic activity and cytokine release; however, little is known regarding their capability to release NETs. METHODS: We analysed the prolongation of neutrophil survival in vitro under various culture conditions using granulocyte colony-stimulating factor (G-CSF), lipopolysaccharide (LPS) or tumour necrosis factor alpha (TNF-α) by flow cytometry and a viability assay. Additionally, we assessed NET formation following stimulation with phorbol 12-myristate 13-acetate (PMA) by immunofluorescence staining, myeloperoxidase (MPO)-DNA sandwich-ELISA and fluorometric assays for cell-free DNA (cfDNA), neutrophil elastase (NE) and myeloperoxidase (MPO). RESULTS: Untreated neutrophils could form NETs after stimulation with PMA for up to 24 h. Incubation with LPS extended their ability to form NETs for up to 48 h. At 48 h, NET release of neutrophils cultured with LPS was significantly higher compared to that of untreated cells; however, no significantly different enzymatic activity of NE and MPO was observed. Similarly, incubation with G-CSF resulted in significantly higher NET release at 48 h compared to untreated cells. Furthermore, NETs showed significantly higher enzymatic activity of NE and MPO after incubation with G-CSF. Lastly, incubation with TNF-α had no influence on NET release compared to untreated cells although survival counts were altered by TNF-α. CONCLUSIONS: G-CSF, LPS or TNF-α each at low concentrations lead to prolonged survival of cultured neutrophils, resulting in considerable differences in NET formation and composition. These results provide new information for the use of neutrophils in long-term experiments for NET formation and provide novel insights for neutrophil behaviour under inflammatory conditions.

Thyroid-stimulating hormone levels in euthyroid patients 8 years following bariatric surgery.

BACKGROUND: Bariatric surgery (BS) was shown to promote a decline in thyroid-stimulating hormone (TSH) in euthyroid patients with severe obesity in the short-term. Aim of the present study was to assess the effect of weight loss on thyroid function in euthyroid patients in the long-term following different bariatric procedures. METHODS: In a retrospective cohort study including 135 patients at baseline, thyroid function was assessed at six time points up to 8 years after surgery. Patients were stratified by TSH levels at baseline and divided into two groups to compare the change in TSH at long-time. We used log-linear regression to assess the relation between thyroid hormones and TSH and linear regression analyses to identify variables that were thought to determine TSH and fT3/fT4-ratio as well as their change long-term. RESULTS: Over a mean follow-up of 8 years, TSH and fT3/fT4-ratio declined (both p < 0.001). Patients with high-normal TSH showed a greater decline in TSH than those with normal TSH compared to baseline. Thyroid hormones and TSH displayed a negative log-linear correlation at long-term follow-up. Change in TSH at long-time showed a negative correlation with TSH at baseline (B = -0.55; p < 0.001). With regard to type of surgery, there were no significant differences in TSH. CONCLUSION: BS promotes a decline of TSH in euthyroid patients up to 8 years after intervention despite weight regain. The greatest change in TSH was seen among patients with high-normal baseline-TSH. Results of log-linear regression suggest recovery of the pituitary-thyroid axis. Type of surgery did not affect the change in TSH levels over time.

High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study.

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.

Long-Term Improvement of Chronic Low-Grade Inflammation After Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) was shown to improve inflammatory markers in previous short-term follow-up studies. The aim of the present study was to assess the long-term effects of BS on chronic low-grade inflammation markers related to severe obesity. Moreover, the meaning of the type of BS procedure as well as the remission of type 2 diabetes (T2D) for inflammatory status up to 4 years after BS was analyzed. MATERIALS AND METHODS: In a retrospective cohort study including 163 patients at baseline, inflammatory and metabolic parameters were assessed at 4 time points: before surgery (baseline), 6 months after surgery (visit 1), 2 years after surgery (visit 2), and 4 years after surgery (visit 3). Univariate regression analysis was used to identify variables that were thought to determine change in inflammatory parameters. RESULTS: CRP, hs-CRP, leucocytes, and ferritin significantly declined in the mid- and long-term according to the U-shaped curve of weight loss (p<0.001). Change in body mass index (BMI) at long-time follow-up showed a significant linear effect on change in leucocytes (B=0.082; p<0.001) and change in hs-CRP (B=0.03; p<0.05). There was a strong, positive correlation between T2D and hs-CRP at visit 2 (rs=0.195; p<0.05) and visit 3 (rs=0.36; p=0.001). With regard to type of surgery and gender, there were no significant differences in inflammatory parameters. CONCLUSION: BS is able to reduce obesity-related chronic low-grade inflammation up to 4 years after surgical intervention. The improvement in metaflammation is related to the change in BMI and remission of T2D in the long-term.

Bariatric Surgery Is Protective Against Renal Function Decline in Severely Obese Patients in the Long-Term.

PURPOSE: This study aims to assess the long-term renal effects of bariatric surgery (BS) in severely obese patients over a follow-up period of up to 11 years. MATERIALS AND METHODS: In a retrospective cohort study including 102 patients, patients were stratified by eGFR at baseline and divided into three groups: (1) reduced, (2) normal, and (3) increased filtration rate. Adjustments for age- and sex-related decline in eGFR were performed. We used uni- and multivariate regression analysis to identify variables that were thought to determine change in eGFR. RESULTS: Over a median follow-up of 8.5 years (interquartile range 2.7), eGFR declined from 96.1 ± 20.7 to 84.9 ± 21.0 ml/min (p < 0.001). Among patients with (1), eGFR remained stable (69.1 ± 19.3 ml/min). Among patients with (2), eGFR declined from 99.7 ± 13.3 ml/min to 88.7 ± 19.4 ml/min (p < 0.001). Among patients with (3), eGFR decreased to normal levels (94.2 ± 17.7 ml/min, p < 0.001). Age- and sex-adjusted eGFR increased (6.4 ± 14.4 ml/min; p < 0.05) among patients with reduced filtration rate. Among patients with normal filtration rate, adjusted eGFR remained stable during follow-up (-1.3 ± 15.2 ml/min; n.s.). Among patients with increased filtration rate, adjusted eGFR decreased and remained within the normal range (-13.2 ± 12.2 ml/min; p < 0.001). Change in eGFR showed a negative correlation with eGFR at baseline (B = -0.31; p < 0.001), change in LDL-cholesterol (B = -0.09; p < 0.05), and a negative correlation with treatment requiring hypertension (B = -9.36; p = 0.001). CONCLUSION: BS is protective against renal function decline in severely obese patients in the long term.