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Christos Bagias,1 Angeliki Xiarchou,1 Alexandra Bargiota,2 Stelios Tigas1 1Department of Endocrinology, University of Ioannina, Ioannina, Greece; 2Department of Endocrinology, University of Thessaly, Larissa, GreeceCorrespondence: Stelios TigasDepartment of Endocrinology, University of Ioannina, Ioannina 45110, GreeceTel +30 2651007800Email stigas@uoi.grAbstract: Lipodystrophies are a heterogeneous group of congenital or acquired disorders, characterized by partial or generalized loss of adipose tissue. Familial partial lipodystrophy (FPLD) presents with genetic and phenotypic variability with insulin resistance, hypertriglyceridemia and hepatic steatosis being the cardinal metabolic features. The severity of the metabolic derangements is in proportion with the degree of lipoatrophy. The underpinning pathogenetic mechanism is the limited capacity of adipose tissue to store lipids leading to lipotoxicity, low-grade inflammation, altered adipokine secretion and ectopic fat tissue accumulation. Advances in molecular genetics have led to the discovery of new genes and improved our knowledge of the regulation of adipose tissue biology. Diagnosis relies predominantly on clinical findings, such as abnormal fat tissue topography and signs of insulin resistance and is confirmed by genetic analysis. In addition to anthropometry and conventional imaging, new techniques such as color-coded imaging of fat depots allow more accurate assessment of the regional fat distribution and differentiation of lipodystrophic syndromes from common metabolic syndrome phenotype. The treatment of patients with lipodystrophy has proven to be challenging. The use of a human leptin analogue, metreleptin, has recently been approved in the management of FPLD with evidence suggesting improved metabolic profile, satiety, reproductive function and self-perception. Preliminary data on the use of glucagon-like peptide 1 receptor agonists (GLP1 Ras) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in cases of FPLD have shown promising results with reduction in total insulin requirements and improvement in glycemic control. Finally, investigational trials for new therapeutic agents in the management of FPLD are underway.Keywords: lipodystrophy, partial lipodystrophy, familial lipodystrophy, leptin

Theodora Tsirouki,1 Alexandra Bargiota,2 Stelios Tigas,3 Agathi Vasileiou,2 Eftichia Kapsalaki,4 Zoe Giotaki,3 Ioannis Asproudis,5 Agathokles Tsatsoulis,3 Georgios Koukoulis,2 Evangelia E Tsironi1 1Department of Ophthalmology, University Hospital of Larissa, Larissa, 2Department of Endocrinology, University Hospital of Larissa, Larissa, 3Department of Endocrinology, University Hospital of Ioannina, Ioannina, 4Department of Diagnostic Radiology, University Hospital of Larissa, Larissa, 5Department of Ophthalmology, University Hospital of Ioannina, Ioannina, Greece Objective: The aim of this study was to evaluate the safety and efficacy of an individualized steroid regimen in patients with moderate-to-severe Graves’ orbitopathy (GO) by monitoring clinical and imaging parameters. Methods: In total, 47 patients with active, moderate-to-severe GO were enrolled in this study. All the patients received the proposed treatment regimen by European Group on GO of 4.5 g of intravenous (IV) methylprednisolone for 12 weeks. At the end of the IV treatment, patients with persistent active GO (Group 1) who were assessed by clinical examination and orbital imaging with short tau inversion recovery-sequence magnetic resonance imaging (STIR MRI) received additional treatment with oral prednisolone, and those with inactive GO (Group 2) received no further treatment. Results: Of the 42 patients who completed the study, 22 (52.4%) patients formed Group 1 and 20 (47.6%) patients Group 2. At the 12th week, the overall response to IV treatment was 76.2%, and clinical activity score (CAS) improvement was 69%. At the 24th week, the overall response was 92.8%, and CAS improvement was 97.6%, without statistically significant difference in CAS and total eye score between these two groups (P=0.157 and P=0.856, respectively). Ophthalmic manifestations were improved, being absent or minimal in 78.6% of patients at the 24th week follow-up. Recurrence of disease activity occurred in 9.5% of patients up to 24 weeks after the completion of treatment, and major adverse events occurred in 6.4% of patients. Conclusion: In patients with moderate-to-severe GO, IV steroid treatment, followed by oral treatment, when needed, is an effective regimen with low rates of adverse events and recurrences. STIR MRI is a significant tool for recognizing patients who need additional steroid treatment. Keywords: Graves’ orbitopathy, magnetic resonance imaging, MRI, glucocorticoids

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize druginduced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention. [ABSTRACT FROM AUTHOR]

Abstract Background Type 2 diabetes mellitus (T2DM) is independently associated with an increased risk for cardiovascular diseases that is primarily due to the early development of advanced atherosclerotic vascular changes. The aim of our study was to investigate the predictors of vascular dysfunction in T2DM patients. Methods We studied 165 T2DM patients without known macrovascular or microvascular disease. Standard demographic (age, gender, cardiovascular risk factors, medications), clinical (body mass index, blood pressure) and laboratory (glucose, glycated hemoglobin, lipids, renal function) parameters were included in analyses. Brachial artery flow-mediated dilation (FMD), nitrate mediated dilation (NMD) and Carotid-Femoral Pulse Wave Velocity (PWV) were measured. Results Median age was 66 years and duration since T2DM diagnosis was 10 years, 70% were females and 79% hypertensives, while only 10% had a glycated hemoglobin Conclusions In T2DM patients, impairment of endothelium-dependent vasodilation was independently associated only with longer diabetes duration while no association with other established risk factors was found. Vascular smooth muscle dysfunction and increased arterial stiffness were more prominent in older T2DM patients with hypertension. Worse glycemic control was associated with impaired vascular smooth muscle function.

Background/Objectives : Obesity and overweight have become increasingly prevalent in different populations of people with type 1 diabetes (PwT1D). This study aimed to assess the effect of body weight on glycaemic indices in PwT1D. Methods : Adult PwT1D using continuous glucose monitoring (CGM) and followed up at a regional academic diabetes centre were included. Body weight, body mass index (BMI), waist circumference, glycated haemoglobin (HbA1c), and standard CGM glycaemic indices were recorded. Glycaemic indices were compared according to BMI, and correlation and linear regression analysis were performed to estimate the association between measures of adiposity and glycaemic indices. Results : A total of 73 PwT1D were included (48% normal weight, 33% overweight, and 19% obese). HbA1c was 7.2% (5.6-10), glucose management indicator (GMI) 6.9% (5.7-8.9), coefficient of variation (CV) for glucose 39.5% ± 6.4, mean glucose 148 (101-235) mg/dL, TIR (time in range, glucose 70-180 mg/dL) 66% (25-94), TBR 70 (time below range, 54-69 mg/dL) 4% (0-16), TBR 54 (<54 mg/dL) 1% (0-11), TAR 180 (time above range, 181-250 mg/dL) 20% ± 7, and TAR 250 (>250 mg/dL) 6% (0-40). Glycaemic indices and achievement (%) of optimal glycaemic targets were similar between normal weight, overweight, and obese patients. BMI was associated negatively with GMI, mean glucose, TAR 180 , and TAR 250 and positively with TIR; waist circumference was negatively associated with TAR 250 . Conclusions : CGM-derived glycaemic indices were similar in overweight/obese and normal weight PwT1D. Body weight and BMI were positively associated with better glycaemic control. PwT1D should receive appropriate ongoing support to achieve optimal glycaemic targets whilst maintaining a healthy body weight.

Diabetes and dyslipidemia are common in patients with psychosis and may be related to adverse effects of antipsychotic medications. Metabolic disturbances in first-episode patients with psychosis are common, even prior to any antipsychotic treatment, and antipsychotic medications are implicated in the development of metabolic syndrome, at least in the long run. We therefore aimed to follow a group of drug-naïve, first-episode patients with psychosis at different time points (baseline, six months, and 36 months after the initiation of antipsychotic treatment) in order to evaluate the progression of metabolic abnormalities after antipsychotic therapy and the time-course of their onset. We assessed glucose and lipid metabolism during the fasted state in 54 drug-naïve patients with first-episode psychosis (FEP) before the initiation of any antipsychotic treatment and compared them with matched controls. The same parameters were assessed in the patient group (n=54) after six months of antipsychotic treatment and in a subgroup of patients (n=39) after three years of continuous and stable treatment in comparison to baseline. Measurements were obtained for fasting serum concentrations of total cholesterol, triglycerides, high density lipoprotein (HDL), glucose, insulin, connecting peptide (C-peptide), homeostatic model assessment index (HOMA-IR), glycated hemoglobin (HbA1c) and body mass index (BMI). Insulin, C-peptide, triglyceride levels, and HOMA-IR index were significantly higher compared to controls. Total cholesterol, triglyceride levels and BMI, increased significantly in the patient group after six months of antipsychotic treatment. After three years of continuous antipsychotic treatment, we found statistically significant increases in fasting glucose, insulin, total cholesterol, triglyceride levels, HbA1c, HOMA-IR index, and BMI compared to baseline. In conclusion, FEP patients developed significant increases in BMI and serum lipid levels as soon as six months after antipsychotic treatment. These metabolic abnormalities persisted following 36 months of treatment and in addition, increases in fasting glucose, insulin, HbA1c and HOMA-IR were observed compared to baseline.

Background: This systematic review and meta-analysis aims to explore in heart failure (HF) patients with reduced ejection fraction (EF) undergoing exercise-based cardiac rehabilitation the following: 1) the comparison of temporal changes between peak oxygen uptake (VO2peak) and first ventilatory threshold (VO2VT1), 2) the association of VO2peak and VO2VT1 changes with physiological factors, and 3) the differential effects of continuous aerobic exercise (CAE) and interval training (IT) on VO2peak and VO2VT1., Methods: A systematic literature search was conducted in PubMed, CENTRAL, and Scopus. Inclusion criteria were 1) original research articles using exercise-based cardiac rehabilitation, 2) stable HF patients with reduced EF, 3) available values of VO2peak and VO2VT1 (in mL/kg/min) both at baseline and after exercise training with comparison between these time points., Results: Among the 30 eligible trials, 24 used CAE, 5 IT, and one CAE and IT. Multivariable meta-regression with duration of exercise training and percentage of males as independent variables and the change in VO2peak as a dependent variable showed that the change in VO2peak was negatively associated with duration of exercise training (coefficient=-0.061, p=0.027), implying the possible existence of a waning effect of exercise training on VO2peak in the long term. Multivariable meta-regression demonstrated that both age (coefficient=-0.140, p<0.001) and EF (coefficient=-0.149, p<0.001) could predict the change in VO2VT1, whereas only age (coefficient=-0.095, p=0.022), but not EF (coefficient = 0.082, p = 0.100), could predict the change in VO2peak. The posttraining peak respiratory exchange ratio, as an index of maximum effort during exercise testing, correlated positively with the change in VO2peak (coefficient=-0.021, p=0.044). The exercise-induced changes of VO2peak (p = 0.438) and VO2VT1 (p = 0.474) did not differ between CAE and IT groups., Conclusions: Improvement of endurance capacity during cardiac rehabilitation may be detected more accurately with the assessment of VO2VT1 rather than VO2peak., Competing Interests: Declaration of Competing Interest Declarations of interest: none., (Copyright © 2024 Hellenic Society of Cardiology. All rights reserved.)

Evidence suggests that genome-wide hypomethylation may promote genomic instability and cellular senescence, leading to chronic complications in people with diabetes mellitus. Limited data are however available on the Alu methylation status in patients with type 1 diabetes (T1D). Methods : We investigated DNA methylation levels and patterns of Alu methylation in the peripheral blood of 36 patients with T1D and 29 healthy controls, matched for age and sex, by using the COmbined Bisulfite Restriction Analysis method (COBRA). Results : Total Alu methylation rate (mC) was similar between patients with T1D and controls (67.3% (64.4-70.9%) vs. 68.0% (62.0-71.1%), p = 0.874). However, patients with T1D had significantly higher levels of the partial Alu methylation pattern (mCuC + uCmC) (41.9% (35.8-45.8%) vs. 36.0% (31.7-40.55%), p = 0.004) compared to healthy controls. In addition, a positive correlation between levels of glycated hemoglobin (HbA1c) and the partially methylated loci (mCuC + uCmC) was observed (Spearman's rho = 0.293, p = 0.018). Furthermore, significant differences were observed between patients with T1D diagnosed before and after the age of 15 years regarding the total methylation mC, the methylated pattern mCmC and the unmethylated pattern uCuC ( p = 0.040, p = 0.044 and p = 0.040, respectively). Conclusions : In conclusion, total Alu methylation rates were similar, but the partial Alu methylation pattern (mCuC + uCmC) was significantly higher in patients with T1D compared to healthy controls. Furthermore, this pattern was associated positively with the levels of HbA1c and negatively with the age at diagnosis.

Purpose: Bone mineral density (BMD) was measured in uncomplicated young adult patients with type 1 diabetes mellitus (T1DM) and sex- and age-matched controls, using both dual X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) to investigate their diagnostic ability in detecting abnormal values in these patients., Methods: 118 patients with T1DM (65 females, mean age 30.12 ± 8.78 years) and 94 sex- and age-matched controls were studied. BMD was assessed in all participants by DXA and QCT at lumbar spine (LS). Biochemical markers of bone metabolism were also measured., Results: T1DM was associated with lower BMD at L1-L3 vertebrae measured by both DXA and QCT and lower bone turnover compared to sex- and age-matched controls. In T1DM subjects, QCT detected more patients with abnormal BMD values compared to DXA. BMI and HbA1c levels were the only determinants of BMD. Bone turnover markers were lower in patients with longer duration of diabetes., Conclusion: QCT provides a higher sensitivity compared to DXA in detecting abnormal BMD values in patients with uncomplicated T1DM. In these patients, the diabetes-related decreased BMD may be present early, before it is detected by DXA, the clinical gold standard for BMD measurements, and before the presence of any other diabetes complications, stressing the importance of an early intervention for fracture prevention., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2023 Eleftheria Barmpa et al.)

Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.

Diabetes mellitus' (DM) prevalence worldwide is estimated to be around 10% and is expected to rise over the next decades. Monitoring blood glucose levels aims to determine whether glucose targets are met to minimize the risk for the development of symptoms related to high or low blood sugar and avoid long-term diabetes complications. Continuous glucose monitoring (CGMs) systems emerged almost two decades ago and have revolutionized the way diabetes is managed. Especially in Type 1 DM, the combination of a CGM with an insulin pump (known as a closed-loop system or artificial pancreas) allows an autonomous regulation of patients' insulin with minimal intervention from the user. However, there is still an unmet need for high accuracy, precision and repeatability of CGMs. Graphene was isolated in 2004 and found immediately fertile ground in various biomedical applications and devices due to its unique combination of properties including its high electrical conductivity. In the last decade, various graphene family nanomaterials have been exploited for the development of enzymatic and non-enzymatic biosensors to determine glucose in biological fluids, such as blood, sweat, and so on. Although great progress has been achieved in the field, several issues need to be addressed for graphene sensors to become a predominant material in the new era of CGMs.

Purpose: Pheochromocytomas are rare tumors and biochemically silent ones with normal catecholamine levels are even rarer. Up to date, biochemically inactive pheochromocytomas are poorly investigated. We aimed to systematically assess the pre- and peri-operative characteristics and the outcomes of patients with these tumors who had been treated and followed-up in 2 tertiary centers., Methods: Clinical, laboratory and imaging data, treatment outcomes and follow-up of biochemically silent pheochromocytoma patients were recorded., Results: Ten patients (5 men) [median age at diagnosis 52.5 years (24-72)] were included. Adrenal masses were incidentally discovered in all patients except from one who presented with pheochromocytoma-related manifestations. Twenty-four-hour urine metanephrine and normetanephrine levels were in the low-normal, normal and high-normal range in 4, 4 and 2 patients and in 1, 6 and 3 patients, respectively. Tumors were unilateral [median size 46 mm (17-125)] and high density on pre-contrast CT imaging or high signal intensity on T2-weighted MRI scans were found in all cases. Pre-operatively, 5 patients were treated with phenoxybenzamine [median total daily dose 70 mg (20-100)]. Intra-operatively, 4 patients developed hypertension requiring vasodilator administration and 8 developed hypotension; vasoconstrictors were required in 5 cases. One patient, not pre-operatively treated with phenoxybenzamine, developed Takotsubo cardiomyopathy. During a median 24-month (12-88) follow-up period, one patient had disease progression., Conclusions: The majority (90%) of patients with biochemically silent pheochromocytomas developed hemodynamic instability during adrenal surgery. In patients with biochemically silent adrenal lesions and a high suspicion index for pheochromocytoma based on tumor imaging characteristics, pre-operative alpha-blockade treatment may be advisable., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glucose prediction is used in diabetes self-management as it allows to take suitable actions for proper glycemic regulation of the patient. The aim of this work is the short-term personalized glucose prediction in patients with Type 1 diabetes mellitus (T1DM). In this scope, we compared two different models, an autoregressive moving average (ARMA) model and a long short-term memory (LSTM) model for different prediction horizons. The comparison of two models was performed using the evaluation metrics of root mean square error (RMSE) and mean absolute error (MAE). The models were trained and tested in 29 real patients. The results shown that the LSTM model had better performance than ARMA with RMSE 3.13, 6.41 and 8.81 mg/dL and MAE 1.98, 5.06 and 6.47 mg/dL for 5-, 15- and 30-minutes prediction horizon.

Monomodal systemic glucocorticoids remain the mainstay of treatment for bullous pemphigoid (BP). In this retrospective, single-arm study, we evaluated the feasibility (efficacy and tolerability) of the combination of methylprednisolone and low-dose (up to 12.5 mg/week) methotrexate (MP + MTX) for BP. At week 12, 53/55 (96.4%) patients initiated on MP + MTX during a five-year period (potential follow up time: ≥4 years) remained on treatment. At this time-point, BP remission was achieved in all compliant patients (including n = 24 cases of dipeptidyl peptidase-4 inhibitors-associated BP; 12-week remission rate: 100% [95% CI: 91.9-100.0%]; mean time to remission: 29.5 days, SEM: 2.3 days) at a mean cumulative MP dose to disease control of 678.4 mg (SEM = 49.4 mg). Eight patients relapsed during follow up (10.81 [95% CI: 5.16-21.72] relapses/100 person years, py), and seven manifested a severe adverse event (6.80 [95% CI: 3.00-14.28] severe adverse events/100 py); however, 73.4% (±7.9%) had suffered neither a relapse nor a SAE at the three-years follow up. Continuing low dose MP intake (≤8 mg/day) beyond week 12 in combination with MTX minimized the risk of a feasibility limiting event ( p = 0.013). Conclusively, the combination of methylprednisolone with methotrexate is a promising, safe, and efficient modality for BP patients, which enables rapid glucocorticoid tapering.

Aims: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes., Methods: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA 1c (IQR) and proportions of individuals with HbA 1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA 1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA 1c category compared to previous estimates were calculated., Results: Median HbA 1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA 1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA 1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA 1c ≥ 75 mmol/mol (≥9.0%) decreased., Conclusions: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes., (© 2021 Diabetes UK.)

Parathyromatosis is a rare cause of persistent or recurrent primary hyperparathyroidism and hypercalcemia due to the presence of hyperfunctioning foci of parathyroid tissue in the neck and/or mediastinum. We describe the case of a male patient who presented with severe hypercalcemia and a left-sided palpable parathyroid mass. Over the course of the next 18 years, the patient underwent neck exploration surgery on multiple occasions due to recurrent primary hyperparathyroidism and refractory hypercalcemia, complicated by nephrolithiasis and impairment of renal function, while bone mineral density was preserved. Histological findings and the natural course of the disease were consistent with parathyromatosis. Medical interventions with oral bisphosphonates or high-dose cinacalcet failed to control the patient's hypercalcemia. The combination of monthly denosumab and cinacalcet was, however, successful in maintaining the patient's serum calcium in the normal/upper-normal range over a 36-month period with no significant side effects. This is the first report of off-label denosumab use in combination with cinacalcet in the long-term management of parathyromatosis-related refractory hypercalcemia., (© 2021. Hellenic Endocrine Society.)

The aim of this study was to assess the factors associated with impaired vascular function in patients with poorly controlled type 2 diabetes (DM2) with and without overt cardiovascular disease (CVD). Ninety-five patients with DM2 and poor glycemic control were recruited and divided into two groups: Group 1, with known CVD ( n = 38), and Group 2, without CVD ( n = 57). Patients in Group 2 were further subdivided into those with short (<5 years, group 2b) and long (>5 years, group 2a) diabetes duration. Subclinical markers of atherosclerosis were assessed. Glycemic control was similar in the two groups (HbA1c: 9.2% (1.5) vs. 9.4% (1.8), p = 0.44). In Group 1, lower FMD (3.13 (2.16)% vs. 4.7 (3.4)%, p < 0.05) and higher cIMT (1.09 (0.3) mm vs. 0.96 (0.2) mm, p < 0.05) was seen compared with Group 2, whereas PWV was similar (12.1 (3.4) vs. 11.3 (3.0) m/s, p = 0.10). Patients in Group 2b had significantly lower PWV and cIMT and higher FMD compared to Group 1 ( p < 0.05). Among patients with poorly controlled T2D, more pronounced vascular dysfunction was present in those with overt macrovascular disease. In patients with T2D without known CVD, vascular dysfunction was associated with disease duration. The use of vascular indices for cardiovascular risk stratification in patients with T2D requires further study.

Introduction: Immune response following viral infections has been suggested as a probable mechanism leading to subacute thyroiditis (SAT). A few cases of SAT following SARS-CoV-2 infection have been described since the outbreak of the pandemic in 2019. Cases of SAT after vaccination against influenza have also been reported. We describe two female patients with thyroiditis after vaccination against SARS-CoV-2., Presentation of Cases: The first patient presented with fever and pain in the thyroid area typical of SAT two weeks after vaccination with the BNT162B2 mRNA (Pfizer-BioNTech) COVID-19 vaccine. The second patient presented with biochemical and imaging features consistent with silent thyroiditis three weeks after vaccination with the ChAdOx1-S (AstraZeneca) vaccine. Both patients were asymptomatic prior to vaccination and PCR of nasopharyngeal swab for SARS-CoV-2 and other respiratory viruses associated with SAT was negative. Serology testing for measles, mumps, rubella, CMV and EBV viruses was suggestive of immunity. Antibody titre against spike S protein of SARS-CoV-2 was measured for both patients and was indicative of adequate post vaccination antibody response. Two months after initial assessment, both patients were euthyroid and asymptomatic., Conclusions: Subacute as well as silent thyroiditis may rarely occur after vaccination against COVID-19. Further research is needed to investigate the prevalence and pathogenesis of thyroid dysfunction following vaccination against COVID-19., Competing Interests: The authors declare no competing interest relevant to the contents of this article., (© 2021 The Authors.)

Purpose: The aim of the present study was to investigate the effect of intensive antidiabetic therapy on vascular indices in type 2 diabetes mellitus (T2DM) patients., Methods: Poorly controlled T2DM patients (n = 62, mean age 64 years, T2DM duration 14 years, HbA1c ≥ 7.5%) were studied at baseline and following intensive treatment to achieve optimal glycemic control. Brachial artery flow-mediated dilation, carotid-femoral pulse wave velocity, central augmentation index, large and small (C2) artery compliance, carotid intima-media thickness (cIMT), and ankle-brachial index were assessed at baseline and follow-up., Results: HbA1c decreased from 8.8% (8.1, 10.1) (median, interquartile range-IQ) to 7.4% (6.9, 7.8), p < 0.001. Triglycerides and high-sensitivity C-reactive protein levels were decreased by ~ 10% and 50%, respectively (p < 0.05). Maximum cIMT and C2 increased at follow-up (0.97 ± 0.25 to 1.03 ± 0.27 mm and 3.3 (2.7, 4.2) to 4.2 (3.2, 5.4) ml/mmHg × 10, respectively, p < 0.05). In subgroup analysis, the observed changes in vascular indices were not affected by diabetes duration, presence of cardiovascular disease, or insulin treatment., Conclusion: In patients with long-standing T2DM, short-term aggressive glycemic control was associated with an improvement of microvascular function (C2) and deterioration of carotid atherosclerosis (IMT) without any effect on the elastic properties of large arteries., (© 2021. Hellenic Endocrine Society.)

Background and Aims: The definition of relative adrenal insufficiency (RAI) in patients with cirrhosis remains controversial. We investigated the serum and salivary cortisol (SalC) response after low-dose and standard-dose Synacthen test in patients with stable cirrhosis and ascites., Methods: Ninety-five cirrhotic patients with ascites were prospectively evaluated from January 2014 to January 2018. Low-dose [adrenocorticotrophic hormone (ACTH): 1 μg] and standard-dose (ACTH: 250 μg) Synacthen test were successively performed. Paired serum total and saliva cortisol were taken at baseline, 30 min (low-dose test) and 60 min (standard-dose test). Salivary and Δserum total cortisol criteria included post-ACTH SalC < 12.7 ng/ml and/or SalC increase <3 ng/ml and serum total cortisol increase <9 μg/dl, respectively., Results: The prevalence of RAI varied according to the definition used. SalC-defined RAI was significantly more common after low-dose than standard-dose test (54.7% vs. 20%; P < 0.001). Δserum total cortisol-defined RAI was also significantly more frequent after low-dose than standard-dose test (66.3% vs. 24.2%; P < 0.001). Considering low-dose test/SalC criteria as reference diagnostic criteria, standard-dose/salivary and Δserum total cortisol criteria showed low specificity for RAI diagnosis (43.9% and 52.7%, respectively). Survival probability was significantly lower in patients with low-dose test/SalC-defined RAI compared to those without (53.8% vs. 79.1%; P = 0.01). SalC-defined RAI after low-dose test was significantly more common than that defined after standard-dose test (72.7% vs. 30.3%; P < 0.001) among patients who died., Conclusion: Low-dose test/SalC definition can identify RAI in about half of patients with stable cirrhosis and ascites and is associated with increased mortality., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiovascular disease is the predominant cause of death in type 2 diabetes mellitus (T2DM). Evidence suggests a strong association between duration and degree of hyperglycemia and vascular disease. However, large trials failed to show cardiovascular benefit after intensive glycemic control, especially in patients with longer diabetes duration. Atherosclerosis is a chronic and progressive disease, with a long asymptomatic phase. Subclinical atherosclerosis, which is impaired in T2DM, includes impaired vasodilation, increased coronary artery calcification (CAC), carotid intima media thickness, arterial stiffness, and reduced arterial elasticity. Each of these alterations is represented by a marker of subclinical atherosclerosis, offering a cost-effective alternative compared to classic cardiac imaging. Their additional use on top of traditional risk assessment strengthens the predictive risk for developing coronary artery disease (CAD). We, herein, review the existing literature on the effect of glycemic control on each of these markers separately. Effective glycemic control, especially in earlier stages of the disease, attenuates progression of structural markers like intima-media thickness and CAC. Functional markers are improved after use of newer anti-diabetic agents, such as incretin-based treatments or sodium-glucose co-transporter-2 inhibitors, especially in T2DM patients with shorter disease duration. Larger prospective trials are needed to enhance causal inferences of glycemic control on clinical endpoints of CAD., Competing Interests: Conflict-of-interest statement: No conflict of Interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Tyrosine kinase inhibitors (TKIs) have been used in patients with advanced medullary thyroid carcinoma (MTC); however, data on their effectiveness and safety are limited. The aim of this systematic review and meta-analysis was to document clinical response and toxicities of TKIs in advanced MTC., Methods: We systematically searched major databases for articles or abstracts on TKI use in MTC patients until May 2018. Objective response (OR), defined as the sum of complete + partial response, expressed as percentage, was our primary endpoint, while disease stability, disease progression (DP), median progression-free survival (PFS), and drug discontinuation rate due to adverse events (AEs) were secondary endpoints. Pooled percentages, PFS time, and 95% CIs were reported., Results: Thirty-three publications were finally included in the analysis: 1 phase IV, 2 phase III trials evaluating vandetanib and cabozantinib, respectively, 20 phase I or II studies, and the remaining 10 studies of retrospective-observational nature. OR was documented in 28.6% (95% CI 25.9-31.9) of patients. Stable disease was recorded in 46.2% (95% CI 43.3-49.1). Overall, DP was observed in 22.9% (95% CI 20.4-27.6). Grade 3 or more AEs occurred in 48.5% (95% CI 45.5-51.5) of patients, and drug discontinuation was reported in 44.7% (95% CI 41.7-47.6). In general, use of TKIs conferred a PFS of 23.3 months (95% CI 21.07-25.5). In particular, vandetanib induced an OR in 33.8% (95% CI 29.6-38.0) of patients and cabozantinib in 27.7% (95% CI 22.05-33.4). DP occurred in 23.7% (95% CI 19.9-27.6) with vandetanib use and in 22.6% (95% CI 17.4-27.9) in cabozantinib-treated patients. Sorafenib, the third most frequently studied drug, showed intermediate efficacy, but higher discontinuation rates., Conclusion: Treatment with TKIs in MTC patients with progressive disease is associated with a moderate therapeutic benefit, with achievement of either disease stability or partial response in 73%. The toxicity of these drugs is not negligible, but it is, nonetheless, manageable., Competing Interests: S.T. has participated in educational, research or advisory activities supported by Amgen, Astra-Zeneca, Ipsen, Novartis, and Sanofi-Aventis. M.A. has served in the advisory board for the use of vandetanib in MTC and has received lecture fees from Sanofi. All other authors have no conflict of interest., (Copyright © 2020 by S. Karger AG, Basel.)

Purpose: We have recently demonstrated that absolute counts of circulating proinflammatory monocytes were lower in obese patients without metabolic syndrome (MS) (metabolically healthy obese, MHO) compared with those with MS (metabolically unhealthy obese, MUO), but higher compared with healthy lean controls (MHL). We hypothesized that circulating resistin, a cytokine secreted by white blood cells (WBC), is involved in obesity-related low-grade inflammation. The aim of this study was to (a) determine serum resistin levels among MUO and MHO subjects and (b) investigate the role of circulating WBC subsets as potential determinants of resistin., Methods: Study participants were 58 obese (33 MUO, 25 MHO) and 25 MHL individuals. Serum levels of resistin, high-sensitivity C-reactive protein (hsCRP), and absolute counts of circulating WBC subpopulations were determined. Comparisons were sex- and age-adjusted., Results: Serum resistin levels in MHL were lower compared with those of obese (p = 0.041), but similar to those of MHO (p = 0.856) individuals. Both resistin (p = 0.005) and absolute neutrophil count (NeuA) (p = 0.025) were higher in MUO compared with MHO. The difference in resistin levels between obese and MHL individuals disappeared after adjustment for NeuA. Resistin correlated positively with absolute total monocyte count (p = 0.037) in MHL and with body mass index (BMI) (p = 0.023), hsCRP (p = 0.022), and NeuA (p = 0.044) in obese subjects. Resistin association with ΒΜΙ disappeared after adjustment for hsCRP, while association with hsCRP disappeared after further adjustment for NeuA., Conclusion: Circulating resistin was higher in MUO compared with MHO. The increased secretion of resistin by the greater number of neutrophils in the former may have contributed to this regulation.

Background: Several methods exist for flow-cytometric estimation of human peripheral blood CD4 + T regulatory cells (CD4 + Tregs)., Methods: We report our experience with the estimation of human CD4 + Tregs via three different characterizations using flow cytometry (CD25 high FoxP3 + , CD25 high CD127 low/- FoxP3 + , and CD4 + CD25 high/int CD45ROFoxP3 + ) in normal subjects. We have used these methods on the control populations from two studies (32 and 36 subjects, respectively), the latter two methods retrospectively on the subjects of the first study. The six CD4 + T cell fractions obtained by the third method were differentially colored to ascertain the distribution of these cell fractions in the CD25/FoxP3, CD45RO/FoxP3, and CD25/CD127 dot plots from CD4/CD25/CD45RO/FoxP3 and CD4/CD25/CD45RO/CD127 panels., Results: Each approach gives significantly different estimates of Tregs (expressed as percentage of CD4 + T cells), with the second almost invariably yielding higher percentages than the other two. Only the third approach can distinguish among effector and naïve Tregs and FoxP3 + non-Tregs. Analysis of CD25/CD127 dot plots reveals that Treg delineation via the widely used definition of CD4 + CD25 high CD127 low/- cells unavoidably yields a mixture of nearly all effector and most of naïve Tregs, as well as FoxP3 + non-Tregs plus other cells. Delineation of effector/naïve Tregs and FoxP3 + non-Tregs is possible via CD45RO/CD25 dot plots but not by CD45RO/FoxP3 counterparts (as done previously) because of overlapping FoxP3 intensities among Tregs and non-Tregs., Conclusion: Our comparison shows that CD4/CD25/CD45RO/FoxP3 panels are an objective means of estimating effector and naïve Tregs via colored dot plots, aiding thus in Treg delineation in health and detecting aberrations in disease., (© 2019 International Clinical Cytometry Society.)

The CANVAS program detected a 2-fold increased risk of lower limb amputation in patients treated with canagliflozin compared with those with placebo. This adverse effect was not confirmed in the CREDENCE trial. Moreover, randomized controlled trials with other agents in this class, dapagliflozin and empagliflozin, did not detect increased risk of amputation. Observational studies, cohort studies, and pharmacovigilance reports with sodium-glucose cotransporter 2 inhibitor (SGLT2i) have reported conflicting results. Whether this adverse event is a drug effect specific to canagliflozin, or a SGLT2i class effect, remains controversial. Until more evidence emerges, clinicians should avoid using SGLT2i, especially canagliflozin, in patients with previous amputations or existing foot ulceration.

Aim: Sex differences have long been reported in schizophrenia leading to the hypothesis that sex hormones may be implicated in the pathophysiology of the disorder. We assessed gonadal hormones during the fasted state in drug-naïve patients with psychosis. Method: Fasting serum concentrations of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), testosterone, free-testosterone, Sex Hormone Binding Globulin (SHBG) and oestradiol (E 2 ) were compared between a group of 55 newly diagnosed, drug-naïve, first-episode men with psychosis and a group of 55 healthy controls, matched for age, smoking status and BMI. Testosterone, free-testosterone and SHBG were compared between a group of 32 drug-naïve, first-episode females with psychosis and a group of 32 healthy controls matched for age, smoking status and BMI. Results: Testosterone and free-testosterone levels were significantly lower in the patients' group and SHBG levels significantly higher in the patients' group compared to those in healthy controls. The two female groups had similar values in the hormones which were measured. Conclusion: Our findings provide evidence of lower testosterone and free-testosterone levels and increased SHBG levels in drug-naïve, first-episode males with psychosis.KEY POINTSReduced testosterone and free-testosterone levels in drug-naive, first-episode males with psychosis.Increased SHBG levels in drug-naive first-episode males with psychosis.No difference in FSH, LH and E2 levels between drug-naive first episode males with psychosis and controls.No difference in testosterone, free-testosterone and SHBG levels between drug-naive, first-episode women with psychosis and controls.

Background: Obesity is associated with macrophage infiltration in adipose tissue that induces insulin resistance and contributes to the development of metabolic syndrome (MS). The aim of this study was to investigate whether circulating monocyte subsets (macrophage precursors) differ among obese subjects with MS [metabolically unhealthy obese (MUO)], obese subjects without MS [metabolically healthy obese (MHO)], and metabolically healthy lean (MHL) individuals. Methods: Fifty-eight obese (33 MUO, 25 MHO) and 25 MHL individuals participated in the study. Absolute blood counts of classical (Mon1A), intermediate (Mon2A), and nonclassical (Mon3A) monocyte subsets were measured by flow cytometry. Results: Increased proinflammatory monocyte counts (Mon2A, Mon3A) were observed in obese compared with MHL individuals ( P  = 0.001 and P  = 0.017 respectively). Mon2A count in MHO was lower compared with that in MUO subjects ( P  = 0.036) but higher compared with MHL controls ( P  = 0.032). Mon2A was positively associated with serum triglyceride levels ( r  = 0.328, P  = 0.023) and mean blood pressure (BP) ( r  = 0.457, P  = 0.001) in obese subjects. Among MS components, only the presence of elevated BP (≥130/85 mmHg) was independently associated with increased Mon2A in obese subjects ( P  < 0.001). Conclusions: Absolute counts of proinflammatory monocytes were lower in metabolically healthy compared with MUO individuals, but higher compared with healthy lean controls. The presence of low-grade inflammation suggests that "metabolically healthy" obesity is not a benign condition. ClinicalTrials.gov identifier: NCT03241394.