Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS.

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

Trends in the Nontuberculous Mycobacterial Disease Mortality Rate in Japan: A Nationwide Observational Study, 1997-2016.

BACKGROUND: The incidence of nontuberculous mycobacterial (NTM) infections has been increasing worldwide, becoming a significant healthcare burden especially among elderly people. This study aimed to evaluate the trends in NTM-associated mortality in Japan. METHODS: This study used vital statistics data and data on all NTM-associated deaths (N = 18 814) among individuals aged ≥40 years in Japan from 1997 to 2016. We calculated the crude and age-adjusted mortality rates by age and sex and used joinpoint regression to analyze trends and estimate the average annual percentage change (AAPC). We compared crude NTM- and tuberculosis-associated mortality rates by sex. RESULTS: The overall crude annual mortality rate increased from 0.63/100 000/year in 1997 to 1.93/100 000/year in 2016 and was the highest among individuals aged 80-84 years. The AAPC of the crude mortality rates among men of all ages and women aged 40-59 years were stable but increased among women aged 60-79 years (3.5%; 95% confidence interval [CI], 2.8-4.3) and ≥80 years (4.3%; 95% CI, 3.7-4.9). Among men, the age-adjusted mortality rates did not show a significant trend, while among women, the rates increased over the study period (AAPC, 4.6%; 95% CI, 2.7-6.6). In women, the crude NTM-associated mortality rate exceeded the tuberculosis mortality rate in 2014, 2015, and 2016. CONCLUSIONS: NTM mortality increased in Japan between 1997 and 2016, especially among the elderly female population. Given the increasing NTM-associated mortality and the susceptible aging population, public health authorities in Japan should pay greater attention to NTM infections.

Involvement of serum dehydroepiandrosterone sulfate in erythropoietic activity.

PURPOSE: The aim of the present study was to determine how age-related decreases in serum dehydroepiandrosterone sulfate (DHEAS) levels affect various physiological processes. METHODS: We retrospectively reviewed the medical records of patients in whom serum DHEAS levels were measured in our department and assessed the relationships between serum DHEAS levels and various patient characteristics. RESULTS: Among the 149 patients included in our analysis (mean age: 52.7 ± 17.6 years, range: 15-84 years), 54 (36.2%) were men. Serum DHEAS levels inversely correlated with age in men (R = -0.810, p < .01) and to a lesser extent in women (R = -0.391, p < .01). Of note, there were significant positive associations between DHEAS levels and hemoglobin (R = 0.317, p ≤ .01) and hematocrit (R = 0.324, p ≤ .01) levels, which were observed in men, but not in women. CONCLUSIONS: Our study suggests that reduced DHEAS secretion inhibits erythropoietic activity in aging men, perhaps owing to the erythropoietic androgenic actions of DHEAS. Importantly, it suggests that the age-associated decline in DHEAS secretion might decrease erythropoietic activity in aging men. It is also possible that the adrenal cortex, the source of DHEAS, is dysfunctional in anemic men.

Clinical relevance of insulin-like growth factor-1 to cardiovascular risk markers.

OBJECTIVE: Insulin-like growth factor-1 (IGF-1) is an anabolic hormone, the levels of which decline with age. The present study aimed to determine the impact of age-related declines in serum IGF-1 levels on various physiological processes. DESIGN: We retrospectively reviewed the medical records of patients whose serum IGF-1 levels were estimated in our department, and assessed the relationships between serum IGF-1 levels and various physiological parameters. RESULTS: A total of 427 patients with a mean (± standard deviation) age of 52.8 (± 17.1) years were included in the analysis. The levels of serum IGF-1 showed significant positive correlation with those of hemoglobin and hematocrit, and negative correlation with the presence of inflammatory and fibrin-related markers including C-reactive protein (CRP) and procalcitonin (PCT), and D-dimer and fibrin degradation products (FDP). These tendencies persisted after exclusion of patients with pituitary disease. CONCLUSIONS: In this study population of diverse diseases and backgrounds, a decline in serum IGF-1 levels with age was associated with an increase in inflammatory and fibrin-related markers. This may explain the correlation between low serum IGF-1 levels and an increased risk of cardiovascular events. Our findings suggest that serum IGF-1 is a clinically relevant marker of cardiovascular risk, particularly in males.

A rare case of oncocytic adrenocortical carcinoma clinically presented as an incidentaloma.

Adrenocortical carcinoma (ACC) is a rare aggressive tumor originating from adrenocortical parenchymal cells and its incidence is approximately 1 per million population per year. An oncocytic ACC is a recently identified entity among the several known histopathological variants of ACC, which is characterized by oncocytic cells, and only a few cases in the available literature have reported this tumor. In contrast to conventional ACCs, oncocytic ACCs usually manifest as solitary lesions presenting in adults without any sex predilection. We report a case of a 70-year-old Japanese man who presented with an incidentally discovered retroperitoneal mass without any evidence of excessive corticosteroid secretion. Laboratory and imaging studies, as well as transgastric endoscopic ultrasound-guided fine needle aspiration failed to establish a definitive diagnosis. Thus, the patient underwent surgical resection of the left-sided peritoneal tumor. Weiss score was positive in 6/9 points and the tumor met two major criteria of the Lin-Weiss-Bisceglia (LWB) system leading to a diagnosis of an oncocytic variant of ACC. Based on our findings in this patient, we conclude that a combination of the Weiss and LWB criteria is required to determine the malignant potential of oncocytic adrenal tumors because ACCs and oncocytomas could be frequently indistinguishable. Careful histopathological examination is pivotal in confirming the oncocytic component in the lesion and hence definitive diagnosis of ACCs.

A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1.

Adrenocortical carcinoma (ACC) is a rare malignancy arising from adrenocortical parenchymal cells. Myxoid ACC is one of the newly identified, rare, but important histological variants of ACC, characterized by the presence of abundant extracellular Alcian Blue-positive myxoid material. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer predisposition syndrome, and the incidence of ACC in MEN1 patients has been reported to be between 1.4% and 6%. Here, we report the case of a 68-year-old Japanese woman harboring the past history of MEN1 associated with insulinoma, pituitary tumor, and hyperparathyroidism. She presented to our hospital with hypertension and hypokalemia. Imaging studies revealed a right adrenal tumor, and histological examination revealed myxoid ACC. Despite surgical resection of the tumor and mitotane therapy, the patient died 6 months after the surgery. To the best of our knowledge, this is the first reported case of the myxoid variant of ACC in a patient with MEN1. The patient's clinical course was characterized by the development of both multiple endocrine and non-endocrine neoplasm, hyperaldosteronism, and aggressive biological behavior. This case confirmed that myxoid morphology was also associated with aggressive behavior in ACC, but further studies are required to clarify the association between MEN1 and myxoid ACC.

Clinical relevance of low androgen to gastroesophageal reflux symptoms.

The aim of this study was to determine the relationships between free testosterone (FT) level and parameters including laboratory data and data from questionnaires and to determine symptoms leading to the detection of late onset hypogonadism (LOH). We retrospectively reviewed medical records of patients in whom serum FT was measured in our hospital. Aging Male Symptoms (AMS) score, self-rating depression scale (SDS) and frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) score were used for questionnaires. A total of 205 patients were included in the analysis (55.2 ± 15.6 years of age, mean ± SD). Among them, 119 patients (58.0%) had an FT level of less than 8.5 pg/mL, which fulfills the diagnostic criterion of LOH syndrome according to the clinical practice manual for LOH in Japan. It was revealed that FSSG score was inversely correlated to serum FT levels (r = -0.3395, p < 0.001), although SDS and AMS scales did not show significant correlations to FT levels. Our study revealed a high prevalence of LOH syndrome among patients in whom the majority complained of general symptoms. Although GERD symptoms are generally not considered to be typical symptoms of LOH, our study indicates that those symptoms might be clues for the detection of LOH.

Female paraurethral leiomyoma successfully excised through a vaginal approach: A case report.

Paraurethral leiomyomas are extremely rare, and few cases have been reported in the literature. Because of the rarity of the disease and its anatomical complexity, diagnosis and management is challenging for clinicians. Here, we herein report the case of a 50-year-old woman who complained of a protruding mass at the urethral opening. Magnetic resonance imaging revealed a sharply defined tumor measuring 43 × 36 × 26 mm in diameter, located in the anterior vaginal wall, compressing the urethra. Based on the perioperative diagnosis of leiomyoma, the paraurethral tumor was excised via the vaginal approach. The patient was discharged 4 days postoperatively without any complications. Pathological features confirmed the diagnosis of leiomyoma. This case implies that, although there is the possibility of complications due to the surgical procedure, tumor removal is a reasonable choice for management to exclude malignancy and relieve symptoms.

An Uncommon Manifestation of Fitz-Hugh-Curtis Syndrome with Right-side Chest Pain.

Fitz-Hugh-Curtis syndrome is characterized by an inflammation of the perihepatic capsules associated with pelvic inflammatory disease. The typical symptom is severe right upper quadrant abdominal pain. We report a patient with Fitz-Hugh-Curtis syndrome who presented with an atypical chief complaint of right-side chest pain unaccompanied by symptoms specific to pelvic inflammatory disease. This case indicates that Fitz-Hugh-Curtis syndrome should be considered in the differential diagnosis of right-side chest pain in young women, because early diagnosis and treatment of the disease are essential to prevent chronic complications.

Trends in childhood obesity in Japan: A nationwide observational study from 2012 to 2021.

The persistent ascension of childhood obesity on a global scale constitutes a significant quandary. The prevalence of childhood obesity in Japan peaked in the early 2000s and has been reported to have declined since then, but recent data and its trend including the novel coronavirus disease 2019 (COVID-19) pandemic era are not available. Moreover, there is a dearth of studies examining the correlation between the trend in childhood obesity and exercise habits over the past decade. This study aims to examine the changes in the prevalence of obesity, physical fitness, and exercise habits over the past 10 years in Japanese children. We investigated the prevalence of childhood obesity in Japan, using the School Health Statistics Survey data from 2012 to 2021. The dataset has a sample size representative of children nationwide and includes variables for obesity, such as height, weight, and age. Data were classified into groups by sex and age (6-8, 9-11, and 12-14 years age). Children weighing 20% or more of the standard body weight are classified as obese. The annual percentage changes and average annual percentage changes were estimated using the joinpoint regression model. We also examined the trends in the physical fitness test score and exercise time. Average annual percentage changes of boys increased, especially in the 6- to 8-year age group (3.4%-4.6%). For girls, average annual percentage changes had increased in 6- to 8-year (2.5%-4.0%) and 9- to 11-year (0.9%-2.2%) age groups. Since the late 2010s, significantly increasing annual percentage changes were observed in 12- to 14-year age boys (6.7%-8.9%) and girls of many age groups (2.6%-8.6%). The physical fitness test score and exercise time showed decreasing trends since the late 2010s. Childhood obesity may have generally risen in Japan, in the last decade. Encouraging healthy eating and physical activity through school policies and curricula is necessary.

Burden of depressive disorders in Vietnam from 1990 to 2019: A secondary analysis of the Global Burden of Disease Study 2019.

Depressive disorders are among the leading causes of disability globally. However, information on the burden of depressive disorders in Vietnam is limited. We aimed to analyse the burden of depressive disorders in Vietnam from 1990 to 2019. Using data from the Global Burden of Disease Study 2019, prevalence and disability-adjusted life-years (DALYs) were used as indicators to analyse the burden of depressive disorders by age and sex. In 2019 in Vietnam, depressive disorders comprised 2629.1 thousand (95% uncertainty interval (UI): 2233.3-3155.9) estimated cases and 380.6 thousand (95% UI: 258.9-533.8) estimated DALYs. The crude prevalence rate of depressive disorders was higher among females than among males. The DALYs of depressive disorder accounted for a higher percentage of the total all-cause DALYs in the 10-64-year age group than in other age groups. Major depressive disorder was the largest contributor to the burden of depressive disorders. From 1990 to 2019, the crude prevalence and DALY rates per 100 000 population due to depressive disorders increased significantly, whereas age-standardised rates of prevalence and DALYs decreased significantly; the respective average annual percent changes were 0.88% (95% confidence interval: 0.87 to 0.89), 0.68% (0.66 to 0.70), -0.20% (-0.21 to -0.19), and -0.27% (-0.28 to -0.25). Although the age-standardised prevalence rate was lower than that seen globally, depressive disorders were considerable mental health issues in Vietnam. This study will help governments and policymakers to establish appropriate strategies to reduce the burden of these disorders by identifying the priority areas and individuals.

International Trends in Adverse Drug Event-Related Mortality from 2001 to 2019: An Analysis of the World Health Organization Mortality Database from 54 Countries.

BACKGROUND AND OBJECTIVE: Adverse drug events (ADEs) are becoming a significant public health issue. However, reports on ADE-related mortality are limited to national-level evaluations. Therefore, we aimed to reveal overall trends in ADE-related mortality across the 21st century on an international level. METHODS: This observational study analysed long-term trends in ADE-related mortality rates from 2001 to 2019 using the World Health Organization Mortality Database. The rates were analysed according to sex, age and region. North America, Latin America and the Caribbean, Western Europe, Eastern Europe and Western Pacific regions were assessed. Fifty-four countries were included with four-character International Statistical Classification of Disease and Related Health Problems, Tenth Revision codes in the database, population data in the World Population Prospects 2019 report, mortality data in more than half of the study period, and high-quality or medium-quality death registration data. A locally weighted regression curve was used to show international trends in age-standardised rates. RESULTS: The global ADE-related mortality rate per 100,000 population increased from 2.05 (95% confidence interval 0.92-3.18) in 2001 to 6.86 (95% confidence interval 5.76-7.95) in 2019. Mortality rates were higher among men than among women, especially in those aged 20-50 years. The population aged ≥ 75 years had higher ADE-related mortality rates than the younger population. North America had the highest mortality rate among the five regions. The global ADE-related mortality rate increased by approximately 3.3-fold from 2001 to 2019. CONCLUSIONS: The burden of ADEs has increased internationally with rising mortality rates. Establishing pharmacovigilance systems can facilitate efforts to reduce ADE-related mortality rates globally.

Nuclear and chloroplast DNA phylogeography reveals Pleistocene divergence and subsequent secondary contact of two genetic lineages of the tropical rainforest tree species Shorea leprosula (Dipterocarpaceae) in South-East Asia.

Tropical rainforests in South-East Asia have been affected by climatic fluctuations during past glacial eras. To examine how the accompanying changes in land areas and temperature have affected the genetic properties of rainforest trees in the region, we investigated the phylogeographic patterns of a widespread dipterocarp species, Shorea leprosula. Two types of DNA markers were used: expressed sequence tag-based simple sequence repeats and chloroplast DNA (cpDNA) sequence variations. Both sets of markers revealed clear genetic differentiation between populations in Borneo and those in the Malay Peninsula and Sumatra (Malay/Sumatra). However, in the south-western part of Borneo, genetic admixture of the lineages was observed in the two marker types. Coalescent simulation based on cpDNA sequence variation suggested that the two lineages arose 0.28-0.09 million years before present and that following their divergence migration from Malay/Sumatra to Borneo strongly exceeded migration in the opposite direction. We conclude that the genetic structure of S. leprosula was largely formed during the middle Pleistocene and was subsequently modified by eastward migration across the subaerially exposed Sunda Shelf.

Human Immunodeficiency Virus-associated Immune Complex Kidney Disease Progressing to End-stage Kidney Disease.

A 58-year-old man with human immunodeficiency virus (HIV) infection presented with a week-long history of gross hematuria, nephrotic proteinuria, and acute kidney injury. The patient was non-adherent with combination antiretroviral therapy. A kidney biopsy showed cellular crescents with disruption of Bowman's capsule, C3-dominant immune complex deposition, consistent with HIV-associated immune complex kidney disease (HIVICK). During the course, his worsening kidney function warranted initiation of hemodialysis. This case highlights the fact that HIV patients are at an increased risk of developing HIVICK, especially in the setting of non-adherence. A greater understanding of HIVICK among HIV patients should promote additional investigation into its etiology and viable treatments.

Trends in the Incidence of Japanese Spotted Fever in Japan: A Nationwide, Two-Decade Observational Study from 2001-2020.

The worldwide spread of tick-borne diseases (TBDs) has become a public health concern. Therefore, this study aimed to clarify trends in the incidence of Japanese spotted fever (JSF), one of Japan's most prevalent TBDs. Weekly infectious disease reports were used to calculate the annual incidence rates (AIRs) of JSF. Data were stratified by age and sex, and joinpoint regression analysis was performed to estimate the annual percentage change (APC). AIR and APC were geographically compared among the 47 prefectures. A total of 3,453 JSF cases were observed from 2001 to 2020. The AIR per 100,000 population was 0.03 in 2001, which increased approximately 10-fold to 0.33 in 2020. The average APC (AAPC) during the study period was 12.3% (95% CI: 10.7-13.9). By age group, the incidence of JSF increased more rapidly among the older population: 11.5% (95% CI: 10.1-12.9) in those aged ≥ 65 years and 8.9% (95% CI: 6.4-11.5) in those aged < 50 years. Although the AIR over the past two decades was higher in climatically warm regions located in southwestern Japan and on the Pacific coast, increases in the AAPC were notable in colder regions located in eastern Japan. The incidence of JSF continues to increase in Japan, especially among older populations and in eastern prefectures, where the disease has not been previously diagnosed.

Trends in Head and Neck Cancer Mortality from 1999 to 2019 in Japan: An Observational Analysis.

Globally, the numbers of head and neck cancer (HNC) cases and related deaths have recently increased. In Japan, few studies have examined crude or age-adjusted HNC mortality rates. Therefore, this study aimed to determine the trends in crude and age-adjusted mortality rates for HNC per million individuals in Japan from 1999 to 2019. Data on HNC-associated deaths were extracted from the national death certificate database using the International Classification of Diseases, Tenth Revision (n = 156,742). HNC mortality trends were analysed using joinpoint regression models to estimate annual percentage change (APC) and average APC (AAPC). Among men, no significant change was observed in the age-adjusted death rate trend from 1999 to 2014; however, a marked decrease was observed from 2014 to 2019. No changing point was observed in women. Age-adjusted mortality rates continuously decreased over the 21-year period, with an AAPC of -0.7% in men and -0.6% in women. In conclusion, the overall trend in age-adjusted rates of HNC-associated deaths decreased, particularly among men, in the past 5 years. These results will contribute to the formulation of medical policies to develop targeted screening and prevention programmes for HNC in Japan and determine the direction of treatment strategies.

Effect of a mobile app chatbot and an interactive small-group webinar on COVID-19 vaccine intention and confidence in Japan: a randomised controlled trial.

INTRODUCTION: We investigated the effect of social media-based interventions on COVID-19 vaccine intention (VI) and confidence in Japan. METHODS: We conducted a three-arm randomised controlled trial between 5 November 2021 and 9 January 2022 during a low incidence (<1000/day) of COVID-19 in Japan in the midst of the second and the third waves. Japanese citizens aged ≥20 who had not received any COVID-19 vaccine and did not intend to be vaccinated were randomly assigned to one of the following three groups: (1) a control group, (2) a group using a mobile app chatbot providing information on COVID-19 vaccines and (3) a group using interactive webinars with health professionals. VI and predefined Vaccine Confidence Index (VCI) measuring confidence in the importance, safety and effectiveness were compared before and after the interventions under intention-to-treat principle. Logistic regression models were used to investigate the effect of each intervention on postintervention VI and changes of VCI compared with control. RESULTS: Among 386 participants in each group, 359 (93.0%), 231 (59.8%) and 207 (53.6%) completed the postsurvey for the control, chatbot and webinar groups, respectively. The average duration between the intervention and the postsurvey was 32 days in chatbot group and 27 days in webinar group. VI increased from 0% to 18.5% (95% CI 14.5%, 22.5%) in control group, 15.4% (95% CI 10.8%, 20.1%) in chatbot group and 19.7% (95% CI 14.5%, 24.9%) in webinar group without significant difference (OR for improvement=0.8 (95% CI 0.5, 1.3), p=0.33 between chatbot and control, OR=1.1 (95% CI 0.7, 1.6), p=0.73 between webinar and control). VCI change tended to be larger in chatbot group compared with control group without significant difference (3.3% vs -2.5% in importance, OR for improvement=1.3 (95% CI 0.9, 2.0), p=0.18; 2.5% vs 1.9% in safety, OR=1.1 (95% CI 0.7, 1.9), p=0.62; -2.4% vs -7.6% in effectiveness, OR=1.4 (95% CI 0.9, 2.1), p=0.09). Improvement in VCI was larger in webinar group compared with control group for importance (7.8% vs -2.5%, OR=1.8 (95% CI 1.2, 2.8), p<0.01), effectiveness (6.4% vs -7.6%, OR=2.2 (95% CI 1.4, 3.4), p<0.01) and safety (6.0% vs 1.9%, OR=1.6 (95% CI 1.0, 2.6), p=0.08). CONCLUSION: This study demonstrated that neither the chatbot nor the webinar changed VI importantly compared with control. Interactive webinars could be an effective tool to change vaccine confidence. Further study is needed to identify risk factors associated with decreased vaccine confidence and investigate what intervention can increase VI and vaccine confidence for COVID-19 vaccines. TRIAL REGISTRATION NUMBER: UMIN000045747.