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Kyeong Jin Kim, Sujung Jang, Kyoung Jin Kim, Jee Hyun An, Nam Hoon Kim, Dong Yeob Shin, Hye Jin Yoo, Hee Young Kim, J. A. Seo, Nan Hee Kim, Juneyoung Lee, Kyung Mook Choi, Sei Hyun Baik and Sin Gon Kim

Objective: Thyroid cancer (TC) incidence has increased robustly in Korea. However, the actual cause of death, overall mortality risk, and cause-specific mortality risk in TC patients have not been clearly elucidated.

Design: Retrospective cohort study

Methods: We analyzed 4,082 TC patients from the Korean National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS, 2002–2013) with a median of 48 months follow-up. We compared these patients with 12,246 controls matched for age, sex, and histories of major cardiovascular disease (CVD) to investigate the cause of death and risks of overall and cause-specific mortality.

Results: Overall, 61 deaths (1.5%) occurred in the TC group. The most common cause of death was TC-specific mortality (32.8%), followed by other malignancy-related mortality (31.1%) and CVD mortality (13.1%). The overall mortality risk was comparable between the TC and control groups (unadjusted hazard ratio [HR], 1.17; 95% confidence interval [CI], 0.87–1.58); the adjusted HR remained at 1.25 (95% CI, 0.90–1.74) after multivariate adjustment for body mass index (BMI), socioeconomic status (SES), smoking, alcohol consumption, and histories of hypertension, diabetes mellitus, and dyslipidemia. In addition, there was not enough evidence against the surmise that the CVD mortality risk was similar between the TC and control groups, with an HR of 0.50 (95% CI, 0.22–1.16) after adjustment for CVD risk factors.

Conclusions: Excellent overall survival was observed in TC patients. The most common cause of death was TC-specific mortality, suggesting the importance of thyroid cancer treatment. The overall and cause-specific mortality risks, particularly CVD mortality risk, did not differ between TC patients and the general population.

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Steven W J Lamberts and Leo J Hofland

Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.

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Ida Kim Wium-Andersen, Merete Osler, Martin Balslev Jørgensen, Jørgen Rungby and Marie Kim Wium-Andersen

Objective

Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia.

Design

We performed a nested case–control study within a cohort of all 176 250 patients registered with type 2 diabetes in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (insulin, metformin, sulfonylurea and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 (GLP1) analogs, sodium-glucose transport protein 2 (SGLT2) inhibitors and acarbose).

Methods

Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders.

Results

Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89–0.99), 0.80 (95% CI 0.74–0.88), 0.58 (95% CI: 0.50–0.67), and 0.58 (95% CI: 0.42–0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment.

Conclusion

Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes.

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Oliveira Flávia R, Marcelo Mamede, Mariana F Bizzi, Rocha Ana Luiza L, Cláudia N Ferreira, Karina B Gomes, Ana L Cândido and Fernando M Reis

Objective

To evaluate whether brown adipose tissue (BAT) activity is altered in women with polycystic ovary syndrome (PCOS), and whether BAT activity correlates with plasma levels of irisin, a myokine that can induce BAT formation.

Design

We performed a cross-sectional study including women with PCOS (n = 45) and a healthy control group (n = 25) matched by age and body mass index (BMI).

Methods

BAT activity was measured using 18F-FDG positron emission tomography-computed tomography (PET-CT) and plasma irisin levels were measured by a validated enzyme immunoassay.

Results

Total BAT activity was significantly reduced in women with PCOS (maximal standardized uptake value (SUVmax): median 7.4 g/mL, interquartile range 0.9–15.4) compared to controls (median 13.0 g/mL, interquartile range 4.7–18.4, P = 0.047). However, this difference was no longer significant after adjustment for waist circumference, a surrogate marker of central adiposity. In the PCOS group, BAT activity correlated negatively with BMI (Spearman’s r = −0.630, P = 0.000) and waist circumference (r = −0.592, P = 0.000) but not with plasma irisin levels.

Conclusions

BAT activity was reduced in women with PCOS possibly due to increased central adiposity. In PCOS women, BAT activity did not correlate with plasma irisin levels.

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Ute I Scholl

Germline mutations in the chloride channel gene CLCN2 have been described as cause of familial hyperaldosteronism type II. In this issue, Dutta and colleagues in a groundbreaking study identify a somatic (tumor-specific) CLCN2 mutation in an aldosterone-producing adenoma, expanding the disease spectrum associated with CLCN2 mutations.

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Julia Vergier, Frederic Castinetti, Alexandru Saveanu, Nadine Girard, Thierry Brue and Rachel Reynaud

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

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Oluwatoyosi Bello, Meera Ladwa, Olah Hakim, Chinmay Marathe, Fariba Shoajee-Moradie, Geoff Charles-Edwards, Janet L Peacock, Margot A Umpleby, Stephanie Amiel and Louise Goff

Objectives: In men of black west African (BAM) and white European (WEM) ethnicity, we aimed to 1) compare adipose tissue, peripheral and hepatic insulin sensitivity, and 2) investigate associations between ectopic fat and insulin sensitivity by ethnicity.

Design and Methods: In overweight BAM (n=21) and WEM (n=23) with normal glucose tolerance, we performed a two-step hyperinsulinaemic–euglycaemic clamp with infusion of [6,6 2H2]-glucose and [2H5]-glycerol to measure whole body, peripheral, hepatic and adipose tissue insulin sensitivity (lipolysis). Visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular (IMCL) lipids were measured using magnetic resonance imaging and spectroscopy. Associations between insulin sensitivity and ectopic fat were assessed using Pearson’s correlation coefficient by ethnicity and regression analysis.

Results: There were no ethnic differences in whole body or tissue-specific insulin sensitivity (all p>0.05). Suppression of lipolysis was inversely associated with VAT and IHL in WEM but not BAM (VAT: WEM r=-0.68, p<0.01; BAM r=0.07, p=0.79. IHL: WEM r=-0.52, p=0.01; BAM r=-0.12, p=0.63). IMCL was inversely associated with skeletal muscle insulin sensitivity in WEM but not BAM (WEM r=-0.56,p<0.01; BAM r=-0.09, p=0.75) and IHL was inversely associated with hepatic insulin sensitivity in WEM but not BAM (WEM r=-0.53, p=0.02; BAM r=-0.13, p=0.62).

Conclusions: Ectopic fat deposition may play a lesser role in reducing insulin sensitivity in men of black African ethnicity, and may not be driven by lipolysis. Resistance to storing VAT, IHL and IMCL may enable men of black African ethnicity to maintain comparable insulin sensitivity to white Europeans.

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Haixia Guan, Nathalie Silva de Morais, Jessica Stuart, Sara Ahmadi, Ellen Marqusee, Mathew I Kim and Erik K. Alexander

Objective

To investigate the concordance of serologic and sonographic evidence of Hashimoto’s thyroiditis with its gold standard histopathologic identification.

Design

We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto’s thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance.

Results

Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto’s thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto’s thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto’s thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto’s thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb.

Conclusion

Only moderate concordance exists between serological evidence of Hashimoto’s thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.

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Liron Yoffe, Avital Polsky, Avital Gilam, Chen Raff, Federico Mecacci, Agostino Ognibene, Fatima Crispi, Eduard Gratacós, Hannah Kanety, Shali Mazaki-Tovi, Noam Shomron and Moshe Hod

Design

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and its prevalence is constantly rising worldwide. Diagnosis is commonly in the late second or early third trimester of pregnancy, though the development of GDM starts early; hence, first-trimester diagnosis is feasible.

Objective

Our objective was to identify microRNAs that best distinguish GDM samples from those of healthy pregnant women and to evaluate the predictive value of microRNAs for GDM detection in the first trimester.

Methods

We investigated the abundance of circulating microRNAs in the plasma of pregnant women in their first trimester. Two populations were included in the study to enable population-specific as well as cross-population inspection of expression profiles. Each microRNA was tested for differential expression in GDM vs control samples, and their efficiency for GDM detection was evaluated using machine-learning models.

Results

Two upregulated microRNAs (miR-223 and miR-23a) were identified in GDM vs the control set, and validated on a new cohort of women. Using both microRNAs in a logistic-regression model, we achieved an AUC value of 0.91. We further demonstrated the overall predictive value of microRNAs using several types of multivariable machine-learning models that included the entire set of expressed microRNAs. All models achieved high accuracy when applied on the dataset (mean AUC = 0.77). The significance of the classification results was established via permutation tests.

Conclusions

Our findings suggest that circulating microRNAs are potential biomarkers for GDM in the first trimester. This warrants further examination and lays the foundation for producing a novel early non-invasive diagnostic tool for GDM.