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The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.

Background The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population.Methods We stratified 177 individuals who participated in the Japanese Alzheimer’s Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)tau and AT(N)NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles.Results We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer’s disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)tau and AT(N)NfL classifications. When we used t-tau as the N marker (AT(N)tau), those who had T− were more frequently assigned to (N)−, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)tau and AT(N)NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)tau classification, but not in the AT(N)NfL classification.Conclusions AT(N)tau and AT(N)NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

Research and development of personalized cancer vaccines as precision medicine are ongoing. We predicted human leukocyte antigen (HLA)-compatible cancer antigen candidate peptides based on patient-specific cancer genomic profiles and performed a Phase I clinical trial for the safety and tolerability of cancer vaccines with human platelet lysate-induced antigen-presenting cells (HPL-APCs) from peripheral monocytes. Among the five enrolled patients, two patients completed six doses per course (2–3 × 107 cells per dose), and an interim analysis was performed based on the immune response. An immune response was detected by enzyme-linked immunosorbent spot (ELISpot) assays to HLA-A*33:03-matched KRASWT, HLA-DRB1*09:01-compliant KRASWT or G12D, or HLA-A*31:01-matched SMAD4WT, and HLA-DRB1*04:01-matched SMAD4G365D peptides in two completed cases, respectively. Moreover, SMAD4WT-specific CD8+ effector memory T cells were amplified. However, an attenuation of the acquired immune response was observed 6 months after one course of cancer vaccination as the disease progressed. This study confirmed the safety and tolerability of HPL-APCs in advanced and recurrent cancers refractory to standard therapy and is the first clinical report to demonstrate the immunoinducibility of personalized cancer vaccines using HPL-APCs. Phase II clinical trials to determine immune responses with optimized adjuvant drugs and continued administration are expected to demonstrate efficacy.

Abstract Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed “HLA-guided treatment schedule” and the “current schedule” being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the “HLA-guided treatment schedules,” we considered a situation wherein the HLA test performed before clozapine initiation could provide “a priori information” by detecting patients harboring risk of HLA variants (HLA-B*59:01 and “HLA-B 158T/HLA-DQB1 126Q” for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% “prevention rate”). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of “HLA-guided treatment schedule” and “current schedule” used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the “HLA-guided treatment schedule” was more cost effective than the “current schedule”; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the “current schedule” of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

Abstract Objective We developed a silver-containing hydroxyapatite (Ag-HA) coating to prevent periprosthetic joint infection (PJI). Methicillin-resistant Staphylococcus aureus (MRSA) is the main PJI-causing bacteria. Previously, we had reported the combined effect of Ag-HA coating and vancomycin (VCM) on MRSA biofilm formation 24 h after MRSA inoculation. In this study, we investigated the time-dependent efficacy of Ag-HA coating and VCM on MRSA biofilm formation on Ti discs in vitro by three-dimensional confocal laser scanning microscopic analysis. Results For the Ti VCM and HA VCM groups, the total biofilm volumes per area at 96 h after MRSA inoculation were significantly larger than those at 48 h after MRSA inoculation, respectively (p

Abstract SLC6A4, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (N = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.

Direct planting – in which small storage roots are planted instead of transplanting stem cuttings – has been studied as a labor-saving system in sweet potato. Early vigor is important for cultivars used in direct planting because it affects their ability to compete with weeds. In this study, the genotypic difference in early vigor was evaluated. Twelve genotypes were tested in 2018 and 2019. Days to emergence, shoot dry matter yield, plant height, and NDVI were investigated as indicators of early vigor. Significant differences in days to emergence and shoot dry matter yields were observed among genotypes in both years. ‘Kyushu No.198ʹ was outstanding in terms of early vigor. A strong relationship between plant height and shoot dry matter yield was observed; this relationship was also observed with NDVI. Growth traits that can be monitored in a non-destructive way, such as plant height, are reliable predictors of shoot dry matter yield during early growth.

Eco-friendly flexible humidity sensors with high sensing performance are desired for the next-generation wearable electronics. In this work, we developed a high-performance fully printed flexible humidity sensor using all-carbon functional materials. The electrodes and sensing layer of the sensor were printed using all-carbon-based cellulose nanofiber/graphene nanoplatelet (CNF/GNP) composites. The newly developed CNF/GNP ink can be prepared by simple mixing without any complex processes. These sensors showed a high resistive response of 240% over the relative humidity (RH) range of 30% to 90%, with response and recovery times of 17 s and 22 s, respectively, and good mechanical flexibility. Since CNF and GNPs are abundant in nature, degradable, and biocompatible, this work suggests the possibility of manufacturing inexpensive, eco-friendly sensors with high performances. As a proof-of-concept, we demonstrate the application of our sensor in human respiration detection, non-contact proximity sensing, and baby-diaper wetness monitoring.

Abstract Background CDKN2A hypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations between CDKN2A methylation status and MIF polymorphisms (rs755622 and rs5844572). Methods One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status of p14 ARF and p16 INK4a was determined by MSP; MIF genotypes were identified by PCR-SSCP. Results We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylated p14 ARF or p16 INK4a . Carrying the rs755622 C allele indicated a significantly higher risk for p14 ARF methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08–4.32; p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk for p16 INK4a methylation (OR, 2.57; 95% CI, 1.26–5.24; p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of both p14 ARF and p16 INK4a when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22–6.01; p = 0.015 and OR, 2.87; 95% CI, 1.25–6.62; p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55–262.6; p = 0.0059 and OR, 4.38; 95% CI, 1.12–17.2; p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46–144.3; p = 0.022). Conclusions Taken together, our findings suggest that MIF genotypes associated with inflammation may also be involved in promoting carcinogenesis via CDKN2A hypermethylation in patients diagnosed with UC.

Abstract Background CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. Methods We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14 ARF , p16 INK4a , DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/μL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. Results The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14 ARF , p16 INK4a , DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14 ARF ). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. Conclusions Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.

Mitochondrial tRNA modifications are important for tRNA stability and accurate decoding. By employing RNA mass spectrometry and deep sequencing, here the authors provide a comprehensive analysis of post-transcriptional modifications of 22 species of human mitochondrial tRNAs.

Abstract Background Philadelphia‐negative (Ph‐negative) myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are exceptionally rare during childhood. Thus, clinical features of pediatric Ph‐negative MPNs remain largely unknown. This study was therefore performed to address this. Methods We performed a retrospective study to collect clinical information of children diagnosed with Ph‐negative MPNs from 2000 to 2016 using questionnaires in qualified institutions in Japan. The results obtained from the questionnaire survey were then combined with those from the national registry data. Results Among 50 children identified, five had PV, 44 had ET, and one had PMF. Median age at diagnosis was 14.0, 9.0, and 0 years, respectively. Male to female ratio was 4:1, 21:23, and 1:0, respectively. Detection rates of the JAK2 V617F variant were 0/5 in PV and 9/39 in ET. Frequencies of complications, such as thrombosis and subsequent leukemia, were lower than complication frequencies in adults. We identified two children who developed subsequent leukemia, which has not been reported previously, and one of them died. Conclusion This is the first nationally representative survey of pediatric Ph‐negative MPNs. Given its rarity, an international collaboration with comprehensive genetic analyses might be needed to fully elucidate the clinical and genetic features.

Abstract Background Spontaneous pneumothorax occurs more often in younger, slim, and shallow-chested men. Although less common, differential diagnoses for secondary pneumothorax in children are asthma, emphysematous blebs, catamenial pneumothorax, and others. We report a patient who presented with pneumothorax and was found to have an inflammatory myofibroblastic tumor (IMT)-like lesion, and present a review of the related literature. Case presentation A 14-year-old girl visited her physician for chest pain that developed while exercising. Although chest drainage was performed, the symptoms associated with a collapsed lung did not improve, and she was referred to our hospital. Computed tomography revealed the presence of a 19 × 17-mm cyst with a thick wall in the apex of the right lung. She was tested for infectious diseases, namely tuberculosis, but the results were not definitive. Catamenial pneumothorax was also suspected because she was menstruating when she presented to our hospital. As a therapeutic diagnosis, we performed a thoracoscopic partial resection of the right upper lobe of the lung. Three small openings were identified inside the cyst, suggesting connection with the bronchiole. The lesion was pathologically diagnosed as an IMT-like lesion. Considering the progress so far, we considered that the final diagnosis to be an IMT. The patient was discharged on postoperative day 3, and we have followed her for the past 6 months with no local recurrence or metastasis. Conclusions IMT is not uncommon in children. Therefore, this lesion should be considered as a possible diagnosis if children and young adults develop spontaneous pneumothorax.

Recent advances in the Internet of Things (IoT) have brought great opportunities for geographical information systems (GIS) to be integrated with cyber-physical systems (CPS) in urban management. However, the term IoT and CPS are new in the GIS realm. This article reviews the concepts of IoT and CPS from the perspective of geospatial spaces and proposes the concept of Geo CPS to develop the potential of new technology in the geographic dimension. Two forms of Geo CPS are discussed: pseudo-CPS (PCPS), which projects spatial data onto a display without interaction among data sources, and true-CPS (TCPS), which handles data sources deeply and semantically. While PCPS already has wide industrial applications, TCPS is still in its infancy. The spatial challenge for CPS in geo space involves operating conditions in an open environment, and here, the human-machine system interface will be key. A transformation of our mindset relating to GIS can lead to the creation of new value-added geographical information services. This will require new schemes and platforms for data sharing, processing, security, and privacy, etc. Keywords: Internet of things (IoT), Space integration, Cyber-physical systems (CPS), Sensing, Processing and Accutation (SPA)

This dataset includes two kinds of data (for inventory analysis in Table A1 to A13, and precondition of waste and recycle for plastic and cardboard in Table A14) for conducting life cycle assessment (LCA) of strawberry-package supply chain with considering food loss during transportation Inventory analysis includes input data for LCA analysis. The data in the inventory was referenced from the publication of Plastic Waste Management Institute Plastic Waste Management Institute, (2017) and calculated based on the damage area ratio measured in our co-submitted article (Sasaki et al., 2022). This data helps to reproduce the article (Sasaki et al., 2022) for inventory analysis and re-analyze the environmental impact through the life cycle of strawberry assessed in the co-submitted article. Data of waste (incineration and landfill) and recycle ratios for plastic was collected from the previous reports of the publication Basic Knowledge of Plastic Recycle 2021 (Plastic Waste Management Institute, 2021), and data of the ratios for cardboard was referenced from Transition of Collect Rate on Cardboard (Ministry of the Environment (MOE), 2016). Ratios in this data show Japan-specialized values and is useful for creating the inventory.

Purpose: In recent years, a method for improving gummy smiles in adults using an orthodontic anchor screw has been reported, but there is yet to be a treatment for the gummy smiles of those in the growth period. Methods: We improved the gummy smiles of three class II patients with vertical excessive growth of the upper jaw, during their growth period, using a simple bite jumping appliance (SBJA) and a high pull J-hook headgear. Results: It was found that SBJA promoted mandibular growth and the high-pull J-hook headgear inhibited the vertical growth of the maxillary anterior teeth. Conclusion: It is suggested that a combined use of high-pull J-hook headgear and SBJA is an effective way of improving gummy smiles in class II patients with vertical excessive growth of the upper jaw during their growth period.

In Japan, the working-age population will roughly halve by 2060 from its peak in the late 1990s. Therefore, significant labor saving is required to maintain quality in the railway business at its current level. One such approach is the trend toward introducing vehicle monitoring devices which can automatically monitor the condition of the vehicle and facilitate efficient maintenance. However, there is no equipment for conducting a non-dismantling functional inspection on the stiffness of critical bogie rubber components subjected to forces of several kilonewtons or more, so we decided to develop such equipment. The equipment monitors the status of the bogie by using a wayside high-speed camera to measure the vibration of the bogie when it passes over iron plates approximately 5 mm thick placed on the track. This report outlines the diagnostic method, demonstrates the accuracy of vibration measurement from camera images, and presents the results of a rubber stiffness evaluation test, where axle beams with different rubber stiffness values due to the status of cracks were attached to an actual vehicle. The axle beam, which has a rubber portion at the end, supports the axle box mainly in the longitudinal direction. In addition, by creating a numerical model for quantitative evaluation and assigning a suitable stiffness value to the replacement component, we show that the model gives the same results as the test and that the longitudinal stiffness of the axle beam can be evaluated quantitatively by a wayside camera.

Advances in high-throughput sequencing have revolutionized the manner with which we can study T cell responses. We describe a woman who received a human papillomavirus (HPV) therapeutic vaccine called PepCan, and experienced complete resolution of her cervical high-grade squamous intraepithelial lesion. By performing bulk T cell receptor (TCR) β deep sequencing of peripheral blood mononuclear cells before and after 4 vaccinations, 70 putatively vaccine-specific clonotypes were identified for being significantly increased using a beta-binomial model. In order to verify the vaccine-specificity of these clonotypes, T cells with specificity to a region, HPV 16 E6 91-115, previously identified to be vaccine-induced using an interferon-γ enzyme-linked immunospot assay, were sorted and analyzed using single-cell RNA-seq and TCR sequencing. HPV specificity in 60 of the 70 clonotypes identified to be vaccine-specific was demonstrated. TCR β bulk sequencing of the cervical liquid-based cytology samples and cervical formalin-fixed paraffin-embedded samples before and after 4 vaccinations demonstrated the presence of these HPV-specific T cells in the cervix. Combining traditional and cutting-edge immunomonitoring techniques enabled us to demonstrate expansion of HPV-antigen specific T cells not only in the periphery but also in the cervix. Such an approach should be useful as a novel approach to assess vaccine-specific responses in various anatomical areas.