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Open access

Punith Kempegowda, Eka Melson, Agnes Johnson, Lucy Wallett, Lucretia Thomas, Dengyi Zhou, Catherine Holmes, Agata Juszczak, Mohammed Ali Karamat, Sandip Ghosh, Wasim Hanif, Parth Narendran, and Srikanth Bellary

Objective: COVID-19 in people with diabetes is associated with a disproportionately worse prognosis. DKA is an acute complication of diabetes with a mortality rate of approximately 0.67%. Little is known about the natural history of DKA in the presence of COVID-19. This study aimed to explore the effects of COVID-19 on presentation, clinical course and outcome in patients presenting with DKA.

Design: Retrospective cohort study.

Methods: All patients treated for DKA between 1 March 2020 and 30 May 2020 were included. Patients were categorised as COVID-positive or COVID-negative based on swab test. A pre-COVID group was established using data from 01 March 2019 to 30 May 2019 as external control. Data regarding demographics, diabetes type, pH, bicarbonate, lactate, glucose, DKA duration, complications and outcome were collected.

Results: A total of 88 DKA episodes were included in this study. There was no significant difference in the severity or duration of DKA between the three groups. COVID-positive T1DM were more hyperglycaemic on admission compared to COVID-negative and pre-COVID patients. There was an over representation of T2DM in COVID-positive patients with DKA than in pre-COVID or COVID-negative groups.

Conclusion: COVID-19 appears to influence the natural history of DKA differently in T1DM and T2DM. Patients with T1DM and COVID-19 presented with more hyperglycaemia (60mmol/l (35.9-60.0) vs. 31.4mmol/l (28.0-39.1) vs. 24mmol/l (20.2-33.75), respectively). Patients with T2DM were unusually presenting in DKA when infected with COVID-19 with greater ICU need and higher mortality rates. A collaborative, multi-centre study is needed to provide more definitive results.

Open access

Laura Potasso, Julie Refardt, Irina Chifu, Martin Fassnacht, Wiebke Kristin Fenske, and Mirjam Christ-Crain

Objective: Hyperkalemia has been reported upon different hypertonic saline infusion protocols. Since hypertonic saline test has recently been validated for the differential diagnosis of diabetes insipidus (DI), we aimed to investigate the course of plasma potassium during the test.

Design: We analyzed data of 90 healthy volunteers and 141 patients with polyuria-polydipsia syndrome (PPS) from two prospective studies evaluating the hypertonic saline test. Our primary outcome was the incidence rate of hypertonic saline induced hyperkalemia >5mmol/L.

Methods: Participants received a 250 ml bolus of 3% NaCl solution, followed by 0.15ml/min/kg body weight continuously infused targeting a plasma sodium level of 150mmol/L. Blood samples and clinical data were collected every 30 minutes.

Results: Of the 231 participants, 16% (n=37/231) developed hyperkalemia. The incidence of hyperkalemia was higher in healthy volunteers and in patients with primary polydipsia (25.6% (n=23/90) and 9.9% (n=14/141) respectively), and only occurred in 3.4% (n=2/59) of patients with diabetes insipidus. Hyperkalemia developed mostly at or after 90-minute test duration (81.1%, n= 30/37). Predictors of hyperkalemia (OR (95% CI)) were male sex (2.9 (1.2-7.4), p=0.02), a plasma potassium at baseline >3.9mmol/L (5.2, (1.8-17.3), p=0.004), normonatremia at 30-minute test duration (3.2 (1.2-9.5), p=0.03), and an increase in potassium levels already at 30-minute test duration as compared to baseline (4.5 (1.7-12.3), p=0.003). Hyperkalemia was transient and resolved spontaneously in all cases.

Conclusion: The hypertonic saline test can lead to hyperkalemia, especially in patients with primary polydipsia who experience a longer test duration. Monitoring potassium levels in these patients is recommended.

Open access

Haojie Zhang, Yuke Cui, Ruihua Dong, Wen Zhang, Shihan Chen, Heng Wan, Chi Chen, Yi Chen, Yuying Wang, Chunfang Zhu, Bo Chen, Ningjian Wang, and Yingli Lu

Background: Bone is thought to be the reservoir of the human lead burden, and vitamin D is associated with bone turnover. We aimed to explore whether exposure to lower 25-hydroxy vitamin D (25(OH)D) levels was associated with higher blood lead levels (BLLs) by increasing the bone turnover rate in individuals with type 2 diabetes.

Methods: A total of 4103 type 2 diabetic men and postmenopausal women in Shanghai, China, were enrolled in 2018. Their 25(OH)D, β-C-terminal telopeptide (β-CTX), N-MID osteocalcin and procollagen type 1 N-peptide (P1NP) levels were detected. Their BLLs were determined by atomic absorption spectrometry. Mediation analyses were performed to identify the possible role that bone turnover played in the underlying mechanisms.

Results: In both the men and postmenopausal women, all three bone turnover markers were inversely associated with 25(OH)D and positively associated with the BLL (all P<0.01) after adjusting for age, current smoking habits, metabolic parameters, duration of diabetes, vitamin D intake, and use of anti-osteoporosis medication. In the mediation analyses, none of the direct associations between 25(OH)D and BLL was significant for the three bone turnover markers, but all three bone turnover markers were found to be significant mediators of the indirect associations between 25(OH)D and BLL.

Conclusion: The association between vitamin D and BLL was fully mediated by bone turnover markers in type 2 diabetic patients (mediation effect). This finding suggested that vitamin D may protect against blood lead exposure from the bone reservoir by decreasing bone turnover in individuals with type 2 diabetes.

Open access

Ayako Sato, Katsuya Matsuda, Takahiro Motoyama, Zhanna Massazhanova, Ryota Otsubo, Hisayoshi Kondo, Yuko Akazawa, Miyoko Higuchi, Ayana Suzuki, Mitsuyoshi Hirokawa, Akira Miyauchi, Takeshi Nagayasu, and Masahiro Nakashima

We have previously reported that the expression of p53-binding protein 1 (53BP1) in nuclear foci (NF), a marker reflecting DNA damage response (DDR), detected using immunofluorescence (IF) is useful to estimate the malignant potency of diverse cancers. In this prospective study, we clarified the impact of 53BP1 expression via IF as a biomarker to differentiate thyroid follicular tumors (FTs) with liquid-based cytology (LBC). A total of 183 consecutively obtained-LBC samples, which were preoperatively suspected as FTs, were analyzed. Before histological diagnosis, the type of 53BP1 immunoreactivity in LBC was classified as follows: low DDR type, one or two NF; high DDR type, three or more NF; large foci type, larger than 1.0 μm; abnormal type, intense nuclear staining. Among the 183 cases, 136 cases were postoperatively diagnosed as FTs including adenomatous goiter (AG, n=30), follicular adenoma (FA, n=60), FT-uncertain malignant potency (FT-UMP, n=18), and follicular carcinoma (FC, n=28), and 47 cases were diagnosed as tumors other than FTs or technically inadequate materials. Total 136 FT cases were collated with the type of 53BP1 immunoreactivity in LBC. The mean incidence expressing abnormal 53BP1 expression was significantly higher in FC than FA (9.5% vs. 2.6%, p-value <0.001). When adopting 4.3% as a cut-off value to distinguish FC from FA, the sensitivity, specificity, positive predictive value, and negative predictive value were 89.3, 83.3, 71.4, and 94.3%, respectively. Therefore, IF analysis of 53BP1 expression can be employed as a novel technique to diagnosis FTs and distinguish between different types of FTs using LBC.

Open access

W N H Koek, N Campos-Obando, B C J van der Eerden, Y B De Rijke, Ma Ikram, Ag Uitterlinden, Jptm Van Leeuwen, and Mc Zillikens

Background: Sex differences in calcium and phosphate have been observed. We aimed to assess a relation with age.

Methods: We used laboratory values of serum calcium, phosphate and albumin from three different samples (years 2005, 2010 and 2014) using the hospital information system of Erasmus MC, Rotterdam. The samples were divided into 3 age groups: 1-17, 18-44 and ≥45 years. Sex differences in calcium and phosphate were analyzed using ANCOVA, adjusting for age and serum albumin. Furthermore, sex by age interactions were determined and we analyzed differences between age groups stratified by sex

Results: In all 3 samples there was a significant sex*age interaction for serum calcium and phosphate, whose levels were significantly higher in women compared to men above 45 years. No sex differences in the younger age groups were found.

In men, serum calcium and phosphate levels were highest in the youngest age group compared to age groups 18-44 and ≥45 years. In women, serum calcium levels were also significantly higher in the age group 1-17 and the age group ≥45 years compared to the 18-44 years age group. In women, serum phosphate was different between the three different age groups with highest level in the group 1-17 years and lowest in the group 18-44 years.

Conclusion: There are age dependent sex differences in serum calcium and phosphate. Furthermore, we found differences in serum calcium and phosphate between different age groups. Underlying mechanisms for these age- and sex differences are not yet fully elucidated.

Open access

Bo Zhu, Yumei Chen, Fang Xu, Xiaolu Shen, Xuanyu Chen, Jieqiang Lv, and Songying Zhang

Background: Androgens excess results in endoplasmic reticulum (ER) stress, which is an important cause of β cells dysfunction. Here, we investigated the molecular regulation of androgens excess, ER stress, and β-cell function in polycystic ovary syndrome (PCOS).

Methods: PCOS mouse model was established by injection of dehydroepiandrosterone (DHEA). Primary cultured mouse islets were used to detect testosterone (TE)-induced ER stress. The response of ER stress, apoptosis, and hyperinsulinemia were analyzed in INS-1 cells with or without TE exposure. Androgen receptor (AR) antagonist and ER stress inhibitor treatment was performed to evaluate the role of TE in ER stress and proinsulin secretion of PCOS mice.

Results: PCOS mice had higher ER stress in islets. TE exposure induced ER stress and apoptosis significantly through sustaining insulin overexpression in β cells, which in turn impaired proinsulin maturation and secretion. Blocking this process could significantly relieve ER stress and apoptosis and improve insulin homeostasis.

Conclusion: ER stress activated by androgens excess in PCOS contributes to β cell dysfunction and hyperinsulinemia.

Open access

Jens F. Rehfeld

The birth certificate for endocrinology was Bayliss’ and Starling’s demonstration in 1902 that regulation of bodily functions is not only neuronal, but due also to blood-borne messengers. Starling named these messengers hormones. Since then, transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones not only are produced and released to blood from endocrine cells. They are released also from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin, which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Todays’ multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells – irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone; growth factor; neurotransmitter; adipokine; cytokine; myokine; or fertility factor.

Open access

Selma Flora Nordqvist, Victor Brun Boesen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Laszlo Hegedüs, Steen Joop Bonnema, Per Karkov Cramon, Torquil Watt, Mogens Groenvold, and Jakob Bue Bjorner

Objective: ThyPRO is the standard thyroid patient-reported outcome (PRO). The change in scores that patients perceive as important remains to be ascertained. The purpose of this study was to determine values for minimal important change (MIC) for ThyPRO.

Methods: A total of 435 patients treated for benign thyroid diseases completed ThyPRO at baseline and 6 weeks following treatment initiation. At 6-weeks follow-up, patients also completed Global Rating of Change items. For each 0-100 scale, two MIC values were identified: an MIC for groups, using the ROC curve method and an MIC for individual patients, using the reliable change Index.

Results: ROC analyses provided group-MIC estimates of 6.3 to 14.3 (score range 0-100). Evaluation of area under the curve (AUC) supported the robustness for 9 of 14 scales (AUC > 0.7). Reliable change index estimates of individual-MIC were 8.0 to 21.1. For all scales but two, the individual-MIC values were larger than the group-MIC values.

Conclusions: Interpretability of ThyPRO was improved by the establishment of MIC values, which was 6.3 to 14.3 for groups and 8.0 to 21.1 for individuals. Thus, estimates of which changes are clinically relevant, are now available for future studies. We recommend using MIC values found by ROC analyses to evaluate changes in groups of patients, whereas MIC values identified by a dual criterion, including the reliability of changes, should be used for individual patients, e.g. to identify individual responders in clinical studies or practice.

Open access

Irfan Vardarli, Manuel Weber, Frank Weidemann, Dagmar Fuehrer, Ken Herrmann, and Rainer Görges

Objective: The usefulness of routine calcitonin measurement for early detection of medullary thyroid carcinoma (MTC) in patients with nodular thyroid disease (NTD) has been investigated in various studies. Recently, a Cochrane review has been published on this issue, but a meta-analysis is lacking yet. Therefore, we performed this meta-analysis.

Methods: We performed an electronic search using PubMed/Medline, Embase and the Cochrane Library. Studies assessing the diagnostic accuracy of routine calcitonin measurement for detecting MTC in patients with NDT were selected. Statistics were performed by using Stata software, risk of bias was assessed using Review Manager version 5.3.

Results: 17 studies, involving 74,407 patients were included in the study. Meta-analysis, using the bivariate random effects model and the hierarchical summary receiver operating characteristic (HSROC) curve revealed the following pooled estimates: sensitivity 0.99 (95% CI, 0.81-1.00), specificity 0.99 (95% CI, 0.97-0.99), positive likelihood ratio (L+) 72.4 (95% CI, 32.3-162.1), and negative likelihood ratio (L-) 0.01 (95% CI, 0.00-0.23). Meta-regression analysis showed that the threshold of basal calcitonin is an independent factor, but in particular performing of stimulation test is not an independent factor.

Conclusions: We showed that routine basal serum calcitonin measurement in the management of patients with thyroid nodules is valuable for the detection of MTC. However, the published cut-off values should be considered and, if applicable, the patients monitored in a wait-and-see strategy by experienced physicians to avoid overtreatment.

Open access

Marc Ingenwerth, Tim Brandenburg, Dagmar Führer-Sakel, Moritz Goetz, Frank Weber, Henning Dralle, Hans-Ulrich Schildhaus, Kurt Werner Schmid, and Sarah Theurer

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbour somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behaviour and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥ 50 %) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (p < 0.0001) and lymph node metastases (p < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behaviour. DLL3 expression in >50% of tumor cells virtually excludes MTC without stromal desmoplasia.DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.