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Objective: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up-and downregulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. Design: Prospective observational study.Setting: Tertiary university hospital in Queensland, Australia. Patients and Measurements:Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours.Results: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre-to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. Conclusions:The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans. K E Y W O R D Sadrenal insufficiency, biomarker, Cushing's syndrome, glucocorticoid | 729 CESANA-NIGRO Et Al.

Context Arginine stimulates pituitary hormones, like growth hormone and vasopressin, but its effect on the hypothalamic–pituitary–adrenal (HPA) axis is unknown. Arginine may also stimulate the HPA axis, possibly through a mechanism involving vasopressin. Objective To investigate the effect of arginine on adrenocorticotropic hormone (ACTH) and cortisol in subjects with and without vasopressin deficiency. Design Prospective study, University Hospital Basel. Participants 38 patients with central diabetes insipidus, 58 patients with primary polydipsia, and 50 healthy controls. Intervention Arginine infusion with measurement of ACTH, cortisol and copeptin at baseline and 30, 45, 60, 90, and 120 minutes. Results We found different response patterns to arginine: in patients with diabetes insipidus (and low stimulated copeptin levels) median (interquartile range [IQR]) ACTH and cortisol increased from 22.9 (16.8, 38.7) to 36.6 (26.2, 52.1) ng/L and from 385 (266, 463) to 467 (349, 533) nmol/L, respectively. In contrast, median (IQR) ACTH and cortisol levels decreased in patients with primary polydipsia (despite high stimulated copeptin levels): ACTH from 17.3 (12.3, 23) to 14.8 (10.9, 19.8) ng/L and cortisol from 343 (262, 429) to 272 (220.8, 360.3) nmol/L; likewise, in healthy controls: ACTH from 26.5 (17.6, 35.7) to 14.8 (12.1, 22.7) ng/L and cortisol from 471 (393.3, 581.8) to 301.5 (206.5, 377.8) nmol/L. Conclusion Diabetes insipidus is associated with increased responsiveness of ACTH/cortisol to arginine. In contrast, arginine does not stimulate the HPA axis in healthy controls or in primary polydipsia.

Objective The syndrome of inappropriate antidiuresis (SIAD) is a common condition in hospitalized patients. It is crucial to establish the cause of SIAD, especially in order to exclude underlying malignancy. As malignant SIAD may be due to a paraneoplastic synthesis of arginine vasopressin, we hypothesized that its stable surrogate marker copeptin can be used as a diagnostic tool to differentiate between malignant and non-malignant SIAD. Methods Prospective observational study. We analyzed data from 146 SIAD patients of two different cohorts from Switzerland and Germany. Patients were included while presenting at the emergency department and underwent a standardized diagnostic assessment including the measurement of copeptin levels. Results Thirty-nine patients (median age: 63 years, 51% female) were diagnosed with cancer-related SIAD and 107 (median age: 73 years, 68% female) with non-malignant SIAD. Serum sodium levels were higher in cancer-related versus non-malignant SIAD: median (IQR) 124 mmol/l (120; 127) versus 120 mmol/l (117; 123) (P<0.001). Median (IQR) copeptin levels of patients with cancer-related SIAD were 11.1 pmol/l (5.2; 37.1) and 10.5 pmol/l (5.2; 25.2) with non-malignant SIAD (P = 0.38). Among different cancer entities, patients suffering from small-cell lung cancer showed the highest copeptin values, but overall no significant difference in copeptin levels between cancer types was observed (P = 0.46). Conclusions Copeptin levels are similar in cancer-related and non-malignant SIAD. Therefore, Copeptin does not seem to be suitable as a marker of malignant disease in SIAD.

Glucocorticoids are frequently prescribed in inflammatory diseases and have recently experienced a boom in the treatment of COVID‐19. Small studies have shown an effect of glucocorticoids on inflammatory marker levels, but definitive proof is lacking. We investigated the influence of prednisone on inflammatory biomarkers in a previous placebo‐controlled, randomized‐controlled multicenter trial which compared a 7‐day treatment course of 50 mg prednisone to placebo in patients hospitalized with community‐acquired pneumonia (CAP). We compared levels of C‐reactive protein (CRP), procalcitonin (PCT), leukocyte and neutrophil count between patients with and without glucocorticoid treatment at baseline and on days 3, 5, 7, and at discharge by Wilcoxon tests and variance analysis. 356 patient data sets in the prednisone group and 355 in the placebo group were available for analysis. Compared to placebo, use of prednisone was associated with reductions in levels of CRP on days 3, 5, and 7, (mean difference of 46%, p < 0.001 for each time point). For PCT, no such difference was observed. Leukocyte and neutrophil count were higher in the prednisone group at all time points (mean difference of 27% for leukocytes and 33% for neutrophils, p < 0.001 for all time points). We conclude that after administration of glucocorticoids in CAP, patients had lower CRP levels and increased leukocyte and neutrophil count as compared to the placebo group. PCT levels were not different between treatment groups. PCT levels thus may more appropriately mirror the resolution of infection compared to more traditional inflammatory markers. This article is protected by copyright. All rights reserved

contributed equally to this study.

Background: Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has increased but so have long-term sequelae. New-onset posttransplant diabetes mellitus (PTDM) occurs frequently following allo-HSCT. Patients and Methods: Study endpoints were incidence and risk factors of PDTM. We studied 599 adult patients suffering from either acute myeloid leukemia n=220), acute lymphoblastic leukemia (n=79), chronic myeloid leukemia (n=22), myelodysplastic syndrome/myeloproliferative neoplasm (n=105), chronic lymphocytic leukemia (n=37), lymphoma/myeloma (n=116, or non-malignant disorders (e.g. bone marrow failure, hemoglobinopathies) (n=20) who underwent myeloablative (466; 77.8%) or non-myeloablative (131; 21.9%) allo-HSCT between 2006 and 2016. Results: Altogether, 39 patients (6.5%) developed PTDM. In a competing-risk analysis, time to PTDM was associated with acute grade 2-4 graft-versushost-disease (p=0.017). Further cardiovascular risk factors were hypertension (n=145; 24.2%), coronary artery disease (n=36, 6%), dyslipidemia (n=139; 23.3%), and stroke (n=12; 2%). Conclusion: After allo-HSCT, a significant number of patients developed PTDM and patients with acute graft-versus-host-disease were found to have a higher risk for PTDM. Long-term and continuous follow-up for diabetes and cardiovascular risk factors after HSCT is important in order to be able to provide timely and appropriate treatment.Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established therapy for hematological malignancies (1). HSCT is associated with many non-diseaserelated late effects (2). Furthermore, endocrinopathies such as ovarian insufficiency, spermatogenesis damage and hypothyroidism are among the most common late effects after allo-HSCT (3, 4). Advances in transplantation strategies and supportive care have contributed to the improvement in outcome and to a growing number of long-term survivors. However, due to this development, new health issues are arising. One major problem is that of metabolic syndrome, a cluster characterized by diabetes mellitus (DM), abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance and proinflammatory and prothrombotic state (5-7). Post transplantation diabetes mellitus (PTDM) occurs in 10-30% of patients undergoing allo-HCST (8, 9). Despite its burden, its physiology remains poorly understood (9). A timely identification of cardiovascular risk factors can lead to early initiation of risk modification therapy, which in turn reduces the risk of late cardiovascular morbidity and mortality (2, 6, 10). We herein conducted a retrospective observational study to ascertain incidence and causes of PTDM and other features of metabolic syndrome in patients after allo-HCST.