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We aimed to validate a newly developed antigen-detecting rapid diagnostic test (Ag-RDT) for SARS-CoV-2 using anterior nasal specimens.Between February 12 and September 30, 2021, 16 patients (age range,1 month-76 years) were enrolled, and samples were collected simultaneously from anterior nasal and nasopharyngeal sites continuously during hospitalization. The primary end points were the diagnostic accuracy of the Ag-RDT and utility of anterior nasal specimens.In total, 226 sets of paired samples were obtained. In 88.2% of specimens, the viral load was high at the nasopharyngeal site. The mean cycle threshold values for the anterior nasal and nasopharyngeal sites were 32.4 and 29.9, respectively. Using the real-time polymerase chain reaction results as a reference, the Ag-RDT showed a 100% sensitivity up to day 6 of the illness, using specimens with moderate or high viral load (cycle threshold30) from either site. From day 7, the sensitivity was 70.4-90.6% and 83.9-84.6% for the anterior nasal and nasopharyngeal sites, respectively. The specificity remained at 100%.Our novel Ag-RDT meets the World Health Organization criteria and provides stable sensitivity and specificity and accurate results with anterior nasal specimens.

Hypertrophic cardiomyopathy is a common cardiac complication in mitochondrial disorders, and the morbidity rate in neonatal cases is up to 40%. The mortality rate within 3 months for neonatal-onset mitochondrial cardiomyopathy is known to be high because there is currently no established treatment.We report the case of a male infant with neonatal-onset mitochondrial disorder presenting lactic acidosis and hypertrophic cardiomyopathy. Genetic analysis of the patient revealed recurrent m.13513GA, p.Asp393Asn in mitochondrially encoded NADH dehydrogenase 5 gene (MT-ND5). Low-dose propranolol was initially administered for cardiomyopathy; however, he developed hypertrophic obstructive cardiomyopathy (HOCM) at 3 months of age. To reduce the risk of hypoglycemia associated with high-dose propranolol, cibenzoline, a class Ia antiarrhythmic drug, was added at a dose of 2.5 mg/kg/day and increased weekly to 7.5 mg/kg/day with monitoring of the blood concentration of cibenzoline. Left ventricular outflow tract stenosis (LVOTS) dramatically improved from 5.4 to 1.3 m/second in LVOTS peak velocity after 6 weeks, without notable adverse effects. The plasma N-terminal pro-brain natriuretic peptide level decreased from 65,854 to 10,044 pg/mL. Furthermore, myocardial hypertrophy also improved, as the left ventricular mass index decreased from 173.1 to 108.9 g/m

We investigated the association between subjective cognitive complaints (SCCs) and dental visits in older Japanese adults.This was a cross-sectional study from the Japan Gerontological Evaluation Study (carried out in 2019). The participants were independent older adults aged ≥65 years without dementia. The presence/absence of dental treatment visits and dental checkup visits within the past 12 months were used as outcome variables. The SCC score measured using the Kihon Checklist was set as the explanatory variable. Possible confounders were also included as covariates. Prevalence ratios and 95% confidence intervals were estimated using a Poisson regression model.The mean age was 74.1 years (standard deviation 6.0 years). Among the 19 677 eligible participants, 12 359 (62.8%) had dental treatment visits and 11 063 (56.3%) had dental checkup visits. Of these, 5966 (30.3%) had an SCC score of ≥1. The proportion of participants with dental treatment and dental checkup visits within the past 12 months was 63.2% and 56.7% among those with SCC score = 0, and 52.8% and 35.2% among those with SCC score = 3, respectively. In the fully adjusted model, no significant association was observed for participants with SCC scores of 1 and 2. Those with SCC score = 3 had less frequent dental checkup visits (prevalence ratio 0.74, 95% confidence interval 0.57-0.95).Our study highlights that SCC was not associated with limited access to dental care among those with mild SCC. However, those with the highest SCC score seemed to have disturbed access to dental care. Geriatr Gerontol Int 2022; 22: 773-778.

Although the feasibility of randomized trials for investigating the long-term association between oral health and cognitive decline is low, deriving causal inferences from observational data is challenging. We aimed to investigate the association between poor oral status and subjective cognitive complaints (SCC) using fixed-effects model to eliminate the confounding effect of unobserved time-invariant factors.We used data from Japan Gerontological Evaluation Study (JAGES) which was conducted in 2010, 2013, and 2016. β regression coefficients and 95% confidence intervals [CIs] were calculated using fixed-effects models to determine the effect of deteriorating oral status on developing SCC. Onset of SCC was evaluated using the Kihon Checklist-Cognitive function score. Four oral status variables were used: awareness of swallowing difficulty, decline in masticatory function, dry mouth, and number of teeth.We included 13,594 participants (55.8% women) without SCC at baseline. The mean age was 72.4 (standard deviation [SD], 5.1) years for men and 72.4 (SD, 4.9) years for women. Within the 6-year follow-up, 26.6% of men and 24.9% of women developed SCC. The probability of developing SCC was significantly higher when participants acquired swallowing difficulty (β = 0.088; 95% CI, 0.065-0.111 for men and β = 0.077; 95% CI, 0.057-0.097 for women), decline in masticatory function (β = 0.039; 95% CI, 0.021-0.057 for men and β = 0.030; 95% CI, 0.013-0.046 for women), dry mouth (β = 0.026; 95% CI, 0.005-0.048 for men and β = 0.064; 95% CI, 0.045-0.083 for women), and tooth loss (β = 0.043; 95% CI, 0.001-0.085 for men and β = 0.058; 95% CI, 0.015-0.102 for women).The findings suggest that good oral health needs to be maintained to prevent the development of SCC, which increases the risk for future dementia.

An 81-year-old man was admitted for general fatigue of one month’s duration. Two sets of blood cultures revealed bacteremia, due to Pasteurella multocida, while computed tomography (CT) revealed a 47-mm descending aortic saccular aneurysm. After transfer to our hospital, the saccular aneurysm rapidly grew to 54 mm. An emergency thoracic endovascular aortic repair was performed, due to the aneurysm immediately rupturing after the CT scan. The patient was discharged on postoperative day 28.

This study aimed to analyze the incidence of subclinical rejection (SCR) in kidney transplantation patients and risk factors associated with SCR.We assessed 80 protocol biopsies taken within 2 years postoperatively in 41 adult patients who underwent living donor kidney transplantation between 2017 and 2020. All patients were on immunosuppressant therapy that included tacrolimus, mycophenolate mofetil, and steroids.The prevalence of Banff Borderline classification at 3, 6, and 12 months after transplantation was 4%, 5%, and 8 %, respectively, whereas none of the biopsies met the Banff criteria for acute T cell-mediated rejection throughout the study period. Active antibody-mediated rejection (ABMR) was only present in 8% of patients at 3 months after transplantation and chronic active ABMR at 6, 12, and 24 months after transplantation was detected in 10%, 13%, and 11% of the patients, respectively. Subgroup analysis revealed that 50% of the 6 patients with preformed anti-donor specific antibodies (DSAs) developed clinical or subclinical active ABMR within 3 months after transplantation, followed by chronic active ABMR according to serial histologic assessment. Conversely, only a small proportion of patients (3%) without preformed DSAs exhibited clinically active ABMR.SCR occurs too infrequently in patients with low immunologic risk and strong contemporary immunosuppression therapy to justify the diagnostic effort of serial protocol biopsies. However, protocol biopsies remain an indispensable tool in renal transplant monitoring and may be especially important in immunologically high-risk patients with pre-existing DSAs.

Few studies have examined whether maintaining moderate or vigorous physical activity (PA) reduces the risk of low back pain in older people. This study aimed to examine the magnitude of the associations of changes in PA on the risk of low back pain at 4 years of follow-up. We analyzed 4,882 participants in the English Longitudinal Study of Ageing who were initially free from low back pain (mean age, 65.6 ± 8.9 years at baseline). Self-reported PA, which was assessed at wave 6 (2012–2013) and wave 7 (2014–2015), was used as the exposure. The PA of the respondents was categorized into “no PA at all,” “up to moderate PA,” and “up to vigorous PA” groups. Self-reported moderate/severe low back pain assessed at 4 years of follow-up (2016–2017) was used as the outcome. Maintaining moderate (relative risk [RR], 0.59; 95% confidence interval [CI], 0.36–0.99) or vigorous (RR, 0.46; 95% CI, 0.27–0.77) PA at least 1–3 times a month was negatively associated with prevalence of low back pain compared with no PA at all. Interventions for maintaining either moderate or vigorous PA might be beneficial in preventing the incidence of low back pain in the older population. Perspective Perspective: This study examined the magnitude of the association between changes in physical activity over time and the risk of low back pain. The findings suggest that encouraging people to maintain at least moderate physical activity over 2 years is useful for reducing the risk of low back pain at 4 years of follow-up.

The prognostic significance of combining intra-aortic balloon pumping (IABP) with extracorporeal membrane oxygenation (ECMO) for acute myocardial infarction (AMI) patients is still unclear. We investigated whether combining IABP with veno-arterial (VA)-ECMO is associated with a lower risk of short-term mortality.Among 12,093 AMI cases enrolled in the Osaka Acute Coronary Insufficiency Study (OACIS), we identified 519 who were administered VA-ECMO during hospitalization. Among these, 459 received IABP support (IABP group) and 60 cases did not (no-IABP group). The primary endpoint was 30-day all-cause death; the secondary endpoint was major bleeding. Logistic regression analysis using original data was conducted. We also established weighted logistic regression models with inverse probability of treatment weighting (IPTW).Logistic regression analysis revealed that IABP use was significantly associated with a reduced risk of 30-day death in the original data [odds ratio (OR) 0.504, 95% confidence interval (CI) 0.282-0.901, p = 0.021]. After IPTW-adjustment for clinically relevant covariates with the use of IABP, patients receiving VA-ECMO with IABP had a lower risk of 30-day death (OR 0.816, 95% CI 0.746-0.892, p0.001) compared to those without IABP. The incidence of major bleeding was comparable between the groups (IABP 29.0% vs. non-IABP 21.7%, p=0.302). However, the risk of major bleeding was higher in the IABP group after IPTW-adjustment (OR 1.092, 95% CI 1.008-1.184, p=0.032).IABP support for AMI patients with VA-ECMO was significantly associated with reduced risk of short-term mortality, suggesting that the addition of IABP support might contribute to improved survival in AMI patients requiring VA-ECMO.

Semen analysis has long been used to evaluate male fertility. Recently, several sperm function tests have been developed. Of those, the sperm DNA fragmentation index (DFI), which describes the status of the sperm DNA, is thought to be a suitable parameter for evaluating male fertility. However, there have been no large-scale studies on the sperm DFI of Japanese men. Therefore, we investigated the feasibility of using an in-house flow cytometry-based sperm DFI analysis based on the sperm DNA fragmentation test of sperm chromatin structure assay (SCSA) to assess male fertility in Japan. This study enrolled 743 infertile and 20 fertile Japanese men. To evaluate reproducibility, inter- and intraobserver precision was analyzed. A receiver operating characteristic curve analysis was used to set a cutoff value for the sperm DFI to identify men who could father children by timed intercourse or intrauterine insemination. The variability of the sperm DFI among fertile volunteers was determined. The relationship between semen parameters and the sperm DFI was assessed by Spearman's rho test. A precision analysis revealed good reproducibility of the sperm DFI. The cutoff value of sperm DNA fragmentation in infertile men was 24.0%. Semen volume had no relationship with the sperm DFI. Sperm concentration, sperm motility, total motile sperm count, and percentage of normal-shaped sperm were significantly and negatively correlated with the sperm DFI. The median sperm DFI was smaller in fertile volunteers (7.7%) than that in infertile men (19.4%). Sperm DNA fragmentation analysis can be used to assess sperm functions that cannot be evaluated by ordinary semen analysis.

Purpose We aimed to determine root caries annual incidence (RCAI) and root caries annual progression (RCAP) and risk factors for them among older people requiring nursing care. Methods The target population comprised 186 dentate individuals aged ≥ 65 years who required nursing care while living in nursing homes (NHs) or their own homes (OHs) in Okayama, Japan. Survey items included presence/absence and severity of root caries, age, sex, living environment (NH or OH), the Clinical Dementia Rating, and the Barthel Index (BI). Baseline surveys were conducted from 2015 to 2017; subjects were followed up for one year. RCAI and RCAP per tooth and per person were calculated, and risk factors for them were identified using generalized estimating equations. Results In total, 104 individuals (mean age: 82.0 ± 12.4 years) completed the follow-up survey. RCAIs per tooth and per person were 14.6% (173/1188) and 59.6% (62/104), respectively. RCAP per tooth was 22.5% (51/227 teeth with root caries at baseline). Significant risk factors for RCAI were living environment (OH, odds ratio [OR]: 2.14), sex (male, OR: 1.84), clasped tooth (OR: 1.82), and older age (OR: 1.05) at baseline. Significant risk factors for RCAP were sex (male, OR: 5.20), regular dental checkup (OR: 2.74), and high BI score (OR: 1.02) at baseline. Conclusions At one-year follow-up, 59.6% of the subjects developed at least one root caries. Risk factors for RCAI were living environment (OH), male, clasped tooth, and older age, whereas those for RCAP were male, regular dental checkup, and high BI score.

AIMS/INTRODUCTION Metformin is associated with the risk of gastrointestinal complications, and probiotic Bifidobacterium bifidum G9-1 (BBG9-1) can improve the symptoms of diarrhea. This study aimed to clarify the effects of probiotic BBG9-1 on the gastrointestinal symptoms of type 2 diabetes mellitus patients using metformin. MATERIALS AND METHODS In this open-label single-arm exploratory study, 40 patients (mean age 64.0 ± 9.4 years) were given probiotic BBG9-1 for 10 weeks. Changes in the gastrointestinal symptom rating scale total score, which was the primary end-point, gastrointestinal symptom rating scale subscale scores, glycated hemoglobin levels and gut microbiota after the administration of probiotic BBG9-1 were evaluated by the Student's t-test. RESULTS The gastrointestinal symptom rating scale total score significantly improved (from 2.02 ± 0.51 to 1.59 ± 0.43, change, -0.43 ± 0.49, P

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Background Existing evidence suggest that those who are socially isolated are at risk for taking up or continuing smoking. This study investigated country-based differences in social isolation and smoking status. Methods We performed a repeated cross-sectional study using two waves of data from two ongoing aging studies: the English Longitudinal Study of Ageing and the Japan Gerontological Evaluation Study. Participants from both studies aged ≥65 years were included. We applied a multilevel Poisson regression model to examine the association between social isolation and smoking status and adjusted for individual sociodemographic characteristics. We used the social isolation index which comprises the following domains: marital status; frequency of contact with friends, family, and children; and participation in social activities. Interaction terms between each country and social isolation were also entered into the mode. Results After exclusion of never smokers, we analyzed 75,905 participants (7,092 for ELSA and 68,813 for JAGES, respectively). Taking ex-smokers as the reference, social isolation was significantly associated with current smoking; the prevalence ratios (PRs) were 1.06 (95% credible interval [CrI], 1.05-1.08) for men and 1.08 (95% CrI, 1.04-1.11) for women. Taking Japan as a reference, the interaction term between country and social isolation was significant for both sexes, with increased PRs of 1.32 (95% CrI, 1.14-1.50) for men and 1.30 (95% CrI, 1.11-1.49) for women in England. Conclusions Older people who were less socially isolated were more likely to quit smoking in England than in Japan, possibly explained by the strict tobacco control policies in England.

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here, we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition significantly suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.

This report describes a 76-year-old man with diabetes mellitus who developed coronary artery stenosis from infiltration of a primary malignant pericardial mesothelioma. Three months before referral to the treating hospital, elevated liver function values and cardiac enzymes led to echocardiography, which revealed a motion abnormality in the anterior wall of the heart. The patient was diagnosed with congestive heart failure and admitted to the hospital, where chest computed tomography showed a tumor above the left atrial appendage that compressed the origin of the left anterior descending artery. He was referred to the treating hospital for surgery. Minimally invasive direct coronary artery bypass grafting was performed, but the mass was not resected because of its infiltrating nature and the potential for medical complications. Histologic examination of a biopsy specimen confirmed a primary malignant pericardial mesothelioma. The bypass procedure resolved the coronary artery stenosis caused by the tumor. Although the optimal treatment for primary malignant pericardial mesothelioma is controversial, minimally invasive methods, such as minimally invasive direct coronary artery bypass grafting, may be used successfully.

Aldosterone-producing adenomas (APAs) have different steroid profiles in serum, depending on the causative genetic mutation. Ion mobility is a separation technique for gas-phase ions based on their m/z values, shapes, and sizes. Human serum (100 µL) was purified by liquid–liquid extraction using tert-butyl methyl ether/ethyl acetate at 1/1 (v/v) and mixed with deuterium-labeled steroids as the internal standard. The separated supernatant was dried, re-dissolved in water containing 20% methanol, and injected into a liquid chromatography–ion mobility–mass spectrometer (LC/IM/MS). We established a highly sensitive assay system by separating 20 steroids based on their retention time, m/z value, and drift time. Twenty steroids were measured in the serum of patients with primary aldosteronism, essential hypertension, and healthy subjects and were clearly classified using principal component analysis. This method was also able to detect phosphatidylcholine and phosphatidylethanolamine, which were not targeted. LC/IM/MS has a high selectivity for known compounds and has the potential to provide information on unknown compounds. This analytical method has the potential to elucidate the pathogenesis of APA and identify unknown steroids that could serve as biomarkers for APA with different genetic mutations.

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4–5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap (p

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.

Background The active hip abduction test (AHAbd) is widely used to evaluate lumbopelvic stability, but the onset of trunk muscle activation during the test in individuals with recurrent low back pain (rLBP) has not been investigated so far. It is important to investigate the pattern of trunk muscle activation during the AHAbd test to provide insight into the interpretation of observation-based assessment results; this may help to create exercise therapy interventions, from a movement control perspective, for people seeking treatment for rLBP. The purpose of this study was to compare the timing of trunk muscle activation between individuals with and without rLBP and to assess potential differences. Methods Seventeen subjects in remission from rLBP and 17 subjects without rLBP were recruited. We performed surface electromyography of the transversus abdominis/internal abdominal oblique, external oblique, erector spinae, and gluteus medius muscles during the AHAbd test on both sides. The onset of trunk muscle activation was calculated relative to the prime mover gluteus medius. The independent-samples t- and Mann-Whitney U tests were used to compare the onset of trunk muscle activation between the two groups. Results The onset of transversus abdominis/internal abdominal oblique activation on the ipsilateral (right AHAbd: −3.0 ± 16.2 vs. 36.3 ± 20.0 msec, left AHAbd: −7.2 ± 18.6 vs. 29.6 ± 44.3 ms) and contralateral sides (right AHAbd: −11.5 ± 13.9 vs. 24.4 ± 32.3 ms, left AHAbd: −10.1 ± 12.5 vs. 23.3 ± 17.2 ms) and erector spinae on the contralateral side (right AHAbd: 76.1 ± 84.9 vs. 183.9 ± 114.6 ms, left AHAbd: 60.7 ± 70.5 vs. 133.9 ± 98.6 ms) occurred significantly later in individuals with rLBP than in individuals without rLBP (p 0.05). Conclusions Our results suggest that individuals with rLBP possess a trunk muscle activation pattern that is different from that of individuals without rLBP. These findings provide an insight into the underlying muscle activation patterns during the AHAbd test for people with rLBP and may support aggressive early intervention for neuromuscular control.

This study aimed to assess outcomes of microdissection testicular sperm extraction (MD-TESE) and identify predictors for sperm retrieval (SR) in patients with non-mosaic Klinefelter syndrome (NM-KFS). We retrospectively evaluated 37 patients with NM-KFS who underwent MD-TESE. Data of age at operation, body mass index (BMI), testicular volume, serum luteinizing hormone (LH), follicle stimulating hormone (FSH), preoperative and postoperative testosterone levels with reduction ratio between the two values, and FSH/preoperative testosterone ratio were analysed. These patients were divided into two groups according to success or failure of SR: the successful and failure groups. Factors related to SR were evaluated by statistical analyses using the Mann-Whitney U test and logistic regression modelling. Regarding these factors, the cut-off level was specified using the receiver operating characteristics (ROC) curve. Moreover, the percentage of SR at that level was assessed. A simple scoring model was developed based on the multivariate analysis. Fourteen patients underwent successful SR, whereas 23 experienced failure SR. Statistical analysis found preoperative testosterone and FSH levels to be significant factors associated with SR. On the ROC curve, the cut-off levels for preoperative testosterone and FSH were 2.34 ng/ml and 33.2 mIU/ml respectively. A new scoring model was developed, consisting of preoperative testosterone (≥2.34 ng/ml) and FSH (≤33.2 mIU/ml). The sperm retrieval rates (SRRs) were clearly discriminated by stratification according to the scoring model. The SRR of the cases of scores of 2, 1 and 0 were 87.5%, 31.6% and 10% respectively. At our hospital, the SRR of MD-TESE in patients with NM-KFS was 37.8%. The patients with high testosterone and low FSH levels tended to demonstrate successful SR.

Background and Objectives: Brain atrophy is related to cognitive decline. However, the heritability of brain atrophy has not been fully investigated in the Eastern Asian population. Materials and Methods: Brain imaging of 74 Japanese twins registered in the Osaka University Twin Registry was conducted with voxel-based morphometry SPM12 and was processed by individual voxel-based morphometry adjusting covariates (iVAC) toolbox. The atrophy of the measured lobes was obtained by comparing the focal volume to the average of healthy subjects. Classical twin analysis was used to measure the heritability of its z-scores. Results: The heritability of brain atrophy ranged from 0.23 to 0.97, depending upon the lobes. When adjusted to age, high heritability was reported in the frontal, frontal-temporal, and parietal lobes, but the heritability in other lobes was lower than 0.70. Conclusions: This study revealed a relatively lower heritability in brain atrophy compared to other ethnicities. This result suggests a significant environmental impact on the susceptibility of brain atrophy the Japanese. Therefore, environmental factors may have more influence on the Japanese than in other populations.

In 2021, the World Health Organization included silver diamine fluoride (SDF) as an essential medicine to manage caries in adults and children. SDF was developed in the 1960s, but its use for children became unpopular in Japan because of the decline and low prevalence of early childhood caries. This mixed methods study explored the knowledge, practices and attitudes towards SDF therapy among dentists promoting fluoride use in Japan. It also investigated senior dentists’ perceptions of SDF therapy in Japan. The quantitative study invited all 173 members of the largest organisation promoting fluoride use in Japan to complete a web-based questionnaire survey. Sixty (60/173; 35%) dentists promoting fluoride use in Japan completed the questionnaire survey. All dentists knew of SDF treatment, and 50 (50/60; 83%) used SDF for dental care. Fifty-nine dentists (59/60; 98%) agreed that SDF therapy was simple and quick. All 60 dentists agreed that SDF was effective to arrest caries; 51 dentists (51/60; 85%) agreed that SDF was effective to prevent caries. Most dentists (51/60; 85%) were concerned about SDF’s unaesthetic staining. Fifty-seven dentists (57/60; 95%) used SDF to arrest primary posterior teeth, and 52 dentists (52/60; 87%) used SDF to arrest root caries. However, 25 dentists (25/60; 42%) did not use SDF to prevent caries in permanent teeth. The qualitative study interviewed 12 senior dentists using snowball sampling and achieved data saturation. The dentists opined that SDF therapy was effective, simple, painless, non-invasive and inexpensive. SDF is seldom used in Japan at present because of the unaesthetic black staining and the low prevalence of early childhood caries; however, it can regain popularity by arresting root caries in the aging population.

Aims At present, the clinical significance of admission hyperglycaemia in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. This study was designed to evaluate the relationship between admission hyperglycaemia and clinical outcome in HFpEF patients, especially in non‐diabetic patients. Methods and results We enrolled 486 non‐diabetic HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure from the PURSUIT‐HFpEF registry, a prospective, multicentre observational study. We divided non‐diabetic patients into two groups, an admission hyperglycaemia group whose blood glucose on admission was ≥7.0 mmol/L (148 patients) and a normoglycaemic group whose blood glucose on admission was

Aim We aimed to develop an application to calculate mean amplitude of glycaemic excursions (MAGE) automatically and to evaluate its accuracy. Materials and methods We named the application intermittently scanned continuous glucose monitoring (isCGM) calculator KAMOGAWA (Kyoto Auto MAGE Of Glucose cAlcutator With isCGM Application). The isCGM data from 20 patients, 10 with and 10 without diabetes, were used to compare manually calculated MAGE values with those calculated using KAMOGAWA. The rate of agreement for the MAGE values was calculated. Results Comparing the MAGE values calculated manually with those calculated using KAMOGAWA, the total mean rate of agreement was 81.6%. Nonmatching values were checked and it was found that the inconsistencies were all attributable to errors in manual calculations. After correcting errors in the manual calculation, the MAGE values matched to one decimal place for all data in the manual and KAMOGAWA calculations. Conclusions KAMOGAWA can help diabetologists use MAGE in clinical practice, which could contribute to improving glycaemic control in patients who use isCGM.

Objectives Weight loss is a critical health issue in older adults. Oral function is essential for nutrient intake and can be restored using dental prosthetic treatments in patients with tooth loss. This study aimed to investigate the relationship between tooth loss and weight loss among the older adults and to evaluate the magnitude of its risk reduction by dental prosthetic treatment. Design Three-year follow-up longitudinal study based on a self-reported questionnaire. Setting Community-dwelling older adults in Japan. Participants Adults aged 65 and older (n = 53,690). Measurements We used >10% weight loss during follow-up, the number of remaining teeth, and the use of dental prostheses as the outcome variable, exposure variable, and mediator, respectively. We fitted the logistic regression model including possible confounders and calculated the odds ratios (ORs) and 95% confidence intervals (95% CIs) of the controlled direct effect (CDE) at the level of use or nonuse of the dental prosthesis based on a causal mediation analysis framework. Additionally, we calculated the proportion eliminated by the dental prosthesis. Results The mean age of participants was 72.6 years (1 SD = 5.5), and 47.4% were males. About 5.8% (n = 3132) of them experienced >10% weight loss during the follow-up. Weight loss was observed in 6.8% of the participants with 0-19 remaining teeth and in 4.3% of them with ≥20 remaining teeth. The CDE of 0-19 remaining teeth was greater when no one used dental prosthesis (OR = 1.41; 95% CI = 1.26-1.59) compared with that when all participants used dental prosthesis (OR = 1.26; 95% CI = 1.08-1.46). This indicated that dental prosthesis decreased the risk of weight loss by 37.3%. Conclusion Our study revealed that tooth loss increased the risk of clinically critical levels of weight loss among community-dwelling older adults. However, this risk was reduced by dental prosthetic treatment.

Niemann–Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μL) and cisterna magna (10 μL) of Npc1 homo-knockout (Npc1−/−) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1−/− mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1−/− mice (n = 11) and untreated Npc1−/− mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1−/− mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1−/− mice increased until 15 weeks. AAV-treated Npc1−/− mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1−/− mice. In contrast, untreated Npc1−/− mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1−/− mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1−/− mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

Aims The prognostic importance of admission systolic blood pressure (SBP) in heart failure with preserved ejection fraction (HFpEF) is elusive. We aimed to clarify the pathophysiological differences between patients categorized with admission SBP among HFpEF patients. Methods and results We studied 1008 inpatients from PURSUIT‐HFpEF, a multicentre prospective observational registry. We classified patients as having elevated (>140 mmHg), preserved (90–140 mmHg), or low (

Aims The impacts of high density lipoprotein cholesterol (HDL‐C) as an anti‐inflammatory and C reactive protein (CRP) as inflammatory properties on the pathogenesis of heart failure were reported. At present, the clinical significance of the HDL‐C/CRP ratio in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Methods and results We examined the data on 796 consecutive HFpEF (left ventricular ejection fraction ≥50%) patients hospitalized due to acute decompensated heart failure from the PURSUIT‐HFpEF registry, a prospective, multicentre observational study. We calculated the HDL/CRP ratios and evaluated the relationship between the values and clinical outcomes, including degree of cardiac function. The mean follow‐up duration was 420 ± 346 days. All‐cause death occurred in 118 patients, of which 51 were cardiac deaths. HDL/CRP ≤ 4.05 was independently and significantly associated with all‐cause death (odds ratio = 1.84, 95% CI: 1.06–3.20, P = 0.023), and HDL/CRP ≤ 3.14 was associated with cardiac death by multivariate Cox proportional hazard analysis (odds ratio = 2.86, 95% CI: 1.36–6.01, P = 0.003). HDL‐C/CRP ratio significantly correlated with the product of the left atrial volume and left ventricular mass index as well as the tricuspid annular plane systolic excursion by multiple regression analysis (standardized beta‐coefficient = −0.085, P = 0.034 and standardized beta‐coefficient = 0.081, P = 0.044, respectively). Conclusions HDL‐C/CRP ratio was a useful marker for predicting all‐cause death and cardiac death and correlated with left ventricular diastolic function and right ventricular systolic function in HFpEF patients.

Background Depression is a major health problem among older adults, for which previous studies have suggested tooth loss as a risk factor. This study examined the mediating effect of oral function and orofacial appearance in the relationship between tooth loss and depression. Methods This three-year follow-up longitudinal study was based on a self-reported questionnaire targeting community-dwelling older adults aged ≥65 years. We used the incidence of depressive symptoms during follow-up as the outcome, the number of remaining teeth (≥20/≤19) as the exposure, and the deterioration of oral function and orofacial appearance (speaking, smiling, and eating) as mediators. We fitted the logistic regression model including confounders and calculated the natural indirect effect (NIE), natural direct effect, and the proportion mediated (PM) by the deterioration of oral functions by applying the causal mediation analysis framework. Results The mean age of the 8,875 participants was 72.7 years (1SD=5.5) and 48.0% were male. Depressive symptoms developed during follow-up in 11.5% of the participants (n=1,024). The incidence for those with ≤19 and ≥20 remaining teeth was 13.1% and 9.2%, respectively. Total effect of fewer remaining teeth (≤19) on depressive symptoms was OR=1.30 (95%CI=1.12–1.51). Difficulty in speaking (NIE OR=1.03, 95%CI=1.00–1.06, PM=12.4%), problems in smiling (NIE OR=1.04, 95%CI=1.01–1.07, PM=16.9%), and difficulty in chewing (NIE OR=1.05, 95%CI=1.02–1.09, PM=21.9%) significantly mediated the relationship. Limitation Selection bias due to dropout. Conclusion Deterioration of oral function and orofacial appearance were mediating factors of the mechanism for the relationship between tooth loss and the incidence of depressive symptoms.

Objectives To evaluate whether the long-term usage of mirabegron, which was reported to have potential side effects on male reproductive organs in animal studies, was harmful to spermatogenesis in human testis. Methods Thirty consecutive patients with spinal cord injury (20-48 years old) who performed clean intermittent catheterization were involved in this study. Ten patients were treated with mirabegron (50 mg/d) for more than 2 years and refrained from using an antimuscarinic agent due to the side effects of constipation and dry mouth. Twenty patients were treated with neither anticholinergic agents nor mirabegron. All underwent conventional testicular sperm extraction. The sperm recovery rate and histopathologic findings of the retrieved testicular tissue were compared between both groups. Results We found no difference in the sperm recovery rate (P = .083) between both groups. Spinal cord injury patients treated with mirabegron had better spermatogenesis than those not treated with mirabegron (P Conclusions From these data, we conclude that the therapeutic dose of mirabegron had no harmful effect on spermatogenesis in spinal cord injury patients of reproductive age.

Leukocytes play an important role in vascular inflammation prior to atherosclerosis. In particular, monocyte adhesion and migration to the endothelium contribute to the development of vascular inflammation. Previously, we showed the importance of neutrophils and complement C5a in the early phase of vascular inflammation in mice fed a high‐fat diet. However, the relationship between monocytes and neutrophils is not well understood. In this study, we elucidated the involvement of neutrophils in the migration of monocytes. We observed that C5a induces CCL2 expression in neutrophil‐like dHL‐60 cells. To investigate the physiological significance of CCL2 secretion, we performed a chemotaxis assay. Interestingly, dHL‐60 culture supernatant in the presence of C5a enhanced the migration of THP‐1 in comparison with the absence of C5a. Furthermore, CCL2 expression and secretion significantly increased in C5a‐stimulated dHL‐60 through the phosphorylation of NF‐κB p65. Actin polymerization on THP‐1 was enhanced by the presence of C5a compared with the absence of C5a when stimulated by a dHL‐60‐cultured medium. These results suggest that crosstalk between neutrophils and monocytes via CCL2 may play an important role in vascular inflammation., In this study, we found that neutrophil‐like dHL‐60 stimulated with C5a induces the migration of monocytic THP‐1 through phosphorylation of p65 NF‐κB and that dHL‐60‐derived CCL2 plays an important role in the crosstalk between these cells. These results suggest that there may be a transition process from acute to chronic inflammation in atherosclerotic vascular inflammation.

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, result in the systemic accumulation of ammonia to toxic levels. Sodium 4-phenylbutyrate (NaPB), a standard therapy for UCDs for over 20 years, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the accepted use of NaPB. However, this regimen is not based on clinical evidence. Here, an open-label, single-dose, five-period crossover study was conducted in healthy adults to investigate the effect of food on the pharmacokinetics of NaPB and determine any subsequent change in amino acid availability. Twenty subjects were randomized to one of four treatment groups. Following an overnight fast, NaPB was administered orally at 4.3 g/m2 (high dose, HD) or 1.4 g/m2 (low dose, LD) either 30 min before or just after breakfast. At both doses, compared with post-breakfast administration, pre-breakfast administration significantly increased systemic exposure of PB and decreased plasma glutamine availability. Pre-breakfast LD administration attenuated plasma glutamine availability to the same extent as post-breakfast HD administration. Regardless of the regimen, plasma levels of branched-chain amino acids (BCAA) were decreased below baseline in a dose-dependent manner. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of the drug and thereby its potency to consume plasma glutamine. This finding may improve poor medication compliance because of the issues with odor, taste, and pill burden of NaPB and reduce the risk of BCAA deficiency in NaPB therapy.

The native tricuspid leaflets are sometimes preserved with tricuspid valve replacement to prevent atrioventricular block or maintain right ventricular function. However, after a tricuspid valve replacement using bioprosthetic valve, a rare complication involving adhesion of the pannus formation to the prosthetic valve may occur. We report the case of a 48-year-old woman who underwent a third tricuspid valve replacement with a bioprosthetic valve for severe tricuspid regurgitation 2.5 years after the redo tricuspid valve replacement.

Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM.We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy.Exome sequencing revealed a de novo mutation, c.980 T A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells.Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.

Triple-negative breast cancer (TNBC) is a highly aggressive and invasive type of breast cancer. In addition, type 2 diabetes mellitus (T2DM) is recognized as a risk factor for cancer metastasis, which is associated with mortality in patients with breast cancer. Cancer-associated fibroblasts (CAFs) generated from adipose tissue-derived mesenchymal stem cells (AT-MSCs) play a vital role in the progression of TNBC. However, to date, whether T2DM affects the ability of AT-MSCs to differentiate into CAFs is still unclear. In this study, we found that in coculture with TNBC cells [breast cancer cells (BCCs)] under hypoxic conditions, AT-MSCs derived from T2DM donors (dAT-MSCs) were facilitated to differentiate into CAFs, which showed fibroblastic morphology and the induced expression of fibroblastic markers, such as fibroblast activation protein, fibroblast-specific protein, and vimentin. This was involved in the higher expression of transforming growth factor beta receptor 2 (TGFβR2) and the phosphorylation of Smad2/3. Furthermore, T2DM affected the fate and functions of CAFs derived from dAT-MSCs. While CAFs derived from AT-MSCs of healthy donors (AT-CAFs) exhibited the markers of inflammatory CAFs, those derived from dAT-MSCs (dAT-CAFs) showed the markers of myofibroblastic CAFs. Of note, in comparison with AT-CAFs, dAT-CAFs showed a higher ability to induce the proliferation and in vivo metastasis of BCCs, which was involved in the activation of the transforming growth factor beta (TGFβ)-Smad2/3 signaling pathway. Collectively, our study suggests that T2DM contributes to metastasis of BCCs by inducing the myofibroblastic CAFs differentiation of dAT-MSCs. In addition, targeting the TGFβ-Smad2/3 signaling pathway in dAT-MSCs may be useful in cancer therapy for TNBC patients with T2DM.

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Anti-vascular endothelial growth factor treatment for macular edema secondary to branch retinal vein occlusion generally provides good visual acuity (VA) improvement but may require repeated injections for years. To reduce the number of patients who suffer from avoidable VA loss caused by treatment drop-out, providing prospects of the correlation between expected vision improvement and required number of injections at the early stages of treatment may be helpful. In this post hoc analysis of the phase IV, randomized, open-label ZIPANGU study, we investigated the correlation between the data from Month 2 and Month 12 in terms of VA and required ranibizumab injection numbers. Fifty-nine patients were evaluated (ranibizumab monotherapy, 29; combination therapy, 30). In the monotherapy group, patients who received 1 and 3 injections by Month 2 received a mean total of 2.8 and 8.3 injections during the year, respectively. Data from the combination group were similar. The correlation coefficients for VA scores at Months 2 and 12 were 0.60 and 0.51 for the monotherapy and combination groups, respectively (both p

Sodium-glucose cotransporter-2 (SGLT2) inhibitors exhibit cardioprotective properties in patients with diabetes. However, SGLT2 is not expressed in the heart, and the underlying molecular mechanisms are not fully understood. We investigated whether the SGLT2 inhibitor luseogliflozin exerts beneficial effects on high glucose-exposed cardiomyocytes via the suppression of sodium-hydrogen exchanger-1 (NHE-1) activity.Mouse cardiomyocytes were incubated under normal or high glucose conditions with vehicle, luseogliflozin, or the NHE-1 inhibitor cariporide. NHE-1 activity and gene expression were evaluated by the SNARF assay and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis, respectively. Six-week-old male db/db mice were treated with vehicle or luseogliflozin for 6 weeks, and the hearts were collected for histological, RT-PCR, and western blot analyses.High glucose increased NHE-1 activity and transforming growth factorLuseogliflozin may suppress cardiac hypertrophy in diabetes by reducing

This study examined the effects of a "community-based center" intervention to prevent the onset of functional disability among residents in disaster-affected areas.We used data from a prospective cohort study conducted from 2010 to 2016 in Iwanuma City, Japan. Participants were community-dwelling independent adults aged ≥65 years. The exposure variable was the experience of using a community-based center. The outcome variable was functional disability onset. The average treatment effect on the treated (ATET) was estimated by adjusting for possible confounders. Additional analysis stratified by sex was conducted considering the sex differences in social participation rates.Among 3794 participants (mean ± SD age = 72.9 ±5.3 years, 46.0% men), 196 (5.2%) used the community-based center, and 849 (22.4%) exhibited disability onset. Of those with functional disabilities, 40 (20.4%) used the community-based center, while 809 (22.5%) did not. The ATET for functional disability onset with community-based center activities across all participants were not significant (ATET: 0.51 years [95% confidence interval [CI] = -0.23; 1.27]). However, the direction of the effect of community-based center activities differed by sex (ATET: -0.14, 95% CI = -2.59; 2.31 for men [n = 18], and 0.66, 95% CI = 0.18; 1.16 for women [n = 178]). Women exhibited a 15.63% (95% CI = 3.58; 27.68) increase in the time until functional disability onset.The use of community-based centers was associated with a longer period without functional disability in women. Geriatr Gerontol Int 2022; 22: 465-470.

IntroductionSarcopenia index (SI), calculated by (serum creatinine/cystatin C)×100, is reported to be associated with sarcopenia. Few studies reported the association between SI and subclinical atherosclerosis. We evaluated the association between SI and subclinical atherosclerosis, assessed by brachial-ankle pulse wave velocity (baPWV).Research design and methodsOne hundred seventy-four patients with type 2 diabetes were included in this cross-sectional study. The relationship between SI and baPWV was assessed by Pearson’s correlation coefficient. To calculate area under the receiver operator characteristic (ROC) curve (AUC) of SI for the presence of subclinical atherosclerosis, which was defined as baPWV >1800 cm/s, ROC analysis was performed. Logistic regression analyses were performed to assess the effect of SI on the prevalence of subclinical atherosclerosis adjusting for covariates.ResultsMean age, duration of diabetes, baPWV, and SI were 66.9 (10.1) years, 17.7 (11.6) years, 1802 (372) cm/s, and 77.6 (15.8), respectively. There was an association between SI and baPWV (men; r=−0.25, p=0.001, and women; r=−0.37, p=0.015). The optimal cut-off point of SI for the presence of subclinical atherosclerosis was 77.4 (sensitivity=0.72, specificity=0.58, pConclusionsSI is associated with the prevalence of subclinical atherosclerosis in patients with type 2 diabetes.

Background: The trend of the diffusion of heated tobacco products (HTPs) is a great concern because HTPs have become available worldwide. This study examined the sociodemographic characteristics of HTPs users in Japan, where HTPs were first launched. Methods: This cross-sectional study used data from an online survey conducted in 2017. A total of 4,926 participants, aged 20–69 years, were included. The dependent variable was the type of tobacco products used. The independent variables were age and equivalent income. Two analyses estimated the odds ratios (ORs) for 1) being smokers compared to “non-smokers,” and 2) being “HTP smokers” compared to “only combustible cigarette smokers.” Analyses were stratified by sex. Educational attainment and occupation were also used in the sensitivity analyses. Results: The percentages of “non-smokers,” “only combustible cigarette smokers,” and “HTP smokers” were 82.8%, 14.2%, and 3.0%, respectively. When compared to the oldest participants (aged 60–69), the youngest participants (aged 20–29) tended to be “HTP smokers” (OR 7.90; 95% confidence interval [CI], 3.09–20.22 for men and OR 9.28; 95% CI, 2.14–40.28 for women). Compared to participants with the lowest incomes (

Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social development is unclear. Here, we identify non-canonical interactions between NLGN3 and protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed a splicing-dependent interaction mode and competition mechanism between PTPδ and NRXNs. Mice carrying a NLGN3 mutation that selectively impairs NLGN3-NRXN interaction show increased sociability, whereas mice where the NLGN3-PTPδ interaction is impaired exhibit impaired social behavior and enhanced motor learning, with imbalance in excitatory/inhibitory synaptic protein expressions, as reported in the Nlgn3 R451C autism model. At neuronal level, the autism-related Nlgn3 R451C mutation causes selective impairment in the non-canonical pathway. Our findings suggest that canonical and non-canonical NLGN3 pathways compete and regulate the development of sociality., Mutations of Neuroligin 3 (NLGN3) have been associated with autism spectrum disorder (ASD). Here, the authors identify a previously undescribed interaction between NLGN3 and a splice variant of protein tyrosine phosphatase δ (PTP δ) and its role in development of social behaviour in mice.

Summary The bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes. Impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis. Compensatory mechanisms to regulate the intracellular bile acid concentration in human hepatocytes with BSEP deficiency remain unclear. To define pathways that prevent cytotoxic accumulation of bile acid in hepatocytes, we developed a human induced pluripotent stem cell-based model of isogenic BSEP-deficient hepatocytes in a Transwell culture system. Induced hepatocytes (i-Heps) exhibited defects in the apical export of bile acids but maintained a low intracellular bile acid concentration by inducing basolateral export. Modeling the autoregulation of bile acids on hepatocytes, we found that BSEP-deficient i-Heps suppressed de novo bile acid synthesis using the FXR pathway via basolateral uptake and export without apical export. These observations inform the development of therapeutic targets to reduce the overall bile acid pool in patients with BSEP deficiency., Graphical Abstract, Highlights • Human isogenic iPSCs were generated by CRISPR to study a truncating mutation of BSEP • iPSC-derived hepatocytes recapitulate pathophysiology of BSEP deficiency in patients • BSEP-deficient hepatocytes induce alternative basolateral bile acid export • Activation of FXR suppresses de novo bile acid synthesis in BSEP-deficient hepatocytes, In this study, Asai and colleagues provide proof of concept of novel disease modeling for human genetic liver disorders caused by bile acid transport defects. A bile salt export pump (BSEP) mutation in isogenic iPSC-derived hepatocytes recapitulated the disease phenotype. This novel model revealed adaptive reverse bile acid exports in BSEP-deficient hepatocytes while maintaining regulatory feedback of de novo bile acid synthesis.

Purpose Recently, guidelines recommended the use of direct oral anticoagulants (DOACs) for the management of non-valvular atrial fibrillation (NVAF). Postoperative atrial fibrillation (POAF) is the most common post-surgical complication of cardiac surgery, but the efficacy and safety of DOAC for POAF have rarely been investigated. We conducted a prospective observational study to investigate the efficacy and safety of DOAC administered immediately after POAF. Materials and methods In all, 135 patients that experienced POAF after cardiac surgery were treated with a DOAC. Primary endpoints were either bleeding or thromboembolic events. Secondary endpoints included changes in hemoglobin (Hb), prothrombin time (PT), activated partial thromboplastin time (APTT), serum creatinine (sCr), estimated glomerular filtration rate (eGFR), and pleural/pericardial effusion. Results Patients were treated with apixaban (n = 31), edoxaban (n = 87), and rivaroxaban (n = 17). Major bleeding (p = 0.011) and gastrointestinal (GI) bleeding (p = 0.047) were significantly more frequent in the rivaroxaban group. Stroke was observed in one rivaroxaban group patient and none in the other two groups. Conclusion DOAC as anticoagulation therapy for the early intervention of POAF following cardiac surgery is associated with a low incidence of major bleeding; a favorable safety profile and excellent efficacy were demonstrated for DOAC. Furthermore, our results indicate that the safety and efficacy of apixaban and edoxaban are better than rivaroxaban.

Background/aim Curcumin is a natural compound of turmeric, which inhibits prostate cancer cell proliferation. This study examined whether treatment of LNCaP prostate cancer cells with the combination of curcumin and dutasteride, a 5-alpha reductase inhibitor, affect proliferation and the amount of testosterone and dihydrotestosterone. Materials and methods LNCaP Cells were incubated with curcumin or the combination of curcumin and dutasteride and cell proliferation was measured at 72 h. LC-MS/MS was used to determine testosterone and dihydrotestosterone concentrations in prostate cancer cells. Results Curcumin combined with dutasteride suppressed proliferation and affected apoptosis of LNCaP cells. The combination of curcumin and dutasteride also reduced the amount of testosterone and dihydrotestosterone in LNCaP cells. The secretion of prostate-specific antigen was inhibited by the combination treatment in a dose-dependent manner. Conclusion Treatment with the combination of curcumin and dutasteride may interfere with the intra-tumoral androgen activity.

Herein, we compared the connectivity of resting-state networks between participants with high and low working memory capacity groups. Brain network connectivity was assessed under both resting and working memory task conditions. Task scans comprised dual-task (reading sentences while memorizing target words) and single-task (reading sentences) conditions. The low capacity group showed relatively stronger connectivity during resting-state in most brain regions, and the high capacity group showed a stronger connectivity between the medial prefrontal and posterior parietal cortices. During task performance, the dorsal attention and salience networks were relatively strongly connected in the high capacity group. In the comparison between dual- and single-task conditions, increased coupling between the anterior cingulate cortex and other attentional control-related areas were noted in the high capacity group. These findings suggest that working memory differences are related with network connectivity variations in attentional control-associated regions during both resting and task performance conditions.

Severe acute respiratory syndrome coronavirus 2 rapid antigen detection (RAD) test kits are widely used as primary screening test in Japan because rapid diagnosis of coronavirus disease 2019 (COVID-19) is critical for infection control. We report cases with RAD test false-positive results in a ward for patients with disabilities. RAD tests potentially evoke hospital operational risk. It is desirable that performing PCR test appropriately when patients admitted to a medical treatment ward with COVID-19 symptoms instead of RAD test.