Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11ß-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

Effects of Switching from Degludec to Glargine U300 in Patients with Insulin-Dependent Type 1 Diabetes: A Retrospective Study.

Background and Objectives: Degludec (Deg) and glargine U300 (Gla-300) are insulin analogs with longer and smoother pharmacodynamic action than glargine U100 (Gla-100), a long-acting insulin that has been widely used for many years in type 1 and type 2 diabetes. Both improve glycemic variability (GV) and the frequency of hypoglycemia, unlike Gla-100. However, it is unclear which insulin analog affects GV and hypoglycemia better in patients with insulin-dependent type 1 diabetes. We evaluated the effects of switching from Deg to Gla-300 on the day-to-day GV and the frequency of hypoglycemia in patients with insulin-dependent type 1 diabetes treated with Deg-containing basal-bolus insulin therapy (BBT). Materials and Methods: We conducted a retrospective study on 24 patients with insulin-dependent type 1 diabetes whose treatment was switched from Deg-containing BBT to Gla-300-containing BBT. We evaluated the day-to-day GV measured as the standard deviation of fasting blood glucose levels (SD-FBG) calculated by the self-monitoring of blood glucose records, the frequency of hypoglycemia (total, severe, and nocturnal), and blood glucose levels measured as fasting plasma glucose (FPG) levels and hemoglobin A1c (HbA1c). Results: The characteristics of the patients included in the analysis with high SD-FBG had frequent hypoglycemic events, despite the use of Deg-containing BBT. For this population, SD-FBG and the frequency of nocturnal hypoglycemia decreased after the switch from Deg to Gla-300. Despite the decrease in the frequency of nocturnal hypoglycemia, the FPG and HbA1c did not worsen by the switch. The change in the SD-FBG had a negative correlation with the SD-FBG at baseline and a positive correlation with serum albumin levels. Conclusions: Switching from Deg to Gla-300 improved the SD-FBG and decreased the frequency of nocturnal hypoglycemia in insulin-dependent type 1 diabetes treated with Deg-containing BBT, especially in cases with low serum albumin levels and a high GV.

Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1.

Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each gene, and methylation has been reported to be involved in steroid hormone production and disease. Angiotensin II or potassium regulates the aldosterone synthase gene, CYP11B2. The adrenocorticotropic hormone controls the 11b-hydroxylase, CYP11B1. DNA methylation negatively controls the CYP11B2 and CYP11B1 expression and dynamically changes the expression responsive to continuous stimulation of the promoter gene. Hypomethylation status of the CYP11B2 promoter region is seen in aldosterone-producing adenomas. Methylation of recognition sites of transcription factors, including cyclic AMP responsive element binding protein 1 or nerve growth factor-induced clone B, diminish their DNA-binding activity. A methyl-CpG-binding protein 2 cooperates directly with the methylated CpG dinucleotides of CYP11B2. A low-salt diet, treatment with angiotensin II, and potassium increase the CYP11B2 mRNA levels and induce DNA hypomethylation in the adrenal gland. A close association between a low DNA methylation ratio and an increased CYP11B1 expression is seen in Cushing's adenoma and aldosterone-producing adenoma with autonomous cortisol secretion. Epigenetic control of CYP11B2 or CYP11B1 plays an important role in autonomic aldosterone or cortisol synthesis.

A case of adrenocortical carcinoma diagnosed 9 years after the discovery of adrenal incidentaloma.

Adrenocortical carcinoma (ACC) is an uncommon cause of adrenal incidentaloma (AI). ACCs generally occur in large sizes, >4 cm in diameter, at initial presentation and grow rapidly. Therefore, there have been few reports of cases with long-term follow-up with imaging before ACC was diagnosed. Herein, we present a case of an adrenal mass that had remained small and unchanged for 5 years but later grew rapidly and was finally diagnosed as ACC. A 77-year-old hypertensive woman was referred to our hospital for the examination of a 5.4-cm left adrenal mass. Upon reviewing her previous unenhanced computed tomography (CT) scan, a 1.6-cm and 30 Hounsfield units (HU), homogeneous, round, left adrenal mass was incidentally detected 9 years ago. This mass remained unchanged until 4 years ago. One year ago, the mass enlarged to 3.0-cm and changed into an irregular form with heterogeneous density. The hormonal evaluation during the 9 years from the discovery of the AI was inadequate. The present examination diagnosed this case as ACC with subclinical Cushing's syndrome. The patient underwent laparoscopic left adrenalectomy, and a histological diagnosis of high-grade ACC was made. The resected tumor had the CTNNB1 gene mutation. High unenhanced CT attenuation values (>10 HU) are one of the findings that raise suspicion of malignancy. This case suggests that patients with findings atypical of adenomas on an initial unenhanced CT might be carefully followed up given the possibility of development of ACCs, even if the initial tumor size is small.

Impact of salt intake on urinary albumin excretion in patients with type 2 diabetic nephropathy: a retrospective cohort study based on a generalized additive model.

Diabetic kidney disease is an important and common cause of end-stage renal disease. Measurement of urinary albumin excretion (UAE) requires the diagnosis of the stage of diabetic nephropathy and the prognosis of renal function. We aimed to analyze the impact of lifestyle modification on UAE in patients with stage 2 and 3 type 2 diabetic nephropathy who received comprehensive medical care, using a generalized additive model (GAM), an explanatory machine learning model. In this retrospective observational study, we used changes in HbA1c, systolic blood pressure (SBP), and diastolic blood pressure (DBP) levels; body mass index (BMI); and daily salt intake as factors contributing to changes in UAE. In total, 269 patients with type 2 diabetic nephropathy were enrolled (stage 2, 217 patients; stage 3, 52 patients). The rankings that contributed to changes in UAE over 6 months by permutation importance were the changes in daily salt intake, HbA1c, SBP, DBP, and BMI. GAM, which predicts the change in UAE, showed that with increase in the changes in salt intake, SBP, and HbA1c, the delta UAE tended to increase. Salt intake was the most contributory factor for the changes in UAE, and daily salt intake was the best lifestyle factor to explain the changes in UAE. Strict control of salt intake may have beneficial effects on improving UAE in patients with stage 2 and 3 diabetic nephropathy.

Spontaneous Remission of Primary Aldosteronism with Mineralocorticoid Receptor Antagonist Therapy: A Review.

In this review, we describe previous basic and clinical studies on autonomous aldosterone production. Over the past decades, mineralocorticoid receptor antagonists (MRAs) have been found to concentration-dependently inhibit steroidogenesis in different degrees. However, many studies have proven the suppressive effects of MRAs on the activities of hormone synthase. The probable factors of cytochrome P-450 reduction, both in microsomes and mitochondria, have also been considered: (1) one of the spironolactone metabolite forms had destructive function, except canrenone, (2) 7α-thio-spironolactone was an obligatory intermediate in the spironolactone-induced CYP450 decrease, and (3) the contributing steroids should have 7α-methylthio or 7α-methylsulfone groups. In previous clinical research, spironolactone-body-containing cells showed a type II pattern of enzyme activity (i.e., enhanced 3ß-hydroxysteroid dehydrogenase, glucose-6-phosphate, and NADP-isocitrate dehydrogenase activities and weaken succinate dehydrogenase activity), and the subcapsular micronodules composed of spironolactone-body-containing cells also exhibited a type II pattern and excess aldosterone secretion, indicating that the subcapsular micronodules might be the root of aldosterone-producing adenoma. Moreover, combined with the potential impeditive function to aldosterone secretion, a few cases of spontaneous remission of primary aldosteronism, with normal ranges of blood pressure, plasma potassium, plasma renin activity, and aldosterone renin ratio, have been reported after long-term treatment with MRAs.

Comprehensive Steroid Assay with Non-Targeted Analysis Using Liquid Chromatography Ion Mobility Mass Spectrometry.

Aldosterone-producing adenomas (APAs) have different steroid profiles in serum, depending on the causative genetic mutation. Ion mobility is a separation technique for gas-phase ions based on their m/z values, shapes, and sizes. Human serum (100 µL) was purified by liquid-liquid extraction using tert-butyl methyl ether/ethyl acetate at 1/1 (v/v) and mixed with deuterium-labeled steroids as the internal standard. The separated supernatant was dried, re-dissolved in water containing 20% methanol, and injected into a liquid chromatography-ion mobility-mass spectrometer (LC/IM/MS). We established a highly sensitive assay system by separating 20 steroids based on their retention time, m/z value, and drift time. Twenty steroids were measured in the serum of patients with primary aldosteronism, essential hypertension, and healthy subjects and were clearly classified using principal component analysis. This method was also able to detect phosphatidylcholine and phosphatidylethanolamine, which were not targeted. LC/IM/MS has a high selectivity for known compounds and has the potential to provide information on unknown compounds. This analytical method has the potential to elucidate the pathogenesis of APA and identify unknown steroids that could serve as biomarkers for APA with different genetic mutations.

Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Worsen after the Administration of Dulaglutide.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical polyarthritis and limb pitting edema. Although the detailed mechanisms of this syndrome have not been clearly understood, some agents including dipeptidyl peptidase-4 inhibitors have been reported to induce RS3PE syndrome. However, glucagon-like peptide-1 (GLP-1) analogues have not been reported to be associated with this syndrome. A 91-year-old woman was admitted to our hospital with complaints of severe polyarthritis and limb edema. She was diagnosed with RS3PE syndrome. Oral prednisolone improved her symptoms. However, her symptoms worsened after the administration of dulaglutide, with elevated serum inflammatory markers. Discontinuation of dulaglutide without additional treatment improved her symptoms and laboratory findings. This case might indicate the possibility of development and worsening of RS3PE syndrome caused after GLP-1 analogue.

Artificial Intelligence in Current Diabetes Management and Prediction.

PURPOSE OF REVIEW: Artificial intelligence (AI) can make advanced inferences based on a large amount of data. The mainstream technologies of the AI boom in 2021 are machine learning (ML) and deep learning, which have made significant progress due to the increase in computational resources accompanied by the dramatic improvement in computer performance. In this review, we introduce AI/ML-based medical devices and prediction models regarding diabetes. RECENT FINDINGS: In the field of diabetes, several AI-/ML-based medical devices and regarding automatic retinal screening, clinical diagnosis support, and patient self-management tool have already been approved by the US Food and Drug Administration. As for new-onset diabetes prediction using ML methods, its performance is not superior to conventional risk stratification models that use statistical approaches so far. Despite the current situation, it is expected that the predictive performance of AI will soon be maximized by a large amount of organized data and abundant computational resources, which will contribute to a dramatic improvement in the accuracy of disease prediction models for diabetes.

Carcinoma of unknown primary origin with isolated adrenal metastasis: a report of two cases.

The adrenal glands are one of the most common sites of malignant tumor metastasis. However, metastatic adrenal carcinoma of unknown primary origin with localized adrenal gland involvement is an extremely rare condition. Herein, we reported two cases of carcinoma of unknown primary origin with isolated adrenal metastasis. In the first case, back pain was the trigger; while in the second case, the triggers were low fever and weight loss. Metabolic abnormalities such as hypertension and obesity were not detected in either case. Neither patient had relevant previous medical histories, including malignancy. However, both had a long-term history of smoking. Systemic imaging studies revealed only adrenal tumors and surrounding lesions. Primary adrenocortical carcinoma was initially suspected, and chemotherapy including mitotane was considered. However, due to difficulty in complete resection of the tumor, core needle tumor biopsies were performed. Histopathological examination of biopsy specimens led to the diagnosis of carcinoma of unknown primary origin with isolated adrenal metastasis. In both cases, additional laboratory testing showed high levels of serum squamous cell carcinoma-related antigen and serum cytokeratin fragment. Malignant lesions confined to the adrenal glands are rare. As in our cases, it could be occasionally difficult to differentiate non-functioning primary adrenocortical carcinoma from metastatic adrenal carcinoma of unknown primary origin localized to the adrenal gland. If the lesion is unresectable and there are elevated levels of several tumor markers with no apparent hormonal excess, core needle tumor biopsy should be considered to differentiate the primary tumor from the metastatic tumor.

Effect of sodium-glucose cotransporter-2 inhibitors on aldosterone-to-renin ratio in diabetic patients with hypertension: a retrospective observational study.

BACKGROUND: Plasma aldosterone-to-renin ratio (ARR) is popularly used for screening primary aldosteronism (PA). Some medications, including diuretics, are known to have an effect on ARR and cause false-negative and false-positive results in PA screening. Currently, there are no studies on the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, which are known to have diuretic effects, on ARR. We aimed to investigate the effects of SGLT2 inhibitors on ARR. METHODS: We employed a retrospective design; the study was conducted from April 2016 to December 2018 and carried out in three hospitals. Forty patients with diabetes and hypertension were administered SGLT2 inhibitors. ARR was evaluated before 2 to 6 months after the administration of SGLT2 inhibitors to determine their effects on ARR. RESULTS: No significant changes in the levels of ARR (90.9 ± 51.6 vs. 81.4 ± 62.9) were found. Body mass index, diastolic blood pressure, heart rate, fasting plasma glucose, and hemoglobin A1c were significantly decreased by SGLT2 inhibitors. Serum creatinine was significantly increased. CONCLUSION: SGLT2 inhibitor administration yielded minimal effects on ARR and did not increase false-negative results in PA screening in patients with diabetes and hypertension more than 2 months after administration.

Effect of sodium glucose cotransporter 2 inhibitors on obstructive sleep apnea in patients with type 2 diabetes.

Obstructive sleep apnea syndrome (OSAS) is often associated with metabolic disorders such as obesity and type 2 diabetes and may contribute to cardiovascular events. A novel class of antidiabetic drugs, the sodium glucose cotransporter 2 inhibitors (SGLT2i) reduce body weight (BW), although there is limited data on their impact on OSAS. We therefore evaluated the effect of SGLT2i on OSAS in patients with type 2 diabetes. The presented study was a retrospective design in 18 patients with type 2 diabetes with OSAS (4 males, age range 39-81 yr) administrated a SGLT2i. HbA1c, BW, body mass index (BMI), blood pressure (BP) and apnea hypopnea index (AHI) were evaluated before and after SGLT2i administration. The relationships between the reduction in AHI and the other variables were examined using Pearson correlation analysis. We have got result that SGLT2i reduced AHI from 31.9 ± 18.0 to 18.8 ± 11.5 events per hr (p = 0.003). HbA1c, BW and BMI decreased significantly, whereas BP did not. The Pearson correlation analysis showed a significant relationship between the reduction in AHI and pre-administration of AHI. In conclusion, SGLT2i reduced not only HbA1c, BW and BMI but also AHI significantly and therefore has potential as an effective treatment of OSAS.

Prevalence of primary aldosteronism without hypertension in the general population: Results in Shika study.

OBJECTIVE: Recent studies have reported a high prevalence of primary aldosteronism (PA) among hypertensive patients. However, few data exist regarding the prevalence of PA in the general population. Therefore, we examined the prevalence of PA in the general population including normotensive subjects. METHODS: Plasma renin activity (ng/mL/hr), plasma aldosterone concentration (pg/mL) and aldosterone renin ratio (ARR) were determined in 309 subjects aged >40 years in Horimatsu and Higashi-Matsuho district, Shika-machi, Ishikawa, Japan. RESULTS: Among them, 195 subjects (78 males, mean age: 62 ± 11 years) did not take antihypertensive agents: 113 normotensive subjects and 82 hypertensive subjects. Under these conditions, 68 subjects (13 males, age 62 ± 10 years) had an ARR >200. In 14 subjects who underwent captopril suppression test, PA was documented in 5 subjects, yielding a minimum prevalence of 2.6% in total subjects (1.8% in normotensive subjects and 3.7% in hypertensive subjects). Interestingly, females subjects demonstrated significant differences in ARR between subjects with age <50 (172 ± 105) and those with age 51-60 (388 ± 531), although there were no differences in male subjects. CONCLUSIONS: These results demonstrate that PA including normotensive subjects exists more commonly than that expected in the general population. We suggest further investigation about the cause and progression of PA associated with sex and aging.

[The status of glycemic control and hypoglycemia in elderly patients visiting the outpatient department specializing in diabetes].

AIM: The Japan Diabetes Society (JDS)/Japan Geriatrics Society (JGS) Joint Committee reported 'Glycemic Targets for Elderly Patients with Diabetes' in 2016. Based on this recommendation, we aimed to clarify 1) the achievement status of glycemic targets in the elderly and 2) the presence of hypoglycemia in real life among elderly individuals with an HbA1c below the lower limit. SUBJECTS AND METHODS: [Analysis I] In 326 elderly with diabetes ≥65 years of age visiting the outpatient department specializing in diabetes, the proportions of patients with HbA1c values below the lower limit and the use of drugs potentially associated with severe hypoglycemia (e.g. insulin formulations, sulfonylureas, glinides) were investigated. [Analysis II] Of the patients with HbA1c values below the lower limit, seven were tested for hypoglycemia in real life using a continuous glucose monitoring system (CGM). RESULTS: [Analysis I] Among the 326 subjects, 235 (72.1%) were using drugs potentially associated with severe hypoglycemia, and 63 (19.3%) had an HbA1c value below the lower limit. [Analysis II] In the seven patients examined using CGM, hypoglycemia was detected in five, all of whom were unaware. CONCLUSIONS: A considerable number of elderly patients were taking drugs associated with hypoglycemic risks and had an HbA1c value below the lower limit, some of whom actually had hypoglycemia as detected by CGM. Using tools such as CGM, preventive measures against hypoglycemia should be taken.

Angiotensin II receptor blocker combined with eplerenone or hydrochlorothiazide for hypertensive patients with diabetes mellitus.

Experimental models recently suggested an interaction between aldosterone and adipose tissue, but clinical investigation has been limited. We studied the effects of eplerenone compared to hydrochlorothiazide (HCTZ) on blood pressure (BP), glucose, and lipid levels in 50 patients with essential hypertension (EHT) and type 2 diabetes mellitus whose BP failed to reach target levels with 8 mg of candesartan alone. BP improved similarly in both groups over the 12-month study period, but BMI, waist circumference, and LDL-cholesterol were decreased in the eplerenone group, while glycohemoglobin was elevated in the HCTZ group.

Thyrotoxicosis Misdiagnosed as Long Covid by Telemedicine - A Cautionary Tale.

Introduction: Individuals who have had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop post-coronavirus disease conditions, also known as long COVID. The symptoms of long COVID are nonspecific, and there are similarities between the symptoms of long COVID and those of Graves' disease (GD). Therefore, it is important to rule out GD in patients suspected of having long COVID. Telemedicine is widely used to avoid the risk of SARS-CoV-2 infection. However, owing to the lack of in-person examinations, diagnostic errors can occur. Case description: A 27-year-old Japanese woman presented complaining of persistent fatigue, dyspnea, and low-grade fever, and after in-person examination was finally diagnosed with GD. She had been diagnosed with SARS-CoV-2 infection four months earlier and her symptoms had resolved within 5 days but then recurred. Subsequently, she had 3 telemedicine visits and had been diagnosed with long COVID. Discussion: With telemedicine there may be delayed diagnosis of GD in patients with a recent history of SARS-CoV-2 infection. Some symptoms and abnormalities cannot be confirmed in telemedicine visits performed using a simple mobile phone. Therefore it is important to know which findings obtained in telemedicine visits with a simple mobile phone are suggestive of GD. Low-grade fever and tachycardia are often observed in patients with GD, but rarely occur in patients with long COVID. Conclusion: Tachycardia and persistent low-grade fever after SARS-CoV-2 infection, which can be confirmed by telemedicine, can be clues for the diagnosis of GD. Therefore, in-person examination should be added if these symptoms are confirmed by telemedicine. LEARNING POINTS: The symptoms of Graves 'disease (GD) and long COVID may overlap.With telemedicine there may be delayed diagnosis of GD, in patients with recent history of severe acute respiratory syndrome mediated by coronavirus 2 (SARS-CoV-2) infections.In telemedicine visits, tachycardia and persistent low-grade fever could be clues for the diagnosis of GD after SARS-CoV-2 infections on telemedicine.

Prediction and causal inference of cardiovascular and cerebrovascular diseases based on lifestyle questionnaires.

Cardiovascular and cerebrovascular diseases (CCVD) are prominent mortality causes in Japan, necessitating effective preventative measures, early diagnosis, and treatment to mitigate their impact. A diagnostic model was developed to identify patients with ischemic heart disease (IHD), stroke, or both, using specific health examination data. Lifestyle habits affecting CCVD development were analyzed using five causal inference methods. This study included 473,734 patients aged ≥ 40 years who underwent specific health examinations in Kanazawa, Japan between 2009 and 2018 to collect data on basic physical information, lifestyle habits, and laboratory parameters such as diabetes, lipid metabolism, renal function, and liver function. Four machine learning algorithms were used: Random Forest, Logistic regression, Light Gradient Boosting Machine, and eXtreme-Gradient-Boosting (XGBoost). The XGBoost model exhibited superior area under the curve (AUC), with mean values of 0.770 (± 0.003), 0.758 (± 0.003), and 0.845 (± 0.005) for stroke, IHD, and CCVD, respectively. The results of the five causal inference analyses were summarized, and lifestyle behavior changes were observed after the onset of CCVD. A causal relationship from 'reduced mastication' to 'weight gain' was found for all causal species theory methods. This prediction algorithm can screen for asymptomatic myocardial ischemia and stroke. By selecting high-risk patients suspected of having CCVD, resources can be used more efficiently for secondary testing.

Performance of Generative Pretrained Transformer on the National Medical Licensing Examination in Japan.

The remarkable performance of ChatGPT, launched in November 2022, has significantly impacted the field of natural language processing, inspiring the application of large language models as supportive tools in clinical practice and research worldwide. Although GPT-3.5 recently scored high on the United States Medical Licensing Examination, its performance on medical licensing examinations of other nations, especially non-English speaking nations, has not been sufficiently evaluated. This study assessed GPT's performance on the National Medical Licensing Examination (NMLE) in Japan and compared it with the actual minimal passing rate for this exam. In particular, the performances of both the GPT-3.5 and GPT-4 models were considered for the comparative analysis. We initially used the GPT models and several prompts for 290 questions without image data from the 116th NMLE (held in February 2022 in Japan) to maximize the performance for delivering correct answers and explanations of the questions. Thereafter, we tested the performance of the best GPT model (GPT-4) with optimized prompts on a dataset of 262 questions without images from the latest 117th NMLE (held in February 2023). The best model with the optimized prompts scored 82.7% for the essential questions and 77.2% for the basic and clinical questions, both of which sufficed the minimum passing scoring rates of 80.0% and 74.6%, respectively. After an exploratory analysis of 56 incorrect answers from the model, we identified the three major factors contributing to the generation of the incorrect answers-insufficient medical knowledge, information on Japan-specific medical system and guidelines, and mathematical errors. In conclusion, GPT-4 with our optimized prompts achieved a minimum passing scoring rate in the latest 117th NMLE in Japan. Beyond its original design of answering examination questions for humans, these artificial intelligence (AI) models can serve as one of the best "sidekicks" for solving problems and addressing the unmet needs in the medical and healthcare fields.

Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

Acquisition of Interleukin-6 Production Ability Over Time With Pheochromocytoma.

Pheochromocytoma is a tumor of chromaffin cells causing catecholamines overproduction. Interleukin-6 (IL-6), a cytokine, is central to inflammation and immunity. Few studies have reported IL-6-producing pheochromocytoma whose underlying mechanism has not been elucidated. Herein, we present a case of pheochromocytoma whose clinical manifestations changed, and IL-6 levels elevated over time. A 48-year-old woman was referred to our hospital for fever and hepatic dysfunction. Six years prior, a right adrenal tumor was detected during the examination for ovarian teratoma without C-reactive protein (CRP) elevation. Several imaging studies at our hospital showed no abnormalities except for an increase in the size of the adrenal tumor and hepatomegaly. In addition, antibiotics did not improve the fever. Laboratory tests showed elevated levels of CRP with IL-6 elevation. An enlarged adrenal tumor was detected. Administering doxazosin lowered the CRP and IL-6 levels, then IL-6-producing pheochromocytoma was suspected, and adrenalectomy was performed. After surgery, fever and hepatic function were improved, and the CRP and IL-6 levels were normalized. Immunostaining of the resected tissue showed IL-6 focal positivity, which meant the phenotype of tumor cells focally changed their phenotypes over time. IL-6-producing pheochromocytoma should be considered in patients with adrenal tumors and fever of unknown origin.