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During the 2020–2021 winter season, we detected 6 gamma‐ray glows at Kanazawa University, Japan. Negative surface electric fields (E‐fields; in the sign convention of atmospheric electricity) were observed by a field mill during all the glow cases. In five of the six cases, the peak E‐field reached around −12 kV m−1, and the E‐field during the glow detection was the strongest in the interval including 3 hr before and after the detection time. Therefore, negative charges should have been dominant in the thunderclouds that produced the gamma‐ray glows, and electrons were probably accelerated and multiplied by the E‐fields between a predominantly negative charge layer and a localized positive charge layer below. In addition, we extracted 8 non‐detection cases in the 2020–2021 winter season, in which surface E‐fields were stronger than −12 kV m−1. In 5 of the 8 cases, radar echoes were inadequately developed, suggesting insufficient charge accumulation. On the other hand, the remaining 3 cases had well‐developed radar echoes, and there was no significant difference from the detection cases. Plain Language Summary: Gamma‐ray glow is a minute‐lasting burst of high‐energy photons associated with thunderclouds. High‐energy photons are considered to originate from high‐energy electrons accelerated and multiplied in strong electric fields inside thunderclouds. When a gamma‐ray glow is detected on the ground, electrons are considered to be accelerated downward by upward electric fields. In the 2020–2021 winter season, we detected a total of 6 gamma‐ray glows during winter thunderstorms at Kanazawa University, Japan. An electric‐field monitor recorded negative electric fields at the surface during all the glow detections, indicating negative charges overhead. It suggests that the thunderclouds that produced the gamma‐ray glows were strongly charged negatively, and a localized positive charge layer existed in the lower part to produce an upward electric field for downward electron acceleration. Key Points: In the 2020–2021 winter season, 6 gamma‐ray glows were detected at Kanazawa University, Japan, with electric‐field measurementSurface electric fields were negative during the detection of all the gamma‐ray glowsHigh‐energy electrons seemed to be produced between a well‐developed negative charge region and a localized positive charge region below [ABSTRACT FROM AUTHOR]

Electric field of thunderclouds modifies components and energy spectra of the cosmic‐ray air shower. In particular, thunderstorms accelerate charged particles, resulting in an enhancement of gamma‐ray fluxes on the ground, known as a gamma‐ray glow. This phenomenon has been observed in recent years by the Gamma‐Ray Observation of Winter THunderclouds collaboration from winter thunderstorms in the Hokuriku area of Japan. The present work examines the ambient conditions required to produce spectral features of the previously detected gamma‐ray glows, by using Monte Carlo simulations of particle interactions in the atmosphere. We focus on three parameters, the strength and length of the electric field, and the length of a null‐field attenuation region below the electrified region. The average spectrum of observed gamma‐ray glows in winter thunderstorms of Japan requires an electric field intensity close to 0.31 MV/m, slightly exceeding the Relativistic Runaway Electron Avalanche threshold of 0.284 MV/m. The vertical size of the electric field region should be comparable to 1 km. The estimated attenuation region size is 300–500 m, necessary to reduce the low‐energy photon flux of the average gamma‐ray glows. There is still a wide range of acceptable parameter sets with degeneracy to make a similar spectrum. Plain Language Summary: Thunderclouds modify the incident cosmic‐ray flux due to their electric field. In particular, thunderstorms accelerate charged particles inducing enhancement of the gamma‐ray flux at the ground, known as the gamma‐ray glow. Throughout recent years, the community observes gamma‐ray glows on the Japanese Hokuriku coast. This paper examines the ambient conditions required to produce the characteristic gamma‐ray glow spectrum using Monte Carlo simulation. We focus on the electric field strength, and electric field length and introduced a null‐field attenuation region following previously reported features of Japanese winter thunderclouds. We conclude that most observed gamma‐ray glows at the Hokuriku region require electric fields close to 0.32 MV/m along approximately 1 km and an attenuation region of 300–500 m to reproduce the observations. Finally, the three studied variables can be differently combined to generate similar spectra regarding a space of phase of three coordinates being electric field strength, electric field length, and attenuation space length. Key Points: We use Monte Carlo simulations of electron and gamma‐ray interactions in thunderstorms to explain observed gamma‐ray glowsWe successfully simulated gamma‐ray glow spectra and extracted an acceptable set of ambient atmospheric factors of the glowFit configurations have electric fields as ∼0.30 MV/m with a ∼1 km size scale and a null field region of ∼0.5 km below that [ABSTRACT FROM AUTHOR]

Winter thunderstorms in Japan have been recognized as an ideal target to observe high‐energy atmospheric phenomena thanks to low‐charge‐center cloud structures. During four winter seasons in Japan (from 2016 October to 2020 March), seven downward terrestrial gamma‐ray flashes (TGFs) were detected by gamma‐ray and broadband low‐frequency (LF: 0.8–500 kHz) monitors. All the detected TGFs took place at the initial stage of lightning flashes. Based on the LF observation, the seven downward TGFs in the present study can be classified into two types: energetic‐bipolar and small‐bipolar types. Three of them are energetic‐bipolar events, coincident with a high peak‐current LF pulse that originates from a negative return stroke with a peak current larger than 100 kA. The others are small‐bipolar events, followed by a negative bipolar LF pulse with a moderate peak current. Three of the four small‐bipolar events are multi‐pulse TGFs, while all of the energetic‐bipolar events in this study are single‐pulse TGFs. Plain Language Summary: Terrestrial gamma‐ray flashes (TGFs) are a transient high‐energy emission from lightning discharges. While a lot of upward TGFs have been detected by satellites, a few downward TGF have been detected by ground‐based experiments. Our detection network in Japan has detected seven downward TGFs in winter thunderstorms for 4 years. Lightning discharges associated with the downward TGFs were also monitored in the low‐frequency radio band. The low‐frequency pulses associated with the downward TGFs can be classified into two types. Correlation analysis of downward TGFs with gamma‐ray and low‐frequency observations is a powerful approach to reveal the production mechanism of TGFs. Key Points: Downward terrestrial gamma‐ray flashes (TGFs) in winter thunderstorms of Japan can be classified into two types based on low‐frequency (LF) observationsThree events were single‐pulse TGFs coincident with high peak‐current LF pulses of return strokesFour events were followed by moderate peak‐current LF pulses, and three of them are multi‐pulse TGFs [ABSTRACT FROM AUTHOR]

In order to investigate the strain accumulation process around the Niigata-Kobe Tectonic Zone in central Japan, we estimate a precise GPS velocity field around a representative fault area, the Atotsugawa fault system. The velocity profiles obtained from two dense GPS arrays crossing the Atotsugawa fault demonstrate the existence of a laterally heterogeneous deformation pattern along the fault strike. The West Array suggests the possibility of surface fault creep, which disagrees with inferences gleaned from previous EDM measurements. High shear strain rate, which is calculated from wider velocity field, distributes around not only the Atotsugawa fault system, but also the Takayama-Oppara fault zone, which is located 50 km south from the Atotsugawa fault. In order to consider the effect of interaction between those active faults, we conduct a block-fault model analysis. Our block model consists of nine blocks and 33 fault segments. Relative motion between two blocks at the northern and southern ends of the fault system is calculated to be 9.9 mm yr. The intervening region between these two blocks corresponds to the Niigata-Kobe Tectonic Zone with a strain rate of 0.2 ppm yr. Slip deficit rates at the Atotsugawa, Ushikubi, and Takayama-Oppara fault zones are estimated to be 2.2, 3.9 and 2.3 mm yr, respectively. Although the ratio of slip deficit rate (2.2 : 3.9 : 2.3 ≈ 1 : 2 : 1) of these three faults is similar to that of geological long-term slip rates (1 : 2 : 0.7), the magnitude of geodetic slip deficits is 30 per cent to 50 per cent larger than long-term slip rates. This systematic difference may be due to inelastic deformation of the crust in this region. Since the total slip deficit rate between the Ushikubi and the Takayama-Oppara fault zone is 8.4 mm yr, about 85 per cent of the relative block motion, the deformation is mostly accommodated by elastic strain accumulation on these three faults. [ABSTRACT FROM AUTHOR]

The current status of replacement therapy for haemophilia and the role played by nurses in Japan were investigated at 16 facilities (17 specialties) each providing care to 20 or more haemophilia A or B patients without inhibitor. The questionnaire was mailed to the nurse or physician in charge of haemophilia at each facility in August 2006, asking the nurse to fill in the questionnaire. Responses were collected on 1318 patients (haemophilia A: 1078 patients; haemophilia B: 240 patients). About 70% of these patients were reported to be severe haemophilia A or B. Overall, 26% were receiving regular prophylaxis while 74% received on-demand therapy with or without temporary prophylaxis before special events. The percentage of patients receiving primary prophylaxis was only 2%. The percentage of adherence to prophylaxis decreased with age (lowest at age 19–29) but this percentage for each age group in Japan was higher than that in the western countries. Of the nurses working at the facilities surveyed, 88% considered prophylaxis as an optimal therapy for severe haemophilia patients, although the percentage of patients receiving prophylaxis for the entire population surveyed was lower than that in the western countries. The main factor precluding introduction of prophylaxis was ‘difficulty in venous access’ for infants and small children. On the other hand, ‘unwillingness of family members’ and ‘poor adherence’ were the main factors precluding introduction of this therapy for those aged over 6 years. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 506-508 (2012) Abstract Aims It has been recognized that blood pressure shows a seasonal variation, but it remains unknown whether diabetic nephropathy shows a seasonal variation. In the present study, we investigated the change in urinary albumin/creatinine ratio in relation to the season in Japanese patients with Type 2 diabetes. Methods A total of 430 subjects (275 male, 155 female) with Type 2 diabetes and early nephropathy (defined by UACR 30-300 mg/g creatinine) were included. One year was divided into four seasons and each season was defined as winter (December-February), spring (March-May), summer (June-August), and fall (September-November), and systolic and diastolic blood pressure, serum creatinine levels, and the urinary albumin/creatinine ratio were examined. The estimated glomerular filtration rate was also calculated and evaluated. Results The mean age (± SE) was 64.8 ± 0.8 years. The mean systolic blood pressure was significantly higher in winter than in summer (136 ± 0.68 vs. 133 ± 0.68 mmHg, P < 0.001). The urinary albumin/creatinine ratio showed a significantly higher value in winter than in summer (72.8 ± 4.4 vs. 54.6 ± 3.4 mg/g creatinine, P < 0.001). The curve of seasonal variation of this ratio showed a similar change to that of systolic blood pressure. No significant seasonal variation was observed in estimated glomerular filtration rate and diastolic blood pressure. Conclusions Our results suggest that there is a hitherto unknown seasonal variation in the urinary albumin/creatinine ratio, and that it may be necessary to consider this seasonal change, especially when performing an intervention study of nephropathy. [ABSTRACT FROM AUTHOR]

Parathyroid hormone-related protein (PTHrP), which causes hypercalcemia associated with malignant tumors, is known to be present in milk. Gene expression of PTHrP in the mammary gland increases markedly during parturition and with the onset of lactation. Even when circulating PTHrP levels are extremely low or below the detection limit, milk PTHrP levels are remarkably high. Parathyroid hormone-related protein derived from the mammary gland is assumed to play a role in maintaining the maternal calcium homeostasis and calcium transport from blood to milk. In previous studies that determined the PTHrP concentrations in milk, the pretreatments and diluent composition were not standardized. Here, we investigated the effect of various pretreatment procedures and diluent constitutions and the consequent PTHrP concentrations in commercial milk and milk products in Japan. Significant differences were found in PTHrP concentrations in raw milk samples subjected to different combinations of pretreatments (mixing, centrifugation, acidification, and heating) and diluents (0 pM standard solution of PTHrP, plasma treated with protease inhibitors, and original diluent). We measured the PTHrP concentrations in normal liquid milk, processed milk, milk drinks, formulated milk powders, and skim milk powder by using the appropriate combination of pretreatment (acidification) and diluent (plasma treated with protease inhibitors). The PTHrP concentration in normal liquid milk, processed milk, and skim milk powder was as high as that in raw milk (>5 nM), whereas that in milk drinks differed considerably. The PTHrP concentration in infant formulas (<2 nM) was lower than that in the other milk products. These results indicate that a certain amount of PTHrP is ingested when milk and milk products are consumed. [ABSTRACT FROM AUTHOR]

High-altitude pulmonary edema (HAPE) is a life-threatening, noncardiogenic pulmonary edema that occurs in unacclimatized individuals rapidly ascending to high altitudes above 2,500 m above sea level. Until the entity of HAPE was first identified in a case report published in Japan in 1966, the symptoms of severe dyspnea or coma occurring in climbers of the Japan Alps were incorrectly attributed to pneumonia or congestive heart failure. The Shinshu University Hospital serves as the central facility for rescuing and treating patients with HAPE in the region. Over the past 50 years, a series of studies have been conducted at Shinshu University to gain a better understanding of the characteristics of HAPE. This review summarizes the major achievements of these studies, including their clinical features, management, and pathogenesis of HAPE, particularly in the Japanese population.

In recent years, bedside ultrasound examinations have been used in many clinical departments and are called point-of-care ultrasound (POCUS). Regarding POCUS in the cardiac field, a protocol called focus (focused) cardiac ultrasound (FoCUS) has been developed in Europe and the United States, is being used clinically, and an educational syllabus has been created. According to them, FoCUS is defined as a point-of-care cardiac ultrasound examination using standardized limited sections and protocols. FoCUS is primarily intended to be performed by non-cardiologists, and in order to avoid making mistakes in judgment, it is important to be familiar with its limitations and it is necessary to understand pathological conditions that can only be diagnosed using conventional comprehensive echocardiography. The Japanese Society of Echocardiography has edited this clinical guideline because we believe that FoCUS should be used effectively and appropriately in Japan, and that appropriate education is essential to popularize FoCUS in Japan. Furthermore, lung POCUS has recently come into clinical use. Lung POCUS is useful for the diagnosis and follow-up of heart failure when used in conjunction with FoCUS, and is especially useful in primary care where chest X-rays are not available. The working group that created this manual agreed that it is desirable to educate patients about lung POCUS in conjunction with FoCUS, so we decided to include the basic techniques of lung POCUS and how to use them in this manuscript., (© 2024. Japanese Society of Echocardiography.)

Objective: The study aimed to investigate treatment options for older women with pelvic organ prolapse (POP) and postoperative outcomes based on their long-term care (LTC) status., Methods: We used the medical and LTC insurance claims databases of Tochigi Prefecture in Japan, covering 2014 to 2019. We included women 65 years and older with POP and evaluated their care status and treatment, excluding women with an observation period <6 months. Among women with a postsurgical interval ≥6 months, we compared care level changes and deaths within 6 months and complications within 1 month postoperatively between those with and without LTC using Fisher exact test., Results: We identified 3406 eligible women. Of the 447 women with LTC and 2959 women without LTC, 16 (3.6%) and 415 (14.0%), respectively, underwent surgery. Among 393 women with a postsurgical interval ≥6 months, 19 (4.8%) required LTC at surgery. Two of the 19 women with LTC (10.5%) and eight of 374 women without LTC (2.1%) experienced worsening care-needs level. No deaths were recorded. Urinary tract infection (UTI) was significantly more frequent in women with LTC than in women without LTC (36.8% vs 8.6%). Other complications were rare in both groups., Conclusion: The proportion of patients who underwent surgery for POP was lower in women with LTC than in women without LTC. Postoperative UTI was common and 11% had a worsening care-needs level postoperatively, whereas other complications were infrequent. Further detailed studies would contribute to providing optimal treatment to enhance patients' quality of life., (© 2024 International Federation of Gynecology and Obstetrics.)

Purpose: Galactose mutarotase (GALM) deficiency was first reported in 2019 as the fourth type of galactosemia. This study aimed to investigate the clinical and genotypic spectra of GALM deficiency., Methods: This was a questionnaire-based retrospective survey conducted in Japan between February 2022 and March 2023., Results: We identified 40 patients with GALM deficiency in Japan (estimated prevalence: 1:181,835). Four of 38 patients (10.5%) developed cataracts, which resolved with lactose restriction in 3 out of 4 patients. Transient transaminitis was the most common symptom (23.1%). All of the patients followed lactose restriction; discontinuation of the restriction after infancy did not cause any complications. Moreover, none of the participants experienced long-term complications. Two variants, GALM NM&#95;138801.3: c.294del and c.424G>A, accounted for 72.5% of the identified pathogenic variants. The patients showed moderately elevated blood galactose levels with lactose intake; however, the elevation was lower than that observed in galactokinase deficiency., Conclusion: GALM deficiency is characterized by a similar but milder phenotype and lower blood galactose elevation than in galactokinase deficiency. Diagnosis and initiation of lactose restriction in early infancy should be essential for prevention of cataracts, especially in cases of irreversible opacity., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease., Methods and results: This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD., Conclusions: Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.

Background: Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K + channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated., Objective: We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants., Methods: The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated., Results: We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect., Conclusion: The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis., Competing Interests: Disclosures The authors have no conflicts to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP-allied diseases., Methods: We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines., Results: A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases., Conclusion: A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies., Competing Interests: Competing interests: KMN reports grants from JCR Pharmaceuticals Co, Sysmex and Novartis Pharma Co; consulting fees from Sysmex and Novartis Pharma Co; and lecture fees from Sysmex, Novartis Pharma Co and Janssen Co. KMN has patents related to gene therapy for retinitis pigmentosa. In addition, KMN is an advisory board member of Sysmex and Novartis Pharma Co., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Since 2022, fertility treatments have been partially covered by insurance in Japan. Women who wish to become pregnant may explore various means of conception as fertility treatments have shown low success rates. Therefore, we aimed to clarify the state of knowledge, behavior, and attitudes toward health foods among women who are actively trying to become pregnant., Methods: A web-based research company surveyed the eating attitudes and behaviors towards healthy foods of 900 women seeking to become pregnant. Regression analysis for the total amount spent on pregnancy was conducted, with "amount spent on actions undertaken to conceive" as the dependent variable. Multiple regression analysis on actions undertaken to conceive was performed using age, family income, body mass index, duration of hospital visits, duration of actions undertaken to conceive, cumulative amount incurred to conceive, awareness of dietary guidelines, adherence to dietary practices, number of types of health foods and supplements, whether participants considered consumption of nutritious foods and supplements to be important, and cumulative amount spent on healthy foods and supplements. The effect size for the Chi-square test was determined with Cramer's coefficient of association., Results: Increasing age was associated with a longer time to conceive, longer hospital visits, higher conception costs (including fertility treatment), and a higher intake of healthy food products. The number of healthy food types had the greatest impact on the cost incurred to conceive. Folic acid was the most commonly consumed healthy food, followed by iron and calcium., Conclusions: This study clarified the real-world situation regarding healthy foods for women seeking pregnancy in Japan. The information necessary for pregnant women to select safe healthy foods was clarified, which may lead to the establishment of risk-communication measures to ensure safety., Competing Interests: Declaration of competing interest Wada Y, Shimpo M, and Shimada M declare no conflicts of interest associated with this study. Kamioka H has supervised the systematic reviews of five corporations (FANCL CORPORATION; Morishita Jintan Co., Ltd.; KAGOME Co., Ltd.; MARUZEN PHARMACEUTICAL CO., LTD.; and SUNTORY WELLNESS LIMITED)., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate whether conisation increases chorioamnionitis (CAM) and assess whether this risk differs between preterm and term periods. Furthermore, we estimated mediation effects of CAM between conisation and preterm birth (PTB)., Design: A nationwide observational study., Setting: Japan., Population: Singleton pregnant women derived from the perinatal registry database of the Japan Society of Obstetrics and Gynaecology between 2013 and 2019., Methods: The association between a history of conisation and clinical CAM was examined using a multivariable logistic regression model with multiple imputation. We conducted mediation analysis to estimate effects of CAM on PTB following conisation., Main Outcome Measures: Clinical CAM., Results: Of 1 500 206 singleton pregnant women, 6961 (0.46%) underwent conisation and 1 493 245 (99.5%) did not. Clinical CAM occurred in 150 (2.2%) and 11 484 (0.8%) women with and without conisation, respectively. Conisation was associated with clinical CAM (odds ratio [OR] 3.09; 95% confidence interval (CI) 2.63-3.64; p < 0.001) (risk difference 1.57%; 95% CI 1.20-1.94). The association was detected among 171 440 women with PTB (OR 3.09; 95% CI 2.57-3.71), whereas it was not significant among 1 328 284 with term birth (OR 0.88; 95% CI 0.58-1.34). OR of total effect of conisation on PTB was 2.71, OR of natural indirect effect (effect explained by clinical CAM) was 1.04, and OR of natural direct effect (effect unexplained by clinical CAM) was 2.61. The proportion mediated was 5.9%., Conclusions: Conisation increased CAM occurrence. Obstetricians should be careful regarding CAM in women with conisation, especially in preterm period. Bacterial infections may be an important cause of PTB after conisation., (© 2023 John Wiley & Sons Ltd.)

Objectives: Narrow-band imaging (NBI) contributes to real-time optical diagnosis and classification of colorectal lesions. The Japan NBI Expert Team (JNET) was introduced in 2011. The aim of this study was to explore the diagnostic accuracy of JNET when applied by European and Japanese endoscopists not familiar with this classification., Methods: This study was conducted by 36 European Society of Gastrointestinal Endoscopy (ESGE) and 49 Japan Gastroenterological Endoscopy Society (JGES) non-JNET endoscopists using still images of 150 lesions. For each lesion, nonmagnified white-light, nonmagnified NBI, and magnified NBI images were presented. In the magnified NBI, the evaluation area was designated by region of interest (ROI). The endoscopists scored histological prediction for each lesion., Results: In ESGE members, the sensitivity, specificity, and accuracy were respectively 73.3%, 94.7%, and 93.0% for JNET Type 1; 53.0%, 64.9%, and 62.1% for Type 2A; 43.9%, 67.7%, and 55.1% for Type 2B; and 38.1%, 93.7%, and 85.1% for Type 3. When Type 2B and 3 were considered as one category of cancer, the sensitivity, specificity, and accuracy for differentiating high-grade dysplasia and cancer from the others were 59.9%, 72.5%, and 63.8%, respectively. These trends were the same for JGES endoscopists., Conclusion: The diagnostic accuracy of the JNET classification was similar between ESGE and JGES and considered to be sufficient for JNET Type 1. On the other hand, the accuracy for Types 2 and 3 is not sufficient; however, JNET 2B lesions should be resected en bloc due to the risk of cancers and JNET 3 can be treated by surgery due to its high specificity., (© 2023 Japan Gastroenterological Endoscopy Society.)

It remains unclear how the various environmental factors are combined in practice to influence vegetable preferences in school-aged children. This study aimed to clarify the environmental factors during infancy and their association with vegetable preference in school-aged children. To find clusters of early childhood environmental factors, we conducted a factor analysis on 58 items related to early childhood environmental factors and a k-means cluster analysis using the factors obtained. The association of the extracted factors and clusters with vegetable preferences was assessed by multiple regression analysis. Twelve factors relating to vegetable eating, cooking and harvesting experience, and parental attitudes were extracted by factor analysis. Three clusters, "low awareness of experiences", "high awareness" and "low positive encouragement", were then extracted. In the multiple regression analysis, all 12 factors were found to be associated with vegetable preferences. Furthermore, it was found that the "high awareness" group had a significantly higher score for vegetable preference than the "low awareness of experiences" group (β = 0.56, 95% CI: 0.37-0.74). Thus, the study found that environmental factors during infancy, in isolation and combination, influenced vegetable preferences in school-aged children. Assessing the combination of various environmental factors during infancy may contribute to a better understanding of future vegetable preferences.

Aim: We aimed to identify the factors contributing to subjective well-being in community-dwelling older adults in rural Japan. This study explored the relationship among physical and mental health, socioeconomic status, and activity levels with regard to the subjective well-being of older adults., Methods: In the Frail Elderly in the Sasayama-Tamba Area study, a cohort investigation of independent older adults in a rural Japanese community, 541 of 844 participants completed a 2-year follow-up survey. Subjective well-being was assessed as a binary based on three factors - "happiness," "satisfaction with life" and "meaning in life" - using a subset of the World Health Organization's Quality of Life questionnaire. The improvement group transitioned from not having subjective well-being during the baseline survey to having subjective well-being during the follow-up survey. Furthermore, we used multivariable log-Poisson regression models to calculate the prevalence ratios of subjective well-being., Results: The cross-sectional study showed that sleep satisfaction, health services access satisfaction and having a higher-level functional capacity were positively associated with having "happiness" and "satisfaction with life." Furthermore, being aged ≥ 80 years and having financial leeway were positively associated with having "meaning in life." The longitudinal study showed that having a higher-level functional capacity was positively associated with improving "happiness" and "satisfaction with life." Being female was positively associated with improving "happiness" and "meaning in life," and health services access satisfaction and alcohol drinking were positively associated with improving "satisfaction with life" and "meaning in life," respectively., Conclusions: These findings offer promising avenues for enhancing the subjective well-being of older adults. Geriatr Gerontol Int 2024; 24: 311-319., (© 2024 The Authors. Geriatrics & Gerontology International published by John Wiley & Sons Australia, Ltd on behalf of Japan Geriatrics Society.)

Dairy products formulated with bioactives are widely distributed in Japan, but it remains to be clear whether a regular consumption of these products would help reduce the risks of incidental functional disability and dementia in older adults. This study aimed to investigate Japanese subjects aged ≥65 y (n=629) that routinely consumed three functional dairy products, a calcium-enriched milk supplemented with Bifidobacterium longum BB536, a yogurt supplemented with lactoferrin, B. longum BB536 and heat-killed Lacticaseibacillus paracasei MCC1849, and a drinkable yogurt supplemented with lactoferrin, B. longum BB536 and heat-killed L. paracasei MCC1849, through a home delivery service. Intake frequency and intake duration of these functional dairy products were compared with the risk scores of incident functional disability and dementia, developed by the Japan Gerontological Evaluation Study. In the participants aged <75 y, the incident functional disability risk was significantly maintained or decreased in the participants with the long intake duration level compared with the short intake duration level (OR, 95% CI: 0.48, 0.25-0.93). In the participants aged ≥75 y, the dementia risk was significantly maintained or decreased in the participants with the high intake frequency level compared with the low intake frequency level (OR, 95% CI: 0.46, 0.22-0.95). A high intake frequency or long term duration of these functional dairy products may be effective in preventing an aging-related increase in the risks of incident functional disability and dementia in older adults, but this warrants further investigation using different products containing different bioactives.

Scientific grant applications are subjected to scholarly peer review. Studies show that the success rates of grant applications are often higher for male than for female applicants, suggesting that gender bias is common in peer review. However, these findings mostly come from studies in Europe, North America and Australia. Here we report the analyses of gender-specific success rates of applications to the fellowships offered by Japan Society for the Promotion of Science (JSPS). Because we analyze the observational data (i.e., not experimental), our aim here is to describe the possible gender gaps in the success rates, rather than the examination of gender bias per se. Results show that the success rates are consistently higher for male applicants than for female applicants among five different fellowship categories. The gender gaps in the success rates varied significantly between research fields in some Fellowship categories. Furthermore, in some fellowship categories, the gender gaps were significantly associated with the representation of female applicants (both positive and negative correlations were found). Though the causes of the gender gaps are unknown, unintentional gender bias during the review process is suggested. Pre-application gender gaps may also be contributing to the gender gaps in success rates. At least some of the observed gender gaps were relatively small, which may be partly explicable by the designs of the review process. However, gender gaps or biases acting prior to the application, such as self-selection bias, may have reduced the superficial gender gaps in the success rates. Further investigations that control for the effects of covariates (e.g., scientific merits of each applicant, which were not accessible to us) and those of other funding agencies, especially of non-Western countries, are warranted., Competing Interests: The authors declare no conflict of interests., (Copyright: © 2023 Kyogoku, Wada. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Despite optimal treatment, a residual inflammatory risk often remains in patients with atherosclerotic cardiovascular disease. In a US-based phase 2 trial, ziltivekimab, a fully human monoclonal antibody targeting the interleukin-6 ligand, significantly reduced biomarkers of inflammation compared with placebo in patients at high atherosclerotic risk. Here, we report the efficacy and safety of ziltivekimab in Japanese patients., Methods: RESCUE-2 was a randomized, double-blind, 12-week, phase 2 trial. Participants aged ≥20 years with stage 3-5 non-dialysis-dependent chronic kidney disease and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to receive placebo (n = 13) or subcutaneous ziltivekimab 15 mg (n = 11) or 30 mg (n = 12) at Weeks 0, 4, and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT; mean of Week 10 and Week 12 values)., Results: At EOT, median hsCRP levels were reduced by 96.2 % in the 15 mg group (p < 0.0001 versus placebo), by 93.4 % in the 30 mg group (p = 0.002 versus placebo), and by 27.0 % in the placebo group. Serum amyloid A and fibrinogen levels were also reduced significantly. Ziltivekimab was well tolerated and did not affect total cholesterol to high-density lipoprotein cholesterol ratios. There was a small, but statistically significant increase in triglyceride levels with ziltivekimab 15 mg and 30 mg compared with placebo., Conclusions: The efficacy and safety results support the development of ziltivekimab for secondary prevention and the treatment of patients at high atherosclerotic risk., Clinicaltrials: gov identifier, NCT04626505., Competing Interests: Declaration of competing interest Yukihiro Wada has no conflict of interest. Camilla Jensen, Sina Meyer, and Amir Mohseni Zonoozi, are employees of Novo Nordisk A/S. Hirokazu Honda is a scientific advisor for Astellas Pharma, Bayer Yakuhin, Kyowa Kirin, Mitsubishi Tanabe Pharma, and Torii Pharmaceutical. He has received research funds from Chugai Pharmaceutical, Kyowa Kirin, Otsuka Pharmaceutical, and Torii Pharmaceutical, as well as lecture fees from Astellas Pharma, Bayer Yakuhin, Chugai Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Mitsubishi Tanabe Pharma, and Torii Pharmaceutical., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Protein-energy undernutrition is potentially prevalent among Japanese pregnant women, and biomarkers that objectively indicate the protein nutritional status during pregnancy may help in implementing appropriate protein supplementation to these women. We hypothesized that a serum parameter of pregnant women, the ratio of reduced to total albumin (reduced ALB ratio), would be associated with protein intake during pregnancy. The serum reduced ALB ratio of pregnant women was compared with protein intake and with gestation outcomes (gestation length and infant birth weight) in an observational study of 115 Japanese pregnant women. The serum reduced ALB ratio in the third trimester tended to be positively correlated with gestation length (P = .07). Infant birth weights tended to be different between protein intake tertiles (P = .09); the mean infant birth weight was higher in the third tertile compared with the first and second tertiles. The protein intake of pregnant women was significantly and positively correlated with the serum reduced ALB ratio in the second trimester. The serum reduced ALB ratio reflects protein nutritional status during pregnancy and may contribute to healthier gestation outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The Foods with Function Claims (FFC) was introduced in Japan in April 2015 to make more products available that are labeled with health functions. The products' functionality of function claims must be explained by scientific evidence presented in systematic reviews (SRs), but the quality of recent SRs is unclear. This study assessed the quality of SRs in the FFC registered on the Consumer Affairs Agency (CAA) website in Japan., Methods: We searched the database from 1 April to 31 October 2022. Confidence in the methodological quality of each SR was evaluated by the AMSTAR 2 checklist., Results: Forty SRs were randomly extracted on the basis of the eligibility criteria and recruitment procedures. Overall confidence was rated as "high" ( N = 0, 0%), "moderate" ( N = 0, 0%), "low" ( N = 2, 5%), or "critically low" ( N = 38, 95%). The mean AMSTAR 2 score was 51.1% (SD 12.1%; range 19-73%). Among the 40 SRs, the number of critical domain deficiencies was 4 in 7.5% of SRs, 3 in 52.5% of SRs, 2 in 35% of SRs, and 1 in 5% of SRs. Registering the review's protocol and comprehensive search strategies were particularly common deficiencies. Additionally, the risk of bias (RoB) was insufficiently considered., Conclusion: Overall, the methodological quality of the SRs based on the FFC, introduced eight years earlier, was very poor. This was especially true in the interpretation and discussion of critical domains, which had many deficiencies in terms of protocol registration, a comprehensive literature search strategy, and accounting for the RoB.

Maternal diet may affect human milk macronutrients, but it remains to be elucidated whether this is also influential in infant growth. This study aimed to examine (1) how maternal diet influences human milk macronutrients, and (2) to what extent the variation in milk macronutrients affects infant growth during the first month of life. In 71 Japanese lactating women, maternal dietary information was collected from the brief-type self-administered diet history questionnaire, and anthropometry of mother-infant dyads was collected from medical records. Macronutrients in milk were analyzed by a Human Milk Analyzer. Maternal retinol intake was associated with the carbohydrate content in human milk at 1-month postpartum (standardized β coefficient: 0.287; p = 0.038). Moreover, the energy content in human milk was associated with an increase in the weight standard deviation score based on the WHO growth standard at 1 month of age (standardized β coefficient: 0.399; p = 0.046). Nevertheless, the milk macronutrient was not associated with the risk of infant growth abnormalities. In conclusion, a part of the maternal diet impacts macronutrient contents in human milk, but milk macronutrients have a limited effect on infant growth only within the normal growth curve during the first month of life.

Background: Intraperitoneal adhesion is a common complication of cesarean section, and adhesion barriers are often used to prevent postoperative adhesion. However, the association between the use of adhesion barriers and infections after cesarean section remains unknown. This study aimed to evaluate the association., Methods: Using the administrative claims database of a single prefecture in Japan, we identified all patients who underwent cesarean section from June 2014 to February 2019. A multivariable logistic regression model fitted with a generalized estimating equation was used to compare the postoperative outcomes between patients who received intraperitoneal adhesion barriers during cesarean section and those who did not. The primary outcome was intraperitoneal or uterine infections within 3 months after cesarean section, including intraperitoneal abscess, pelvic inflammatory disease, peritonitis, uterine wound infection, endometritis, and adnexitis., Results: A total of 1,392 patients with 1,498 cesarean section cases were reviewed. Adhesion barriers were used in 1,153/1,498 (77.0%) cases. One hundred and fourteen (9.9%) intraperitoneal or uterine infections occurred in the group with and 15 (4.3%) in the group without adhesion barriers. The proportion of intraperitoneal or uterine infections was significantly higher in the group with than in the group without adhesion barriers (9.9% and 4.3%, respectively; adjusted odds ratio = 2.59; 95% confidence interval, 1.40-4.77; P = .002)., Conclusion: The use of adhesion barriers was associated with an increase in intraperitoneal or uterine infections after cesarean section., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: We aimed to clarify the factors that contribute to the improvement or progression of frailty in rural Japanese community-dwelling older adults., Methods: Of the 840 participants in the cohort study of independent older adults aged 65 years and older living in the Tamba-Sasayama area of Hyogo Prefecture (FESTA study) from September 2016 to December 2017, 551 participated in the 2-year follow-up survey from September 2018 to December 2019., Methods: We evaluated clinical background, physical and cognitive function, total physical activity, daily protein intake, quality of life (QOL) using the WHOQOL-BREF (WHOQOL-26), and frailty status diagnosed using the Japanese version of the Cardiovascular Health Study. We compared the frailty status at the initial and follow-up examinations and classified the participants into three groups: improvement, unchanged, and worsening. Each parameter was compared among the three groups and the factors contributing to the improvement or worsening of frailty status were analyzed using a modified Poisson regression analysis., Results: The median age at the first survey was 72 years (range: 68-76); 190 men and 361 women were enrolled. The improvement group consisted of individuals with a change in status from frail to prefrail/robust and from prefrail to robust (n = 114); the worsening group consisted of individuals with a change in status from robust to prefrail/frail and from prefrail to frail (n = 92). The physical domain of QOL was significantly associated with an improvement in frailty status independent of the frailty status at baseline. Contrastingly, any domains of QOL were not significantly associated with a worsening frailty status., Conclusions: This study demonstrated for the first time that QOL has a significant impact on the future improvement and progression of frailty status and that QOL conditions and frailty status affect older adults bidirectionally., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We report clinical and molecular findings in three Japanese patients with N-acetylneuraminic acid synthetase-congenital disorder of glycosylation (NANS-CDG). Patient 1 exhibited a unique constellation of clinical features including marked hydrocephalus, spondyloepimetaphyseal dysplasia (SEMD), and thrombocytopenia which is comparable to that of an infant reported by Faye-Peterson et al., whereas patients 2 and 3 showed Camera-Genevieve type SMED with intellectual/developmental disability which is currently known as the sole disease name for NANS-CDG. Molecular studies revealed a maternally inherited likely pathogenic c.207del:p.(Arg69Serfs*57) variant and a paternally derived likely pathogenic c.979&#95;981dup:p.(Ile327dup) variant in patient 1, a homozygous likely pathogenic c.979&#95;981dup:p.(Ile327dup) variant caused by maternal segmental isodisomy involving NANS in patient 2, and a paternally inherited pathogenic c.133-12T>A variant leading to aberrant splicing and a maternally inherited likely pathogenic c.607T>C:p.(Tyr203His) variant in patient 3 (reference mRNA: NM&#95;018946.4). The results, together with previously reported data, imply that (1) NANS plays an important role in postnatal growth and fetal brain development; (2) SMED is recognizable at birth and shows remarkable postnatal evolution; (3) NANS-CDG is associated with low-normal serum sialic acid, obviously elevated urine N-acetylmannosamine, and normal N- and O-glycosylation of serum proteins; and (4) NANS-CDG is divided into Camera-Genevieve type and more severe Faye-Peterson type., (© 2022. The Author(s).)

Background: Sarcopenia is prevalent in patients with chronic kidney disease (CKD), which is defined as a low estimated glomerular filtration rate (eGFR). It has been reported that oral hypofunction characterized by decreased tongue pressure is related to sarcopenia. Although there are several previous reports regarding the association of renal dysfunction with oral hypofunction characterized by low tongue pressure, the association between tongue pressure and renal function is not fully understood., Methods: This cross-sectional study included 68 men aged 79.0 ± 4.8 years and 145 women aged 77.3 ± 5.4 years from a rural area in Hyogo Prefecture, Japan. We examined the relationships between cystatin C-based CKD (CKDcys), creatinine-based CKD (CKDcre), ratio of cystatin C-based GFR (eGFRcys) divided by creatinine-based GFR (eGFRcre): eGFRcys/eGFRcre, and tongue pressure in community-dwelling older adults., Results: Tongue pressure was significantly lower in participants with CKDcys than in those without CKDcys in men and women. However, there were no significant differences in tongue pressure with or without CKDcre. Tongue pressure was significantly lower in participants with eGFRcys/eGFRcre <1.0, than in those with eGFRcys/eGFRcre ≧ 1.0 in men. According to the receiver operating characteristic analysis, the optimal cut-off value of tongue pressure for the presence of CKDcys was 36.6kPa, area under the curve (AUC) 0.74 (specificity 54.8%, sensitivity 84.6%) in men and 31.8kPa, AUC 0.65 (specificity 67.3%, sensitivity 60.5%) in women., Conclusions: CKDcys but not CKDcre is associated with low tongue pressure. In addition, a lower eGFRcys/eGFRcre ratio is a useful screening marker of low tongue pressure in community-dwelling older adults., (© 2022 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Aim: We aimed to examine the association of obesity-related cancer and cardiovascular disease (CVD) with body mass index (BMI) and the estimated population attributable fraction in lean Asians., Methods: We studied 102,535 participants aged 40-79 years without histories of cancer or CVD at baseline between 1988 and 2009. The cause-specific hazard ratios (csHRs) of BMI categories (＜18.5, 18.5-20.9, 21.0-22.9 [reference], 23.0-24.9, 25.0-27.4, and ≥ 27.5 kg/m 2 ) were estimated for each endpoint. The events considered were mortalities from obesity-related cancer (esophageal, colorectal, liver, pancreatic, kidney, female breast, and endometrial cancer) and those from CVD (coronary heart disease and stroke). Population attributable fractions (PAFs) were calculated for these endpoints., Results: During a 19.2-year median follow-up, 2906 died from obesity-related cancer and 4532 died from CVD. The multivariable-adjusted csHRs (95% confidence interval) of higher BMI categories (25-27.4 and ≥ 27.5 kg/m 2 ) for obesity-related cancer mortality were 0.93 (0.78, 1.10) and 1.18 (0.92, 1.50) in men and 1.25 (1.04, 1.50) and 1.48 (1.19, 1.84) in women, respectively. The corresponding csHRs for CVD mortality were 1.27 (1.10, 1.46) and 1.59 (1.30, 1.95) in men and 1.10 (0.95, 1.28) and 1.44 (1.21, 1.72) in women, respectively. The PAF of a BMI ≥ 25 kg/m 2 for obesity-related cancer was -0.2% in men and 6.7% in women and that for CVD was 5.0% in men and 4.5% in women., Conclusion: A BMI ≥ 25 kg/m 2 is associated with an increased risk of obesity-related cancer in women and CVD in both sexes.

Objective: To generate appropriate reference values for the single-breath diffusing capacity of the lungs for carbon monoxide (DLCO), alveolar volume (VA), and the transfer coefficient of the lungs for carbon monoxide (KCO, often denoted as DLCO/VA) in the Japanese population. We also intended to assess the applicability of these values for the Japanese population by comparing them to those published by the Global Lung Function Initiative in 2017 (GLI-2017) and previous values., Methods: In this retrospective study, we measured the spirometric indices, DLCO, VA, and KCO of the Japanese population aged 16-85 years. The lambda, mu, and sigma (LMS) method and the generalized additive models for the location, scale, and shape program in R were used to generate the reference values., Results: We conducted a total of 390 tests. The GLI-2017 z-scores of DLCO were approximately zero, whereas those of KCO and VA were far from zero. In the present study, the mean square errors of the DLCO, VA, and KCO reference values were lower than the reference values derived from GLI-2017 and previous linear regression equations., Conclusions: Reference values obtained in this study were more appropriate for our sample than those reported in GLI-2017. Differences between the two equations were attributed to underestimating KCO (DLCO / VA) and overestimating VA, respectively, by the GLI-2017 for the Japanese population., Competing Interests: The authors have declared that no competing interests exist.

Background: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes., Methods: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations., Results: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required., Conclusions: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future., Competing Interests: Conflict of Interest None of the authors have any conflicts of interest., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Objective biomarkers are crucial in the development of personalized medicines, such as Japanese traditional medicine (Kampo). To date, some objective markers to predict the response of Kampo medicines have been reported, but the information is somewhat limited. The aim of this study was to search for objective markers and combinations thereof to estimate the effect of the Japanese traditional medicine daikenchuto (DKT) on colon contraction intensity in guinea pigs. Specifically, the microbiome biomarkers were employed as candidate, using the Fisher ratio and the nearest neighbor classifier for statistical pattern recognition. The combination of the ratio between gut microbes of family Ruminococcaceae/Rikenellaceae, Ruminococcaceae/Paraprevotellaceae, and genus Ruminococcus/unknown genus in family Rikenellaceae of guinea pig gut microbes was found to influence the activity of DKT with 0.8 accuracy for test samples. These findings suggest that statistical pattern recognition can contribute to identifying target markers of multi-target drugs such as Kampo., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Sarcopenia is defined as a combination of low skeletal muscle mass index (SMI), weak muscle strength, and reduced physical function. Recently, many studies have reported that the creatinine/cystatin C ratio (Cr/CysC) is useful for evaluating muscle mass. We designed a cross-sectional study with separate model development and validation groups to develop a prediction equation to estimate bioimpedance analysis (BIA)-measured SMI with Cr/CysC., Design: The current study was a retrospective cross-sectional study., Setting and Participants: The model development group included 908 subjects (288 men and 620 women) from the Frail Elderly in the Sasayama-Tamba Area (FESTA) study, and the validation group included 263 subjects (112 men and 151 women) from participants in the medical checkup program at the Anti-Aging Center in Ehime Prefecture., Measures: Multivariate regression analysis indicated that age, hemoglobin (Hb), body weight (BW), and Cr/CysC were independently associated with SMI in both men and women. The SMI prediction equation was developed as follows: Men:4.17-0.012×Age+1.24×(Cr/CysC)-0.0513×Hb+0.0598×BW Women:3.55-0.00765×Age+0.852×(Cr/CysC)-0.0627×Hb+0.0614×BW RESULTS: The SMI prediction equation was applied to the validation group and strong correlations were observed between the BIA-measured and predicted SMI (pSMI) in men and women. According to the receiver operator characteristic (ROC) analysis, the areas under the curve were 0.93 (specificity 89.0%, sensitivity 87.2%) among men and 0.88 (specificity 83.6%, sensitivity 79.6%) among women for using pSMI to identify low SMI in the model development group. The pSMI also indicated high accuracy in ROC analysis for low SMI in the validation group. The Bland-Altman plot regression showed good agreement between BIA-measured and pSMI., Conclusions and Implications: Our new prediction equation to estimate SMI is easy to calculate in daily clinical practice and would be useful for diagnosing sarcopenia., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Citrin deficiency is an autosomal recessive disorder caused by mutations in the SLC25A13 gene. The disease can present with age-dependent clinical manifestations: neonatal intrahepatic cholestasis by citrin deficiency (NICCD), failure to thrive, and dyslipidemia by citrin deficiency (FTTDCD), and adult-onset type II citrullinemia (CTLN2). As a nationwide study to investigate the clinical manifestations, medical therapy, and long-term outcome in Japanese patients with citrin deficiency, we collected clinical data of 222 patients diagnosed and/or treated at various different institutions between January 2000 and December 2019. In the entire cohort, 218 patients were alive while 4 patients (1 FTTDCD and 3 CTLN2) had died. All patients <20 years were alive. Patients with citrin deficiency had an increased risk for low weight and length at birth, and CTLN2 patients had an increased risk for growth impairment during adolescence. Liver transplantation has been performed in only 4 patients (1 NICCD, 3 CTLN2) with a good response thereafter. This study reports the diagnosis and clinical course in a large cohort of patients with citrin deficiency and suggests that early intervention including a low carbohydrate diet and MCT supplementation can be associated with improved clinical course and long-term outcome., (© 2022 SSIEM.)

Objectives: Microscopic polyangiitis (MPA) affects various organs. However, echocardiographic findings of MPA are unclear. We aimed to evaluate the echocardiographic features of acute-phase MPA in Japanese patients., Methods: This single-centre retrospective study included 15 patients with MPA who underwent echocardiography within 2 weeks of commencing steroid therapy for induction or reinduction. The echocardiography parameters of thetients were compared with those of 30 age- and sex-matched controls., Results: No significant differences in left ventricular (LV) diameter, LV ejection fraction, or e' were observed between the two groups. However, the MPA group showed a significantly higher left atrial (LA) diameter and LA volume index, as well as higher early diastolic filling velocity, diastolic pulmonary venous flow velocity, and trans-tricuspid pressure gradient, and a shorter deceleration time (DCT). Serum C-reactive protein levels were positively correlated with E wave, E/A, and DCT. These results may indicate that increased LV stiffness, rather than impairment of LV relaxation, contributed to LV diastolic function, resulting in LA enlargement., Conclusions: Patients with acute-phase MPA had LA dilatation associated with LV diastolic dysfunction. This finding indicates the importance of cardiac assessment in patients with MPA, especially in patients with a strong inflammatory reaction., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aims of the present study are to evaluate non-invasive screening tests for autoimmune gastritis (AIG) and re-evaluate histopathological classification., Methods: We screened candidates of AIG in JCHO Shiga Hospital between May 2012 and January 2020. The screening criteria were as follows: endoscopic O-p atrophy with Updated Kimura-Takemoto classification, 3 + pepsinogen (PG) test, low serum vitamin B 12 or elevated serum gastrin with positive anti-parietal cell (PC) or intrinsic factor antibodies. We evaluated the screening criteria in the patients who were histopathologically confirmed as AIG, and re-evaluated histopathological staging in clinical aspects., Results: Twenty-two of 28 (78.6%) patients who met the screening criteria were histopathologically confirmed as AIG. Common clinical findings in the AIG patients were 10 × or greater anti-PC antibody, elevated serum gastrin greater than 172 pg/mL and endoscopic atrophy O-1 or greater. The areas under the curve of PG I, PG II and PG I/II ratio were 0.81, 0.29 and 0.98, respectively. Among histopathologically confirmed AIG patients, 4 and 18 patients were histopathologically classified into florid and end stages, respectively, while no patients into early stage. We could not find a significant difference between florid and end stages in the screening items studied., Conclusions: Florid and end stages in histopathological classification are both advanced-stage AIG in clinical aspects. Our screening criteria without biopsy are applicable to screen clinically-advanced AIG with 78.6% positive predictive value. PG I and PG I/II ratio may be useful to screen AIG. However, we may need other criteria to screen early stage of AIG., (© 2022. The Author(s).)

Exostosin 1 and exostosin 2 (EXT1/EXT2) on glomerular basement membrane (GBM) were recently reported as novel putative antigens in secondary membranous nephropathy with autoimmune disease. However, the clinical significance of glomerular EXT1/EXT2 remains elusive in patients with lupus nephritis (LN). The immunofluorescence staining pattern of glomerular EXT1/EXT2 is also undetermined in membranous LN (MLN) or proliferative LN (PLN). We cross-sectionally analyzed patients with MLN (pure class V, n = 11) and PLN (class III, IV, and mixed class III/IV + V, n = 22) who underwent renal biopsies between 2010 and 2020 at Showa University Hospital. Glomerular EXT1/EXT2 expressions were evaluated by immunofluorescence. T-helper (Th) cell-related serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The positivity for both EXT1/EXT2 was higher in patients with MLN than PLN (90.9% vs 63.6%, P = 0.212). MLN showed global and bright granular EXT1/EXT2 expressions along GBM, while PLN showed segmental and moderate expressions on GBM. Additionally, glomerular EXT1/EXT2 positivity was not associated with the degree of proteinuria or renal function in MLN and PLN patients, but the levels of serum anti-dsDNA antibody and circulating immune complexes were lower in patients with EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Moreover, serum complement levels and IL-4/IFN-γ ratios were elevated in EXT1/EXT2-positive MLN than EXT1/EXT2-negative PLN. Collectively, immunofluorescence staining for glomerular EXT1/EXT2 had characteristic patterns between MLN and PLN. Glomerular EXT1/EXT2 expressions tended to be high in Th2-dominant MLN patients without severe hypocomplementemia and elevated autoantibodies. Thus, EXT1/EXT2 might be involved in the unique developmental mechanism of MLN., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: We aimed to evaluate the characteristics, quality, and related factors of the Japanese Clinical Practice Guidelines (CPGs) published in recent years., Study Design and Setting: In this cross-sectional, meta-epidemiological study, we conducted a Google search for CPGs published by 30 Japanese medical societies that are the basis for training specialties between 2018 and 2019. We used the Appraisal of Guidelines for Research & Evaluation II (AGREE II) tool and the Reporting Items for practice Guidelines in HealThcare (RIGHT) statement to evaluate the quality., Results: We included 53 systematic review-based CPGs. The median score was 0.54 (IQR, 0.38-0.62) for Stakeholder involvement, 0.57 (IQR, 0.51-0.66) in Rigor of development, 0.33 (IQR 0.21-0.46) in Applicability, and 0.63 (IQR 0.46-0.73) in Editorial independence. The number of guideline developers/clinical question ratio (odds ratio [OR]: 4.14, 95% confidence interval [CI]: 1.97, 8.70) and the adopted guideline development methods (OR: 3.69, 95% CI: 1.14, 12.0) were significantly related to the Rigor of development., Conclusion: The quality of Japanese CPGs published in recent years remains low. Our study suggests that increasing contributors and adopting the latest guideline development methods at the beginning of the project may improve the quality of the Japanese CPGs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: Recently, activities of daily living (ADL) were identified as a prognostic factor among elderly patients with heart disease; however, a specific association between ADL and prognosis after cardiac and aortic surgery is not well established. We aimed to clarify the impact of ADL capacity at discharge on prognosis in elderly patients after cardiac and aortic surgery.This retrospective cohort study included 171 elderly patients who underwent open operation for cardiovascular disease in a single center (median age: 74 years; men: 70%). We used the Barthel Index (BI) as an indicator for ADL. Patients were classified into 2 groups according to the BI at discharge, indicating a high (BI ≥ 85) or low (BI < 85) ADL status. All-cause mortality and unplanned readmission events were observed after discharge.Thirteen all-cause mortality and 44 all-cause unplanned readmission events occurred during the median follow-up of 365 days. Using Kaplan-Meier analysis, a low ADL status was determined to be significantly associated with all-cause mortality and unplanned readmission. In the multivariable Cox proportional hazard models, a low ADL status was an independent predictor of all-cause mortality and unplanned readmission after adjusting for age, sex, length of hospital stay, and other variables (including preoperative status, surgical parameter, and postoperative course).A low ADL status at discharge predicted all-cause mortality and unplanned readmission in elderly patients after cardiac and aortic surgery. A comprehensive approach from the time of admission to postdischarge to improve ADL capacity in elderly patients undergoing cardiac and aortic surgery may improve patient outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

There are two types of pyloric gland-like metaplasia in the corpus of stomach: pyloric and pseudopyloric metaplasias. They show the same morphology as the original pyloric glands in H&E staining. Pseudopyloric metaplasia is positive for pepsinogen (PG) I immunohistochemically, whereas pyloric metaplasia is negative. Recently, spasmolytic polypeptide-expressing metaplasia (SPEM) is proposed for pyloric gland-like metaplasia mainly in animal experiments. SPEM expresses trefoil factor family 2 (TFF2) and is often considered synonymous with pseudopyloric metaplasia. We reviewed consecutive 22 Japanese patients with autoimmune gastritis (AIG) to investigate TFF2 expression in pyloric and pseudopyloric metaplasias by counting all pyloric gland-like glands in biopsy specimens taken from greater curvature of the middle corpus according to the Updated Sydney System. Pyloric metaplasia was seen in all the 22 cases, and pseudopyloric metaplasia was found in 15 cases. Of 1567 pyloric gland-like glands in all the cases, 1381 (88.1%) glands were pyloric metaplasia glands, and the remaining 186 (11.9%) glands were pseudopyloric metaplasia glands. TFF2 expression was observed in pyloric or pseudopyloric metaplasia glands in 20 cases. TFF2 expression was recognized in 409 of 1381 (26.9%) pyloric metaplasia glands and 27 of 186 (14.5%) pseudopyloric metaplasia glands (P<0.01, chi-square test). In conclusion, SPEM was not always the same as pseudopyloric metaplasia in human AIG, and the majority of metaplasia in AIG was not pseudopyloric but pyloric metaplasia., (© 2021. The Author(s).)

Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A total of 229 patients with UCDs were enrolled in this study: 73 males and 53 females with ornithine transcarbamylase deficiency (OTCD), 33 patients with carbamoylphosphate synthetase 1 deficiency, 48 with argininosuccinate synthetase deficiency, 14 with argininosuccinate lyase deficiency, and 8 with arginase deficiency. Survival rates at 20 years of age of male and female patients with late-onset OTCD were 100% and 97.7%, respectively. Blood ammonia levels and time of onset had a significant impact on the neurodevelopmental outcome (P < .001 and P = .028, respectively). Hemodialysis and liver transplantation did not prevent poor neurodevelopmental outcomes. While treatment including medication, hemodialysis, and liver transplantation may aid in decreasing blood ammonia and/or preventing severe hyperammonemia, a blood ammonia level ≥ 360 μmol/L was found to be a significant indicator for a poor neurodevelopmental outcome. In conclusion, although current therapy for UCDs has advanced and helped saving lives, patients with blood ammonia levels ≥ 360 μmol/L at onset often have impaired neurodevelopmental outcomes. Novel neuroprotective measures should therefore be developed to achieve better neurodevelopmental outcomes in these patients., (© 2021 SSIEM.)

Citrin deficiency develops in different symptomatic periods from the neonatal period to adulthood. Some infantile patients are diagnosed by newborn mass screening or symptoms of neonatal intrahepatic cholestasis caused by citrin deficiency, some patients in childhood may develop hepatopathy or dyslipidemia as failure to thrive and dyslipidemia caused by citrin deficiency, and some adults are diagnosed after developing adult-onset type 2 citrullinemia (CTLN2) with hyperammonemia or encephalopathy. A diagnosis is needed before the development of severe phenotypic CTLN2 but is often difficult to obtain because newborn mass screening cannot detect all patients with citrin deficiency, and undiagnosed patients often appear healthy in childhood. There are only a few reports that have described patients in childhood. To explore the clinical features of undiagnosed patients with citrin deficiency in childhood, we studied 20 patients who were diagnosed after the first year of life. Of these patients, 45% experienced hypoglycemic attacks in childhood. The acetoacetic acid level during hypoglycemic attacks was lower than expected. Growth failure at diagnosis (45%) was also noted. From the patients' history, fat- and protein-rich food preferences (80%), a low birth weight (70%), and prolonged jaundice or infantile hepatopathy (40%) were identified. To diagnose citrin deficiency in childhood, we should ask about food preferences and a history of infantile hepatopathy for all children with severe hypoglycemia or growth failure and consider the genetic test for citrin deficiency if the patient has characteristic food preferences or a history of infantile hepatopathy., (© 2021 SSIEM.)

Background: Plasma albumin (ALB) reflects protein nutritional status in rats, but it is not clear whether it is associated with dietary protein insufficiency in pregnant women and/or their risk of low birth weight delivery. This study aimed to investigate whether maternal serum ALB redox state reflects maternal protein nutritional status and/or is associated with infant birth weights., Methods: The relationship between the serum reduced ALB ratio and infant birth weight was examined in an observational study of 229 Japanese pregnant women. A rat model simulating fetal growth restriction, induced by protein-energy restriction, was used to elucidate the relationship between maternal nutritional status, maternal serum ALB redox state, and birth weight of the offspring., Results: In the human study, serum reduced ALB ratio in the third trimester was significantly and positively correlated with infant birth weight. In the rat study, serum reduced ALB ratio and birth weight in the litter decreased as the degree of protein-energy restriction intensified, and a significant and positive correlation was observed between them in late pregnancy., Conclusions: Maternal serum reduced ALB ratio in the third trimester is positively associated with infant birth weight in Japanese pregnant women, which would be mediated by maternal protein nutritional status.

Serum zinc (Zn) levels tend to be low in chronic kidney disease (CKD) patients. This cohort study was conducted to investigate the relationship between zinc deficiency and CKD progression. Patients were classified into two groups based on Zn levels < 60 μg/dl (low-Zn group, n = 160) and ≥ 60 μg/dl (high-Zn group, n = 152). The primary outcome was defined as end-stage kidney disease (ESKD) or death and was examined over a 1-year observation period. Overall, the mean Zn level was 59.6 μg/dl and the median eGFR was 20.3 ml/min/1.73 m2. The incidence of the primary outcome was higher in the low-Zn group (p<0.001). Various Cox proportional hazards models adjusted for baseline characteristics showed higher risks of the primary outcome in the low-Zn group than in the high-Zn group. Competing risks analysis showed that low Zn levels were associated with ESKD but not with death. Moreover, in propensity score-matched analysis, the low-Zn group showed a higher risk of the primary outcome [adjusted hazard ratio 1.81 (95% confidence interval 1.02, 3.24)]. Furthermore, an interaction was observed between Zn and serum albumin levels (interaction p = 0.026). The results of this study indicate that zinc deficiency is a risk factor for CKD progression., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan STUDY DESIGN: Retrospective multicenter study METHODS: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions., Results: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P = .99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region., Conclusion: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

Competing Interests: The authors have no funding and conflicts of interests to disclose.