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A letter to the editor is presented discussing Xmn1-Gγ polymorphism analysis conducted to determine its influence to the production of fetal hemoglobin (HbF) in patients with β-thalassemia/hemoglobin E (HbE).

The pollutant lead (Pb-plumbum-black lead) is toxic. Organisms in nature cannot naturally suppres its concentration. Special Capital Region of Jakarta is a metropolitan city with densest highway traffic in the world, especially in and around the Marunda area, which is the location 24-hour non-stop loading and unloading activities of various businesses. With that environmental condition, in the Marunda area of Jakarta lies the Naval base where the Marine Taskforce Personnel are stationed. The environmental condition allows the personnel to be quite frequently exposed to lead. This research aims to detect the ALAD gen mutation in the Marine Taskforce personnel as a mapping of the level of ALAD gene mutation frequency in the Marines of the Jakarta area. The research was conducted in a period of [insert data]. The sampling applied the purposive sampling method with a sample size of 100 Marines. The research results show that there was no ALAD gene mutation in the 100 Marines. This could depict a good energy status of the 100 Marines stationed in the Marunda area. With no mutation found in the ALAD gene, that means the process of oxygen binding with hemoglobin has no disruption in energy synthesis.

Purpose: Recurrence and contralateral metachronous inguinal hernia (CMIH) are important postoperative complications in patients with inguinal hernia (IH) who undergo laparoscopic percutaneous extraperitoneal closure (LPEC). This study aimed to evaluate the incidence and causes of recurrence and CMIH after LPEC., Methods: Among the included patients, 2484 hernias were included in the analysis of recurrence. CMIH was analyzed in 2094 cases with unilateral IH without a history of contralateral IH., Results: Overall, 21 hernias (0.85%) recurred and seven patients (0.34%) experienced CMIH. Based on the video inspection, injury and skipping of the peritoneum were suspected as the cause of recurrence in eight cases, while loose ligation was suspected in five cases. The cause of recurrence could not be predicted in the remaining eight patients. Of the seven patients with CMIH, three had a mild depression around the internal inguinal ring at the first surgery. In the remaining four CMIH cases, no noteworthy findings were noted around the internal ring., Conclusions: More than half of the recurrences, in which skipping of the peritoneum and loose ligation were suspected, could have been prevented by secure ligation during the first surgery. Extending the indications of prophylactic surgery for shallow depressions may reduce CMIH., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

An 81-year-old man with hypertension and a history of smoking presented with renal enlargement and progressive renal dysfunction despite no family history of kidney disease. A renal biopsy revealed diffuse tubular, dilated, and atrophic distal tubules with cystic formation and thin irregularities in the tubular basement membrane. Although no known genetic abnormalities were detected, the patient was diagnosed with medullary cystic kidney disease (MCKD). In addition, idiopathic nodular glomerulosclerosis, which is characterized by significant mesangial expansion and accentuated glomerular nodularity and is associated with hypertension and cigarette smoking, was identified as a complication of MCKD. We herein report a rare case of sporadic MCKD with idiopathic nodular glomerulosclerosis.

The accurate estimation of lower-limb joint angles and moments is crucial for assessing the progression of orthopedic diseases, with continuous monitoring during daily walking being essential. An inertial measurement unit (IMU) attached to the lower back has been used for this purpose, but the effect of IMU misalignment in the frontal plane on estimation accuracy remains unclear. This study investigated the impact of virtual IMU misalignment in the frontal plane on estimation errors of lower-limb joint angles and moments during walking. Motion capture data were recorded from 278 healthy adults walking at a comfortable speed. An estimation model was developed using principal component analysis and linear regression, with pelvic accelerations as independent variables and lower-limb joint angles and moments as dependent variables. Virtual IMU misalignments of -20°, -10°, 0°, 10°, and 20° in the frontal plane (five conditions) were simulated. The joint angles and moments were estimated and compared across these conditions. The results indicated that increasing virtual IMU misalignment in the frontal plane led to greater errors in the estimation of pelvis and hip angles, particularly in the frontal plane. For misalignments of ±20°, the errors in pelvis and hip angles were significantly amplified compared to well-aligned conditions. These findings underscore the importance of accounting for IMU misalignment when estimating these variables.

One-carbon metabolism (OCM) is a complex and interconnected network that undergoes drastic changes during pregnancy. In this study, we investigated the longitudinal distribution of OCM-related metabolites in maternal and cord blood and explored their relationships. Additionally, we conducted cross-sectional analyses to examine the interrelationships among these metabolites. This study included 146 healthy pregnant women who participated in the Chiba Study of Mother and Child Health. Maternal blood samples were collected during early pregnancy, late pregnancy, and delivery, along with cord blood samples. We analyzed 18 OCM-related metabolites in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry. We found that serum S-adenosylmethionine (SAM) concentrations in maternal blood remained stable throughout pregnancy. Conversely, S-adenosylhomocysteine (SAH) concentrations increased, and the total homocysteine/total cysteine ratio significantly increased with advancing gestational age. The betaine/dimethylglycine ratio was negatively correlated with total homocysteine in maternal blood for all sampling periods, and this correlation strengthened with advances in gestational age. Most OCM-related metabolites measured in this study showed significant positive correlations between maternal blood at delivery and cord blood. These findings suggest that maternal OCM status may impact fetal development and indicate the need for comprehensive and longitudinal evaluations of OCM during pregnancy., Competing Interests: The research fund for this research was a donation from Amway Japan G.K. The funding company played no role in the design of the study, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Objectives: Although going out has been reported to be associated with the incidence of disability, few studies have investigated the effect of community-based programs to promote going out on the incidence of disability. This study aimed to estimate the effects of a program fostering going-out on the incidence of disability in community-dwelling older adults., Design: Longitudinal, observational study., Setting and Participants: Nonengaged (n = 1086) and engaged older adults (n = 1086) enrolled in the National Center for Geriatrics and Gerontology Study of Geriatric Syndrome by using a one-to-one nearest neighbor propensity score-matching scheme., Methods: After the baseline assessments, participants in the community-based going-out program received a specialized physical activity tracker, monitored their daily physical activity, and received personalized feedback on going out to community facilities with a system for reading the device for 12 months. Disability onset was defined as a new case of long-term care under the public insurance certification in Japan within 48 months of program completion. The absolute risk reduction and the number needed to treat for the incidence of disability were calculated for the nonengaged and engaged groups. Cox proportional hazard regression analysis, using inverse probability weighting was used to obtain the hazard ratio., Results: Disabilities occurred in 112 individuals in the matched nonengaged group and 51 individuals in the engaged group. The absolute risk reduction was 5.67% (95% CI 3.46%-7.88%). The number needed to treat was 18 (95% CI 13-29). The hazard ratio, with the nonengaged group as the reference, was 0.49 (95% CI 0.36-0.67)., Conclusions and Implications: This longitudinal observational study suggested that a community-based program could prevent 1 disability in every 18 participants. This program does not require a professional instructor, only the distribution of devices and system installation, and it could be beneficial as a population-based approach to preventing disabilities., Competing Interests: Disclosure The authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives　Although the effectiveness of status-to-interview-guided exercise therapy to improve urinary incontinence has been reported, reports on non-face-to-face guided exercise therapy are lacking. This study aimed to analyze the effect of using non-face-to-face training guidance for walking and strength training on the frequency and degree of urinary incontinence and improvement in the urinary incontinence-induced decline in the quality of life (QoL) of community-dwelling middle-aged and older women.Methods　This study included 68 women, aged 46-64 years, having self-evaluated stress urinary incontinence. The participants in the intervention group watched a video that guided them on how to walk effectively and gradually increase their number of steps. Additionally, a non-face-to-face lecture was conducted on the comprehensive training content, including muscle strengthening exercises necessary for walking at home, as muscle weakness is one of the causes of urinary incontinence. The control group was instructed to continue living as usual without any interventions. The intervention period was 12 weeks. The primary endpoints included the urinary leakage frequency score, urinary leakage volume score, and degree of decline in the QoL, and these were compared before and after the intervention using the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). To elucidate the effect of the increase in the step count on the primary outcome, we calculated the rate of increase in the step count before and after the intervention in the intervention group. Moreover, a sub-analysis was performed for the high-step count (n=16) and low step-count (n=16) groups before and after the intervention.Results　Significant differences were observed in the urinary leakage frequency, urinary leakage volume, and ICIQ-SF scores at 12 weeks post-intervention between the groups (P<0.05). In the high-step count group, both the urinary leakage frequency and ICIQ-SF scores showed a significant tendency to improve from 8 weeks compared to the pre-intervention scores.Conclusion　Since this study was conducted as an open-label trial, the possibility of an inherent bias in subjective outcome assessment should be considered during interpretation of the results. Our findings indicate that walking and muscle strength training, even with non-face-to-face guidance, for middle-aged and older community-dwelling women with urinary incontinence can effectively improve the urinary leakage symptoms and degree of decline in the QoL. Furthermore, greater effects could be expected by encouraging an increase in the number of daily steps with the intervention.

Case 1 presented with severe anemia and received an intrauterine blood cell transfusion at 33 weeks of gestation. The anemia spontaneously improved in early infancy. Case 2, the father of Case 1, had an uneventful birth with no evidence of anemia, though microcytic anemia was observed during childhood. The genetic analysis of the β-globin gene cluster identified a novel heterozygous deletion of DNA extending from the Gγ-globin gene downstream to the β-globin gene, confirming a diagnosis of ( G γ A γδβ) 0 -thalassemia. In cases where thalassemia is suspected based on blood tests, a genetic diagnosis should be performed for the sake of the offspring., (© 2023 Wiley Periodicals LLC.)

Aims: Tyrosine kinase (TK) alterations, such as anaplastic lymphoma kinase (ALK) fusion, neurotrophic tyrosine receptor kinase (NTRK) fusion, c-ros oncogene 1 (ROS1) fusion and mesenchymal-epithelial transition factor (MET) exon 14 skipping, have been reported in colorectal cancers (CRC). We have previously reported CRCs with NTRK fusion among our cohort. However, their clinicopathological features have not been fully elucidated., Methods and Results: Tissue microarray (TMA)-based immunohistochemistry (IHC) was performed on 951 CRC lesions from 944 patients. IHC was evaluated as positive or negative for ALK and ROS1 and 0 to 3+ for c-MET. For ALK and ROS1 IHC-positive cases, RNA-based imbalanced gene expression assays, Archer FusionPlex assays and reverse transcription-polymerase chain reaction (RT-PCR) followed by Sanger sequencing were performed. For c-MET IHC 3+ cases, RT-PCR followed by Sanger sequencing were performed. ALK IHC was positive in three cases (0.2%) and all showed imbalanced ALK gene expression. The following ALK fusions were confirmed: EML4 (exon 21)::ALK (exon 20), EML4 (exon 6)::ALK (exon 19) and HMBOX1 (exon 6)::ALK (exon 20). Two showed microsatellite instability-high/mismatch repair (MMR)-deficient, and all were located in the right colon. ROS1 IHC was positive in one case; however, imbalanced expression and ROS1 fusion was negative. Forty-two cases (4.4%) showed c-MET IHC3+. MET exon 14 skipping was confirmed in nine cases. All cases were microsatellite stable/MMR-proficient, and eight were located in the left colon and rectum., Conclusions: CRCs with these TK alterations had distinct clinicopathological features. Together with our previous study, 15 cases (1.6%) harboured targetable TK alterations (three NTRK fusion, three ALK fusion, nine MET exon 14 skipping)., (© 2023 John Wiley & Sons Ltd.)

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis.

Aims: Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodelling. However, the precise regulatory mechanism of vascular remodelling during neointima formation and the source of neointima cells are not entirely understood., Methods and Results: To investigate the origin of neointima cells and their relevance to vascular wall remodelling, we used an endothelial cell (EC)-specific lineage tracing system [VE-Cadherin (Cdh5)-BAC-CreERT2 mice] and carotid artery ligation model and showed evidence that resident ECs transdifferentiate into neointima cells with the expression of CD45. During the early stages of neointima formation, ECs transiently expressed CD45, a haematopoietic marker, accompanied by a host of EndMT markers, and CD31 and αSMA were prominently expressed in developing neointima. In vitro, CD45-positive EndMT was induced by stabilization of HIF1α with cobalt chloride or with a VHL inhibitor in human primary ECs, which mimicked the hypoxic condition of the ligated artery, and promoted the formation of an integrin α11-shank-associated RH domain-interacting protein (SHARPIN) complex. Notably, a CD45 phosphatase inhibitor disrupted this integrin α11-SHARPIN complex, thereby destabilizing cell-cell junctions. Deletion of Hif1α in ECs suppressed expression of CD45 and EndMT markers and ameliorated neointima formation., Conclusion: These results suggest that the HIF-induced CD45 expression is normally required for the retention of an EC fate and cell-cell junctions, CD45-positive EndMT (termed as 'partial EndMT') contributes to neointima formation and vascular wall remodelling., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Human health status can be measured on the basis of many different parameters. Statistical relationships among these different health parameters will enable several possible health care applications and an approximation of the current health status of individuals, which will allow for more personalized and preventive health care by informing the potential risks and developing personalized interventions. Furthermore, a better understanding of the modifiable risk factors related to lifestyle, diet, and physical activity will facilitate the design of optimal treatment approaches for individuals., Objective: This study aims to provide a high-dimensional, cross-sectional data set of comprehensive health care information to construct a combined statistical model as a single joint probability distribution and enable further studies on individual relationships among the multidimensional data obtained., Methods: In this cross-sectional observational study, data were collected from a population of 1000 adult men and women (aged ≥20 years) matching the age ratio of the typical adult Japanese population. Data include biochemical and metabolic profiles from blood, urine, saliva, and oral glucose tolerance tests; bacterial profiles from feces, facial skin, scalp skin, and saliva; messenger RNA, proteome, and metabolite analyses of facial and scalp skin surface lipids; lifestyle surveys and questionnaires; physical, motor, cognitive, and vascular function analyses; alopecia analysis; and comprehensive analyses of body odor components. Statistical analyses will be performed in 2 modes: one to train a joint probability distribution by combining a commercially available health care data set containing large amounts of relatively low-dimensional data with the cross-sectional data set described in this paper and another to individually investigate the relationships among the variables obtained in this study., Results: Recruitment for this study started in October 2021 and ended in February 2022, with a total of 997 participants enrolled. The collected data will be used to build a joint probability distribution called a Virtual Human Generative Model. Both the model and the collected data are expected to provide information on the relationships between various health statuses., Conclusions: As different degrees of health status correlations are expected to differentially affect individual health status, this study will contribute to the development of empirically justified interventions based on the population., International Registered Report Identifier (irrid): DERR1-10.2196/47024., (©Masanobu Hibi, Shun Katada, Aya Kawakami, Kotatsu Bito, Mayumi Ohtsuka, Kei Sugitani, Adeline Muliandi, Nami Yamanaka, Takahiro Hasumura, Yasutoshi Ando, Takashi Fushimi, Teruhisa Fujimatsu, Tomoki Akatsu, Sawako Kawano, Ren Kimura, Shigeki Tsuchiya, Yuuki Yamamoto, Mai Haneoka, Ken Kushida, Tomoki Hideshima, Eri Shimizu, Jumpei Suzuki, Aya Kirino, Hisashi Tsujimura, Shun Nakamura, Takashi Sakamoto, Yuki Tazoe, Masayuki Yabuki, Shinobu Nagase, Tamaki Hirano, Reiko Fukuda, Yukari Yamashiro, Yoshinao Nagashima, Nobutoshi Ojima, Motoki Sudo, Naoki Oya, Yoshihiko Minegishi, Koichi Misawa, Nontawat Charoenphakdee, Zhengyan Gao, Kohei Hayashi, Kenta Oono, Yohei Sugawara, Shoichiro Yamaguchi, Takahiro Ono, Hiroshi Maruyama. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 09.06.2023.)

Background: The current study examines the negative impact of the coronavirus disease 2019 (COVID-19) emergency declarations on physical activity among the community-dwelling older adults, the participants of a physical activity measurement program, in Japan., Methods: This retrospective observational study included 1,773 community-dwelling older adults (aged 74.6 ± 6.3 years, 53.9% women) who had participated in the physical activity measurement project from February 2020 to July 2021. We measured physical activity using a tri-axial accelerometer during 547 consecutive days. Three emergency declarations, requesting people to avoid going outside, occurred during the observational period. We multiply-imputed missing values for daily physical activity, such as steps, light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) for several patterns of datasets according to the maximum missing rates on a person level. We mainly report the results based on less than 50% of the maximum missing rate (n = 1,056). Other results are reported in the supplemental file. Changes in physical activity before and after the start of each emergency declaration were examined by the regression discontinuity design (RDD) within 14-, 28-, and 56-day bandwidths., Results: For all the participants in the multiply-imputed data with the 14-day bandwidth, steps (coefficients [[Formula: see text]][Formula: see text] 964.3 steps), LPA ([Formula: see text] 5.5 min), and MVPA ([Formula: see text] 4.9 min) increased after the first emergency declaration. However, the effects were attenuated as the RDD bandwidths were widened. No consistent negative impact was observed after the second and third declarations. After the second declaration, steps ([Formula: see text]-609.7 steps), LPA ([Formula: see text]-4.6 min), and MVPA ([Formula: see text]-2.8 min) decreased with the 14-day bandwidth. On the other hand, steps ([Formula: see text] 143.8 steps) and MVPA ([Formula: see text] 1.3 min) increased with the 56-day bandwidth. For the third declaration, LPA consistently decreased with all the bandwidths ([Formula: see text]-2.1, -3.0, -0.8 min for the 14, 28, 56-day bandwidth), whereas steps ([Formula: see text]-529 steps) and MVPA ([Formula: see text]-2.6 min) decreased only with the 28-day bandwidth., Conclusions: For the community-dwelling older adults who regularly self-monitor their physical activity, the current study concludes that there is no evidence of consistently negative impacts of the emergency declarations by the COVID-19 pandemic., (© 2023. The Author(s).)

Background: Several studies have reported that the coronavirus disease (COVID-19) pandemic has increased sedentary behaviour and obesity; however, these analyses used self-reported data, and the association between sedentary behaviour and visceral fat and adipocytokines during the COVID-19 pandemic remains unclear. We aimed to investigate the association of the COVID-19 pandemic with objectively measured sedentary behaviour and these obesity-related factors., Methods: Longitudinal analysis was conducted on 257 Japanese participants who underwent health check-ups in 2018 before and in 2020 during the COVID-19 pandemic. For both time points, sedentary behaviour was measured using an accelerometer for at least 7 days, visceral fat area (VFA) was measured using abdominal bioelectrical impedance analysis, and blood adiponectin level was measured using latex agglutination turbidimetric immunoassay. Multiple linear regression was performed to determine the association between sedentary behaviour and these outcomes., Results: Compared with data in 2018, sedentary behaviour and VFA were significantly increased (P < 0.001, P = 0.006) whereas adiponectin level was significantly decreased (P < 0.001) in 2020. Increased sedentary behaviour was significantly associated with an increase in VFA (β = 3.85, 95% CI 1.22-6.49, P = 0.004) and a decrease in adiponectin level (β = -0.04, 95% CI -0.06 to -0.01, P = 0.005). However, the association of sedentary behaviour with adiponectin level was not significant after considering the effects of VFA., Conclusions: The COVID-19 pandemic was associated with objectively measured sedentary behaviour and obesity-related factors in Japanese adults. Additionally, an increase in sedentary behaviour was associated with an increase in VFA, whereas the association of sedentary behaviour with adiponectin was partly mediated by VFA. These results suggest that avoiding increasing sedentary time is important to prevent visceral adiposity thereby ameliorating adiponectin, especially during behavioural limitations such as the COVID-19 pandemic., (© 2023. The Author(s).)

Gait speed over a short distance is associated with cognitive impairment in older adults. Recently, daily gait speed has been assessed using accelerometers. However, because daily gait speed is only weakly correlation with gait speed over a short distance, its association with cognitive impairment needs to be investigated. The present study compared the daily gait speed patterns of normal cognition (NC), mild cognitive impairment (MCI), and general cognitive impairment (GCI) subjects measured every 3 h for two weeks using accelerometers. A total of 1959 participants were classified into the NC (N = 1519), MCI (N = 353), and GCI groups (N = 87). The results showed that the average daily gait speed of the GCI group was significantly lower than that of the NC group (p = 0.03). Furthermore, the average daily gait speeds of the MCI and NC groups were the same. However, the average daily gait speed of the MCI group during a specific time (12-15 o'clock) was significantly lower than that of the NC group (p < 0.01). These results suggest that changes in daily patterns may be detected by measuring daily gait speed, which depends on the degree of cognitive function., (© 2023. The Author(s).)

The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase ( FADS ) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

Background Homeostasis of the vessel wall is cooperatively maintained by endothelial cells (ECs), smooth muscle cells, and adventitial fibroblasts. The genetic deletion of fibulin-4 ( Fbln4 ) in smooth muscle cells ( SMKO ) leads to the formation of thoracic aortic aneurysms with the disruption of elastic fibers. Although Fbln4 is expressed in the entire vessel wall, its function in ECs and relevance to the maintenance of valvulo-arterial integrity are not fully understood. Methods and Results Gene silencing of FBLN4 was conducted on human aortic ECs to evaluate morphological changes and gene expression profile. Fbln4 double knockout ( DKO ) mice in ECs and smooth muscle cells were generated and subjected to histological analysis, echocardiography, Western blotting, RNA sequencing, and immunostaining. An evaluation of the thoracic aortic aneurysm phenotype and screening of altered signaling pathways were performed. Knockdown of FBLN4 in human aortic ECs induced mesenchymal cell-like changes with the upregulation of mesenchymal genes, including TAGLN and MYL9 . DKO mice showed the exacerbation of thoracic aortic aneurysms when compared with those of SMKO and upregulated Thbs1, a mechanical stress-responsive molecule, throughout the aorta. DKO mice also showed progressive aortic valve thickening with collagen deposition from postnatal day 14, as well as turbulent flow in the ascending aorta. Furthermore, RNA sequencing and immunostaining of the aortic valve revealed the upregulation of genes involved in endothelial-to-mesenchymal transition, inflammatory response, and tissue fibrosis in DKO valves and the presence of activated valve interstitial cells. Conclusions The current study uncovers the pivotal role of endothelial fibulin-4 in the maintenance of valvulo-arterial integrity, which influences thoracic aortic aneurysm progression.

It is well established that platinum-based drugs, including oxaliplatin (L-OHP) and cisplatin (CDDP), as well as microtubule inhibitors paclitaxel (PTX) and vincristine (VCR), are associated with chemotherapy-induced peripheral neuropathy (CIPN). In this study, we examined and compared the characteristics of neuropathies induced by L-OHP, CDDP, PTX, and VCR to evaluate whether Caenorhabditis elegans (C. elegans) could serve as a model organism for human CIPN. Worms were cultured on nematode growth medium plates, and L1 larvae synchronized by gel filtration were employed. We then performed bioassays and examined motility. In the motility test, exposure was performed for 2, 24, and 48 hr, and time-dependent effects were measured for each exposure time and 24 hr after terminating exposure. Herein, we observed that L-OHP and CDDP exerted concentration-dependent effects above a certain concentration, and PTX and VCR exerted concentration-dependent negative effects in the bioassay. Motility recovered in L-OHP-, PTX-, and VCR-treated worms on terminating exposure. However, CDDP exposure tended to reduce motility even 24 hr after terminating exposure. L-OHP exposure could decrease motility 2 hr after exposure, with a trend toward recovery 24 hr after terminating drug exposure. The findings of the present study revealed that C. elegans could exhibit neuropathy characteristics suggested to be similar to those observed in humans, indicating that this organism could be a suitable model to explore human CIPN.

Background: Telemonitoring the use of CPAP devices and remote feedback on device data effectively optimizes CPAP adherence in patients with OSA., Research Question: Can expanding the scope of telemonitoring and remote feedback to body weight (BW), BP, and physical activity enhance efforts for BW reduction in Patients with OSA receiving CPAP?, Study Design and Methods: Participants were recruited from patients at 16 sleep centers in Japan with OSA and obesity who were receiving CPAP therapy. Obesity was defined as a BMI of ≥ 25 kg/m 2 , based on Japanese obesity guidelines. Implementation of CPAP telemonitoring was enhanced with electronic scales, BP monitors, and pedometers that could transmit data from devices wirelessly. Participants were randomized to the multimodal telemonitoring group or the usual CPAP telemonitoring group and were followed up for 6 months. Attending physicians provided monthly telephone feedback calls to the usual CPAP telemonitoring group on CPAP data obtained remotely. In the multimodal telemonitoring group, physicians additionally encouraged participants to reduce their BW, after sharing the remotely obtained data on BW, BP, and step count. The primary outcome was set as ≥ 3% BW reduction from baseline., Results: One hundred sixty-eight participants (BMI, 31.7 ± 4.9 kg/m 2 ) completed the study, and ≥ 3% BW reduction occurred in 33 of 84 participants (39.3%) and 21 of 84 participants (25.0%) in the multimodal telemonitoring and usual CPAP telemonitoring groups, respectively (P = .047). Whereas no significant differences were found between the two groups in the change in office and home BP, daily step counts during the study period were significantly higher in the multimodal telemonitoring group than in the usual CPAP telemonitoring group (4,767 steps/d [interquartile range (IQR), 2,864-6,617 steps/d] vs 3,592 steps/d [IQR, 2,117-5,383 steps/d]; P = .02) INTERPRETATION: Multimodal telemonitoring may enhance BW reduction efforts in patients with OSA and obesity., Trial Registry: UMIN Clinical Trials Registry; No.: UMIN000033607; URL: www.umin.ac.jp/ctr/index.htm., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

A 65-year-old woman underwent breast-conserving surgery for right breast cancer 12 years ago. The primary lesion was ER-positive, PgR-negative, presenting no amplification of the HER2 gene, and endocrine therapy was continued. After 10 years postoperation, duodenal stenosis due to peritoneal metastasis was noted, and the positive conversion of the HER2 expression was confirmed in peritoneal metastasis. Peritoneal lesions could be reduced by chemotherapies combined with trastuzumab and pertuzumab; however, hoarseness due to cervical lymph node metastasis appeared. Administration of T- DXd was initiated. After 4 cycles of T-DXd, her cervical lymph nodes shrank, and hoarseness improved. Because of its high drug-to-antibody ratio and the bystander effect, T-DXd was considered effective even in metastatic lesions presenting tumor heterogeneity or low HER2 expression.

Although most bile acids (BAs) in feces are present in noncovalent forms that can be extracted with ethanol, non-negligible amounts of saponifiable BAs are also present. It is a major concern that such saponifiable BAs are routinely omitted from fecal BA measurements. We compared the BA profiles of healthy stools that were obtained with/without alkaline hydrolysis and found that as much as 29.7% (2.1-67.7%) of total BAs were saponifiable. Specifically, alkaline treatment led to significant elevations of isodeoxycholic acid (isoDCA) and isolithocholic acid (isoLCA) concentrations, suggesting that considerable proportions of isoDCA and isoLCA were esterified. Precursor ion scan data from LC/MS suggested the presence of long-chain FA-linked BAs. We chemically synthesized a series of fatty acid 3β-acyl conjugates of isoDCA and isoLCA as analytical standards and analyzed their fecal profiles from newborns to adults (n = 64) by LC/MS. FA-conjugated isobile acids (FA-isoBAs) were constantly present from 2 years of age to adulthood. C16- and C18-chain FA-isoBA esters were predominantly found regardless of age, but small amounts of acetic acid esters were also found. FA-isoBA concentrations were not correlated to fecal FA concentrations. Interestingly, there were some adults who did not have FA-isoBAs. Gut bacteria involved in the production of FA-isoBAs have not been identified yet. The present study provides insight into the establishment of early gut microbiota and the interactive development of esterified BAs.The contribution of FA-isoBAs to gut physiology and their role in pathophysiologic conditions such as inflammatory bowel disease are currently under investigation., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Older people with high cardiovascular risk, including those without cardiovascular diseases, are an at-risk population for dementia. Regular physical activity is generally recommended to maintain brain health; however, the optimal intensity of physical activity for maintaining brain volume in older adults with cardiovascular risk remains unclear. We examined the associations between intensity-specific physical activity and brain volume stratified by absolute cardiovascular risk level in older adults without cardiovascular diseases., Methods and Results: This cross-sectional study involved 725 community-dwelling older Japanese adults without cardiovascular diseases. We estimated absolute cardiovascular risk using the World Health Organization risk estimation charts, which include variables such as age, sex, diabetes mellitus, smoking, systolic blood pressure, and total cholesterol, and stratified cardiovascular risk level into three risk categories: low (≤ 9%), moderate (10-14%), and high (≥15%). We measured daily physical activity using a triaxial accelerometer, and calculated the average time spent in moderate-to-vigorous intensity physical activity (MVPA) and light intensity physical activity (LPA). We performed brain T1-weighted magnetic resonance imaging and calculated the volume of the cortical gray matter, subcortical gray matter, and cerebral white matter, using the FreeSurfer software. In the overall sample, multivariable linear regression analysis showed that greater MVPA was significantly associated with greater volume of the cortical gray matter and cerebral white matter, and greater LPA was significantly associated with greater volume of the cerebral white matter. Additionally, in the analysis of the sample stratified by absolute cardiovascular risk level, cerebral white matter volume was significantly associated with both MVPA and LPA in the high cardiovascular risk group., Conclusions: The association between physical activity and brain volume differed according to cardiovascular risk level in community-dwelling older adults. In a population at high cardiovascular risk, maintaining or increasing LPA might be a practical and achievable strategy for healthy brain aging., (Copyright © 2022 Makino, Lee, Bae, Harada, Chiba, Katayama, Tomida, Morikawa, Yamashiro, Sudo, Takayanagi and Shimada.)

Background and Aim: Juvenile polyposis (JP) is a rare disease known to be associated with mutations either in SMAD4 / BMPR1A . JP is known to often develop into malignant tumors, with a reported probability of 9-50%. However, the mechanisms of its carcinogenesis are not fully understood. We tried to elucidate the mechanisms of malignant transformation underlying this condition in three cases of gastric JP., Methods: We selected polyps from each patient displaying varying degrees of atypia and their nearby normal polyps and compared them using immunohistochemistry, Sanger sequencing, and loss of heterozygosity (LOH) analysis of SMAD4 , BMPR1A , and TP53., Results: Two of the three cases were suspected of having germline SMAD4 mutations based on their familial medical histories; the remaining case was found to have a SMAD4 germline mutation following preoperative genetic testing. All three cases were shown to present with both SMAD4 positive and negative areas across each lesion, with the neoplastic lesions tending to show stronger nuclear SMAD4 expression. This expression was closely associated with the SMAD4 LOH status; however, we also noted paradoxical SMAD4 expression in the neoplastic lesions despite the biallelic inactivation of SMAD4 revealed in the genetic evaluation., Conclusions: These data suggest that strong nuclear expression of SMAD4, even when seemingly paradoxical, seems to be closely associated with dysplastic polyps in JP. Complete inactivation of SMAD4 was not shown to be essential for the development of dysplastic polyps in gastric JP, and other pathways seemed to be involved in the acquisition of the malignant phenotype., (© 2022 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Gait speed is an important indicator of functional decline in older adults. Recently, daily gait speed has been assessed using accelerometers. However, it is unclear whether this parameter can predict the decline in functional abilities. This study investigates whether daily gait speed can be a predictor of incident disability risk as well as in-laboratory gait speed. A sample of 1860 older adults (Male: 728, Female: 1132; 70.1 ± 6.2 years) were instructed to wear accelerometers on the waist. The association between daily gait speed for two weeks and incident disability during a two-year period was analyzed by using the cut-off value for screening prefrailty in the previous study (106.3 cm/s). Furthermore, the associations with in-laboratory gait speed (cut-off value: 100 cm/s), number of steps (cut-off value: 6342.2 steps/day), and incident disability were also analyzed. Cox proportional hazards analysis showed a significant hazard ratio of low daily gait speed (HR, 2.97; p = 0.02) comparable to that of low in-laboratory gait speed (HR: 2.53; p = 0.01). Conversely, the number of steps had no significant association with incident disability (HR: 1.99; p = 0.12). These results suggest that daily gait speed can be a predictor of incident disability risk in older adults., (© 2022. The Author(s).)

Objective: The purpose of the study was to estimate, using an isotemporal substitution model, the effect of replacing sedentary behavior (SB) with physical activity on the incidence of disability in community-dwelling older adults., Methods: This 2-year longitudinal cohort study enrolled 3691 community-dwelling older adults (57.2% women; mean age = 74.0 [SD = 5.0] years). Individuals with dementia, stroke, Parkinson disease, depression, low Mini-Mental State Examination scores, dependence on basic activities of daily living, and missing data were excluded. Physical activity and potential confounding factors were investigated as a baseline survey of disability incidence, defined by Japanese long-term care insurance certification, for 2 years in 2 regions. Physical activity data (SB, light-intensity physical activity, and moderate- to vigorous-intensity physical activity [MVPA]) were measured using triaxial accelerometers for 14 days, and daily mean time spent in each physical activity parameter was computed in increments of 10 minutes. The relationship between baseline physical activity and disability incidence adjusted for potential confounders was analyzed using multilevel Cox proportional hazards regression analyses with an isotemporal substitution model., Results: The disability incidence rate was 3.8%, excluding individuals who could not be followed-up. Replacing 10 minutes of SB per day with MVPA was associated with a decreased disability incidence (hazard ratio = 0.870; 95% CI = 0.766-0.988), whereas no evidence was found for replacing SB with light-intensity physical activity (hazard ratio = 0.980; 95% CI = 0.873-1.10)., Conclusions: Replacing SB with MVPA was associated with a lower risk of disability. These findings are helpful for establishing disability prevention strategies., Impact: These results suggest that feasible changes in daily behavior, such as replacing 10 minutes of SB with MVPA daily, might have a protective effect on disability incidence. Clarifying these associations is useful for developing disability prevention strategies and may help reduce the incidence of disability in community-dwelling older adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The levator ani (LA) complex in high-type imperforate anus (H-IA), low-type imperforate anus (L-IA), and Hirschsprung's disease (HD) patients as controls were documented using magnetic resonance imaging (MRI) and compared for symmetry., Materials and Methods: Mean left:right LA thickness ratio (LA ratio), and deviation of the LA from the pubococcygeal line (PCL; LA angle) were calculated from thin-slice MRI images (axial 2 mm, coronal 2 mm, and sagittal 3 mm) of the puborectalis and pubococcygeus taken parallel to the PCL under sedation in H-IA (n=14), L-IA (n=16), and HD (n=9)., Results: MRI scans were performed between January 2018 and June 2021. LA were significantly thinner in H-IA (1.78±0.46 mm) compared with L-IA (2.97±0.55 mm) and controls (2.87±0.32 mm), p<0.0001. LA ratio was significantly lower in H-IA (0.71±0.15) compared with L-IA (0.93±0.04), and controls (0.91±0.06), p<0.0001. Mean LA-angle was significantly different in H-IA, 10.8° (range 6°-19°), versus L-IA and controls, both zero degrees (range 0°-5°), p<0.0001, respectively., Conclusions: LA was confirmed to be significantly asymmetric in H-IA. Because outcome of surgical repair involving a midline incision, such as posterior sagittal anorectoplasty could be impaired, pediatric surgeons are advised to plan surgical intervention for H-IA carefully and appropriately., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The mucin phenotypes of colorectal carcinoma (CRC) is related to the biological behavior and prognosis. But there has been no studies evaluating phenotypic characteristics in a large number of cases. Furthermore, colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of CRC and having poor prognosis. The aims of this study were to clarify the correlation between mucin phenotypes and tumor development, including biological behavior in CRC, as well as to investigate characteristic of mucin phenotypes in CAED., Methods and Results: 974 CRC cases and 42 CAED cases of CRCs were classified five types (large-intestinal, small-intestinal, gastric, mixed, and unclassified) of mucin phenotypes by using immunohistochemistry (IHC). IHC was performed on tissue microarrays with antibodies against followings: MUC2, MUC5AC, MUC6, and CD10. In CRCs, large-intestine type has a relatively better prognosis, small-intestinal type frequently shows venous invasions, and liver metastases, gastric type has more high-histological grades and lymphatic invasions, mixed type shows originating from the right side of the colon, larger tumor size and mucinous type, but less venous invasions and liver metastasis, whereas the unclassified type showed poorer prognosis in overall survival with statistical significance. The majority of CAED were found to be small-intestinal type or unclassified type., Conclusions: The phenotypic classification is useful for predicting the prognosis of CRCs. Small-intestinal type and unclassified type showed dismal prognosis in CRCs. We speculate that CAED having aggressive behavior and poor prognosis might reflect characteristics of small-intestinal and unclassified types., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Proline:arginine (PR) poly-dipeptides from the GGGGCC repeat expansion in C9orf72 have cytotoxicity and bind intermediate filaments (IFs). However, it remains unknown how PR poly-dipeptides affect cytoskeletal organization and focal adhesion (FA) formation. Here, we show that changes to the cytoskeleton and FA by PR poly-dipeptides result in the alteration of cell stiffness and mechanical stress response. PR poly-dipeptides increased the junctions and branches of the IF network and increased cell stiffness. They also changed the distribution of actin filaments and increased the size of FA and intracellular calcium concentration. PR poly-dipeptides or an inhibitor of IF organization prevented cell detachment. Furthermore, PR poly-dipeptides induced upregulation of mechanical stress response factors and led to a maladaptive response to cyclic stretch. These results suggest that the effects of PR poly-dipeptides on mechanical properties and mechanical stress response may serve as a pathogenesis of C9orf72 -related neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shiota, Nagata, Kikuchi, Nanaura, Matsubayashi, Nakanishi, Kobashigawa, Isozumi, Kiriyama, Nagayama, Sugie, Yamashiro and Mori.)

The association between sedentary behaviour and sleep quality (SQ) remains unclear, partly due to the limited methodology for assessing sedentary time and the influence of obesity. This study aimed to examine the association between objectively measured sedentary time and poor SQ, as well as the association of visceral fat accumulation. This cross-sectional study used health check-up data obtained from 721 Japanese adults. Sedentary time and physical activity were measured using an accelerometer for ≥7 days, with ≥10 measurement hours per day. Poor SQ was determined by a Pittsburgh Sleep Quality Index score of ≥ 6. Visceral fat was measured using the abdominal bioimpedance method. A logistic regression model was used to analyse the association between sedentary time and SQ. We found that higher sedentary time was associated with poorer SQ. This association remained significant after adjustment for several covariates, including visceral fat. Compared with the lowest tertile of sedentary time, the second and highest tertile had a significantly higher OR of poor SQ (Tertile 2: OR = 2.06 [95% CI 1.14,3,73]; Tertile 3: OR = 2.76 [95% CI 1.49, 5.11]). These results suggest that managing sedentary time itself might contribute to improving SQ.

Although the Asian population exhibits excessive sedentary behaviour and has a high susceptibility to metabolic syndrome (MetS), the nature of these associations remains unclear. This study aimed to investigate the association of sedentary time with cardiometabolic health and examine the association of reallocating sedentary time to light physical activity (LPA) or moderate-vigorous physical activity (MVPA) on cardiometabolic health in Japanese adults. A cross-sectional study was performed using data obtained from 758 Japanese adults. We assessed sedentary time, LPA, and MVPA using an accelerometer. Linear and logistic regression models were used to analyse the association between sedentary time and cardiometabolic risk factors. An isotemporal substitution model was used to estimate the theoretical influence of reallocating sedentary time to LPA or MVPA. A longer sedentary time was associated with worse cardiometabolic health, including MetS. Reallocating 30 min of sedentary time to LPA was significantly associated with lower body mass index, visceral fat, insulin resistance, triglyceride, and MetS levels and increased muscle mass and HDL-C (all P < 0.05). Reallocating 30 min of sedentary time to MVPA was strongly associated with the aforementioned factors. These results demonstrate the potential beneficial effects of reallocating sedentary time to LPA and MVPA on cardiometabolic health of Asians., (© 2022. The Author(s).)

The prevalence of sleep-disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously believed, with patients having moderate-to-severe OSA accounting for approximately 20% of adult males and 10% of postmenopausal women not only in Western countries but also in Eastern countries, including Japan. Since 1998, when health insurance coverage became available, the number of patients using continuous positive airway pressure (CPAP) therapy for sleep apnea has increased sharply, with the number of patients about to exceed 500,000 in Japan. Although the "Guidelines for Diagnosis and Treatment of Sleep Apnea Syndrome (SAS) in Adults" was published in 2005, a new guideline was prepared to indicate the standard medical care based on the latest trends, as supervised by and in cooperation with the Japanese Respiratory Society and the "Survey and Research on Refractory Respiratory Diseases and Pulmonary Hypertension" Group, of Ministry of Health, Labor and Welfare and other related academic societies, including the Japanese Society of Sleep Research, in addition to referring to the previous guidelines. Since sleep apnea is an interdisciplinary field covering many areas, this guideline was prepared including 36 clinical questions (CQs). In the English version, therapies and managements for SAS, which were written from CQ16 to 36, were shown. The Japanese version was published in July 2020 and permitted as well as published as one of the Medical Information Network Distribution Service (Minds) clinical practice guidelines in Japan in July 2021., Competing Interests: Conflict of interestYuichi Inoue is receiving daily allowances (lecture fees, etc.) from Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Takeda Pharmaceutical Company Limited, along with research expenses from Astellas Pharma Corporation, Eisai Corporation, Takeda Pharmaceutical Company Limited, and Jassen Pharmaceutical K,K. He is also affiliated with the donated courses provided by Astellas Pharma Corporation, Alfresa Pharma Corporation, Eisai Corporation, MSD Corporation, Otsuka Pharmaceutical Co., Ltd., Koike Medical Co., Ltd., Takeda Pharmaceutical Company Limited, and Philips Japan, Ltd. Naohisa Uchimura is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Mitsubishi Electric Co., Ltd., and Meiji Seika Furuma Co., Ltd.; manuscript fees from Eisai Co., Ltd., MSD Co., Ltd. and Otsuka Pharmaceutical Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd., MSD Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Takatoshi Kasai is receiving research funding from Asahi Kasei Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Paramount Bed Co., Ltd., and ResMed Co., Ltd., along with scholarship (incentives) donations from Philips Japan Co., Ltd. He is also affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Fusae Kawana is an officer of the Japan Sleep Comprehensive Examination Association, and is affiliated with the donated courses provided by Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Shigeru Sakurai is receiving scholarship (incentives) donations from Philips Japan, Ltd. and Kitara Co., Ltd. Takeshi Tanigawa is receiving research funding from Tokyo Electric Power Company Holdings, Inc. Kazuo Chin is receiving daily allowances (lecture fees, etc.) from Philips Japan, Ltd. and Teijin Home Medical Care, and is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Morio Tonogi is receiving research funding from GC Ortholy Corporation. Takeo Nakayama is receiving daily allowances (lecture fees, etc.) from Nippon Boehringer Ingelheim Co., Ltd., Pfizer Co., Ltd., and Janssen Pharmaceutical K.K., as well as receiving scholarship (incentives) donations from JMDC Co., Ltd. Motoo Yamauchi is receiving research funding from Koike Medical Co., Ltd. Toru Oga is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and Fukuda Lifetech Keiji Co., Ltd. Yasuhiro Tomita is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., and ResMed Co., Ltd. Satoshi Hamada is affiliated with a donated course provided by Teijin Pharma Limited. Kimihiko Murase is affiliated with the donated courses provided by Teijin Pharma Limited, Philips Japan, Ltd., Fukuda Denshi Co., Ltd., Fukuda Lifetech Keiji Co., Ltd., and ResMed Co., Ltd. Makoto Uchiyama is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited, along with scholarship (incentives) donations from Eisai Co., Ltd. and Meiji Seika Pharma Co., Ltd. Hiromasa Ogawa is affiliated with a donated course provided by Fukuda Lifetech Co., Ltd. Kazuo Mishima is receiving daily allowances (lecture fees, etc.) from Eisai Co., Ltd., MSD Co., Ltd., and Takeda Pharmaceutical Company Limited; research funds from Taisho Pharmaceutical Co., Ltd. and Nobelpharma Co., Ltd.; and scholarship (incentives) donations from Eisai Co., Ltd. and Takeda Pharmaceutical Company Limited. Tsuneto Akashiba, Motoharu Ohi, Misa Takegami, Ryo Tachikawa, Shintaro Chiba, Satoru Tsuiki, Hiroshi Nakamura, Koji Narii, Asako Yagi, Yoshihiro Yamashiro, Masahiro Yoshida, Hiroyuki Mori, Hiroo Wada, Kazumichi Sato, Seiichi Nakata, and Shinichi Momomura have no COIs to declare., (© The Author(s) 2021.)