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ABSTRACT Background The Asian Working Group for Cachexia (AWGC) proposed a new definition of cachexia; however, its impact on cachexia prevalence and overlaps with other conditions, such as sarcopenia and malnutrition, are unclear. We investigated these aspects and the prognostic value of cachexia based on the AWGC on mortality in older patients with heart failure (HF). Methods This study was a secondary analysis of a prospective multicentre cohort, namely, the FRAGILE‐HF cohort study. Older (≥ 65 years) patients who had been hospitalized due to decompensated HF were enrolled. We assessed the presence/absence of cachexia based on the AWGC and Evans' criteria. Sarcopenia and malnutrition based on the Asian Working Group for Sarcopenia 2014 and the Global Leadership Initiative on Malnutrition criteria were also assessed to compare their prevalence and the overlaps between them. Patients were stratified in relation to the presence/absence of cachexia based on the AWGC criteria, and their mortality rates were compared. Results Of the 861 enrolled patients (median [interquartile range] age, 80 years [73–85 years]; male, 58.9%), cachexia, as evaluated based on the AWGC and Evans' criteria, sarcopenia and malnutrition, was present in 74.1%, 36.2%, 20.6% and 55.2% of patients, respectively. AWGC‐defined cachexia was most common in the four conditions. All‐cause death events occurred in 153 (18.1%) patients in 2 years. AWGC‐defined cachexia (adjusted hazard ratio [aHRs], 1.442; 95% confidence interval [95% CI], 0.931–2.233; p = 0.101) was not associated with all‐cause mortality in older patients with HF after adjusting for other HF prognosis factors, such as the B‐type natriuretic peptide and the Meta‐Analysis Global Group in Chronic risk score, whereas cachexia evaluated based on Evans's criteria (aHRs, 1.547; 95% CI, 1.118–2.141; p = 0.009), sarcopenia (aHRs, 1.737; 95% CI, 1.214–2.485; p = 0.003), and malnutrition (aHRs, 1.581; 95% CI, 1.094–2.284; p = 0.015) was associated with all‐cause mortality. Conclusions Three‐quarters of older patients with HF had cachexia as evaluated by the AWGC criteria, and this was not associated with a worse prognosis. As the new AWGC cachexia criteria will result in a significantly larger proportion of patients being diagnosed with cachexia, the implementation of the criteria in clinical practice requires further consideration. Trial Registration: UMIN‐CTR unique identifier: UMIN000023929

Abstract Aims In heart failure (HF), inflammation is linked to malnutrition and impaired physical function. In this study, we aimed to assess how novel nutritional–inflammatory markers and lymphocyte‐to‐C‐reactive protein ratio (LCR) and score (LCS) are associated with the nutritional status, physical function, and prognosis of patients with HF. Methods and results This study was a secondary analysis of the FRAGILE‐HF study, a prospective observational study conducted across 15 hospitals in Japan. We included 1212 patients (mean age, 80.2 ± 7.8 years; 513 women) hospitalized with HF, who were classified into three groups according to their LCS score: 0 (n = 498), 1 (n = 533), and 2 (n = 181). Baseline data on physical examination, echocardiography, blood test results (including lymphocyte counts and CRP levels), and oral medication usage were collected in a clinically compensated state before discharge. Nutritional status and physical function were evaluated using several indices and tests. The primary outcome of this study was all‐cause death within 2 years. Univariate and multivariate linear regression analyses were performed to evaluate the associations among the nutritional status, physical function, and LCR/LCS. Patients with an LCS score of 2 were older and had a lower body mass index than those in the other two groups. Multivariate linear regression analysis revealed that lower LCR and higher LCS were independently associated with worse nutritional status, lower handgrip strength, shorter physical performance battery score, and shorter 6‐min walk distance. At 2 years, all‐cause death occurred in 254 patients: 86 (17.6%), 113 (21.5%), and 55 (30.9%) with LCS scores of 0, 1, and 2, respectively (P = 0.001). Cox proportional hazards analysis revealed that LCR and LCS were significantly associated with 2‐year mortality even after adjusting for the conventional risk model (LCS score, 0 vs. 2: hazard ratio, 1.64; 95% confidence interval [CI]; 1.14–2.35; P = 0.007; log‐transformed LCR: hazard ratio, 0.88; 95% CI, 0.81–0.95; P = 0.002). LCR yielded additional prognostic predictability compared with the conventional risk model (continuous net reclassification improvement, 0.153; 95% CI, 0.007–0.299; P = 0.041). Conclusions LCR and LCS emerge as potential predictors of nutritional status, physical function, and prognosis in older patients with HF.

Abstract Mutations in proline‐rich transmembrane protein 2 (PRRT2) cause paroxysmal kinesigenic dyskinesia (PKD). Recently, we reported that a Prrt2 mutation exacerbated L‐dopa‐induced motor deficits in mice, suggesting that the basal ganglia might contribute to PKD pathology. Here, we demonstrated that the Prrt2 mutation enhanced depolarization stimuli‐induced extracellular dopamine levels in the mouse striatum, which were attenuated by repeated stimulation. L‐dopa administration maintained high dopamine levels in Prrt2‐KI mice even during repetitive stimuli but did not affect dopamine levels in wild‐type mice. Thus, the enhanced and prolonged responsiveness of dopamine release in nigrostriatal dopaminergic neurons to sequential excitation may be partially implicated in Prrt2‐related dyskinesia.

Abstract Introduction Sex‐determining region Y‐related high‐mobility group box 17 protein (SOX17), a proangiogenic transcription factor, is specifically expressed in tumor endothelial cells (TECs) of implanted Lewis lung carcinoma. However, the expression profile of SOX17 is largely unknown in human lung cancer. We aimed to elucidate SOX17 expression in cancer cells and the tumor microenvironment of lung adenocarcinoma. Methods In the present study, we examined SOX17 expression in whole‐tissue specimens of 83 lung adenocarcinomas by immunohistochemistry. Results SOX17 immunoreactivity was minimal in lung adenocarcinoma cells, except in five non‐mucinous adenocarcinomas in situ. SOX17 was also expressed in cultured A549 lung adenocarcinoma cells, which is widely used as a model of malignant alveolar type II epithelial cells. Notably, SOX17 immunoreactivity was found in endothelial cells of tumor‐penetrating vessels in 19 of 83 lung adenocarcinoma tissue specimens, with statistical significance to stromal infiltration of CD8+ T cells (p

Mushrooms are the fruiting bodies of fungi and are important reproductive structures that produce and disseminate spores. The Pri3 gene was originally reported to be specifically expressed in the primordia (a precursor to the mature fruiting body) of the edible mushroom Cyclocybe aegerita. Here, we cloned a Pri3‐related cDNA from Cyclocybe cylindracea, another species in the same genus, and showed that the gene is specifically expressed at the pileus surface of the immature fruiting body but not in the primordia. Immunohistochemistry showed that the translated protein is secreted into a polysaccharide layer of the pileus surface. The recombinant C‐terminal Cys‐rich domain of the protein showed antifungal activity against three filamentous fungi and inhibited hyphal growth and conidiogenesis. These results suggest that the PRI3‐related protein of C. cylindracea, named cylindracin, plays an important role in the defense against pathogens.

Abstract Background Comprehensive understanding of emergency referrals (EmR), encompassing reasons for encounters (RFEs) and diagnoses, is crucial for primary care physicians (PCPs). Comparing EmR rates and subsequent admission rates can potentially enhance the quality of primary care for EmR practice. However, no study has evaluated RFEs among patients with EmRs. This study aimed to identify RFE/diagnosis in relation to subsequent admission among patients receiving EmR. Methods We conducted a retrospective cohort study at an urban family physician teaching clinic in Kawasaki City, Japan. Our cohort recruited consecutive EmR episodes with their medical records and admissions confirmed through response letters from receiving hospitals. Using the 2nd edition of the International Classification of Primary Care, we explored the frequency of RFEs and diagnoses, calculating EmR rates and admission rates as primary outcomes. Bivariate analyses were employed to compare admission and non‐admission cases. Results The present study encompassed 162 EmR episodes out of 47,901 visits, yielding an EmR rate of 3.38/1000 visits. Among 153 completely followed episodes, 99 patients were emergently admitted, resulting in a 64.7% admission rate. The admission group exhibited significantly higher age and a greater prevalence of dementia. Descriptive analysis revealed fever and pneumonia as the most frequent RFE and diagnosis, respectively, with significant differences between admission and non‐admission groups. Conclusions The present study reports EmR and admission rates following EmR, highlighting differences in patient characteristics, RFEs, and diagnoses. The findings offer insights to enhance PCPs' EmR practices and serve as a benchmark for the scope of EmR practice.

Abstract Background Postpartum mental health care is a public health priority requiring interprofessional and interorganizational collaboration. Primary care physicians (PCPs) have the potential to play an essential role in facilitating access to health care and providing comprehensive and coordinated care for postpartum mental health problems. In Japan, however, there are no previous studies on the extent to which PCPs are involved in postpartum mental health care. Therefore, this study aimed to investigate the practices and experiences of Japanese PCPs in providing such care. Methods This study presents a subset of the findings from a cross‐sectional study using an online questionnaire on postpartum care among Japanese PCPs. We employed descriptive analysis to examine their practices and experiences in providing general and postpartum mental health care. Results We received 339 valid responses from 5811 PCPs. The median proportion of the outpatients with mental health problems that PCPs regularly saw was 15%. Approximately two out of three PCPs (68.7%) reported routinely performing screening for depression and anxiety. Seventy‐six percent of PCPs had the opportunity to provide care for postpartum women. Approximately one in two PCPs (47.8%) had managed cases of postpartum mental health problems and collaborated with various professionals and resources to provide care. Conclusions The majority of Japanese PCP participants in the study provide mental health care and have managed cases of postpartum mental health problems, collaborating with various health professionals.

Abstract Boreal wildfires modify surface climates affecting plant physiology, permafrost thaw, and carbon fluxes. Post‐fire temperatures vary over decades because of successional vegetation changes. Yet, the underlying biophysical drivers remain uncertain. Here, we quantify surface climate changes following fire disturbances in the North American boreal forest and identify its dominant biophysical drivers. We analyze multi‐year land‐atmosphere energy exchange and satellite observations from across North America and find post‐fire daytime surface temperatures to be substantially warmer for about five decades while winter temperatures are slightly cooler. Post‐fire decadal changes are characterized by decreasing leaf area index during the first decade, by sharply increasing surface albedo during the snow cover period, and by a less efficient heat exchange between the forest and the atmosphere caused by decreasing surface roughness for about 2–3 decades. Over the first three decades, the amount of energy used for evapotranspiration increases before returning to lower values. We find that surface warming is mainly explained by less efficient forest‐atmosphere heat exchange while cooling is additionally explained by increasing surface albedo. We estimate that biome‐wide daytime surface temperatures of the Canadian boreal forest in 2024 are 0.27°C warmer in the summer and 0.02°C cooler during the winter because of fire. For a scenario with a strong increase in burned area, we estimate annual warming from fire to increase by a third until 2050. Our study highlights the potential for accelerated surface warming in the boreal biome with increasing wildfire activity and disentangles the biophysical drivers of fire‐related surface climate impacts.

Abstract Skeletal muscle has a high regenerative ability and maintains homeostasis by rapidly regenerating from frequent damage caused by intense exercise or trauma. In sports, skeletal muscle damage occurs frequently due to intense exercise, so practical methods to promote skeletal muscle regeneration are required. Recent studies have shown that it may be possible to promote skeletal muscle regeneration through new pathways, such as promoting autophagy and improving mitochondrial function. Spermidine is a type of polyamine, and oral intake of spermidine promotes autophagy and improves mitochondrial function without inhibiting mTOR. Therefore, we evaluate the effects of spermidine intake on skeletal muscle regeneration after injury using a mouse model of cardiotoxin‐induced muscle injury. Our results showed no significant change in skeletal muscle wet weight with spermidine intake at all time points. In addition, although spermidine intake significantly increased the mean fiber cross‐sectional area 14 days after injury, these effects were not observed at other time points. In addition, we analyzed stem cells, autophagy, mTOR signaling, inflammation, and mitochondria, but no significant effects of spermidine intake were observed at almost all time points and protein expression levels. Therefore, spermidine intake does not affect skeletal muscle regeneration after chemical injury, and if there is any, it is very limited.

Abstract Aim This study aimed to verify the real‐world efficacy and safety of quetiapine fumarate extended‐release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. Methods We performed a post‐marketing surveillance with an observation period of 12 weeks. Results In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and “longer time since the onset of the first episode” (p = 0.011) and “presence of complications” (p

Abstract Aims MitraScore is a novel, simple, and manually calculatable risk score developed as a prognostic model for patients undergoing transcatheter edge‐to‐edge repair (TEER) for mitral regurgitation. As its components are considered prognostic in heart failure (HF), we aimed to investigate the usefulness of the MitraScore in HF patients. Methods and results We calculated MitraScore for 1100 elderly patients (>65 years old) hospitalized for HF in the prospective multicentre FRAGILE‐HF study and compared its prognostic ability with other simple risk scores. The primary endpoint was all‐cause deaths, and the secondary endpoints were the composite of all‐cause deaths and HF rehospitalization and cardiovascular deaths. Overall, the mean age of 1100 patients was 80 ± 8 years, and 58% were men. The mean MitraScore was 3.2 ± 1.4, with a median of 3 (interquartile range: 2–4). A total of 326 (29.6%), 571 (51.9%), and 203 (18.5%) patients were classified into low‐, moderate‐, and high‐risk groups based on the MitraScore, respectively. During a follow‐up of 2 years, 226 all‐cause deaths, 478 composite endpoints, and 183 cardiovascular deaths were observed. MitraScore successfully stratified patients for all endpoints in the Kaplan–Meier analysis (P

Abstract Sugarcane (Saccharum spp.) plays a crucial role in global sugar production; however, the efficiency of breeding programs has been hindered by its heterozygous polyploid genomes. Considering non‐additive genetic effects is essential in genome prediction (GP) models of crops with highly heterozygous polyploid genomes. This study incorporates non‐additive genetic effects and pedigree information using machine learning methods to track sugarcane breeding lines and enhance the prediction by assessing the degree of association between genotypes. This study measured the stalk biomass and sugar content of 297 clones from 87 families within a breeding population used in the Japanese sugarcane breeding program. Subsequently, we conducted analyses based on the marker genotypes of 33,149 single‐nucleotide polymorphisms. To validate the accuracy of GP in the population, we first predicted the prediction accuracy of the best linear unbiased prediction (BLUP) based on a genomic relationship matrix. Prediction accuracy was assessed using two different cross‐validation methods: repeated 10‐fold cross‐validation and leave‐one‐family‐out cross‐validation. The accuracy of GP of the first and second methods ranged from 0.36 to 0.74 and 0.15 to 0.63, respectively. Next, we compared the prediction accuracy of BLUP and two machine learning methods: random forests and simulation annealing ensemble (SAE), a newly developed machine learning method that explicitly models the interaction between variables. Both pedigree and genomic information were utilized as input in these methods. Through repeated 10‐fold cross‐validation, we found that the accuracy of the machine learning methods consistently surpassed that of BLUP in most cases. In leave‐one‐family‐out cross‐validation, SAE demonstrated the highest accuracy among the methods. These results underscore the effectiveness of GP in Japanese sugarcane breeding and highlight the significant potential of machine learning methods.

Abstract Aim This systematic review and frequentist network meta‐analysis used random‐effects models is conducted to determine whether there are differences in the efficacy, acceptability, tolerability, and safety profiles of brexpiprazole (BRE) and aripiprazole (ARI) for Japanese with major depressive disorder (MDD) who were inadequately responsive to antidepressants. Methods Outcome measures were scores on the Montgomery Åsberg Depression Rating Scale (primary), the Clinical Global Impression severity scale, and social functioning scale; the non‐response rate; the non‐remission rate; all‐cause discontinuation; discontinuation due to adverse events (DAE); at least one adverse event (1AE); serious adverse event, akathisia; tremor; weight gain. Results A literature search identified three double‐blind, randomized, placebo‐controlled trials. These comprised one BRE study (with a 1 mg/day [BRE1] and a 2 mg/day [BRE2]) and two ARI studies (with a 3 mg/day arm and a flexible‐dose arm[within the dosage range approved in Japan]) (n = 1736). Both BRE and ARI demonstrated better efficacy than the placebo. BRE but not ARI had a higher DAE than the placebo. ARI but not BRE had a higher 1AE than the placebo. BRE and ARI had a higher risk of akathisia and weight gain than the placebo. There were no significant differences between BRE and ARI for any of the outcomes. Although BRE1 had good efficacy, it carried risk of weight gain. Although BRE2 also had efficacy, it carried risks of DAE, akathisia, and weight gain. However, the risk of akathisia in BRE2 was reduced by an initial dose of 0.5 mg/day rather than 1.0 mg/day. Conclusions Overall BRE showed similar utility to ARI and a good risk–benefit balance.

Abstract Aim To update the major depressive disorder (MDD) treatment guidelines of the Japanese Society of Mood Disorders, we conducted a systematic review and pairwise meta‐analysis of double‐blind, randomized, placebo‐controlled trials of available antidepressants in Japan for older adults with MDD. Methods Outcome measures included response rate (primary), improvement in depressive symptom scale score, remission rate, all‐cause discontinuation, discontinuation due to adverse events, and at least one adverse event. A random‐effects model was used to calculate the risk ratio (RR) and standardized mean difference (SMD) with a 95% confidence interval (95% CI). Results Nine double‐blind, randomized, placebo‐controlled trials (n = 2145) were identified. No study has been conducted in Japan. Our meta‐analysis included the following antidepressants: duloxetine, escitalopram, imipramine, sertraline, venlafaxine, and vortioxetine. Antidepressants have significantly higher response rates than placebo (RR [95% CI] = 1.38 [1.04, 1.83], p = 0.02). Antidepressants outperformed placebo in terms of improving depressive symptom scale score (SMD [95% CI] = −0.62 [−0.92, −0.33], p

Abstract Introduction The question remains to be elucidated: “Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?” It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random‐effects pairwise meta‐analysis including these nine double‐blind, randomized, placebo‐controlled trials. Methods We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). Results Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = −0.20 (−0.27, −0.12), p

Abstract Aim The present study aimed to examine the association between copy number variations (CNVs) in parkin (PRKN) and schizophrenia (SCZ) and autism spectrum disorder (ASD) in a large case–control sample. Method Array comparative genomic hybridization was performed on 3111 cases with SCZ, 1236 cases with ASD, and 2713 controls. We systematically prioritized likely pathogenic CNVs (LP‐CNVs) in PRKN and examined their association with SCZ and ASD. Results In total, 3014 SCZ cases (96.9%), 1205 ASD cases (97.5%), and 2671 controls (98.5%) passed quality control. We found that monoallelic carriers of LP‐CNVs in PRKN were common (70/6890, 1.02%) and were not at higher risk of SCZ (p = 0.29) or ASD (p = 0.72). We observed that the distribution pattern of LP‐CNVs in the Japanese population was consistent with those in other populations. We also identified a patient diagnosed with SCZ and early‐onset Parkinson's disease carrying biallelic pathogenic CNVs in PRKN. The absence of Parkinson's symptoms in 10 other monoallelic carriers of the same pathogenic CNV further reflects the lack of effect of monoallelic pathogenic variants in PRKN in the absence of a second hit. Conclusion The present findings suggest that monoallelic CNVs in PRKN do not confer a significant risk for SCZ or ASD. However, further studies to investigate the association between biallelic CNVs in PRKN and SCZ and ASD are warranted.

Abstract Background Frailty is a severe, common co‐morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co‐transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR‐Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. Methods We calculated a cumulative deficit‐derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR‐Preserved. Patients were classified into four groups: non‐frail (FI

Abstract Retroperitoneal sarcoma (RPS) is a rare tumor classified into many histological types. It is also often detected only after it has grown to a considerable size and requires extensive resection of the surrounding organs, making it difficult to offer optimal patient‐tailored management. Evidence supporting specific treatment modalities for RPS is insufficient, owing to its rarity. The Japanese clinical practice guidelines for RPS were published in December 2021, with the aim of accumulating existing evidence and indicating the optimal practice for RPS. These guidelines provide important clinical questions (CQs) concerning the diagnosis and treatment of RPS. This review, with a particular focus on primary RPS, attempts to introduce clinical problems in the diagnosis and treatment of RPS and to assess those problems along with the CQs in the guidelines. According to these guidelines, although chemotherapy and radiotherapy are expected to have therapeutic effects, the level of evidence to support these treatments is not very high at present. Accordingly, complete resection of the tumor is the first and only option for managing primary RPS. However, as with other tumors, the demand for multidisciplinary treatment for RPS is increasing. These guidelines will undoubtedly represent a milestone in clinical practice in relation to RPS in the future, and further evidence is expected to be accumulated based on the CQs that have been proposed.

Abstract Background Obsessive–compulsive disorder (OCD) is a common neuropsychiatric disorder affecting many behaviors in daily life. Hyperactivity of the fronto‐striato‐thalamic circuit via the orbitofrontal cortex (OFC) is assumed to play a major role in the pathophysiology of OCD; however, its pathogenesis is not fully understood. Several reports have described the development of OCD after traumatic brain injury (TBI); however, the pathogenesis of post‐TBI OCD remains unknown. Moreover, patients with TBI often have a variety of sequelae, including cognitive dysfunction and mood disorders, which make the diagnosis and treatment of OCD more complex. Case presentation We report the case of a 17‐year‐old Japanese male who developed OCD after traffic trauma. The patient developed a fear of contamination and checking compulsion after injuring his right OFC and left temporal lobe when he ran into a running truck during a suicide attempt. We believe that the patient's fear of contamination can be diagnosed as true post‐TBI OCD. However, his memory impairment was significant, and we considered his checking compulsion to be strongly influenced by cognitive dysfunction due to TBI. We attempted behavioral therapy for OCD; however, sufficient results were not achieved because of the interference from the sequelae of TBI. Conclusion It is not rare for OCD symptoms to appear after TBI. Differentiating the OCD symptoms induced by brain injury or cognitive dysfunction associated with TBI is important to determine a treatment strategy.

Background Social factors encompass a broad spectrum of nonmedical factors, including objective (social isolation [SI]) and perceived (loneliness) conditions. Although social factors have attracted considerable research attention, information regarding their impact on patients with heart failure is scarce. We aimed to investigate the prognostic impact of objective SI and loneliness in older patients with heart failure. Methods and Results This study was conducted using the FRAGILE‐HF (Prevalence and Prognostic Value of Physical and Social Frailty in Geriatric Patients Hospitalized for Heart Failure; derivation cohort) and Kitasato cohorts (validation cohort), which included hospitalized patients with heart failure aged ≥65 years. Objective SI and loneliness were defined using the Japanese version of Lubben Social Network Scale‐6 and diagnosed when the total score for objective and perceived questions on the Lubben Social Network Scale‐6 was below the median in the FRAGILE‐HF. The primary outcome was 1‐year death. Overall, 1232 and 405 patients in the FRAGILE‐HF and Kitasato cohorts, respectively, were analyzed. Objective SI and loneliness were observed in 57.8% and 51.4% of patients in the FRAGILE‐HF and 55.4% and 46.2% of those in the Kitasato cohort, respectively. During the 1‐year follow‐up, 149 and 31 patients died in the FRAGILE‐HF and Kitasato cohorts, respectively. Cox proportional hazard analysis revealed that objective SI, but not loneliness, was significantly associated with 1‐year death after adjustment for conventional risk factors in the FRAGILE‐HF. These findings were consistent with the validation cohort. Conclusions Objective SI assessed using the Lubben Social Network Scale‐6 may be a prognostic indicator in older patients with heart failure. Given the lack of established SI assessment methods in this population, further research is required to refine such methods.

Abstract A 77‐year‐old male patient underwent esophagogastroduodenoscopy at his family doctor, and an easily hemorrhagic depressed lesion was noted near the anterior wall of the gastric antrum. A biopsy revealed moderately differentiated tubular adenocarcinoma > poorly differentiated adenocarcinoma, and the patient was referred to our department for further examination. A 15‐mm 0–IIc lesion is seen near the anterior wall of the gastric antrum and narrow band imaging magnifying endoscopy revealed obscured glandular duct structures and corkscrew pattern vascular structures. We diagnosed the patient with early‐stage gastric cancer [L, Ant, 15mm, cType0‐IIc, cT1(M‐SM1), cN0, cM0, cStage IA] after an esopahogastroduodenoscopy examination at our hospital, and endoscopic submucosal dissection was performed. Histopathological images with hematoxylin and eosin staining showed tumor cells with pale cytoplasm and the immunostaining for alpha‐fetoprotein, sal‐like protein 4, and Glypican3 was positive. The patient was pathologically diagnosed with gastric adenocarcinoma with enteroblastic differentiation, pT1b1 (SM, 0.4 mm), type 0–IIc, 15 mm, UL (‐), Ly0, and V0. Gastric adenocarcinoma with enteroblastic differentiation is one of the representative histological types of alpah‐fetoprotein‐producing gastric cancer. Alpha‐fetoprotein‐producing gastric cancer is infrequent, accounting for at least 3% of all gastric cancers, and is generally highly malignant. Most cases are already advanced upon diagnosis, and finding them in the early stage is rare. Therefore, pathological findings that may indicate the gastric adenocarcinoma with enteroblastic differentiation should be noted even in early gastric cancer.

Abstract Endoscopic ultrasound‐guided fine needle aspiration and biopsy have significantly evolved since they offer a minimally invasive approach for obtaining pathological specimens from lesions adjacent to or within the intestine. This paper reviews advancements in endoscopic ultrasound‐guided fine needle aspiration and biopsy techniques and devices, emphasizing the importance of handling specimens for diagnostic accuracy. Innovations of fine needle biopsy needles with features like side holes and Franseen shapes have enhanced histological sampling capabilities. Techniques for specimen handling, including rapid on‐site evaluation and macroscopic on‐site evaluation, play pivotal roles in assessing sample adequacy, thereby influencing diagnostic outcomes. The utility of artificial intelligence in augmenting rapid on‐site evaluation and macroscopic on‐site evaluation, although still in experimental stages, presents a promising avenue for improving procedural efficiency and diagnostic precision. The choice of specimen handling technique is dependent on various factors including endoscopist preference, procedure objectives, and available resources, underscoring the need for a comprehensive understanding of each method's characteristics to optimize diagnostic efficacy and procedural safety.

Abstract Background and Aim Helicobacter pylori eradication therapy effectively improves the abdominal symptoms and bowel habits of patients. Patients in whom dyspepsia is under control by 6 to 12 months after successful H. pylori eradication are defined as having H. pylori‐associated dyspepsia, and patients with dyspepsia that is refractory to successful eradication are defined as having functional dyspepsia. Here, we aimed to investigate the association between H. pylori eradication and improvement of dyspepsia in the short and long term after eradication therapy. Methods Dyspeptic symptoms before treatment and at 2 and 12 months after eradication were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS) in 282 H. pylori‐positive Japanese patients who underwent eradication therapy. Results Of the Japanese H. pylori‐positive patients, 48.2% (136/282) had upper abdominal symptoms. Eradication improved dyspepsia in 34.5% (47/136) of the patients at 2 months post eradication, which continued to be under control up to 12 months. A significant decrease at 2 and 12 months after eradication, compared with before eradication, was observed in total GSRS (from 25.7 ± 10.4 [before eradication, n = 249] to 23.3 ± 7.2 [after 2 months, n = 249] and 24.8 ± 7.8 [after 12 months, n = 81]; P = 0.014 and 0.321, respectively), gastric pain score (from 4.1 ± 1.9 to 3.7 ± 1.3 and 3.7 ± 1.2; P = 0.025 and 0.047), and constipation score (from 5.9 ± 3.1 to 5.2 ± 2.3 and 5.9 ± 3.0; P

Abstract Background The use of robot‐assisted surgery for rectal cancer is increasing, but its short‐term results remain unclear. We compared the short‐term outcomes of robot‐assisted and laparoscopic surgery for rectal cancer using a nationwide inpatient database. Methods We analyzed patients registered in the Japanese Diagnosis Procedure Combination database who underwent robot‐assisted or laparoscopic surgery for rectal cancer from April 2018 to March 2020. Postoperative complication rates, anesthesia time, length of hospital stay, and cost were compared using propensity score matching for low anterior resection (LAR), high anterior resection (HAR), and abdominoperineal resection (APR). Results Among 38 090 rectal cancer cases, 1992 LAR, 357 HAR, and 310 APR pairs were generated by propensity score matching and analyzed. Anesthesia time was longer for robot‐assisted surgery compared with laparoscopic surgery (LAR: 388.6 vs. 452.8 min, p

Abstract Background and Aim An accurate preoperative diagnosis as the basis for deciding the most appropriate surgical procedure is essential for patients with suspected gallbladder cancer (GBC). The aim of this study was to investigate the usefulness of cell‐free DNA (cfDNA) for the preoperative detection of ≥T2 invasion in patients with suspected GBC. Methods Twenty‐four patients who underwent resection for suspected GBC were enrolled. The concentration of cfDNA obtained from blood samples preoperatively was measured and evaluated in two distributions. The first peak (less than 200 base pairs) of cfDNA distribution was defined as the shorter fragment cfDNA, considered to originate mainly from apoptosis; and the second peak (200 base pairs or more) was defined as the longer fragment cfDNA, originating mainly from necrosis. Results Pathological analysis identified benign disease in 12 patients and GBC in 12 patients, of whom 6 patients had ≥pT2 GBC. Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19‐9 were significantly higher in the ≥pT2 GBC group than in the benign/

ABSTRACT Aims/Introduction This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. Materials and Methods We enrolled 811 patients with type 2 diabetes, biopsy‐proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Results Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow‐up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person‐years) and 79 of 134 (11.4 events/100 person‐years) cases with and without polar vasculosis, respectively. Kaplan–Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all‐cause mortality before DKD progression as a competing event. Conclusions This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

Abstract Background Cachexia substantially impacts the prognosis of patients with heart failure (HF); however, there is no standard method for cachexia diagnosis. This study aimed to investigate the association of Evans's criteria, consisting of multiple assessments, with the prognosis of HF in older adults. Methods This study is a secondary analysis of the data from the FRAGILE‐HF study, a prospective multicentre cohort study that enrolled consecutive hospitalized patients aged ≥65 years with HF. Patients were divided into two groups: the cachexia and non‐cachexia groups. Cachexia was defined according to Evans's criteria by assessing weight loss, muscle weakness, fatigue, anorexia, a decreased fat‐free mass index and an abnormal biochemical profile. The primary outcome was all‐cause mortality, as assessed in the survival analysis. Results Cachexia was present in 35.5% of the 1306 enrolled patients (median age [inter‐quartile range], 81 [74–86] years; 57.0% male); 59.6%, 73.2%, 15.6%, 71.0%, 44.9% and 64.6% had weight loss, decreased muscle strength, a low fat‐free mass index, abnormal biochemistry, anorexia and fatigue, respectively. All‐cause mortality occurred in 270 patients (21.0%) over 2 years. The cachexia group (hazard ratio [HR], 1.494; 95% confidence interval [CI], 1.173–1.903; P = 0.001) had a higher mortality risk than the non‐cachexia group after adjusting for the severity of HF. Cardiovascular and non‐cardiovascular deaths occurred in 148 (11.3%) and 122 patients (9.3%), respectively. The adjusted HRs for cachexia in cardiovascular mortality and non‐cardiovascular mortality were 1.456 (95% CI, 1.048–2.023; P = 0.025) and 1.561 (95% CI, 1.086–2.243; P = 0.017), respectively. Among the cachexia diagnostic criteria, decreased muscle strength (HR, 1.514; 95% CI, 1.095–2.093; P = 0.012) and low fat‐free mass index (HR, 1.424; 95% CI, 1.052–1.926; P = 0.022) were significantly associated with high all‐cause mortality, but there was no significant association between weight loss alone (HR, 1.147; 95% CI, 0.895–1.471; P = 0.277) and all‐cause mortality. Conclusions Cachexia evaluated by multi‐assessment was present in one third of older adults with HF and was associated with a worse prognosis. A multimodal assessment of cachexia may be helpful for risk stratification in older patients with HF.

Abstract Background One‐third of individuals who contract novel coronavirus disease 2019 (COVID‐19) reportedly experience persistent symptoms, including respiratory issues, headache, dizziness, taste disorders, fatigue, and various psychiatric and neurological symptoms, known as post‐acute sequelae of SARS‐CoV‐2. In this case report, we present a patient who became aware of brain fog, which is cognitive impairment, approximately 2 months after their COVID‐19 symptoms had resolved, accompanied by anxiety and depression. Case Presentation The patient, a 35‐year‐old Japanese man, was infected with COVID‐19 and resumed work approximately 2 weeks later after symptoms improved. Approximately 1 month after returning to work, the patient's concentration became impaired and he started making noticeable errors at work. These symptoms did not improve, leading him to the outpatient clinic specializing in COVID‐19 sequelae at our hospital. Here, he underwent blood tests, electroencephalography, and head magnetic resonance imaging, which did not reveal any abnormalities. Cognitive decline due to COVID‐19 sequelae was therefore suspected, prompting his evaluation in our department approximately 5 months after his initial COVID‐19 infection. Detailed cognitive function tests were performed. He was monitored without the use of medications, and his cognitive function gradually improved. Approximately 11 months after his initial COVID‐19 infection, the same cognitive function tests were conducted again, because his subjective cognitive function symptoms had disappeared, and improvement was observed in many items. Conclusion Since brain fog is a relatively common sequela, we emphasize the importance of keeping this in mind from the initial consultations and comparing results over time.

Abstract Background Idiopathic basal ganglia calcification (IBGC), also known as Farh's disease, is a rare neurodegenerative disorder characterized by calcification of the basal ganglia and other brain regions. This disease usually occurs in middle‐aged patients and presents with various neurological and psychiatric symptoms. The exact prevalence is unknown; however, population genomic data analysis suggests a prevalence of at least 4.5/10,000 to 3.3/1000, indicating that the disease is more common than previously thought and remains underdiagnosed. Case Presentation We report the case of a middle‐aged Japanese man who attempted suicide twice because of obsessive‐compulsive ideation caused by trivial triggers. The patient's psychiatric symptoms resolved relatively quickly after hospitalization, and imaging and genetic testing led to a diagnosis of IBGC. Conclusion This case report illustrates the importance of including IBGC in the differential diagnosis of psychiatric symptoms that initially develop in middle‐aged patients.

Abstract Background Skeletal‐related events (SREs), including the pathological fracture, surgical treatment or radiation of bone lesions, malignant spinal cord compression, hypercalcemia, are important considerations when managing metastatic bone tumors; however, owing to their rarity, the incidence of SREs in patients with Ewing sarcoma remains unknown. Methods We retrospectively reviewed the clinical data from 146 patients with Ewing sarcoma treated at a single institution from 2005 to 2019. The median age at diagnosis was 22.7 years. Fifty patients (34.2%) had metastatic disease at diagnosis. The primary outcome was the SRE‐free rate among patients with Ewing sarcoma. Moreover, we identified the risk factors for SREs using univariate or multivariate analyses. Results During the observational period (median, 2.6 years), SREs occurred in 23 patients. Radiation to the bone, malignant spinal cord compression, and hypercalcemia were documented as the initial SREs in 12 patients (52.2%), 10 patients (43.5%), and one patient (4.3%), respectively. The SRE‐free rate was 94.2 ± 2.0, 87.3 ± 3.0, and 79.6 ± 3.8% at 1, 2, and 3 years after the initial visit, respectively. Multivariate analysis revealed bone metastasis at diagnosis (hazard ratio [HR] = 4.41, p = 0.007), bone marrow invasion (HR = 34.08, p

Abstract Visual display is a crucial aspect of courtship, and their success relies on both display quality and the surrounding environment, such as the visual background. Cephalopods may release ink when attacked by predators or during aggressive interactions with conspecifics. Here, we report that ink is used as a part of the courtship display by males of the cuttlefish species Sepia andreana. Males of this species engage in a highly ritualized multimodal courtship using a pair of markedly long sexually dimorphic arms. At the climax of the courtship, the male releases a diffuse backdrop of ink near himself and then performs the specific courtship display by extending his sexually dimorphic arms and altering his body pattern to pale in front of this ink backdrop, and then proceeds to mate. This novel use of cephalopod ink could make the surroundings darker and more homogeneous, potentially serving as a temporary modification of the visual environment for courtship display.

Background Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM‐detected AF. Methods and Results We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time‐dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (P=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41–5.28]). In a time‐dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70–4.47]). Conclusions The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM‐detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM‐detected AF.

Abstract Aims Frailty is highly prevalent and associated with poor prognoses in elderly patients with heart failure (HF). However, the potential effects of physical frailty on the benefits of HF medications in elderly patients with HF are unclear. We aimed to determine the influence of physical frailty on the prognosis of HF medications in elderly patients with HF with reduced and mildly reduced ejection fraction (HFr/mrEF). Methods and results From the combined HF database of the FRAGILE‐HF and Kitasato cohorts, hospitalized HF patients with a left ventricular ejection fraction

Abstract Pembrolizumab plus chemotherapy improved progression‐free survival (PFS) and overall survival (OS) compared with placebo plus chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic triple‐negative breast cancer with tumor programmed cell death ligand 1 (PD‐L1) combined positive score (CPS) ≥10 in the global, phase 3, randomized controlled trial KEYNOTE‐355. We report results for patients enrolled in Japan. Patients were randomized 2:1 to pembrolizumab 200 mg or placebo Q3W for 35 cycles plus chemotherapy (nab‐paclitaxel, paclitaxel, or gemcitabine–carboplatin). Primary endpoints were PFS per RECIST version 1.1 by blinded independent central review and OS in patients with PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and the intention‐to‐treat (ITT) population. No alpha was assigned to this exploratory analysis. Eighty‐seven patients were randomized in Japan (pembrolizumab plus chemotherapy, n = 61; placebo plus chemotherapy, n = 26), 66 (76%) had PD‐L1 CPS ≥1, and 28 (32%) had PD‐L1 CPS ≥10. Median time from randomization to data cutoff (June 15, 2021) was 44.7 (range, 37.2–52.9) months in the ITT population. Hazard ratios (HRs; 95% CI) for OS were 0.36 (0.14–0.89), 0.52 (0.30–0.91), and 0.46 (0.28–0.77) in the PD‐L1 CPS ≥10, PD‐L1 CPS ≥1, and ITT populations, respectively. HRs (95% CI) for PFS were 0.52 (0.20–1.34), 0.61 (0.35–1.06), and 0.64 (0.39–1.05). Grade 3 or 4 treatment‐related adverse events occurred in 85% of patients in each group (no grade 5 events). Consistent with the global population, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy in Japanese patients and supports this combination in this setting.

Abstract Wetlands are responsible for 20%–31% of global methane (CH4) emissions and account for a large source of uncertainty in the global CH4 budget. Data‐driven upscaling of CH4 fluxes from eddy covariance measurements can provide new and independent bottom‐up estimates of wetland CH4 emissions. Here, we develop a six‐predictor random forest upscaling model (UpCH4), trained on 119 site‐years of eddy covariance CH4 flux data from 43 freshwater wetland sites in the FLUXNET‐CH4 Community Product. Network patterns in site‐level annual means and mean seasonal cycles of CH4 fluxes were reproduced accurately in tundra, boreal, and temperate regions (Nash‐Sutcliffe Efficiency ∼0.52–0.63 and 0.53). UpCH4 estimated annual global wetland CH4 emissions of 146 ± 43 TgCH4 y−1 for 2001–2018 which agrees closely with current bottom‐up land surface models (102–181 TgCH4 y−1) and overlaps with top‐down atmospheric inversion models (155–200 TgCH4 y−1). However, UpCH4 diverged from both types of models in the spatial pattern and seasonal dynamics of tropical wetland emissions. We conclude that upscaling of eddy covariance CH4 fluxes has the potential to produce realistic extra‐tropical wetland CH4 emissions estimates which will improve with more flux data. To reduce uncertainty in upscaled estimates, researchers could prioritize new wetland flux sites along humid‐to‐arid tropical climate gradients, from major rainforest basins (Congo, Amazon, and SE Asia), into monsoon (Bangladesh and India) and savannah regions (African Sahel) and be paired with improved knowledge of wetland extent seasonal dynamics in these regions. The monthly wetland methane products gridded at 0.25° from UpCH4 are available via ORNL DAAC (https://doi.org/10.3334/ORNLDAAC/2253).

Abstract Objective MRI provides useful information regarding brain maturation and injury in newborn infants. However, MRI studies are generally restricted during acute phase, resulting in uncertainty around upstream clinical events responsible for subtle cerebral injuries. Time‐resolved near‐infrared spectroscopy non‐invasively provides the reduced scattering coefficient (μs′), which theoretically reflects tissue structural complexity. This study aimed to test whether μs′ values of the newborn head reflected MRI findings. Methods Between June 2009 and January 2015, 77 hospitalised newborn infants (31.7 ± 3.8 weeks gestation) were assessed at 38.8 ± 1.3 weeks post‐conceptional age. Associations of μs′ values with MRI scores, mean diffusivity and fractional anisotropy were assessed. Results Univariable analysis showed that μs′ values were associated with gestational week (p = 0.035; regression coefficient [B], 0.065; 95% confidence interval [CI], 0.005–0.125), fractional anisotropy in the cortical grey matter (p = 0.020; B, −5.994; 95%CI, −11.032 to −0.957), average diffusivity in the cortical grey matter (p

Abstract The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair‐defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer‐initiating cells in these patients usually undergo loss of the wild‐type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients.

Abstract Background Impaired renal function is 1 of the poor prognostic factors in dogs with myxomatous mitral valve disease (MMVD). However, the value of cystatin C (Cys‐C), a marker of renal function, as a prognostic marker for MMVD in dogs has not yet been explored. Objective This study aims to investigate the prognostic value of Cys‐C in dogs with MMVD. Animals Fifty client‐owned small‐breed dogs with MMVD were included in this study. Methods This is a retrospective, cross‐sectional study. The prognostic value of serum Cys‐C concentration was assessed using univariable and multivariable Cox hazard regression analyses. Kaplan‐Meier survival curves for MMVD‐specific survival in dogs stratified into high and low Cys‐C groups were generated and analyzed using the log‐rank test. Results Serum Cys‐C concentrations were significantly associated with MMVD‐related death (P

Abstract Background The prognosis of focal segmental glomerulosclerosis patients with nephrotic syndrome is estimated to be 10%–20% in 5 years and 30%–50% in 10 years, leading to end‐stage kidney disease. The response rate with steroid therapy is 40%–60%. Therapeutic low‐density lipoprotein‐apheresis (LDL‐A) may be effective in patients with steroid resistance. Information regarding the long‐term prognosis of patients with focal segmental glomerulosclerosis receiving this therapy is scarce. Methods We investigated the effectiveness of treatment in 50 patients with primary focal segmental glomerulosclerosis diagnosed between 1961 and 2017 at Kanazawa University Hospital and related facilities. The patients were observed at least 12 months after biopsy or until end‐stage kidney disease occurrence or death. Results LDL‐A was performed in four patients who presented with steroid‐resistant nephrotic syndrome (two patients had concurrent acute renal failure for which hemodialysis was performed). In comparison with 17 patients who did not receive LDL‐A after 1989, the LDL‐A group had higher urinary protein excretion (13.7 vs. 5.2 g/day, P = 0.053) and serum creatinine (4.11 vs. 1.65 mg/dL) levels at onset, and a numerically higher remission rate (75.0% vs. 58.7%) compared with the nonlipoprotein‐apheresis group. Conclusion Therapeutic LDL‐A can be performed for critical cases and may improve the remission rate.

Abstract Background This study investigated the sex differences in the risk of end‐stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. Methods This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. Results During a median follow‐up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02–1.75; p = .034) and death (HR 1.64; 95% CI 1.24–2.16; p = .001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo‐ and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. Conclusions In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

Abstract Introduction Kato et al. reported results of a 6‐week, double‐blind, randomized, placebo‐controlled trial of lurasidone in adults with bipolar depression (BDep). Aim We performed a post hoc analysis using data from the lurasidone trial to predict later responses from early improvements. Methods An early improvement was defined as a ≥20% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) total score at Week 2; response was defined as a ≥50% reduction in MADRS total score at Week 6; symptomatic remission were defined as a score of ≤8 on MADRS total score at Week 6. Results Both sensitivity and negative predictive value (NPV) were higher for the remission outcome than for the response outcome. The interpretation of sensitivity and NPV in the lurasidone group when remission is an outcome is as follows. It means (1) that, from all remitters at Week 6, 80.6% was identified as such at Week 2 on the basis of their early improvement and (2) that a patient showing non‐improvement at 2 weeks had 93.5% probability of being a non‐remitters at Week 6. However, the values of specificity for both response and remission in the lurasidone group were not high. Conclusion Patients who did not show an early response at Week 2 cannot be predicted with a high probability to also show poor improvement at Week 6. In fact, some patients who did not show early response at 2 weeks might have marked improvement at 6 weeks.

Abstract Mesenchymal epithelial transition factor receptor (MET) tyrosine kinase inhibitors (MET‐TKIs) have been approved for the treatment of non‐small cell lung cancers with MET exon 14 skipping mutations. Transient asymptomatic pulmonary opacities (TAPOs) associated with epidermal growth factor receptor (EGFR)‐TKIs have been reported. Here, we report a case wherein ground‐glass opacities (GGOs) appeared during the course of treatment with tepotinib, a MET‐TKI, but spontaneously resolved with drug withdrawal, after which treatment was resumed with a reduced dose. Although there have been no reports of TAPOs with MET‐TKIs, the clinical and imaging findings of this case were consistent with TAPOs. For TAPOs occurring because of MET‐TKI, the drug can be continued under careful observation even if GGOs appear.

Abstract Aim Care for people with schizophrenia is shifting the locus from long‐stay mental hospitals to nonspecialized community‐based settings. Knowledge on the care is not a sole property of psychiatric specialists. Community healthcare workers who do not specialize in psychiatry are recommended to learn more about schizophrenia. This review aimed to summarize recent findings on subjective well‐being and physical, psychiatric, and social comorbidities in individuals with schizophrenia. Methods A literature review was conducted. We retrieved findings from existing systematic reviews and meta‐analyses as our preferred method. When data were not available, we referred to other types of studies. Results As per our review, individuals with schizophrenia demonstrated poor subjective well‐being, happiness, and life satisfaction despite individual differences. Pharmacotherapy caused weight gain and constipation, whereas race and hospitalization might affect weight reduction. Individuals with schizophrenia demonstrated poor oral health, a high prevalence of noncommunicable diseases, and unique eating behaviors. Depression, sleep disorders, smoking, and alcohol and drug consumption were frequently found in the individuals. Research findings regarding problematic internet and smartphone use and stress perception were limited. Low health literacy and neglect of preventable behaviors were frequently seen in individuals with schizophrenia. They tended to be less educated, poor, unemployed, unmarried/unattached, and had poor social cognition, resulting in little social support and a small social network. Conclusion Retrieving recent data, we confirmed that individuals with schizophrenia had poor subjective well‐being and suffer from various physical, psychiatric, and social comorbidities.

Abstract Background Pelvic inflammatory disease (PID) is not a mere transient infection. PID can lead to chronic pain, ectopic pregnancy, and infertility. Although the Centers for Disease Control and Prevention have established minimum diagnostic criteria, including pelvic examination, the diagnostic value of pelvic tenderness has recently garnered controversy. Our meta‐analysis aimed to confirm whether pelvic tenderness, cervical motion tenderness, and adnexal tenderness can help diagnose PID. Methods We searched for studies reporting the diagnostic test accuracy of pelvic tenderness, cervical motion tenderness, and adnexal tenderness among female patients at risk for PID, using MEDLINE, EMBASE, CENTRAL, CINAHL, Google, and Google Scholar through May 25th, 2022. After quality assessment using QUADAS‐2, we performed data synthesis using a bivariate random effect model and Bayesian hierarchical summary receiver operating characteristic model. We then conducted sensitivity analysis excluding studies with non‐PID cases. Results The literature search produced 6769 articles. After quality assessment, 14 studies and their 2808 participants were eligible for synthesis on pelvic tenderness. Laparoscopy, either alone or in combination, was the most frequent reference standard. The main results for pelvic tenderness sensitivity and specificity were 0.81, 95% confidence interval (CI) [0.67–0.90] and 0.40, 95% CI [0.25–0.57], respectively. Sensitivity and specificity were 0.72, 95% CI [0.57–0.83] and 0.50, 95% CI [0.34–0.66], for cervical motion tenderness, and 0.87 [0.64–0.96] and 0.27, 95% CI [0.12–0.52] for adnexal tenderness, respectively. Conclusions Our meta‐analysis suggests that pelvic tenderness assessed by pelvic examination may be useful for PID examination with moderate‐to‐high sensitivity, whereas clinicians should be aware of the diagnostic significance of pelvic tenderness.

Abstract Background Hepatojugular reflux is a cardiac physical examination with a long history of use in heart failure diagnosis across many clinical settings. However, the development of new diagnostic methods has thrown the clinical role of hepatojugular reflux into question. Our meta‐analysis aimed to determine the diagnostic accuracy of hepatojugular reflux and assess its usefulness in diagnosing congestive heart failure among at‐risk patients. Methods This meta‐analysis of studies reporting diagnostic hepatojugular reflux values of patients at risk for congestive heart failure followed PRISMA guidelines. We searched MEDLINE, EMBASE, Web of Science, CENTRAL, and Google Scholar for eligible studies from inception through February 1, 2021. After QUADAS‐2 quality assessment, we conducted data synthesis using the random effects model and a hierarchical summary receiver operating characteristic model. As an additional analysis, we sorted the studies by clinical setting and performed synthesis again. We submitted our protocol to PROSPERO (International Prospective Register of Systematic Reviews; ID No. CRD42020215004). Results The literature search provided 4121 studies for evaluation. Seven studies and their 5195 participants were deemed eligible for synthesis. Clinical diagnosis was the most frequent reference standard. Bivariate random‐effects analysis found hepatojugular reflux sensitivity of 0.12, 95% confidence interval (CI) [0.07–0.19], and specificity of 0.96, 95% CI [0.95–0.97]. The DOR was 29.7, 95% CI [18.4–45.3]. The additional analysis of the emergency settings provided a sensitivity of 0.14, 95% CI [0.12–0.17] and specificity of 0.95, 95% CI [0.93–0.96]. Conclusions Our meta‐analysis suggests that hepatojugular reflux has practical value for diagnosis of congestive heart failure with high specificity.

Abstract Aim Understanding the appropriate prescription of psychotropics for hospitalized patients in terms of preventing falls is an important issue. The aim of this study was to assess the associations between the occurrence of falls and the use of various individual psychotropics in hospitalized patients. Methods A retrospective matched case–control study was conducted on adult patients admitted to every department of Tokyo Medical University Hospital, with the outcome being in‐hospital falls. A total of 447 hospitalized patients who had had in‐hospital falls at some point in their hospitalization between January 2016 and December 2016 were included as cases. A total of 447 hospitalized patients who did not have in‐hospital falls, and were individually matched to the cases by sex, age, and clinical department, were included as controls. All data were extracted from electronic medical records. Conditional logistic regression analyses were conducted to assess the association between the exposure to 16 psychotropic medications and the occurrence of in‐hospital falls. The multivariable logistic regression model adjusted sex, age, clinical department, body mass index, fall risk score on the fall risk assessment measure, and use of psychotropic medications. Results The multivariable conditional logistic regression model showed a significant association between the use of risperidone (odds ratio [OR] = 3.730; 95% confidence interval [CI] = 1.229–11.325) and flunitrazepam (OR = 4.120; 95% CI = 1.105–15.364) and an increased OR of falls among hospitalized patients. Conclusion The use of risperidone and flunitrazepam were identified as risk factors for falls among hospitalized patients.

Abstract Aims/Introduction To investigate whether the Fibrosis‐4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease. Materials and Methods Based on fatty liver disease and Fibrosis‐4 index (cut‐off value 1.3), we retrospectively divided 9,449 individuals, who underwent at least two annual health checkups, into four groups stratified by sex: normal; high Fibrosis‐4 index without fatty liver disease; low Fibrosis‐4 index with fatty liver disease; and high Fibrosis‐4 index with fatty liver disease. Results Onset rates for diabetes mellitus in the normal, high Fibrosis‐4 index without fatty liver disease, low Fibrosis‐4 index with fatty liver disease and high Fibrosis‐4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8% and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3% and 7.0%, respectively, in women. Compared with the normal group, the high Fibrosis‐4 index without fatty liver disease, low Fibrosis‐4 index with fatty liver disease and high Fibrosis‐4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female participants. Furthermore, in both sexes, high Fibrosis‐4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis‐4 index with fatty liver disease group: adjusted hazard ratio 4.03, 95% confidence interval 2.19–7.42 [men] and adjusted hazard ratio 6.40, 95% confidence interval 1.77–23.14 [women]). Conclusions Individuals with fatty liver disease and high Fibrosis‐4 index had a higher risk of diabetes mellitus onset. Therefore, Fibrosis‐4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.

Abstract Introduction Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction‐associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. Materials and Methods We retrospectively assessed 9,459 participants who underwent two or more annual health check‐ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non‐overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). Results The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P

Abstract Aim The association of parenting experiences in childhood with anxiety symptoms in adulthood has yet to be clarified. We hypothesized that interpersonal sensitivity (IPS) mediates the impacts of parenting experiences in childhood on anxiety symptoms and negative assessment of life events in adulthood. Methods An observational cross‐sectional study was carried out from January 2014 to August 2014 on 853 adults. Participants provided their demographic information and answered the following four self‐administered questionnaires: Parental Bonding Instrument (PBI), Interpersonal Sensitivity Measure (IPSM), Life Experiences Survey (LES), and State–Trait Anxiety Inventory Form Y (STAI‐Y). The data of a total of 404 participants who agreed to take part in this study were analyzed. Results Multiple regression analysis with the State Anxiety subscale of STAI‐Y as the dependent variable identified the following five out of the 15 independent variables as being statistically significant: IPSM total, LES positive and negative, PBI paternal overprotection, and employment status. This model explains 17.8% of the State Anxiety subscale score. In the structural equation models, the Care subscale showed significant indirect negative effects on State Anxiety subscale and LES negative score through a decrease in IPSM total score (β = –0.061 and –0.042, respectively). The former indirect effect accounted for 31.6%, and the latter accounted for 56.8% of the total effects. In contrast, Overprotection subscale had opposite effects to Care subscale. Conclusion These results suggest that parenting experiences in childhood are related to adult anxiety symptoms and the negative assessment of life events indirectly through IPS.