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Context Adrenal incidentalomas, including nonfunctioning adrenal incidentalomas (NFAI), are associated with a high prevalence of diabetes mellitus (DM). While NFAI is diagnosed by exclusion when no hormone excess exists, subtle cortisol secretion may exist and contribute to DM development. However, it alone cannot explain the increased risk, and whether other steroid metabolites are involved remains unclear. Purpose To investigate steroid metabolites associated with DM in patients with NFAI using plasma steroid profiles. Methods Using liquid chromatography-tandem mass spectrometry, 22 plasma steroid metabolites were measured in 68 patients with NFAI (31 men and 37 women). Data were adjusted for age before normalization. Results Discriminant analysis showed that plasma steroid profiles discriminated between patients with and without DM in men (n = 10 and = 21, respectively) but not women: 11β-hydroxytestosterone, an adrenal-derived 11-oxygenated androgen, contributed most to this discrimination and was higher in patients with DM than in those without DM (false discovery rate =.002). 11β-hydroxytestosterone was correlated positively with fasting plasma glucose (r =.507) and hemoglobin A1c (HbA1c) (r =.553) but negatively with homeostatic model assessment of β-cell function (HOMA2-B) (r = −.410). These correlations remained significant after adjusting for confounders, including serum cortisol after the 1-mg dexamethasone suppression test. Bayesian kernel machine regression analysis verified the association of 11β-hydroxytestosterone with HbA1c and HOMA2-B in men. Main Conclusion Plasma steroid profiles differed between those with and without DM in men with NFAI. 11β-hydroxytestosterone was associated with hyperglycemia and indicators related to pancreatic β-cell dysfunction, independently of cortisol. [ABSTRACT FROM AUTHOR]

We have recently incorporated the occupation probability formalism (OPF) in the simulation model [C. Stehlé and S. Jacquemot, Astron. Astrophys. 271, 348 (1993)] to have a smooth transition from discrete lines to continuum spectrum in the wavelength range near the Balmer series limit. We have analyzed spectra measured for the hydrogen pellet ablation cloud in the Large Helical Device with the revised model, and have found that the electron density in the ablation cloud has a close correlation with the electron temperature of the background plasma. This type of correlation is first confirmed in the present analysis and should give a new insight in the simulation studies of pellet ablation for the magnetically confined fusion plasma. [ABSTRACT FROM AUTHOR]

The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) enhance antitumoral immune mechanisms and are used to treat various types of solid tumors including those that are microsatellite instability (MSI)-high. Uterine endometrial cancer is one of the most frequent tumor types that shows MSI-high, and, consequently, opportunities to use ICIs for endometrial cancer treatment are increasing. While using ICIs, it is important to monitor and manage various immune-related adverse events (irAEs). Here, we report two cases of secondary adrenal insufficiency during treatment of endometrial cancer with pembrolizumab. Both cases showed appetite loss and general fatigue after the 6th or 12th cycle of pembrolizumab. They were admitted to our hospital because of remarkable hyponatremia. Both cases showed no adrenocorticotropic hormone (ACTH) or cortisol response to CRH loading tests. Other pituitary hormone levels were normal, and MRI revealed no sign of hypophysitis in either patient. They were diagnosed with secondary adrenal insufficiency due to isolated ACTH deficiency and recovered soon after the administration of hydrocortisone and hydration. Thus, we should be aware of irAEs with the use of ICIs. In particular, adrenocortical insufficiency is sometimes lethal without appropriate treatment. Because the clinical symptoms are fatigue, appetite loss, and nausea, patients might be misjudged to have symptoms related to cancer. Checking serum morning cortisol before ICIs use and monitoring serum sodium levels could provide clues to diagnose secondary adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Objective: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false‐positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine‐learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. Design: A retrospective cross‐sectional study in referral centres. Patients: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). Measurements: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set. Results: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. Conclusions: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS. [ABSTRACT FROM AUTHOR]

A control method of the divertor configuration using external saddle loop coils is investigated for a quasi‐symmetry stellarator device. Multiple coils are used to modify the divertor configuration while keeping the rotational transform distribution in the core region the same. The external coils successfully shrink the core plasma region and extend the divertor legs. From the transport analysis with the EMC3‐EIRENE code, it is confirmed that the dependence of the electron temperature of the core plasma on the position of the plasma‐facing walls is weakened by the extension of the divertor legs. The increase of the divertor particle flux and the increase of energy loss due to radiation and charge exchange processes are also confirmed. [ABSTRACT FROM AUTHOR]

Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2 , TOP2A , and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2 , VSNL1 , and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Heart failure with preserved ejection fraction is characterized by left ventricular diastolic dysfunction (LVDD). It has been reported that excess cortisol found in patients with Cushing's syndrome was associated with the development of LVDD. However, the relationship between cortisol concentration and LVDD in patients with diabetes mellitus has not been addressed. Materials and Methods: We enrolled 109 patients with diabetes mellitus and 104 patients without diabetes mellitus who had undergone echocardiographic examination at Kyushu University Hospital, Fukuoka, Japan, between November 2016 and March 2019. Left ventricular function was evaluated and the ratio of early diastolic velocity from transmitral inflow to early diastolic velocity (E/eʹ) was used as an index of diastolic function. Plasma cortisol concentrations, glycemic control, lipid profiles, treatment with antidiabetic drugs and other clinical characteristics were evaluated, and their associations with E/eʹ were determined using univariate and multivariate analyses. Results: Multivariate linear regression analysis showed that log E/eʹ was positively correlated with age (P = 0.017), log systolic blood pressure (P = 0.004) and cortisol (P = 0.037), and negatively correlated with estimated glomerular filtration rate (P = 0.016) and the use of sodium–glucose cotransporter 2 inhibitors (P = 0.042) in patients with diabetes mellitus. Multivariate analysis showed that cortisol was positively correlated with age (P = 0.016) and glycated hemoglobin (P = 0.011). There was no association between E/eʹ and cortisol in patients without diabetes mellitus. Conclusions: Increased cortisol levels might increase the risk of developing LVDD in diabetes mellitus patients. [ABSTRACT FROM AUTHOR]

Context: The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone‐producing adenoma. Objective: This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left‐AV absolute aldosterone gradient) indicates unilateral excess aldosterone. Design and setting: A retrospective cross‐sectional study in a single referral centre. Patients and methods: In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left‐AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone‐to‐cortisol ratio between the common trunk vein and central vein was found. Main outcome measure: The prevalence of the unilateral subtype in patients with a significant left‐AV absolute aldosterone gradient. Results: The prevalence of the unilateral subtype was higher in patients with than without a significant left‐AV absolute aldosterone gradient (88.2% [15/17] vs 21.7% [23/106], P <.001). Of 60 patients with spontaneous hypokalemia, left unilateral disease on computed tomography, or both, a significant left‐AV absolute aldosterone gradient was present only in patients with the unilateral subtype on AVS (42.9% [15/35]), but not in those with the bilateral subtype (0.0% [0/25]). These data were validated in an external cohort. Conclusion: The presence of a significant left‐AV absolute aldosterone gradient can be used to diagnose the left unilateral subtype of primary aldosteronism on AVS in patients with spontaneous hypokalemia, left unilateral disease on computed tomography or both. [ABSTRACT FROM AUTHOR]

A predictor model of radiative collapse of stellarator-heliotron plasmas has been developed by means of a machine learning technique and the feature of radiative collapse has been extracted with sparse modeling. The dataset used for training the model is constructed based on density ramp-up experiments in the Large Helical Device. As a result of feature extraction, the line averaged electron density, visible line emissions of CIV and OV, and the electron temperature at the edge have been selected as key parameters of radiative collapse. The likelihood of occurrence of radiative collapse has been quantified by using these parameters and this likelihood has been assessed in terms of predicting capability of the occurrence of radiative collapse. The collapse likelihood also implies the underlying physics of radiative collapse, therefore, the knowledge obtained by this data-driven study is expected to facilitate elucidation of the physics of the radiative collapse. In validation with discharges outside of the dataset, the predictor based on the likelihood has predicted over 85% of radiative collapse about 100 ms prior to this event on average while about 5% of stable discharges have been detected falsely as collapse discharges. The discharges in which the predictor made faults are discussed in order to investigate the cause of failure. [ABSTRACT FROM AUTHOR]