Two years with GIOIA 'Effects of gliflozins and gliptins on markers of cardiovascular damage in type 2 diabetes': A prospective, multicentre, quasi-experimental study on sodium-glucose cotransporter 2 and dipeptidyl peptidase-4 inhibitors in diabetes clinical practice.

AIM: To assess and compare the metabolic and vascular effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) in the clinical practice of patients with type 2 diabetes in Italy. MATERIALS AND METHODS: GIOIA is a 2-year prospective, multicentre, quasi-experimental study that enrolled patients with type 2 diabetes initiating SGLT-2i or DPP-4i for inadequate glycaemic control [glycated haemoglobin (HbA1c) >7%] between March 2018 and March 2021. The primary endpoints were changes in markers of organ damage [carotid intima-media thickness (CIMT), albuminuria, myocardial function] and HbA1c from baseline to year 2. RESULTS: In total, 1150 patients were enrolled in the study (SGLT-2i n = 580, DPP-4i n = 570). Patients initiated on SGLT-2i were younger (about 6 years) and heavier (about 11 kg), had higher HbA1c level (1% more), more albuminuria and cardiovascular events (16% more) than patients initiated on DPP-4i. CIMT and echocardiographic parameters were not significantly different. Propensity score matching yielded two groups, each consisting of 155 patients with diabetes with similar baseline characteristics. Despite a significant similar reduction in HbA1c levels in both groups (-0.8%), more patients on SGLT-2i had regression of CIMT and albuminuria (22% and 10%, respectively, p < .001 vs. DPP-4i); more patients on DPP-4i had progression of CIMT and albuminuria (23% and 28%, respectively, p < .001 vs. SGLT-2i). Left ventricular ejection fraction improved slightly (3%, p = .043) on SGLT-2i only. CONCLUSIONS: In a real-world setting, both SGLT-2i and DPP-4i improve glycaemic control persisting after 2 years of treatment, with a robust effect on both CIMT and albuminuria regression for SGLT-2i as compared with DPP-4i in the propensity score matching.

Biochemical predictors of diabetic foot osteomyelitis: A potential diagnostic role for parathormone.

AIMS: The aims of this study were to evaluate parathormone (PTH) levels in people with diabetic foot ulcers (DFU) and investigate the relationship between PTH levels and osteomyelitis (OM) in this population. MATERIALS AND METHODS: Eighty-eight patients were admitted for DFU in a tertiary-care centre from October 2021 to May 2022. OM was diagnosed by clinical, laboratory, and radiological evaluations. Laboratory measurements and clinical parameters were collected from medical records. Participants in the study were divided into two groups according to the diagnosis of OM (patients with OM, group 1 [n = 54] and patients without OM, group 2 [n = 34]). RESULTS: Compared with group 2, patients in group 1 were younger and had a longer duration of diabetes. Erythrocyte sedimentation rate and fibrinogen were significantly higher in group 1 compared with group 2. PTH levels were significantly lower (group 1 vs. group 2, median [interquartile range] 16.2 (11.6, 31.0) vs. 23.7 (17.0, 38.1), p = 0.008) and alkaline phosphatase was significantly higher (97.0 (79.0, 112.0) vs. 88.0 (63.0, 107.0), p = 0.031) in group 1. In multiple linear regression analysis, the only independent predictors of PTH concentrations were alkaline phosphatase levels (ß-coefficient 0.441, p < 0.001) and the presence of OM (ß-coefficient -0.290, p = 0.038). CONCLUSIONS: In a population of patients with diabetes and OM admitted to a tertiary university centre, PTH levels were lower as compared with diabetic individuals without OM. The OM and alkaline phosphatase levels were independent predictors of PTH levels in this selected population.

Suboptimal accuracy of ultrasound and ultrasound-based risk stratification systems in detecting medullary thyroid carcinoma should not be overlooked. Findings from a systematic review with meta-analysis.

OBJECTIVE: Ultrasound (US) is the pivotal procedure during the diagnostic work-up of thyroid nodule and several US-based risk stratification systems (RSSs) have been recently developed. Since the performance of RSSs in detecting medullary thyroid carcinoma (MTC) has been rarely investigated, the present systematic review aimed to achieve high evidence about (1) how MTC is classified according to RSSs; (2) if RSSs correctly classify MTC at high risk/suspicion, and (3) if MTC is classified as suspicious at US when RSSs are not used. DESIGN: The review was performed according to MOOSE. The online search was performed by specific algorithm on January 2022. A random-effects model was used for statistical analysis. RESULTS: Twenty-five papers were initially included and their risk of bias was generally low. According to ATA system, 65% of MTCs was assessed at high suspicion and 25% at intermediate suspicion. Considering all RSSs, a 54.8% of MTCs was put in a high-risk/suspicion category. Pooling data from studies without data of RSS the prevalence of ultrasonographically suspicious MTCs was 60%. CONCLUSIONS: As conclusion, MTC presentation according to RSSs is partially known and it is classified in a high-risk/suspicion category of RSSs in just over a half of cases. This advises for further studies, ideally supported by international societies, to better define the US presentation of MTC.

Assessment of Neuroendocrine Changes and Hypothalamo-Pituitary Autoimmunity in Patients with COVID-19.

SARS-CoV-2 may affect the hypothalamic-pituitary axis and pituitary dysfunction may occur. Therefore, we investigated neuroendocrine changes, in particular, secondary adrenal insufficiency, using a dynamic test and the role of autoimmunity in pituitary dysfunction in patients with COVID-19. The single-center, prospective, case-control study included patients with polymerase chain reaction (PCR)-confirmed COVID-19 and healthy controls. Basal hormone levels were measured, and the adrenocorticotropic hormone (ACTH) stimulation test was performed. Antipituitary (APA) and antihypothalamic antibodies (AHA) were also determined. We examined a total of 49 patients with COVID-19 and 28 healthy controls. The frequency of adrenal insufficiency in patients with COVID-19 was found as 8.2%. Patients with COVID-19 had lower free T3, IGF-1, and total testosterone levels, and higher cortisol and prolactin levels when compared with controls. We also demonstrated the presence of APA in three and AHA in one of four patients with adrenal insufficiency. In conclusion, COVID-19 may result in adrenal insufficiency, thus routine screening of adrenal functions in these patients is needed. Endocrine disturbances in COVID-19 are similar to those seen in acute stressful conditions or infections. Pituitary or hypothalamic autoimmunity may play a role in neuroendocrine abnormalities in COVID-19.

Neutropenia in patients with hyperthyroidism: Systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Neutropenia, a low absolute neutrophil count (ANC), may be a sign of new-onset hyperthyroidism. The aim of this systematic review and meta-analysis was to provide the most reliable estimates of prevalence, degree and response to treatments of neutropenia in the pure hyperthyroidism setting. METHODS: A comprehensive literature search was performed in PubMed and Scopus databases for retrieving articles in English and non-English languages reporting ANC values/neutropenic cases at presentation and after therapy in patients with hyperthyroidism. A proportion meta-analysis was performed with DerSimonian and Laird method (random-effects model). Pooled data were presented with 95% confidence intervals (95% CI) and displayed in a forest plot. I2 statistic index was used to quantify the heterogeneity among the studies. Sensitivity analyses for the prevalence of neutropenia and the mean of ANC in hyperthyroid patients were performed by excluding the studies without full details. Trim and fill analysis and Egger's linear regression test were carried out to evaluate the publication bias. A two-sided P-value of <.05 was regarded as significant for all analyses. The National Heart, Lung and Blood Institute Quality Assessment Tool was used to evaluate the quality of studies included. RESULTS: The literature search yielded 1880 studies of which 13 studies were included for systematic review and meta-analysis. Results of the meta-analysis demonstrated that the prevalence of neutropenia in newly diagnosed and untreated patients with Graves' hyperthyroidism was 10% (CI 5%-19%, I2 88.6%) and summary mean ANC value in neutropenic was 1.4 ± 0.3 × 109 /L. In all neutropenic patients under ATD therapy neutropenia resolved, thus without the worsening of the baseline ANC values or the development of agranulocytosis. The sensitivity analyses showed similar results as those of the main analyses. For all outcomes, the publication bias was not statistically significant or not calculable. CONCLUSIONS: Graves' disease per se is associated with neutropenia in about 10% of cases. Neutropenia usually appears as a mild to moderate laboratory abnormality with no detectable consequences. Subnormal/mild neutropenia should not be regarded as a contraindication to use ATDs, and clinicians should know that treating hyperthyroidism they have a significant chance to normalize ANC too.

Up and down waves of glycemic control and lower-extremity amputation in diabetes.

Lower extremity amputations (LEA) are associated with a high mortality and medical expenditure. Diabetes accounts for 45% to 70% of LEA and is one of the most potent risk factors for peripheral artery diseases (PAD). The existence of a link between the recent relaxation of glycemic targets and the resurgence of LEA is suggested from the analysis of adult participants in the National Health and Nutrition Examination Survey (NHANES) between 2010 and 2015, when diabetes-related LEA increased by more than 25% associated with a decline in glycemic control. Indeed, in "the perfect wave" of NHANES, including the years 2007-2010, there was the highest number of diabetic people with hemoglobin A1c (HbA1c), non-high-density lipoprotein (HDL) cholesterol and blood pressure levels at their respective targets, associated with the lowest number of LEA. Until now, the ACCORD study, testing the role of aggressive vs conventional glucose control, and the LEADER trial, evaluating the effects of liraglutide versus placebo, have shown a reduced incidence of LEA in people with type 2 diabetes. The results of ongoing clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RA, liraglutide or semaglutide) hopefully will tell us whether the wider use of these drugs may provide additional vascular benefits for diabetic people affected by PAD to decrease their risk of LEA.

GLP-1 receptor agonists vs. SGLT-2 inhibitors: the gap seems to be leveling off.

Cardiovascular disease (CVD) remains the leading cause of death in patients with type 2 diabetes (T2D). Older age, prior heart failure (HF) and CV events, peripheral artery disease, and kidney complications can identify a subgroup of patients with T2D at high risk of mortality who are likely to achieve the greatest benefit from newer glucose-lowering agents. Both glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can reduce CV risk in patients with T2D, and both are recommended by the American Diabetes Association to reduce the risk of major cardiovascular events (MACE). The magnitude of the benefits of GLP-1RA and SGLT-2 inhibitors on MACE are similar, ranging from 12 to 14% reduction of risk, but only GLP-1RA may reduce the risk of stroke. The most striking difference between the two classes of drugs relates to the amelioration on hospitalization for HF, as the benefit of SGLT-2 inhibitors surpass by threefold that obtained with GLP-1RA. Despite this, GLP-1RA also exert a significant benefit on HF which suggest their use when SGLT-2 inhibitors are contraindicated or not tolerated. The difference between the two classes is less impressive for the kidney outcome. Overall, the results of CVOTs published so far seems to suggest that the gap between the cardiorenal benefits of SGLT-2 and GLP-1RA is narrowing.

Sodium-glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes.

Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.

Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression.

BACKGROUND: Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. METHODS: An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS: The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P < 0.001), with significant heterogeneity between studies (I2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = - 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = - 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. CONCLUSIONS: The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs.

BACKGROUND: It has been suggested that sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the cardiorenal risk in patients with type 2 diabetes (T2D). The purpose of this study is to provide an update of all large cardiovascular outcome trials (CVOTs) with SGLT-2 inhibitors to assess their cardiorenal efficacy in patients with and without T2D. METHODS: An electronic search up to 30 September 2021 was conducted in PubMed, EMBASE, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. to determine eligible trials. We included CVOTs comparing any SGLT-2 inhibitor with placebo, reporting desired cardiovascular or renal outcomes and with a follow-up duration of at least 6 months. RESULTS: Eleven CVOTs, with data from five SGLT-2 inhibitors (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) and 77,541 participants, were included. In the overall analysis, the risk of the composite CV mortality or hospitalization for heart failure (HF) was reduced by 23% (HR = 0.77, 95% CI 0.73-0.82, P < 0.001) compared with placebo, with not significant heterogeneity (I2 = 26%, P = 0.20), and irrespective of the presence of T2D (P for interaction = 0.81) and age (> 65 vs ≤ 65 years, P for interaction = 0.78). The risk of CV mortality, total mortality and hospitalization for HF was significantly reduced by 16%, 13%, and 32%, respectively; similarly, the risk of the composite renal outcome was reduced by 35% (HR = 0.65, 95% CI 0.56-0.75), with moderate heterogeneity (I2 = 32%). In the analysis of 6 CVOTs reporting the data, the risk of major cardiovascular events (MACE) was reduced by 12%, with low heterogeneity (I2 = 21.2%, P = 0.19) and irrespective of the presence of established CV disease at baseline (P for interaction = 0.46). CONCLUSIONS: Therapy with SGLT-2 inhibitors in patients with cardiometabolic and renal diseases results in a sustained to moderate reduction of the composite CV death or hospitalization for HF, robust reduction of HF and renal outcomes, moderate reduction of CV mortality, total mortality and MACE.

GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: an updated meta-analysis of eight CVOTs.

BACKGROUND: A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). METHODS: We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). RESULTS: GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79-0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67-0.82, P < 0.001). CONCLUSIONS: GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Thyroid sequelae of COVID-19: a systematic review of reviews.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to cause multi-organ effects including endocrine disorders. The impact of COVID-19 on the thyroid gland has been described but several aspects have to be clarified. The systematic review was conceived to achieve more solid information about: 1) which thyroid disease or dysfunction should be expected in COVID-19 patients; 2) whether thyroid patients have a higher risk of SARS-CoV-2 infection; 3) whether the management has to be adapted in thyroid patient when infected. The literature was searched by two authors independently. A 5-step search strategy was a priori adopted. Only reviews focused on the relationship between thyroid and COVID-19 were included. The last search was performed on February 21st 2021. Two-hundred-forty-seven records was initially found and nine reviews were finally included. The reviews identified several potential thyroid consequences in COVID-19 patients, such as thyrotoxicosis, low-T3 syndrome and subacute thyroiditis, while no relevant data were found regarding the potential impact of COVID-19 on the management of patients on thyroid treatment. The present systematic review of reviews found that: 1) patients diagnosed with COVID-19 can develop thyroid dysfunction, frequently non-thyroidal illness syndrome when hospitalized in intensive care unit, 2) having a thyroid disease does not increase the risk for SARS-CoV-2 infection, 3) thyroid patients do not need a COVID-19-adapted follow-up. Anyway, several factors, such as critical illness and medications, could affect thyroid laboratory tests.

Impact of COVID-19 on the thyroid gland: an update.

Coronavirus disease 2019 (COVID-19) is the pandemic of the new millennium. COVID-19 can cause both pulmonary and systemic inflammation, potentially determining multi-organ dysfunction. Data on the relationship between COVID-19 and thyroid have been emerging, and rapidly increasing since March 2020. The thyroid gland and the virus infection with its associated inflammatory-immune responses are known to be engaged in complex interplay. SARS-CoV-2 uses ACE2 combined with the transmembrane protease serine 2 (TMPRSS2) as the key molecular complex to infect the host cells. Interestingly, ACE2 and TMPRSS2 expression levels are high in the thyroid gland and more than in the lungs. Our literature search provided greater evidence that the thyroid gland and the entire hypothalamic-pituitary-thyroid (HPT) axis could be relevant targets of damage by SARS-CoV-2. Specifically, COVID-19-related thyroid disorders include thyrotoxicosis, hypothyroidism, as well as nonthyroidal illness syndrome. Moreover, we noticed that treatment plans for thyroid cancer are considerably changing in the direction of more teleconsultations and less diagnostic and therapeutical procedures. The current review includes findings that could be changed soon by new results on the topic, considering the rapidity of worldwide research on COVID-19.

Female Sexual Function in Young Women With Type 1 Diabetes and Additional Autoimmune Diseases.

BACKGROUND: Female sexual dysfunctions (FSDs) are frequent concerns in women with type 1 diabetes (T1D), which is frequently associated with other autoimmune diseases (ADs). AIM: To assess sexual function in young type 1 diabetic women with or without additional ADs. METHODS: Women with T1D aged 18-35 years with a stable couple relationship and no oral contraceptive use were enrolled. Diabetic women with concomitant ADs were also identified. All women completed the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale. OUTCOMES: The main outcome was the prevalence of FSD. The FSFI-single domain scores were also evaluated in diabetic women with or without additional ADs. RESULTS: The global population included 154 diabetic women, of whom 66 (42%) had at least one additional AD. The prevalence of FSD was similar among diabetic women with and those without (30% vs 32%, P = .980) additional ADs. The FSFI-desire score was significantly lower among diabetic women with concomitant ADs than those without ADs [median (interquartile range), 4.1 (3.6, 4.8) vs 4.6 (4.0, 5.0), P = .042]. CLINICAL IMPLICATIONS: An early evaluation of sexual function in women with T1D and concomitant ADs should be encouraged. STRENGTHS & LIMITATIONS: Major strengths are the use of 2 validated tools to diagnose FSD and the relatively large number of subjects investigated. The limitations include the cross-sectional nature of the study, which does not allow to make inference regarding the cause and effect. CONCLUSION: Diabetic women with additional ADs show an impairment in sexual desire as compared with those suffering only from diabetes. Longo M, Cirillo P, Scappaticcio L, et al. Female Sexual Function in Young Women With Type 1 Diabetes and Additional Autoimmune Diseases. J Sex Med 2021;18:219-223.

Medical treatment of thyrotoxicosis.

Medical treatment is the primary therapeutic option for thyrotoxicosis/hyperthyroidism. Two groups of causes of thyrotoxicosis (i.e. thyrotoxicosis with hyperthyroidism and thyrotoxicosis without hyperthyroidism) need to be considered for therapeutic reasons. Herein we provide an updated review on the role of conventional medical therapies (i.e. ß-blockers, antithyroid drugs [ATDs], corticosteroids, inorganic iodide, perchlorate, cholecystographic agents, lithium, cholestyramine) in the main causes of thyrotoxicosis, starting from the rationale subtending their clinical application.

Glucagon-Like Peptide-1 Receptor Agonists and Prevention of Stroke Systematic Review of Cardiovascular Outcome Trials With Meta-Analysis.

Background and Purpose- The purpose of this study was to conduct a meta-analysis of CVOTs (cardiovascular outcome trials) to evaluate the effect of glucagon-like peptide-1 receptor agonists therapy in reducing the risk of stroke in patients with type 2 diabetes mellitus. Methods- PubMed and other electronic sources were searched until June 20, 2019, to identify relevant studies. Hazard ratios with 95% CIs were used as a measure of the association between use of glucagon-like peptide-1 receptor agonists and risk of stroke after pooling data across trials. Results- Seven CVOTs with 56 004 participants were identified. Use of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus was associated with 15% lower risk of nonfatal stroke (P=0.002), 19% lower risk of fatal stroke (P=0.150), and 16% lower risk of total stroke (P=0.001). There was no association between reductions of hemoglobin A1c levels or body weight and risk of stroke. Conclusions- Glucagon-like peptide-1 receptor agonists reduce the risk of nonfatal stroke in patients with T2D.

Diagnostic testing for Graves' or non-Graves' hyperthyroidism: A comparison of two thyrotropin receptor antibody immunoassays with thyroid scintigraphy and ultrasonography.

OBJECTIVE: Graves' disease (GD) is the most common cause of hyperthyroidism. In many cases, when the aetiological diagnosis of GD is not evident based on the clinical evaluation and thyroid function testing, it may become challenging to distinguish Graves' hyperthyroidism from other forms of thyrotoxicosis. The current study was primarly carried out to compare the diagnostic effectiveness of two TSH receptor antibody immunoassays (IMAs), ultrasonography and thyroid scintigraphy in hyperthyroidism scenario. METHODS: We retrospectively analysed consecutive patients with newly diagnosed and untreated thyrotoxicosis who underwent thyroid functional tests, both TRAb and TSI measurements, thyroid scintigraphy and ultrasonography. TRAb assessment was carried out by Kryptor® compact PLUS, while TSI by Immulite® . Echo pattern 3 corresponded to 'thyroid inferno', and the final diagnosis of GD vs non-Graves' hyperthyroidism was made according to the thyroid scan (qualitative scintigraphy). Receiver operating characteristic (ROC) curves were drawn using the final diagnosis as reference. Clinical sensitivity and specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were calculated for all the tests. RESULTS: A total of 124 untreated hyperthyroid patients were included in our study (GD, n = 86 vs non-Graves' hyperthyroidism, n = 38). ROC curves showed that the optimal cut-off values associated with the highest diagnostic sensitivity and specificity was 0.7 IU/L for TRAb Kryptor® (93 [85.4-97.4] and 86.8 [71.9-95.5]) and 0.1 IU/L for TSI Immulite® (94.2 [86.9-98.1] and 84.2 [68.7-93.9]), respectively. For the echo pattern 3, we found a good sensitivity (92.1%) and a high PPV (95.2%) but a quite low specificity value (69.8%) and a relative low NPV (57.5%). For thyroid scintigraphy, the TcTU cut-off value of 1.3% corresponded to the best limit for sensitivity and specificity in our patients (95.3 [88.5-98.7] and 96.4 [81.6-99.4]). The Passing-Bablok regression equation and the Bland-Altman test showed a great degree of correlation and agreement existed between TRAb Kryptor® and Immulite® TSI results. CONCLUSIONS: Thyroid scintigraphy remains the most accurate method to differentiate causes of thyrotoxicosis. However, TRAb assays can be alternatively adopted in this setting, limiting the use of thyroid scintigraphy (TcTU evaluation) to TRAb-negative patients. Thyoid US is less accurate than both TRAb/TSI and thyroid scintigraphy, but the 'thyroid inferno' pattern provides a high PPV for GD.

Ultrasound systems for risk stratification of thyroid nodules prompt inappropriate biopsy in autonomously functioning thyroid nodules.

OBJECTIVE: Ultrasound (US) risk stratification systems (RSSs) have been developed to reduce the number of unnecessary fine-needle aspiration (FNA) biopsies in patients with thyroid nodules. Autonomously functioning thyroid nodules (AFTN) account for 5%-10% of palpable lesions and are very rarely malignant. The present study was undertaken to investigate how RSSs classify AFTNs and whether RSSs are able to avoid unnecessary FNA biopsies in such cases. METHODS: Patients with AFTN who had undergone US, scintigraphy and thyroid function evaluation from December 2016 to December 2017 were selected. US images were retrospectively reviewed and AFTN reclassified according to AACE/ACE/AME, ACR-TIRADS, ATA, BTA, EU-TIRADS, K-TIRADS and TIRADS. Risk class and indication for FNA were assessed. RESULTS: A number of 87 AFTNs from 85 consecutive patients were enrolled. A median diameter of 22 mm (range 10-59) was found, with an ovoid isoechoic nodule being the most frequent US presentation. When AFTNs were reclassified according to US RSSs, the most common categories were low and intermediate risk. AFTNs were assessed as being at high risk/high suspicion/malignant in 1%-9%, with good agreement among AACE/ACE/AME, ATA, EU-TIRADS, K-TIRADS and TIRADS. Remarkably, FNA was indicated in 27%-90% of AFTNs. A statistically significant difference among the systems was found; 8% of cases were nonclassifiable by one or more US RSS. CONCLUSIONS: Ultrasound RSSs prompt inappropriate FNA in a significant number of patients with AFTN.

Relationship between improvement of glycaemic control and reduction of major cardiovascular events in 15 cardiovascular outcome trials: A meta-analysis with meta-regression.

AIM: In order to disclose relations between reduction of haemoglobin A1c (HbA1c) levels and risk of major cardiovascular events (MACE), we performed a meta-analysis with metaregression of all cardiovascular outcome trials (CVOTs) so far published in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: An electronic search up to February 10, 2020 was conducted to determine eligible trials. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. RESULTS: The 15 CVOTs included evaluated 138,250 patients. In the pooled analysis, the risk of MACE was significantly reduced by 9% (hazard ratio, HR = 0.91, 0.87-0.95, P <0.001) as compared with placebo, with significant heterogeneity between trials (I2 = 44%, P = 0.060) There was a robust relation between the reduction in achieved HbA1c at the end of the trial and the HR reduction for MACE (beta = -0.3169, P = 0.029), explaining most (78%) of the between-study variance; this relation was totally driven by the risk reduction of non-fatal stroke only, which explained 100% of between-study variance, and apparently restricted to the class of glucagon-like peptide 1 receptor agonists (GLP-1RAs). There was no relation between the reduction in achieved HbA1c and the HR for heart failure (variance explained = 0%) or all-cause mortality (variance explained = 6%). CONCLUSION: The blood glucose reduction observed in CVOTs may play some role in reducing the risk of non-fatal stroke, at least during treatment with GLP-1RAs, without affecting the other two components of MACE.

Impact of Pituitary Autoimmunity and Genetic Disorders on Growth Hormone Deficiency in Children and Adults.

Growth hormone (GH), mostly through its peripheral mediator, the insulin-like growth factor 1(IGF1), in addition to carrying out its fundamental action to promote linear bone growth, plays an important role throughout life in the regulation of intermediate metabolism, trophism and function of various organs, especially the cardiovascular, muscular and skeletal systems. Therefore, if a prepubertal GH secretory deficiency (GHD) is responsible for short stature, then a deficiency in adulthood identifies a nosographic picture classified as adult GHD syndrome, which is characterized by heart, muscle, bone, metabolic and psychic abnormalities. A GHD may occur in patients with pituitary autoimmunity; moreover, GHD may also be one of the features of some genetic syndromes in association with other neurological, somatic and immune alterations. This review will discuss the impact of pituitary autoimmunity on GHD and the occurrence of GHD in the context of some genetic disorders. Moreover, we will discuss some genetic alterations that cause GH and IGF-1 insensitivity and the arguments in favor and against the influence of GH/IGF-1 on longevity and cancer in the light of the papers on these issues that so far appear in the literature.