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Abstract The association of anemia with hyperadiponectinemia (HAN) (≥ 20 μg/mL) was studied in 95 Japanese women aged 65–74 (young–old), 175 women aged 75–84 (old–old), and 51 women aged over 85 (oldest–old) who resided at home alone without wheelchair use. The prevalence of anemia was 21.5% overall and increased with aging stepwise (9.5, 22.9, and 39.2% in young–olds, old–olds, and oldest–olds, respectively, p

Abstract Receptor kinase (RK) families process information from small molecules, short peptides, or glycan ligands to regulate core cellular pathways in plants. To date, whether individual plant RKs are capable of processing signals from distinct types of ligands remains largely unexplored. Addressing this requires the discovery of structurally unrelated ligands that engage the same receptor. Here, we focus on FLAGELLIN-SENSING 2 (FLS2), an RK that senses a peptide of bacterial flagellin to activate antibacterial immunity in Arabidopsis. We interrogate >20,000 potential interactions between small molecules and the sensory domain of FLS2 using a large-scale reverse chemical screen. We discover two small molecules that interact with FLS2 in atypical ways. The surrogate ligands weakly activate the receptor to drive a functional antibacterial response channeled via unusual gene expression programs. Thus, chemical probes acting as biased ligands can be exploited to discover unexpected levels of output flexibility in RKs signal transduction.

Abstract The genetic architecture of white matter lesions (WMLs) in Asian populations has not been well-characterized. Here, we performed a genome-wide association study (GWAS) to identify loci associated with the WML volume. Brain MRI and DNA samples were collected from 9479 participants in the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). The GWAS confirmed three known WML-associated loci (SH3PXD2A, GFAP, and TRIM47). The lead variant of GFAP was a common missense variant (p.D295N) in East Asians. Meta-GWAS using the publicly available summary statistics of UK Biobank identified one previously unreported locus 6q23.2 (SLC2A12). Integration with expression quantitative trait locus data implied the newly identified locus affects SLC2A12 expression. The effect sizes of 20 lead variants at the WML-associated loci were moderately correlated between JPSC-AD and UK Biobank. These results indicate that the alteration in GFAP protein caused by the common missense variant in East Asians influences the WML volume.

X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation. Patients with JMML demonstrate characteristic manifestations such as splenomegaly, monocytosis and the presence of myeloid or erythroid precursors in the peripheral blood. Here, we present the case of a male infant with ectodermal dysplasia, bacterial septicemia, Pneumocystis pneumonia, severe inflammation and transient manifestations mimicking JMML. Genetic analysis revealed a deep intronic germline variant of IKBKG. Full-length IKBKG cDNA and NEMO protein expression were almost inexistent. Peripheral mononuclear cells (PBMCs) from the patient showed increased RAS signaling activation with GM-CSF or Phorbol 12-myristate 13-acetate without the RAS-associated gene variant, although the increased RAS signaling activation in induced-pluripotent stem cell-derived myeloid lineage and bone marrow-derived mesenchymal cells was not evident. The patient with NEMO deficiency demonstrated JMML-like manifestation and severe inflammation. PBMCs of the patient demonstrated increased RAS signaling activation with unknown pathophysiology.

Abstract The increased burden on educators to promote environmental education has recently attracted research interest. Since environmental knowledge has insignificant direct effects on pro-environmental behaviour, it is important to devise effective teaching methods to reduce the burden on educators and promote environmental conservation. In this study, we examined whether the planning and practice of educating others promoted environmental consciousness in the educators. Twenty-four and twenty-two university students participated in the study as part of an experimental and active control group, respectively. The experimental group was asked to plan and manage events meant to educate children about the environment and help them feel comfortable in nature. As a result, compared to the beginning of the study, the experimental group participants exhibited increased environmental consciousness. This improvement could be attributed to the fact that the participants possibly altered their behaviour towards the environment, consistent with the nature conservation practices they presented to the children participating in the abovementioned events. These findings highlight how planning and managing environmental conservation events for others could influence and improve individuals’ environmental consciousness.

This study aimed to systematically find an alternative solvent to replace hexane for the extraction of bio-oil with high γ-oryzanol content from rice bran (RB). The selection involved predicting solubility through Hansen solubility theory, experimental validation, determination of suitable extraction conditions, and comparison of oil quality with that of conventional hexane. A wide variety of solvents: subcritical water (SCW), supercritical carbon dioxide (SCCO2), bio-based solvents (alcohols and terpenes), and liquefied dimethyl ether (LDME), were initially assessed for rice bran oil (RBO) and γ-oryzanol solubility using Hansen solubility spheres. Solvents demonstrating high solubility for both RBO and γ-oryzanol, including LDME, ethyl acetate, acetone, and others (alcohols and SCCO2) known for effective vegetable oil extraction, were selected/identified for experimental extraction comparison. Among these, LDME performed better overall, affording greater solubility and requiring less solvent, shorter duration, lower pressure, and no additional co-solvents for equivalent extractions. Optimal conditions for LDME extraction were identified as 30 °C with a solvent-to-sample ratio of 10 mL/g and an extraction time of 10 min. Oils extracted with LDME and hexane displayed similar fatty acid compositions and no adverse effects on RB protein and carbohydrate structures after LDME extraction were observed. This study demonstrates LDME as a promising alternative to replace hexane for RBO extraction to further valorize this abundant low-cost RB residue into bio-oil and its γ-oryzanol and de-oil RB co-products.

Here, we describe two cases of retained products of conception (RPOC) that were successfully managed with hysteroscopic resection after laparoscopic temporary uterine artery ligation. Both patients were diagnosed with RPOC after early miscarriages. Case 1 was urgently admitted due to massive bleeding and underwent surgery following a blood transfusion. After laparoscopic temporary bilateral uterine artery ligation, the mass was hysteroscopically removed, and the ligation was subsequently released. The patient subsequently achieved an ongoing pregnancy. Case 2 underwent semi-emergency surgery due to intermittent bleeding. Initially, hysteroscopic surgery was planned. However, bleeding resulted in poor visualization of the operative field, and laparoscopic surgery was performed. In many previous reports of RPOC with heavy bleeding, uterine artery embolization was performed. However, there are concerns regarding the effect of a long-term reduction in uterine blood flow on fertility. Our method is not expected to decrease fertility because the ischemic effect is very short.

Abstract NO previous studies have examined the simultaneous effects of obstructive sleep apnea (OSA), hypertension, and the SNP rs68430822 on stroke. We aimed to explore whether these elements together, play a role as risk factors for stroke. Data was obtained from the Taiwan Biobank and the National Health Insurance database. We used logistic regression analysis to investigate the effect of OSA and hypertension as a risk factor for stroke in different genotypes. We found that OSA and hypertension was associated with stroke in those with the rs6843082 genotype. People with OSA and hypertension together with the rs6843082 genotype (GA + AA) showed a statistically significant difference as a risk for stroke (OR,2.57; 95% CI,1.53 to 4.33). However, there was no statistically significant difference in those people with OSA but without hypertension (OR, 0.53; 95% CI,0.13 to 2.25). After further stratification by combination of OSA and hypertension, those with genotype rs6843082 (GG) had higher risk odds than those with OSA and those with hypertension alone (OR,5.46, 95% CI,3.46 to 8.60). Individuals with genotype rs6843082(GA + AA), OSA and hypertension together had the highest risk for stroke (OR,6.25, 95% CI,3.63 to 10.76) and those with OSA and no hypertension (OR,0.57, 95% CI,0.14 to 2.36) had no significant risk. Our findings showed that people with genotype rs6843082 (GG), with or without hypertension had OSA as a risk factor for stroke. For individuals with the genotype rs6843082 (GA + AA), those with hypertension, OSA is a risk factor for stroke, and for those without hypertension, OSA is not associated with stroke.

Abstract This retrospective study evaluated the use of laminin γ2 monomer (LG2m) as a predictive biomarker for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Serum LG2m levels were measured in two cohorts of patients: cohort 1 comprised 56 patients with chronic liver disease for assessing LG2m stability, whereas cohort 2 included 89 patients with chronic HBV infection who did not have HCC for evaluating the usefulness of LG2m measurement in HCC prediction. LG2m was highly stable in cryopreserved serum, and an increased LG2m level was significantly associated with a higher risk of HCC in chronically HBV-infected patients (P = 0.012). Multivariable Cox regression analysis revealed that high LG2m was an independent significant risk factor for HCC (hazard ratio, 7.16; 95% confidence interval, 1.31–39.2; P = 0.023). These findings suggest that LG2m may serve as a useful biomarker for the prediction of future HCC in patients with chronic HBV infection.

Abstract Efficient operating room management is essential and requires precise surgery scheduling. We hypothesized that an estimation formula for the preparation time for anesthesia induction and surgery could be developed by incorporating anesthesia and surgical factors, as well as the ‘clinical department,’ into the formula. This retrospective observational study analyzed 12,528 scheduled surgical cases. A regression analysis that included the clinical department, six anesthesia factors, and five surgical factors was conducted. This analysis aimed to develop both an analytical framework and an equation for estimating the time required for both anesthesia induction and surgical preparation. Our estimation formula wielded high accuracy (R2 = 0.801). Particularly, there was only a difference of less than 3 min for surgeries under general anesthesia. In addition, modeling preparation time using “medical interventions performed in the operating room” as a factor instead of patient characteristics was found to be beneficial. It was possible to develop a highly accurate formula for estimating preparation time of anesthesia induction and surgery by analyzing the anesthesia factors and the surgical factors and incorporating the clinical department as an estimation factor. However, this study represents the development phase of the estimation formula. A multicenter study is essential to validate its generalizability and robustness across different settings before broader application.

Abstract Background Research is needed to better understand the specific challenges for autistic learners in informal STEM learning settings. This study aimed to increase inclusion in STEM museums, with a larger goal of increasing the impact (i.e., learning and application of knowledge during and after visits) of informal STEM learning settings for autistic youth. We conducted an online parent attitudes survey with 93 parents of autistic adolescents and 53 parents of adolescents in the general population to better understand the experiences of autistic adolescents when visiting STEM-related museums. Parent responses informed professional development training for museum staff at four partner museums, which taught strategies to better support autistic learners. Then, autistic adolescents (n = 20) and their parents were randomly assigned to visit one partner and one control museum. They were asked to report their experiences through an online survey and semi-structured interviews. Results Participants who completed the parent attitudes survey indicated significantly lower inclusion, engagement, and general impact of STEM museum visits among autistic adolescents compared to the general population comparison group. Parents of adolescents who visited partner and control museums reported higher STEM impact during visits to partner museums; however, parent-reported inclusion, engagement, and general impact did not differ significantly between partner and control museums. Qualitative analysis identified four themes (Spectrum of Museum Impact; Adolescent-Environment Fit; Barriers to Engagement, and Barrier Breakers), providing context for quantitative findings. Conclusions Findings underscore the need for increased inclusion for autistic individuals in informal STEM learning environments like museums. This project demonstrated feasibility of professional development training of forward-facing staff and identified several themes that should inform future efforts to improve inclusion in informal STEM learning settings.

Abstract Background Interatrial right-to-left shunt flow through a patent foramen ovale (PFO) can be caused by changes in heart position for anastomosis during off-pump coronary artery bypass (OPCAB). We herein present a case in which the direction of PFO shunt flow changed with heart position during OPCAB and the ventilation settings after sternal closure. Case presentation A 66-year-old man with interstitial pneumonia underwent OPCAB. Preoperative transesophageal echocardiography revealed right-to-left shunt flow through a PFO induced by the Valsalva maneuver. During OPCAB, heart displacement resulted in right-to-left shunting and acute hypoxemia, which quickly improved with increase of inspired oxygen fraction. After chest closure, bidirectional shunt flow developed under increased airway pressure. Conclusions Vigilant intraoperative monitoring with TEE and postoperative airway pressure management are important to address shunt flow and hypoxemia due to PFO.

Abstract Fusicoccin-A (FC-A) is a diterpene glucoside produced by a pathogenic fungus. Since its discovery, FC-A has been widely recognized as a phytotoxin that induces stomatal opening and leaf wilting, eventually leading to plant death. In this study, we present the first evidence that FC-A enhances plant growth by stabilizing the protein-protein interaction between plasma membrane (PM) H+-ATPase and 14-3-3 in guard cells. Long-term treatment of Arabidopsis plants with FC-A resulted in ~ 30% growth enhancement. Structurally similar fusicoccin-J (FC-J) showed a similar degree of growth-promotion activity as FC-A, whereas the more hydrophilic fusicoccin-H (FC-H) exhibited no effect on plant growth, indicating that the enhancement of plant growth observed with FC-A and FC-J involves upregulation of the protein-protein interaction between PM H+-ATPase and 14-3-3 in guard cells, which promotes stomatal opening and photosynthesis.

Background: To avoid complete elimination of hen eggs (HE) from diet, we introduced a very-low-dose (VLD) oral food challenge (OFC) in patients with severe HE allergy in 2019. Herein, we investigated the efficacy of VLD HE OFC for achieving the full dose OFC. Methods: Patients with an overt allergic reaction to LD (1/32 HE [≤100 mg]) or less, egg white (EW) protein within 6 months were included. In the VLD group, patients not achieving full-dose OFC (1/2 HE: 1600 mg EW protein) within 2 years were excluded. We retrospectively compared the rate of passing a full-dose OFC between patients who underwent a LD OFC before 2019 (LD group) and those who underwent a VLD OFC (1/100 HE: 32 mg EW protein) after 2019 (VLD group). The period for passing the full-dose OFC was evaluated using Kaplan–Meier survival analysis. Results: We enrolled 411 and 111 patients in the LD and VLD groups, respectively. The median age at OFC initiation was 2.2 [1.5–3.6] and 2.1 [1.4–3.2] years in the LD and VLD groups, respectively. EW- and ovomucoid-specific IgE levels were 38.3 (12.5–72.9) and 21.0 (8.3–46.2) kUA/L in the LD group and 49.8 [18.8–83.9] and 32.1 [15.6–67.8] kUA/L in the VLD group, respectively. Over 4 years, the LD and VLD groups passed the full-dose OFC at rates of 70 and 95%, respectively, with significant differences (log-rank test, P

Abstract Many SAR images have been utilized for geologic disasters investigations with the continuous launch of new Synthetic Aperture Radar (SAR) satellites such as ALOS-2/PALSAR-2. However, to proactively respond to transient slope failures caused by heavy rainfall, rapid extraction of areas of surface change accompanying slope failures is required. This study proposes two methods for quantitatively extracting slope failure areas using L-band SAR observations with slope units (SUs) as the evaluation units. The first method is based on the threshold method, which automates the selection of thresholds for various disaster-affected conditions, such as land use and topography. The second method is a machine-learning-based density ratio estimation method, which uses multi-temporal periodic observation data and pre- and post-disaster data to detect outliers through feature selection optimization. In the observation direction with the shortest satellite observation period, the F1 score (The F1 score is the harmonic mean of the precision and recall) of the threshold method for accuracy evaluation is 61.91%, and the F1 score of the density ratio method is 65.87%. Both methods can reduce the problem of low extraction accuracy caused by the effect of speckle noise. When slope failure occurs, both methods can extract the area of surface change within hours of a disaster. The method proposed in this study displays good applicability in supporting emergency rescue and the prevention of secondary disasters.

Abstract In accordance with recent progress of fracton topological phases, unusual topological phases of matter hosting fractionalized quasiparticle excitations with mobility constraints, new type of symmetry is studied — multipole symmetry, associated with conservation of multipoles. Based on algebraic relation between dipole and global charges, we introduce a series of (d + 1)-dimensional BF theories with p-form gauge fields, which admit dipole of spatially extended excitations, and study their physical properties. We elucidate that gauge invariant loops have unusual form, containing linear function of the spatial coordinate, which leads to the position dependent braiding statistics and unusual ground state degeneracy dependence on the system size. We also show that the theories exhibit a mixed ’t Hooft anomaly between p-form and (d − p)-form dipole symmetries, which is canceled by an invertible theory defined in one dimensional higher via anomaly inflow mechanism.

Abstract Background Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. Methods This retrospective multi‐institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. Results Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19–9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un‐matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p

Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to −0.5) vs. −0.4 (-0.6 to −0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to −0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to −1.3) vs. −0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (−0.9 ± 0.25 vs. −0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19–16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

Introduction The growing obstacles to balancing work and family caregiving responsibilities (work–family care obstacles) have led to heightened difficulties in work–life adjustment among employees, potentially resulting in decreased life satisfaction. Objectives The aims of this study were to investigate whether facing work–family care obstacles is associated with poor life satisfaction and whether it moderates the association between caregiver burden and life satisfaction among working family caregivers in Japan. Methods A cross-sectional descriptive study was conducted involving 141 family caregivers, all of whom were under 65 years old and living with older long-term care recipients. Multiple logistic regression analysis was conducted to examine the primary and moderating effects of work–family care obstacles on life satisfaction in the context of caregiver burden. Results Experiencing significant work–family care obstacles was associated with poor life satisfaction among employed family caregivers. Moreover, work–family care obstacles exacerbated the relationship between caregiver burden and poor life satisfaction. Family caregivers who faced work–family care obstacles and experienced two or more caregiver burdens exhibited poor life satisfaction (odds ratio = 5.51, 95% confidence interval = [1.97, 15.43]) compared to those who had one or fewer caregiver burden. For family caregivers without work–family care obstacle, the risk of poor life satisfaction did not vary depending on the number of caregiver burdens. Conclusion These findings suggest that work–life adaptation is more important than work–life balance for maintaining feelings of satisfaction in both life and work.

Pulmonary alveolar proteinosis (PAP) is a rare disease, which is characterized by the alveolar accumulation of surfactant. A crazy-paving appearance on chest thin-section computed tomography (TSCT) is a characteristic feature of this disease. We report an unusual case of PAP, which presented as multiple localized ground glass opacites (GGOs) on TSCT in an 80-year-old female. As one of these lesions at the apex of the right lung increased in size, it was suspected to be a pulmonary adenocarcinoma. However, the others became smaller during the follow-up period. Right upper lobectomy was performed, and PAP was histologically diagnosed. In cases exhibiting multiple localized GGOs, PAP should be considered, even if GGOs with a crazy-paving-like appearance are distributed in a lobular rather than diffuse manner.

Introduction: About 15–20 % of babies that suffer perinatal asphyxia die and around 25 % of the survivors exhibit permanent neural outcomes. Minimization of this global health problem has been warranted. This study investigated if the offspring of pregnant female rats allowed to spontaneously exercise on running wheels along a 11-day pregnancy period were protected for somatic and neurodevelopmental disturbs that usually follow neonatal anoxia. Methods: spontaneous exercise was applied to female rats which were housed in cages allowing free access to running wheels along a 11-day pregnancy period. Their offspring were submitted to anoxia 24–36 h after birth. Somatic and sensory-motor development of the pups were recorded until postnatal day 21 (P21). Myelin basic protein (MBP)-stained areas of sensory and motor cortices were measured at P21. Neuronal nuclei (NeuN)-immunopositive cells and synapsin-I levels in hippocampal formation were estimated at P21 and P75. Results: gestational exercise and / or neonatal anoxia increased the weight and the size of the pups. In addition, gestational exercise accelerated somatic and sensory-motor development of the pups and protected them against neonatal-anoxia-induced delay in development. Further, neonatal anoxia reduced MBP stained area in the secondary motor cortex and decreased hippocampal neuronal estimates and synapsin-I levels at P21; gestational exercise prevented these effects. Therefore, spontaneous exercise along pregnancy is a valuable strategy to prevent neonatal-anoxia-induced disturbs in the offspring. Conclusion: spontaneous gestational running wheel exercise protects against neonatal anoxia-induced disturbs in the offspring, including (1) physical and neurobehavioral developmental impairments, and (2) hippocampal and cortical changes. Thus, spontaneous exercise during pregnancy may represent a valuable strategy to prevent disturbs which usually follow neonatal anoxia.

ABSTRACTPrion disease is an infectious and fatal neurodegenerative disease. Western blotting (WB)-based identification of proteinase K (PK)-resistant prion protein (PrPres) is considered a definitive diagnosis of prion diseases. In this study, we aimed to detect PrPres using formalin-fixed paraffin-embedded (FFPE) specimens from cases of sporadic Creutzfeldt–Jakob disease (sCJD), Gerstmann–Sträussler–Scheinker disease (GSS), glycosylphosphatidylinositol-anchorless prion disease (GPIALP), and V180I CJD. FFPE samples were prepared after formic acid treatment to inactivate infectivity. After deparaffinization, PK digestion was performed, and the protein was extracted. In sCJD, a pronounced PrPres signal was observed, with antibodies specific for type 1 and type 2 PrPres exhibited a strong or weak signals depending on the case. Histological examination of serial sections revealed that the histological changes were compatible with the biochemical characteristics. In GSS and GPIALP, prion protein core-specific antibodies presented as PrPres bands at 8–9 kDa and smear bands, respectively. However, an antibody specific for the C-terminus presented as smears in GSS, with no PrPres detected in GPIALP. It was difficult to detect PrPres in V180I CJD. Collectively, our findings demonstrate the possibility of detecting PrPres in FFPE and classifying the prion disease types. This approach facilitates histopathological and biochemical evaluation in the same sample and is safe owing to the inactivation of infectivity. Therefore, it may be valuable for the diagnosis and research of prion diseases.

This work presents a copper zinc tin sulfide (CZTS)-based solar cell structure (AI/ITO/C60/CZTS/SnS/Pt) with C60 as a buffer layer, developed using the SCAPS-1D simulator by optimizing each parameter to calculate the output. Optimizing the parameters, the acceptor concentration and thickness were altered from 6.0 × 1015 cm−3 to 6.0 × 1018 cm−3 and 1500 nm to 3000 nm, respectively. Although, in this simulator, we can tune the value for the acceptor concentration to 6.0 × 1022, higher doping might present an issue regarding adjustment in the physical experiment. Thus, tunable parameters need to be chosen according to the reliability of the experimental work. The defect density varied from 1.0 × 1014 cm−3 to 1.0 × 1017 cm−3 and the auger hole/electron capture coefficient was determined to be 1.0 × 10−26 cm6 s−1 for the maintenance of the minorities in theoretical to quasi-proper experimental measurements. Although the temperature was intended to be kept near room temperature, this parameter was varied from 290 K to 475 K to investigate the effects of the temperature on this cell. The optimization of the proposed structure resulted in a final acceptor concentration of 6.0 × 1018 cm−3 and a thickness of 3000 nm at a defect density of 1.0 × 1015 cm−3, which will help to satisfy the desired experimental performance. Satisfactory outcomes (VOC = 1.24 V, JSC = 27.03 mA/cm2, FF = 89.96%, η = 30.18%) were found compared to the previous analysis.

Abstract Background Medical corporations, which are non-profit organizations that aim to operate hospitals, clinics, or long-term care facilities, account for more than half of all hospital beds and play a central role in the health care system in Japan. However, limited analysis of hospital integration has been performed. Examining the hospital integration trends of medical corporations can provide valuable insights for optimizing health care delivery and resource allocation in Japan. This study conducted a comprehensive analysis of trends in the hospital integration of medical corporations and market concentration in Japan using nationwide longitudinal data. Methods This longitudinal study evaluated the hospital integration of medical corporations in Japan between 2017 and 2021 using medical corporation financial data provided by the Neostage Company. The target population was medical corporations that own hospitals in Japan. The primary outcomes were the horizontal and vertical integration of medical corporation hospitals. Horizontal integration was defined as the integration of two or more hospitals within the same corporation, while vertical integration was defined as the integration of a hospital with different types of health care facilities, such as clinics or long-term care facilities, within a single medical corporation. The Herfindahl–Hirschman Index (HHI) was calculated to measure hospital market concentration using hospital bed data for medical corporations in all prefectures. Results The number of hospitals and hospital beds within medical corporations decreased from 5,670 to 848,174 in 2017 to 5,486 and 814,462 in 2021, respectively. Both horizontal and vertical integration among medical corporation facilities showed a gradual upward trend, increasing from 24.92% to 55.75% in 2017 to 26.92% and 59.42% in 2021, respectively. The mean (standard deviation [SD]) HHI increased slightly from 262.7 (178.6) in 2017 to 275.2 (187.9) in 2021, with rural areas being more concentrated than urban areas, although both remained unconcentrated. Conclusions This longitudinal study revealed a gradual downward trend in the number of hospitals and hospital beds owned by medical corporations, while horizontal and vertical integration gradually progressed without any particular medical corporation dominating the market. These findings are expected to contribute to policymaking efforts aimed at providing optimal health care services in Japan.

Abstract The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and β-cell function in middle-aged Japanese individuals, whose BMI averaged

Abstract The incidence of duodenal tumors (DTs) is increasing. However, the mechanisms underlying its development remain unclear. Environmental factors, including the microbiome and bile acids (BAs), are believed to influence tumor development. Therefore, we conducted a single-center, prospective, observational study to investigate the potential differences between patients with DTs and healthy controls (HCs) based on these factors. In addition, the BAs in the duodenal fluid were measured using liquid chromatography-tandem mass spectrometry. We recruited 41 patients and performed 16S rRNA-seq. There was no difference in the observed ASVs or PCoA plot of Bray–Curtis dissimilarity between the DTs and HCs. The lithocholic acid concentration was significantly lower in the DT group than in the control group. The ratio of CDCA to LCA was significantly higher in patients with DTs. No significant differences in microbiota were observed between DTs and HCs. In patients with DTs, the lithocholic acid concentration in duodenal was significantly lower than in HCs.

Abstract Because of the advent of genome-editing technology, gene knockout (KO) hamsters have become attractive research models for diverse diseases in humans. This study established a new KO model of diabetes by disrupting the insulin receptor substrate-2 (Irs2) gene in the golden (Syrian) hamster. Homozygous KO animals were born alive but with delayed postnatal growth until adulthood. They showed hyperglycemia, high HbA1c, and impaired glucose tolerance. However, they normally responded to insulin stimulation, unlike Irs2 KO mice, an obese type 2 diabetes (T2D) model. Consistent with this, Irs2 KO hamsters did not increase serum insulin levels upon glucose administration and showed β-cell hypoplasia in their pancreas. Thus, our Irs2 KO hamster provide a unique T2D animal model that is distinct from the obese T2D models. This model may contribute to a better understanding of the pathophysiology of human non-obese T2D with β-cell dysfunction, the most common type of T2D in East Asian countries, including Japan.

Abstract Background Prostate ductal adenocarcinoma, a rare histology observed in 0.4–0.8% of all prostate cancers, is treated similarly to acinar adenocarcinoma but tends to have a higher likelihood of metastasis, recurrence, and poorer prognosis. Case presentation A 73-year-old Asian-Japanese male presented with gross hematuria, with investigations revealing a prostate ductal adenocarcinoma. Subsequent radical prostatectomy indicated a Gleason score of 8 with no lymph node metastasis. Despite initial prostate-specific antigen level reductions post-prostatectomy and salvage radiation therapy due to recurring elevated prostate-specific antigen levels, no recurrence was evident until 13 years later. A tumor in the anterior urethra was identified as metastasis of his prostate ductal adenocarcinoma. Conclusion This report presents an uncommon case of prostate ductal adenocarcinoma exhibiting a late recurrence in the anterior urethra 13 years post-radical prostatectomy.

Abstract Generation and accumulation of amyloid-β (Aβ) protein in the brain are the primary causes of Alzheimer’s disease (AD). Alcadeins (Alcs composed of Alcα, Alcβ and Alcγ family) are a neuronal membrane protein that is subject to proteolytic processing, as is Aβ protein precursor (APP), by APP secretases. Previous observations suggest that Alcs are involved in the pathophysiology of Alzheimer’s disease (AD). Here, we generated new mouse App NL-F (APP-KI) lines with either Alcα- or Alcβ-deficient background and analyzed APP processing and Aβ accumulation through the aging process. The Alcα-deficient APP-KI (APP-KI/Alcα-KO) mice enhanced brain Aβ accumulation along with increased amyloidogenic β-site cleavage of APP through the aging process whereas Alcβ-deficient APP-KI (APP-KI/Alcβ-KO) mice neither affected APP metabolism nor Aβ accumulation at any age. More colocalization of APP and BACE1 was observed in the endolysosomal pathway in neurons of APP-KI/Alcα-KO mice compared to APP-KI and APP-KI/Alcβ-KO mice. These results indicate that Alcα plays an important role in the neuroprotective function by suppressing the amyloidogenic cleavage of APP by BACE1 in the brain, which is distinct from the neuroprotective function of Alcβ, in which p3-Alcβ peptides derived from Alcβ restores the viability in neurons impaired by toxic Aβ.

Abstract The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

Introduction: TP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non–small cell lung cancer remains unclear. Materials and methods: A cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. Results: Mutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). Conclusions: TP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

Abstract The genome is constantly exposed to DNA damage from endogenous and exogenous sources. Fine modulation of DNA repair, chromatin remodeling, and transcription factors is necessary for protecting genome integrity, but the precise mechanisms are still largely unclear. We found that after ionizing radiation (IR), global trimethylation of histone H3 at lysine 4 (H3K4me3) was decreased at an early (5 min) post-IR phase but increased at an intermediate (180 min) post-IR phase in both human and mouse hematopoietic cells. We demonstrated that PTIP, a component of the MLL histone methyltransferase complex, is required for H3K4me3 upregulation in the intermediate post-IR phase and promotes cell cycle arrest by epigenetically inducing a cell cycle inhibitor, PRDM1. In addition, we found that PTIP expression is specifically downregulated in acute myeloid leukemia patients. These findings collectively suggest that the PTIP-PRDM1 axis plays an essential role in proper DNA damage response and its deregulation contributes to leukemogenesis.

Abstract Background There are few reports of kidney disease caused by cryofibrinogen (CF). There are still many unknowns regarding its diagnosis, treatment, and prognosis. Case presentation A woman in her 70s experienced gross hematuria without any triggers; no urinary abnormalities had been previously detected. At the same time, the urine protein level was 5 g; therefore, a renal biopsy was performed. Light microscopy revealed a membranoproliferative glomerulonephritis-like pattern. And the electron microscopic findings were extremely characteristic and specific. Development of ischemic lesions was observed in the lower legs. A skin biopsy performed at the sites of toe necrosis showed fibrinoid necrotizing vasculitis and thrombi in the blood vessels. Eventually, the patient was diagnosed with cryofibrinogenemia (CF-emia) by mass spectrometry. The effect of steroids was limited. Subsequently, the patient’s renal function rapidly deteriorated, and toe necrosis progressed. The patient died after initiation of hemodialysis. Conclusion Although CF-emia is an unknown disease and has been infrequently reported, no reported cases exhibited rapid worsening of toe necrosis and renal function during the same period. Therefore, this case can be said to be the first case of fulminant cryofibrinogenemia. Due to the development of nephropathy, which is likely to be a factor for poor prognosis, establishment of therapeutic strategies is urgently required.

Abstract Aims The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1 year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission. Methods and results The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all‐cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non‐fatal myocardial infarction, or non‐fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow‐up of 12 months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction

Double aortic arch (DAA) is a rare congenital abnormality characterized by a vascular ring that often requires surgical intervention due to respiratory complications. The DAA and right aortic arch with mirror-image branches (RAA-MB) represent abnormalities in development of the aortic arch. However, prognosis differs significantly, as the DAA forms vascular rings, whereas the RAA-MB typically does not. Distinguishing between the conditions becomes particularly challenging in cases of DAA with closure of the posterior portion of the left aortic arch (LAA) because the postnatal manifestations closely resemble those of RAA-MB. Herein, we present a case of DAA in which longitudinal observation of the LAA and RAA diameters during pregnancy aimed in predicting postnatal closure of the LAA. A 37-year-old female with suspected DAA was referred to our hospital at 26 weeks of gestation. Initial measurements revealed comparable diameters for the LAA and RAA; however, the LAA diameter decreased to approximately half that of the RAA by term owing to growth restrictions. Postnatal contrast computed tomography confirmed the closure of the posterior portion of the LAA and RAA with Kommerell diverticulum. Our findings suggest that careful monitoring of DAA throughout fetal development, especially during the third trimester, may aid in predicting atretic changes in the nondominant arch after birth, allowing an easy distinction between the DAA and RAA-MB after birth.

Many marine red algae species are used as food sources around the world. Here, the study focuses on free radical scavenging properties as a beneficial activity of the red alga Neopyropia yezoensis (Susabi-nori), which is consumed in Japan, and investigates quantitative changes in the compounds that could affect the activity due to processing steps. It was found that the dried and roasted samples showed more active radical scavenging properties detected by the 2,2′-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assay compared to the fresh samples. The contents of phenolic compounds, mycosporine-like amino acids (MAAs), chlorophylls, and carotenoids were evaluated; it was suggested that an increase in phenolic compounds was responsible for the enhancement of the activity. On the other hand, no correlation with the activity was found for MAAs, chlorophylls, and carotenoids. Furthermore, by comparing three different sampling times (early December, early January, and early March), it was found that the sample taken in early December showed the highest radical scavenging activity. These results suggest that the useful activities of N. yezoensis, including its antioxidant activity, can be influenced by its processing steps and harvest time.

The advancement in depth-sensor technology increased the potential for the clinical use of markerless three-dimensional motion analysis (3DMA); however, the accurate quantification of depth-sensor-based 3DMA on gait characteristics deviating from normal patterns is unclear. This study investigated the concurrent validity of the measurements of compensatory movements measured by depth-sensor-based 3DMA compared to those measured by marker-based 3DMA. We induced swing-phase compensatory movements due to insufficient toe clearance by restricting unilateral ankle and knee joint movements in healthy individuals. Thirty-two healthy young adults (nineteen males, aged 20.4 ± 2.0 years, height 164.4 ± 9.8 cm, weight 60.0 ± 9.3 kg [average ± standard deviation]) walked the 6 m walkway in slow speed, very slow speed, and knee–ankle–foot orthosis (KAFO; participants wore KAFOs on the right leg) conditions. Gait kinematics were measured with marker-based and depth-sensor-based 3DMA systems. The intraclass correlation coefficient (ICC3,1) was used to measure the relative agreement between depth-sensor-based and marker-based 3DMA and demonstrated good or moderate validity for swing-phase compensatory movement measurement. Additionally, the ICC2,1 measured absolute agreement between the systems and showed lower validity than the ICC3,1. The measurement errors for contralateral vaulting, trunk lateral flexion, hip hiking, swing-side hip abduction, and circumduction between instruments were 0.01 m, 1.30°, 1.99°, 2.37°, and 1.53°, respectively. Depth-sensor-based 3DMA is useful for determining swing-phase compensatory movements, although the possibility of missing a slight measurement error of 1–2° must be considered.

Abstract Background Endoscopic submucosal dissection (ESD) is a potentially efficient therapeutic intervention for superficial esophageal cancer. Additional treatment such as chemoradiotherapy (CRT) or esophagectomy is recommended in cases of muscularis mucosa invasion with positive resection margins or lymphovascular invasion or submucosal layer invasion, which are considered noncurative ESD, due to an increased risk of lymph node metastasis. However, the adequacy of additional CRT after near-circumferential or full-circumferential noncurative ESD has not been fully discussed. In this study, we retrospectively evaluated the efficacy and toxicity of additional CRT for superficial esophageal squamous cell carcinoma (SCC) after near-circumferential or full-circumferential noncurative ESD, which was defined as a mucosal defect measuring ≥ 3/4 of the esophageal circumference. Methods We retrospectively evaluated 24 patients who received additional CRT for superficial esophageal SCC after near-circumferential or full-circumferential noncurative ESD between 2012 and 2018. Elective nodal irradiation (ENI) was performed in all patients and boost irradiation (BI) was performed after ENI in 4 patients with positive resection margins. The prescription doses of ENI and BI were 41.4 Gy in 23 fractions and 9 Gy in 5 fractions, respectively. Concurrent chemotherapy (a combination of cisplatin or nedaplatin and 5-fluorouracil) was administered to all patients. Results The 3-year and 5-year overall survival rates were 92% and 78%, respectively, while the 3-year and 5-year progression-free survival rates were 83% and 70%, respectively. Grade 2 esophageal stenosis occurred in 8 (33%) patients. There was no case of Grade 3 or worse esophageal stenosis. Among them, 4 (17%) patients developed stenosis before additional CRT, which persisted after the completion of additional CRT. The remaining 4 (17%) patients developed de novo stenosis within 5 months following the completion of additional CRT. One patient (4%) still requires regular bougie dilation. Grade 3 and Grade 4 acute toxicity, including anemia, neutropenia, thrombocytopenia, and esophagitis occurred in 1 (4%) and 0 (0%), 6 (25%) and 1 (4%), 1 (4%) and 0 (0%), and 1 (4%) and 0 (0%) patients, respectively. One (4%) patient who underwent salvage CRT for the out-of-field lymph node recurrence died with acute myeloid leukemia. Conclusions Additional CRT is a viable treatment option even in patients who have undergone near-circumferential or full-circumferential noncurative ESD. Esophageal stenosis after additional CRT following near-circumferential or full-circumferential noncurative ESD is manageable and acceptable.

Abstract Orthostatic intolerance (OI) is a key symptom of long COVID; however, the pathophysiology remains unknown. Among 688 long COVID patients who visited our clinic during the period from February 2021 to April 2023, 86 patients who were suspected of having OI and who underwent an active standing test (ST) were investigated to elucidate the clinical characteristics of OI in patients with long COVID. Of the 86 patients, 33 patients (38%) were ST-positive. Nausea and tachycardia in daily life were frequent complaints in the ST-positive group. The increase in heart rate (HR) during the ST was significantly greater during a 10-min period after standing in the ST-positive group (+ 30 bpm) than in the ST-negative group (+ 16 bpm). The initial increase in diastolic blood pressure (DBP) just after standing was significantly greater in the ST-positive group (+ 14 mmHg) than in the ST-negative group (+ 9 mmHg). Serum cortisol levels in the ST-positive patients aged over 20 years were higher and growth hormone levels in the patients under 20 years of age were lower than those in the ST-negative group. Autonomous nervous symptoms, transient DBP rise with increasing HR after standing, and endocrine dysfunctions are helpful for detecting OI related to long COVID.

Abstract This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab–paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb

Abstract Associations of adipose tissue insulin resistance index (AT-IR, a product of fasting insulin and free fatty acids) with body fat mass and distribution and appendicular skeletal muscle mass (ASM) were compared with results of homeostasis-model assessment-insulin resistance (HOMA-IR) in 284 Japanese female university students and 148 their biological mothers whose BMI averaged

Background: Studies on the association between preserved ratio impaired spirometry (PRISm) and dementia are limited. Indeed, PRISm has often been overlooked or ignored as an index of lung function impairment. Therefore, we investigated the association of PRISm with the risk for the development of dementia in an older Japanese population. Methods: A total of 1,202 community-dwelling, older Japanese participants aged ≥65 years without dementia were followed up for a median of 5.0 years. Participants were categorized by spirometry as follows: normal spirometry (FEV1/FVC ≥0.70 and FEV1 ≥80% predicted), PRISm (≥0.70 and

Abstract Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4–PROTAC–CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

Abstract Background Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM) (OMIM #155,601), which is associated with an increased risk of pancreatic ductal adenocarcinoma and melanoma. FAMMM has been reported globally, but it is quite rare in Japan. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. Case presentation The first case is a 74-year-old woman with a diagnosis of pancreatic carcinoma with multiple liver metastases. She had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. Whole exon sequencing detected a germline CDKN2A variant evaluated as likely pathogenic. The results were disclosed to her daughters after she died, and the same CDKN2A variant was detected in one of the daughter. The daughter was referred to a nearby hospital for her clinical management. The second case is a 65-year-old man with pancreatic ductal adenocarcinoma. He had family histories of pancreatic cancer, but no personal or family history of malignant melanoma. He underwent a comprehensive genomic profiling test using pancreatic cancer tissue, and detected a presumed germline pathogenic variant of CDKN2A. Germline testing confirmed the same CDKN2A variant. Genetic analysis of his relatives produced negative results. Other blood relatives are scheduled for genetic analysis in the future. We report two families with familial pancreatic cancer with suspected pathogenic variants of CDKN2A that were incidentally identified through comprehensive genomic profiling. Conclusions In current Japanese precision medicine, comprehensive genetic analysis can reveal rare genetic syndromes and offer us the opportunity to provide health management for patients and their relatives. However, gene-specific issues are raised in terms of the evaluation of a variant’s pathogenicity and the extent of surveillance of the at-risk organs due to a lack of genetic and clinical data concerning CDKN2A variant carriers in Japan.

Introduction Few studies have reported on administering enfortumab vedotin to patients with metastatic urothelial carcinoma and end‐stage renal disease requiring hemodialysis. Case presentation Case 1: An 85‐year‐old man underwent hemodialysis for progressive renal failure 4 months after right laparoscopic radical nephroureterectomy. Case 2: A 73‐year‐old man underwent hemodialysis after two laparoscopic radical nephroureterectomies for recurrent urothelial carcinoma. In both cases, enfortumab vedotin was administered due to postoperative recurrence and progression despite platinum‐based chemotherapy and pembrolizumab. Partial response and disease progression were observed in cases 1 and 2, respectively. Adverse events included a mild skin rash in both patients and neutropenia in Case 1, both of which resolved with symptomatic treatment. Conclusion The efficacy and safety of enfortumab vedotin in patients with metastatic urothelial carcinoma, and end‐stage renal disease undergoing hemodialysis, were confirmed.

Abstract Background Increase in functional disability in aging societies is an international medical and public health issue. Masticatory function may be a potential risk factor for functional disability, but the role of frailty in the association has not been clarified. Methods Forty thousand five hundred sixty-two community-dwelling older adults aged 65 years and over who were insured by public health insurance as of April 2018 were followed up for a median of 3.0 years. Masticatory function was categorized as good, moderate, or poor based on a self-reported questionnaire. The development of functional disability was defined as a new certification of the need for long-term care. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). Results During the follow-up period, 1,397 individuals experienced functional disability. After adjusting for age, sex, comorbidities, medical history, and lifestyle behaviors, the HR for incident functional disability was significantly higher in the moderate and poor groups compared to the good group (moderate, HR 1.21 [95% CI, 1.07–1.37]; poor, HR 1.64 [95% CI, 1.03–2.62]). However, after additional adjustment for frailty-related factors—namely, underweight, regular exercise, and gait speed—the association was attenuated in both the moderate group (HR 1.06 [95% CI, 0.94–1.21]) and the poor group (HR 1.51 [95% CI, 0.94–2.41]). Conclusions Masticatory dysfunction was significantly associated with incident functional disability in a community-dwelling older Japanese population. Our findings suggest that masticatory dysfunction may be a surrogate of frailty rather than a direct cause of functional disability.