3-epi-18ß-glycyrrhetinic acid or its glucuronide, the metabolites of glycyrrhizinic acid with individual differences, correlated with diagnostic maker for licorice-induced pseudoaldosteronism in humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18ß-glycyrrhetinic acid (GA), 3-epi-GA, 3-oxo-GA, 18ß-glycyrrhetinyl-30-O-glucuronide (GA30G), and 3-epi-GA30G were detected in the serum samples of 65, 47, 63, 62, and 3 participants, respectively. Of the 29 urine samples collected, GA30G and 3-epi-GA30G were detected in 27 and 19 samples. 3-epi-GA30G is a newly found GL metabolite. Moreover, 3-epi-GA, 3-oxo-GA, and 3-epi-GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3-epi-GA in serum and 3-epi-GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3-epi-GA, 3-oxo-GA, GA30G, and 3-epi-GA30G on human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) were almost similar. These findings suggest that 3-epi-GA and/or 3-epi-GA30G are associated with individual differences in the development of PsA. Significance Statement In this study, we detected 3-epi-GA in human serum for the first time. We also identified 3-epi-GA30G as a novel GL metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether or not they appear in the serum/urine. In conclusion, 3-epi-GA/3-epi-GA30G correlates with individual differences in the development of PsA.

Contribution of traditional Japanese Kampo medicines, kakkonto with shosaikotokakikyosekko, in treating patients with mild-to-moderate coronavirus disease 2019: Further analysis of a multicenter, randomized controlled trial.

We previously reported the finding of symptom relief in a randomized controlled trial with the combined use of kakkonto and shosaikotokakikyosekko added to conventional treatment in patients with coronavirus disease 2019 (COVID-19). For further evaluation, we performed post hoc analysis focused on symptom disappearance without recurrence, to determine a clearer effect of Kampo medicine. Patients with mild and moderate COVID-19 were randomly allocated to a control group receiving symptomatic therapy or a Kampo group receiving kakkonto (2.5 g) with shosaikotokakikyosekko (2.5 g) three times daily in addition to symptomatic therapy. The data of 161 patients (Kampo group, n = 81; control group, n = 80) were analyzed post hoc for the time to symptom disappearance. Kaplan-Meier and Cox proportional hazard estimates of disappearance of symptoms showed that all and each symptom targeted in this study disappeared faster in the Kampo group than in the control group, although not statistically significant (all symptomatic cases; hazard ratio [HR] 3.73, 95% confidence interval [CI] 0.46-29.98, log-rank p = 0.1763). In a supplemental assessment using covariate adjustment and competing risk analysis, fever disappeared faster in the Kampo group than in the control group (all symptomatic cases, HR 1.62, 95% CI 0.99-2.64, p = 0.0557; unvaccinated cases, HR 1.68, 95% CI 1.00-2.83, p = 0.0498) and shortness of breath disappeared significantly faster in Kampo group than in control group (all symptomatic cases, HR 1.92, 95% CI 1.07-3.42, p = 0.0278; unvaccinated cases, HR 2.15, 95% CI 1.17-3.96, p = 0.0141). These results demonstrate the advantages of Kampo treatment for acute COVID-19.

Development of a novel drug information provision system for Kampo medicine using natural language processing technology.

BACKGROUND: Kampo medicine is widely used in Japan; however, most physicians and pharmacists have insufficient knowledge and experience in it. Although a chatbot-style system using machine learning and natural language processing has been used in some clinical settings and proven useful, the system developed specifically for the Japanese language using this method has not been validated by research. The purpose of this study is to develop a novel drug information provision system for Kampo medicines using a natural language classifier® (NLC®) based on IBM Watson. METHODS: The target Kampo formulas were 33 formulas listed in the 17th revision of the Japanese Pharmacopoeia. The information included in the system comes from the package inserts of Kampo medicines, Manuals for Management of Individual Serious Adverse Drug Reactions, and data on off-label usage. The system developed in this study classifies questions about the drug information of Kampo formulas input by natural language into preset questions and outputs preset answers for the questions. The system uses morphological analysis, synonym conversion by thesaurus, and NLC®. We fine-tuned the information registered into NLC® and increased the thesaurus. To validate the system, 900 validation questions were provided by six pharmacists who were classified into high or low levels of knowledge and experience of Kampo medicines and three pharmacy students. RESULTS: The precision, recall, and F-measure of the system performance were 0.986, 0.915, and 0.949, respectively. The results were stable even with differences in the amount of expertise of the question authors. CONCLUSIONS: We developed a system using natural language classification that can give appropriate answers to most of the validation questions.

Climacteric symptoms in postoperative patients among endometrial cancer, cervical cancer, and ovarian cancer: a cross-sectional study.

PURPOSE: To date, no studies have assessed climacteric symptoms after hystero-adnexectomy for endometrial, cervical, or ovarian cancer. Thus, this study aimed to compare climacteric symptoms among patients who underwent surgery for these three cancer types. METHODS: In this cross-sectional study, we interviewed patients who were registered at a menopausal outpatient clinic between January 1999 and July 2016 after undergoing total hysterectomy, intrapelvic only or intrapelvic plus para-aortic lymph node dissection, and bilateral adnexectomy performed via laparotomy as a cancer treatment. Climacteric symptoms were assessed using a patient-reported questionnaire covering core domains with five symptoms only at the initial consultation. Each symptom was graded from 0 (no symptoms) to 3 (severe symptoms). We evaluated the frequency of symptom severity according to the time elapsed since surgery and the cancer type. RESULTS: The numbers of patients with endometrial, ovarian, and cervical cancer were 328, 90, and 107, respectively. Overall, climacteric symptoms were more severe in patients with cervical cancer than in those with endometrial or ovarian cancer; symptom severity decreased with increasing time since surgery. However, symptom severity did not decrease significantly over time in patients with cervical cancer even after > 5 years had elapsed since surgery. CONCLUSION: The climacteric symptoms were less severe in patients with endometrial or ovarian cancer with longer time elapsed since surgery but not in those with cervical cancer. Patients with cervical cancer may require more prompt interventions, including symptomatic treatment and longer follow-up period, than those with endometrial or ovarian cancer.

Identification of glycyrrhizin metabolites in humans and of a potential biomarker of liquorice-induced pseudoaldosteronism: a multi-centre cross-sectional study.

Liquorice [main ingredient, glycyrrhizin (GL)] is widely used as a food sweetener and herbal medicine. Occasionally, liquorice consumption causes pseudoaldosteronism as a side effect which causes oedema, hypokalaemia, and hypertension due to hyperactivity of mineral corticoid receptor. We aimed to detect GL metabolites in human blood and urine samples and to determine the pathological relationship between GL metabolites and pseudoaldosteronism. For this multi-centre, retrospective, cross-sectional study, we recruited patients who had visited Center for Kampo Medicine in Keio University Hospital, Department of Japanese Oriental (Kampo) Medicine in Chiba University Hospital, Clinic of Japanese Oriental (Kampo) Medicine in Kanazawa University Hospital, and Department of Oriental Medicine in Kameda Medical Center from November 2011 to July 2018. We collected laboratory data including concentration of serum potassium, plasma activity of renin and aldosterone, and residual blood and/or urine samples of participants who had experienced symptoms/signs of pseudoaldosteronism in the form of increase in blood pressure and occurrence or aggregation of oedema while taking liquorice-containing herbal preparations, and measured GL metabolites using a highly selective liquid chromatography tandem mass spectrometer system. We registered 97 participants (mean age 60 ± 15 years; male:female 14:83). 18ß-glycyrrhetinic acid (GA) was detected in 67 serum samples (median 122 nM, range 5 nM-1.8 µM) and 18ß-glycyrrhetyl-3-O-sulfate (compound 3) in 68 samples (median 239 nM, range 2 nM-4.2 µM). 3-Monoglucuronyl 18ß-glycyrrhetinic acid, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate-30-glucuronide, 22α-hydroxy-18ß-glycyrrhetyl-3-O-sulfate, and GL itself were not or rarely detected. We could not find any correlation between blood pressure or peripheral oedema and serum concentration of GL metabolites. Sulfotransferase 2A1 catalysed the metabolic reaction of GA to compound 3, a major GL metabolite in human blood. High serum concentration of compound 3 was related to lower renin, aldosterone, and potassium levels, suggesting a pathological relationship between compound 3 and liquorice-induced pseudoaldosteronism. This is the first study to identify the association between a novel metabolite, compound 3, and the incidence of pseudoaldosteronism, highlighting it as a promising biomarker.

The use of maoto (Ma-Huang-Tang), a traditional Japanese Kampo medicine, to alleviate flu symptoms: a systematic review and meta-analysis.

BACKGROUND: Influenza is a common viral infection worldwide. Maoto (ma-huang-tang) was developed in ancient China and is used to alleviate flu symptoms. Currently, no meta-analyses have evaluated the efficacy and safety of maoto for alleviating flu symptoms. METHODS: In the present study, we searched MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, a Japanese database (Ichushi), two Chinese databases (China National Knowledge Infrastructure and VIP), and two Korean databases (Korean Medical database and Korean Association of Medical Journal Editors) for studies published in or before October 2017. Clinical studies that compared maoto plus neuraminidase inhibitors (NAIs) vs. NAIs alone, or maoto alone vs. NAIs alone, were included in the present analysis. The primary outcome measure (efficacy) was the length of time from the start of medication to resolution of influenza symptoms (fever, headache, malaise, myalgia, and chills) and virus isolation. The secondary outcome measures (safety) were as follows: (1) side effects and adverse reactions, such as nausea, abnormal behaviour, or discontinuation of symptomatic treatment; (2) morbidity (complications caused by influenza infection) or mortality; and (3) hospitalisation for any reason. RESULTS: Twelve relevant studies were identified, including two randomised controlled trials (RCTs, N = 60) and ten non-randomised studies (NRSs, N = 1110). We found that maoto plus NAIs was superior to NAIs alone in terms of the duration of fever in one RCT (P < 0.05, median difference = - 6 h) and four NRSs (P = 0.003, weighted mean difference = - 5.34 h). The duration of symptoms or virus isolation did not differ between maoto and NAIs. No severe side effects or adverse reactions were reported related to maoto or NAIs. CONCLUSIONS: Although we could not reach a definitive conclusion because of the small sample sizes and high risk of bias in the analysed studies, maoto may lower the duration of fever when it is used alone or in combination with NAIs and may be a well-tolerated treatment. More RCTs are needed to determine the efficacy and safety of maoto.

Predicting Japanese Kampo formulas by analyzing database of medical records: a preliminary observational study.

BACKGROUND: Approximately 90 % of physicians in Japan use Kampo medicine in daily practice. However, it is a challenge for physicians who do not specialize in Kampo medicine to select a proper Kampo formula out of the 148 officially approved formulas, as the decision relies on traditional measurements and traditional medicine pattern diagnoses. The present study tries to evaluate the feasibility of a decision support system for frequently used Kampo formulas. METHODS: Our study included 393 patients who visited the Kampo Clinic at Keio University Hospital for the first time between May 2008 and March 2013. We collected medical records through a browser-based questionnaire system and applied random forests to predict commonly prescribed Kampo formulas. RESULTS: The discriminant rate was the highest (87.0 %) when we tried to predict a Kampo formula from two candidates using age, sex, body mass index, subjective symptoms, and the two essential and predictable traditional medicine pattern diagnoses (excess-deficiency and heat-cold) as predictor variables. The discriminant rate decreased as the candidate Kampo formulas increased, with the greatest drop occurring between three (76.7 %) and four (47.5 %) candidates. Age, body mass index, and traditional medicine pattern diagnoses had higher importance according to the characteristics of each Kampo formula when we utilized the prediction model, which predicted a Kampo formula from among three candidates. CONCLUSIONS: These results suggest that our decision support system for non-specialist physicians works well in selecting appropriate Kampo formulas from among two or three candidates. Additional studies are required to integrate the present statistical analysis in clinical practice.

Exploratory study of cold hypersensitivity in Japanese women: genetic associations and somatic symptom burden.

Temperature perception is essential for humans to discern the environment and maintain homeostasis. However, some individuals experience cold hypersensitivity, characterized by a subjective feeling of coldness despite ambient environmental temperatures being normal, the underlying mechanisms of which are unknown. In this study, we aimed to investigate the relationship between subjective cold symptoms and somatic burden or single nucleotide polymorphisms to understand the causes of cold hypersensitivity. We conducted an online questionnaire survey [comprising 30 questions, including past medical history, subjective symptoms of cold hypersensitivity, and the Somatic Symptom Scale-8 (SSS-8)]. Respondents were 1200 Japanese adult female volunteers (age: 20-59 years), recruited between April 21 and May 25, 2022, who were customers of MYCODE, a personal genome service in Japan. Among the 1111 participants, 599 (54%) reported cold hypersensitivity. Higher cold hypersensitivity severity was positively associated with the SSS-8 scores. Additionally, a genome-wide association study for cold hypersensitivity was conducted using array-based genomic data obtained from genetic testing. We identified 11 lead variants showing suggestive associations (P < 1 × 10-5) with cold hypersensitivity, some of which showed a reasonable change in expression in specific tissues in the Genotype-Tissue Expression database. The study findings shed light on the underlying causes of cold hypersensitivity.

The Integration of Traditional Medicine with Conventional Biomedicine: A Narrative Review of the Japanese Perspective.

Objectives: This is a narrative review of the integration of traditional medicine with conventional biomedicine in present day Japan, whose aging population is considered one of the largest globally. Design: It is focused on the aging population because this age group most avails of healthcare. We also tried to describe the unique Japanese medical situations, clinical outcome of Japanese traditional medicine (Kampo medicine) which may include acupuncture, and education of Kampo medicine workforce. Results: Conventional schools of medicine in Japan are required to teach Kampo medicine, and most Japanese physicians (>80%) prescribe traditional medicine, especially in primary care settings. The universal national healthcare system covers Kampo medicine prescribed by physicians and treatment by acupuncturists (they sometimes refer patients who may need evaluation by physicians), enhancing access to primary healthcare. Additionally, pharmacists who graduated from conventional schools of pharmacy also select and sell Kampo medicine as over-the-counter (OTC) medication. Kampo medicine available as prescription drugs and OTC is effective, and has been proven to be economically beneficial in several clinical settings. Conclusions: An aging population is a global concern for both developed and developing countries. Japan, having a significantly-large aging population, integrates conventional biomedicine and traditional medicine in its universal national healthcare coverage, through its biomedically-trained physicians and pharmacists who also learned traditional medicine, as well as the acupuncturists. By reviewing the current situation in Japan, the authors hope to introduce the future of the global contribution of traditional, complementary, and integrative medicine in primary care.

Patient prognosis and prediction model for taking Kampo formulas in dysmenorrhea: An observational study.

Two representative Kampo formulas, keishibukuryogan and tokishakuyakusan, are frequently prescribed for patients with dysmenorrhea. We previously constructed a model that could predict which of these 2 formulas was most suitable, which is based on 4 subjective symptoms and 3 objective signs. To evaluate the prognosis of patients with dysmenorrhea using the established prediction model and assess the treatment outcomes between those treated in accordance with the prediction model and those who received various other treatments. In this retrospective, observational study, we included patients with menstrual pain who visited the Kampo Clinic at the Keio University Hospital for the first time between October 2014 and December 2020. These patients were monitored over a 90-day follow-up period. Participants were categorized into 2 groups: model-accordance and various-options. The progression of visual analogue scale (VAS) values was evaluated by determining the slopes from regression analysis between these 2 groups, with changes corroborated by the medical records. The study comprised 57 patients: 37 in the model-accordance group and 20 in the various-options group. Notably, the various-options group reported a significantly higher number of subjective symptoms (P = .03). The VAS value showed a decline, as indicated by the negative slope value of the regression line, across both groups - irrespective of their classification. There were no significant differences in the occurrence of adverse events between the 2 groups. The prognosis of patients with dysmenorrhea and the incidence of adverse events remained consistent, regardless of whether the treatment approach was in accordance with the prediction model or varied. Further studies are warranted to assess the prognosis when Kampo formulas are chosen based on the prediction model in the various-options population.

Conventional and Kampo Medicine Treatment for Mild-to-moderate COVID-19: A Multicenter, Retrospective, Observational Study by the Integrative Management in Japan for Epidemic Disease (IMJEDI Study-observation).

Objective Patients in whom coronavirus disease 2019 (COVID-19) was suspected or confirmed between January 1, 2020, and October 31, 2021, were enrolled from Japanese hospitals in this multicenter, retrospective, observational study. Methods Data on the treatment administered (including conventional and Kampo medicine) and changes in common cold-like symptoms (such as fever, cough, sputum, dyspnea, fatigue, and diarrhea) were collected from their medical records. The primary outcome was the number of days without a fever (with a body temperature <37°C). The secondary outcomes were symptomatic relief and the worsening of illness, defined as the presence of a condition requiring oxygen inhalation. The outcomes of patients treated with and without Kampo medicine were compared. Patients We enrolled 962 patients, among whom 528 received conventional and Kampo treatment (Kampo group) and 434 received conventional treatment (non-Kampo group). Results Overall, after adjusting for the staging of COVID-19 and risk factors, there were no significant between-group differences in the symptoms or number of days being afebrile. After performing propensity score matching and restricting the included cases to those with confirmed COVID-19 who did not receive steroid administration and initiated treatment within 4 days from the onset, the risk of illness worsening was significantly lower in the Kampo group than in the non-Kampo group (odds ratio=0.113, 95% confidence interval: 0.014-0.928, p=0.0424). Conclusion Early Kampo treatment may suppress illness worsening risk in COVID-19 cases without steroid use. Further randomized controlled studies are needed to confirm the clinical benefit of Kampo medicine for COVID-19.

Exploring Standardized Scales and Serum Biomarkers to Evaluate Changes in Pruritus due to Eczema after Japanese Kampo Treatment: A Prospective Case Series.

BACKGROUND: We aimed to explore standardized scales and serum biomarkers for tracking changes in the symptoms and severity of pruritus due to eczema in patients treated with Kampo formulas. PATIENTS AND METHODS: This prospective, single-arm, pre-post comparison case series recruited patients with pruritus mostly due to eczema who consulted the Kampo Clinic at the Keio University Hospital from June 2019 to March 2020. The participants were prescribed a personalized Kampo formula for 12 weeks. Patient profiles and symptoms were assessed every 4 weeks using the visual analog scale (VAS), patient-oriented eczema measure (POEM) scale, 5-D itch scale (5D), Skindex-16, and eczema area and severity index (EASI). Blood biomarkers and intestinal permeability indicators were measured at the first consultation and 12 weeks later. RESULTS: Pruritus and eczema severity improved significantly over time. The VAS, POEM, 5D, and Skindex-16 scores were well-correlated. The serum interleukin-31 levels decreased significantly after a 12-week intervention. Changes in the interleukin-31 level correlated with the diamine oxidase level at week 0, suggesting the involvement of the Th2 immune system and intestinal permeability in the mechanism of Kampo formulas. CONCLUSION: The evaluated scales are suitable for evaluating subjective symptoms and eczema severity after Kampo treatment; further studies are required to verify the study findings.

Oral Astragalus Root Supplementation for Mild to Moderate Chronic Kidney Disease: A Self-Controlled Case-Series.

In this self-controlled case series, we aimed to investigate the variation in estimated glomerular filtration rate (eGFR) after taking astragalus-containing preparations in patients with mild to moderate chronic kidney disease (CKD) by retrospectively reviewing their charts in our clinic. We set the inclusion criteria as first-visit patients aged 20 years or older presenting to our clinic between 1 October 2014, and 31 June 2019, and who were prescribed astragalus-containing herbal preparations for any reason. We calculated the mean eGFR from the readings taken 6 months before (pre) and after (post) the intake of astragalus-containing preparations for each participant. Among the 37 patients included in our final analysis, we found a statistically significant improvement in the eGFR after prescribing astragalus-containing preparations (pre, 66 ± 12 ml/min/1.73 m2 vs. post, 70 ± 14 ml/min/1.73 m2; p < 0.001 by paired t-test). Our results were consistent regardless of age, sex, CKD stage of the participants (G2 or G3), daily dosage of astragalus root, or duration of astragalus-containing preparations. No severe adverse reactions were recorded in the charts of the study participants. Our results suggest that there is eGFR improvement after taking astragalus-containing preparations in mild to moderate CKD cases as reported previously. The findings should be considered with caution due to major limitations such as small sample size without optimum control, short follow-up period, and incomplete data. Further adequately powered and designed studies are needed to confirm the efficacy and safety of the long-term use of astragalus root in patients with mild to moderate CKD.

A prediction model of qi stagnation: A prospective observational study referring to two existing models.

OBJECTIVE: To establish a prediction model of qi stagnation referring to two existing models. DESIGN: Prospective observational study. SETTING: We recruited patients who visited the Kampo Clinic at Keio University from February 2011 to March 2013. METHODS: We constructed a random forest algorithm with 202 items as independent variables to predict qi stagnation patterns using full agreement data of the physicians' diagnosis and the result of two existing scores as a reference standard. To compare the new model with the two existing models, we calculated the discriminant ratio (prediction accuracy), precision, sensitivity (recall), specificity, and F-measure of these models. RESULTS: The number of eligible participants was 1,194, and 29.1% of them were diagnosed with qi stagnation by Kampo physicians. The discriminant ratio, precision, sensitivity, specificity, and F-measure in our new model were 0.960, 0.672, 0.911, 0.964, and 0.774, respectively. Our new model had a significantly higher discriminant ratio than the two existing models. CONCLUSIONS: We constructed a better qi stagnation prediction model than the previously established ones. Our results can be utilized to reach an international agreement on qi stagnation pattern diagnosis in traditional East Asian medicine.

Corrigendum: Identification of an alternative glycyrrhizin metabolite causing liquorice-induced pseudohyperaldosteronism and the development of ELISA system to detect the predictive biomarker.

[This corrects the article DOI: 10.3389/fphar.2021.688508.].

Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients.

The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].

Bilateral pneumothorax after acupuncture treatment.

A 31-year-old female physician was diagnosed with bilateral pneumothorax a day after her acupuncture treatment. Her body mass index was 16.9 and she did not have a prior history of respiratory disease or smoking. Acupuncture needles may easily reach the pleura around the end of the suprascapular angle of the levator scapulae muscle where the subcutaneous tissue is anatomically thin. In our patient, the thickness between the epidermis and the visceral pleura in this area was only 22 mm as confirmed by an ultrasound scan. Although she felt chest discomfort 30 min after the procedure, she assumed the symptom to be a reaction to the acupuncture. In light of our case, we advise practitioners to select appropriate acupuncture needles for patients based on the site of insertion and counsel them regarding the appearance of symptoms such as chest pain and dyspnoea immediately after the procedure.

Inter-Rater Reliability of Kampo Diagnosis for Chronic Diseases.

This single-center observational study aimed to assess the inter-rater reliability (IRR) of Kampo medicine pattern diagnosis, which is modularized into three modules for chronic diseases, using 64 participants' information documents. The linearly weighted percentage of agreement and Gwet's agreement coefficient (AC) 2 for the deficiency-excess module, among three specialists, were 85.9% and 0.708, respectively. The unweighted percentage of agreement and Gwet's AC1 were 64.6% and 0.542 for the cold-heat, and 35.9% and 0.254 for the qi-blood-fluid modules, respectively. Our findings suggest that our modularization method may improve the IRR of Kampo medicine pattern diagnosis.

Clinical Risk Factors of Licorice-Induced Pseudoaldosteronism Based on Glycyrrhizin-Metabolite Concentrations: A Narrative Review.

Licorice, the dried root or stolon of Glycyrrhiza glabra or G. ularensis, is commonly used worldwide as a food sweetener or crude drug. Its major ingredient is glycyrrhizin. Hypokalemia or pseudoaldosteronism (PsA) is one of the most frequent side effects of licorice intake. Glycyrrhizin metabolites inhibit type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2), which decomposes cortisol into inactive cortisone in the distal nephron, thereby inducing mineralocorticoid receptor activity. Among the several reported glycyrrhizin-metabolites, 18ß-glycyrrhetyl-3-O-sulfate is the major compound found in humans after licorice consumption, followed by glycyrrhetinic acid. These metabolites are highly bound to albumin in blood circulation and are predominantly excreted into bile via multidrug resistance-associated protein 2 (Mrp2). High dosage and long-term use of licorice are constitutional risk factors for PsA. Orally administered glycyrrhizin is effectively hydrolyzed to glycyrrhetinic acid by the intestinal bacteria in constipated patients, which enhances the bioavailability of glycyrrhizin metabolites. Under hypoalbuminemic conditions, the unbound metabolite fractions can reach 11ßHSD2 at the distal nephron. Hyper direct-bilirubin could be a surrogate marker of Mrp2 dysfunction, which results in metabolite accumulation. Older age is associated with reduced 11ßHSD2 function, and several concomitant medications, such as diuretics, have been reported to affect the phenotype. This review summarizes several factors related to licorice-induced PsA, including daily dosage, long-term use, constipation, hypoalbuminemia, hyper direct-bilirubin, older age, and concomitant medications.