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Sun Fei Wuxi Medical College of Jiangnan University, Wuxi, China

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Min Liu Wuxi Maternity and Child Health Care Hospital, Wuxi, China

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Hu Shanshan Wuxi Maternity and Child Health Care Hospital, Wuxi, China

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Ruijie Xie Department of Microsurgery, University of South China, Hengyang, China

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Wu Danni Wuxi Medical College of Jiangnan University, Wuxi, China

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Zhou Ningying Wuxi Medical College of Jiangnan University, Wuxi, China

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Background

Depression has become a multifaceted global health issue, with complex connections to obesity. Weight-adjusted-waist index (WWI) can effectively evaluate central obesity, but the relationship between WWI and depression has not been well studied. The study aims to investigate the potential correlation between these two health parameters.

Methods

According to the data from National Health and Nutrition Examination Survey, this cross-sectional study used multiple regression analysis, subgroup analysis, and smooth curve fitting to explore the relationship between WWI and depression. The assessment ability of WWI was evaluated and compared to other obesity indicators using the receiver operating characteristic (ROC) curve.

Results

This study analyzed 38,154 participants. Higher WWI is associated with higher depression scores (β = 0.41; 95% CI, 0.36–0.47). After adjusting for various confounding factors, the positive correlation between WWI and depression remained significant (P for trend < 0.0001). Nonlinear positive correlation was detected with a breakpoint of 11.14. ROC analysis shows that compared to other obesity indicators (ROCWWI = 0.593; ROCBMI = 0.584; and ROCWC = 0.581), the correlation between WWI and depression has better discrimination and accuracy. DII mediated 4.93%, SII mediated 5.08%, and sedentary mediated 0.35% of the total association between WWI and depression.

Conclusion

WWI levels were related to an increased likelihood of depression and showed a stronger relationship than BMI and waist circumference. Our findings indicated that WWI may serve as a simple anthropometric index to evaluate depression.

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Weiwei Liang Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Yilin Zhang Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

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Yan Guo Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Pengyuan Zhang Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Jiewen Jin Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Hongyu Guan Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Yanbing Li Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

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Background

Filamin A (FLNA) is a member of the filamin family and has been found to be critical for the progression of several cancers. However, its biological function in papillary thyroid cancer (PTC) remains largely unexplored.

Methods

Data from The Cancer Genome Atlas (TCGA) databases were utilized to analyze the FLNA expression level and its influence on the clinical implications of patients with PTC. Gene Expression Omnibus (GEO) and qRT-PCR was used to verify the expression levels of FLNA in PTC. Kaplan–Meier survival analysis was conducted to evaluate the prognostic value of FLNA in PTC. Transwell assays and wound healing were performed to examine the biological function of FLNA knockdown in PTC cells. Gene set enrichment analysis (GSEA) and Western blotting were conducted to investigate the potential mechanisms underlying the role of FLNA in PTC progression. In addition, the relationship between FLNA expression and the tumor immune microenvironment (TME) in PTC was explored.

Results

FLNA was significantly upregulated in PTC tissues. High expression levels of FLNA was correlated with advanced TNM stage, T stage, and N stage, as well as poor disease-free interval (DFI) and progression-free interval (PFI) time in PTC patients. Moreover, we found that FLNA knockdown inhibited the migration and invasion of PTC cells. Mechanistically, FLNA knockdown inhibited epithelial–mesenchymal transition (EMT) in PTC and affected the activation of the FAK/AKT signaling pathway. In addition, FLNA expression was associated with TME in PTC.

Conclusion

FLNA may be regarded as a new therapeutic target for PTC patients.

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Ayse Nurcan Cebeci Paediatric Endocrinology, Department of Friedrich-Alexander University Hospital, Erlangen, Germany

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Vera Schempp Paediatric Endocrinology, University Hospital, Bonn, Germany

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Katharina Förtsch Paediatric Endocrinology, University Hospital, Düsseldorf, Germany

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Bettina Gohlke Paediatric Endocrinology, University Hospital, Bonn, Germany

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Michaela Marx Paediatric Endocrinology, Department of Friedrich-Alexander University Hospital, Erlangen, Germany

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Helmuth-Guenther Dörr Paediatric Endocrinology, Department of Friedrich-Alexander University Hospital, Erlangen, Germany

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Joachim Woelfle Paediatric Endocrinology, Department of Friedrich-Alexander University Hospital, Erlangen, Germany

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While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves’ disease (GD) is rare (ranges 0.6–3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients’ medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51–4.30), free triiodothyronine, free thyroxine (mean ± s.d .), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5–8.1), 50.2 ± 18.7 pmol/L (NR 12.6–20.9), and 17.0 (2.89–159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was ‘block and replace’ in ten patients and ‘dose titration’ in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.

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Zhenyu Liu Department of Clinical Medicine, Beijing Luhe Hospital, Capital Medical University, Tongzhou District, Beijing, China

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Huixi Kong Department of Clinical Medicine, Beijing Shijitan Hospital, Capital Medical University, Haidian District, Beijing, China

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Baoyu Zhang Center for Endocrine Metabolism and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Tongzhou District, Beijing, China

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To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium–glucose cotransporter 2 inhibitors (SGLT2i), and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.

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Arno Téblick Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Ilse Vanhorebeek Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Inge Derese Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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An Jacobs Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Renata Haghedooren Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Sofie Maebe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Gerdien A Zeilmaker-Roest Department of Neonatal & Pediatric Intensive Care, Division of Pediatric Intensive Care, Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands

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Enno D Wildschut Department of Neonatal & Pediatric Intensive Care, Division of Pediatric Intensive Care, Erasmus MC – Sophia Children’s Hospital, Rotterdam, the Netherlands

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Lies Langouche Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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Greet Van den Berghe Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

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In critically ill adults, high plasma cortisol in the face of low ACTH coincides with high pro-opiomelanocortin (POMC) levels. Glucocorticoids further lower ACTH without affecting POMC. We hypothesized that in pediatric cardiac surgery-induced critical illness, plasma POMC is elevated, plasma ACTH transiently rises intraoperatively but becomes suppressed post-operatively, and glucocorticoid administration amplifies this phenotype. From 53 patients (0–36 months), plasma was obtained pre-operatively, intraoperatively, and on post-operative days 1 and 2. Plasma was also collected from 24 healthy children. In patients, POMC was supra-normal pre-operatively (P < 0.0001) but no longer thereafter (P > 0.05). ACTH was never high in patients. While in glucocorticoid-naive patients ACTH became suppressed by post-operative day 1 (P < 0.0001), glucocorticoid-treated patients had already suppressed ACTH intraoperatively (P ≤ 0.0001). Pre-operatively high POMC, not accompanied by increased plasma ACTH, suggests a centrally activated HPA axis with reduced pituitary processing of POMC into ACTH. Increasing systemic glucocorticoid availability with glucocorticoid treatment accelerated the suppression of plasma ACTH.

Significance statement

Glucocorticoids are often administered during pediatric cardiac surgery. In critically ill children, endogenous systemic glucocorticoid availability is elevated already upon ICU admission while ACTH levels are normal. This hormonal constellation suggests the presence of active feedback inhibition of ACTH. In this study, we have documented that intraoperative administration of glucocorticoids accelerates the suppression of ACTH, resulting in low plasma ACTH already upon ICU admission. Pre-operative plasma POMC, the ACTH precursor, but not ACTH, was increased. This is compatible with a centrally activated HPA axis prior to surgery in young children but reduced processing of POMC into ACTH within the pituitary. These findings suggest that glucocorticoid treatment in the context of pediatric cardiac surgery may amplify pre-existing impaired pituitary processing of the prohormone POMC.

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Bushra Shahida Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
Department of Diabetes & Endocrinology, Skåne University Hospital, Malmö, Sweden

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Tereza Planck Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
Department of Diabetes & Endocrinology, Skåne University Hospital, Malmö, Sweden

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Tania Singh Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden

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Peter Åsman Department of Clinical Sciences Malmö, Ophthalmology, Lund University, Malmö, Sweden
Department of Ophthalmology, Skåne University Hospital, Malmö, Sweden

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Mikael Lantz Department of Clinical Sciences, Genomics, Diabetes and Endocrinology, Lund University, Malmö, Sweden
Department of Diabetes & Endocrinology, Skåne University Hospital, Malmö, Sweden

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Graves’ disease (GD) and Graves’ ophthalmopathy (GO) are complex autoimmune diseases. This study delved into the impact of cigarette smoke extract (CSE), simvastatin, and/or diclofenac on peripheral blood mononuclear cells (PBMCs). Specifically, we explored alterations in IL-1B, IL-6, PTGS2 expression, B- and T-lymphocyte proliferation, and Immunoglobulin G (IgG) production. We also assessed IGF1’s influence on B- and T-lymphocyte proliferation. PBMCs from Graves’ patients were exposed to CSE with/without simvastatin and/or diclofenac. Gene and protein expression was compared with untreated PBMCs. B- and T-lymphocyte proliferation was assessed following IGF1 treatment. PBMCs exposed to CSE exhibited increased expression of IL-1B (6-fold), IL-6 (10-fold), and PTGS2 (5.6-fold), and protein levels of IL-1B (4-fold), IL-6 (16-fold) and PGE2 (3.7-fold) compared with untreated PBMCs. Simvastatin and/or diclofenac downregulated the expression of PTGS2 (0.5-fold), IL-6 (0.4-fold), and IL-1B (0.6-fold), and the protein levels of IL-1B (0.6-fold), IL-6 (0.6-fold), and PGE2 (0.6-fold) compared with untreated PBMCs. CSE exposure in PBMCs increased the proliferation of B and T lymphocytes by 1.3-fold and 1.4-fold, respectively, compared with untreated. CSE exposure increased IgG (1.5-fold) in supernatant from PBMCs isolated from Graves’ patients. IGF1 treatment increased the proliferation of B and T lymphocytes by 1.6-fold. Simvastatin downregulated the proliferation of B and T lymphocytes by 0.7-fold. Our study shows that CSE significantly upregulated the expression and release of the inflammatory markers PTGS2, IL-6 and IL-1B,the IgG levels, and the proliferation of B and T lymphocytes. Additionally, IGF1 increased the proliferation of B and T lymphocytes. Finally, these effects were decreased by diclofenac and/or simvastatin treatment.

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Ayana Suzuki Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Japan

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Mitsuyoshi Hirokawa Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Japan

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Izumi Otsuka Secretary Section, Kuma Hospital, Kobe, Japan

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Akihiro Miya Department of Surgery, Kuma Hospital, Kobe, Japan

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Akira Miyauchi Department of Surgery, Kuma Hospital, Kobe, Japan

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Takashi Akamizu Department of Internal Medicine, Kuma Hospital, Kobe, Japan

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Papillary thyroid carcinoma (PTC) with marked cystic formation (CPTC) is not a subtype of PTC, and its clinical characteristics have not been fully investigated. This study aimed to clarify the clinical and pathological characteristics of CPTC and propose important indicators for its clinical management. Thirty-three CPTC nodules with cystic areas occupying >50% of their volume were examined. Two matched controls (MCs) were prepared, one with tumor diameter matched for whole tumor diameter (WTD) of CPTCs and the other with tumor diameter matched for solid area diameter (SAD) of CPTCs. The mean age of patients with CPTC was 55.2 years significantly older than that in SAD-MCs. Of the CPTCs, 69.7% were classified as highly suspicious by ultrasonography, and the prevalence was lower than that in WTD-MCs (88.9%) and SAD-MCs (91.5%). Total thyroidectomy was performed in 69.7% of CPTC cases, which was significantly less frequent than that in WDT-MCs (91.7%) and similar to that in SAD-MCs (76.1%). Histologically, CPTCs exhibited two characteristic findings: invasion from the solid area into the surrounding normal thyroid tissue and granulation tissue around the cystic wall. The frequencies of the cases with pathological lateral node metastasis, extrathyroidal extension, and Ki-67 labeling index ≥5% in CPTCs were significantly lower than those in WTD-MCs and relatively similar to those in SAD-MCs. In the surgical strategy and prognosis of CPTC, the evaluation of tumor size should be based on SAD rather than on WTD. We advocate measuring not only WTD but also SAD in CPTC.

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M Cherenko Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands

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N M Appelman-Dijkstra Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands

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A L Priego Zurita Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands

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N R Biermasz Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands

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O M Dekkers Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands

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F A Klok Department of Medicine, Division of Thrombosis and Haemostasis, Leiden University Medical Centre, Leiden, Netherlands

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N Reisch Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany

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A Aulinas Department of Endocrinology, Fundacio de Gestio Sanitaria Hospital de la Santa Creu i Sant Pau, IR-SantPau and CIBERER Unit 747 (ISCIII), Barcelona, Spain

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B Biagetti Department of Endocrinology, Hospital Universitari Vall d’Hebron, Barcelona, Spain

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S Cannavo Endocrine Unit, University Hospital AOU Policlinico G. Martino, Messina, Italy

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L Canu University Hospital Florence Careggi, Florence, Italy

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M Detomas Department of Internal Medicine, University Hospital Würzburg, Wuerzburg, Germany

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F Devuyst Department of Endocrinology, Hôpital Universitaire de Bruxelles, Hôpital Erasme, Brussels, Belgium

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H Falhammar Department of Endocrinology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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R A Feelders Department of Internal Medicine, Division of Endocrinology, Erasmus MC, Rotterdam, Netherlands

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F Ferrau Endocrine Unit, University Hospital AOU Policlinico G. Martino, Messina, Italy

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F Gatto IRCCS Ospedale Policlinico San Martino, Genova, Genoa, Italy

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C Grasselli Cardiovascular Medicine Unit, AUSL-IRCCS, Reggio Emilia, Italy

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P van Houten Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands

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C Hoybye Department of Endocrinology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

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A M Isidori Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

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A Kyrilli Department of Endocrinology, Hôpital Universitaire de Bruxelles, Hôpital Erasme, Brussels, Belgium

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P Loli Division of Endocrinology, San Raffaele Vita-Salute University, IRCCS San Raffaele Hospital Milan, Italy

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D Maiter Department of Endocrinology, Cliniques universitaires Saint-Luc – UCLouvain, Brussels, Belgium

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E Nowak Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany

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R Pivonello Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Università “Federico II” di Napoli, Naples, Italy

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O Ragnarsson Sahlgrenska Academy, Wallenberg Centre for Molecular and Translational Medicine, Institute of Medicine (O.R.), University of Gothenburg, Sweden

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R V Steenaard Department of Internal Medicine, Máxima MC, Veldhoven, Netherlands

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N Unger University Hospital Essen, Department of Endocrinology, Diabetes and Metabolism, Essen, Germany

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A van de Ven Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, Netherlands

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S M Webb Department of Endocrinology, Fundacio de Gestio Sanitaria Hospital de la Santa Creu i Sant Pau, IR-SantPau and CIBERER Unit 747 (ISCIII), Barcelona, Spain

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D Yeste Pediatric Endocrinology Service, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. CIBER Enfermedades Raras, Instituto Carlos III, Madrid, Spain

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S F Ahmed Department of Medicine, Division of Endocrinology, Leiden University Medical Centre, Leiden, Netherlands
University of Glasgow, Office for Rare Conditions, Glasgow, UK
University of Glasgow, Developmental Endocrinology Research Group, Royal Hospital for Children, Glasgow, UK

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A M Pereira Department of Endocrinology & Metabolism, Amsterdam University Medical Centre, Amsterdam, Noord-Holland, Netherlands

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Background

Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE).

Objective

The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis.

Design and methods

A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG’s) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022.

Results

Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3–30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years.

Conclusion

Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed.

Significance statement

The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

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Carlijn Hoekx C Hoekx, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Borja Martinez-Tellez B Martinez-Tellez, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Maaike E. Straat M Straat, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Magdalena Verkleij M Verkleij, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Mirjam Kemmeren M Kemmeren, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Sander Kooijman S Kooijman, Division of Endocrinology, Department of Medicine, LUMC, Leiden, Netherlands

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Martin Uhrbom M Uhrbom, Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals RandD, AstraZeneca in Gothenburg, Molndal, Sweden

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Saskia C.A. de Jager S de Jager, Laboratory of Experimental Cardiology, University Medical Centre Utrecht, Utrecht, Netherlands

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Patrick Rensen P Rensen, Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands

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Mariëtte Boon M Boon, Division of Endocrinology, Department of Medicine, LUMC, Leiden, Netherlands

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Objectives: Cold exposure is linked to cardiometabolic benefits. Cold activates brown adipose tissue (BAT), increases energy expenditure, and induces secretion of the hormones fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). The cold-induced increase in energy expenditure exhibits a diurnal rhythm in men. Therefore, we aimed to investigate the effect of cold exposure on serum FGF21 and GDF15 levels in humans and whether cold-induced changes in FGF21 and GDF15 levels differ between morning and evening in males and females.

Method: In this randomized cross-over study, serum FGF21 and GDF15 levels were measured in healthy lean males (n=12) and females (n=12) before, during, and after 90 minutes of stable cold exposure in the morning (7:45am) and evening (7:45pm) with a one-day washout period in between.

Results: Cold exposure increased FGF21 levels in the evening compared to the morning both in males (+61% vs. -13%; P<0.001) and in females (+58% vs. +8%; P<0.001). In contrast, cold exposure did not significantly modify serum GDF15 levels, and no diurnal variation was found. Changes in FGF21 and GDF15 levels did not correlate with changes in cold-induced energy expenditure in the morning and evening.

Conclusion: Cold exposure increased serum FGF21 levels in the evening, but not in the morning, in both males and females. GDF15 levels were not affected by cold exposure. Thus, this study suggests that the timing of cold exposure may influence cold-induced changes in FGF21 levels but not GDF15 levels and seems to be independent of changes in energy expenditure.

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Irfan Vardarli I Vardarli, 5th Medical Department, Division of Endocrinology and Diabetes, Heidelberg University Medical Faculty Mannheim, Mannheim, 68167, Germany

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Susanne Tan S Tan, Department of Endocrinology, Diabetes and Metabolism, Clinical Chemistry – Division of Laboratory Research; Endocrine Tumor Center at WTZ/Comprehensive Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Rainer Görges R Görges, Nuklearmedizin, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Bernhard K. Krämer B Krämer, 5th Medical Department, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany

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Ken Herrmann K Herrmann, Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Christoph Brochhausen C Brochhausen, Institue of Pathology, Heidelberg University Medical Faculty Mannheim, Mannheim, Germany

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Objective: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis.

Methods: We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma Gene Expression Classifier (GEC), Afirma Gene Sequencing Classifier (GSC), ThyroSeq v2 (TSv2) or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata.

Results: 71 samples (GEC, n=38; GSC, n=16; TSv2, n=9; TSv3, n=8) in 53 studies, involving 6,490 fine needle aspirations (FNA) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2 or TSv3) were included in the study. Meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI, 0.94-0.97), specificity 0.35 (0.28-0.43), Positive Likelihood Ratio (LR+) 1.5 (1.3-1.6), and Negative Likelihood Ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)) and GEC (0.82 (0.78-0.85)); with the best rule-out property for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28); with the best rule-in for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). Meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors.

Conclusions: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. For rule-out malignancy, GSC, and for rule-in, TSV2 is superior to other tests.

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