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Amorphous metal oxides with analog resistive switching functions (i.e., continuous controllability of the electrical resistance) are gaining emerging interest due to their neuromorphic functionalities promising for energy efficient electronics. The mechanisms are currently attributed to field-driven migration of the constituent ions, but the applications are being hindered by the limited understanding of the physical mechanisms due to the difficulty in analyzing the causal ion migration, which occurs on a nanometer or even atomic scale. Here, the direct electrical transport measurement of analog resistive switching and angstro''m scale imaging of the causal ion migration is demonstrated in amorphous TaOx (a-TaOx) by conductive atomic force microscopy. Atomically flat thin films of a-TaOx, which is a practical material for commercial resistive random access memory, are fabricated in this study, and the mechanisms of the three known types of analog resistive switching phenomena (current-dependent set, voltage-dependent reset, and time-dependent switching) are directly visualized on the surfaces. The observations indicate that highly analog type of resistive switching can be induced in a-TaOx by inducing the continuous redox reactions for 2.0 < x < 2.5, which are characteristic of a-TaOx. The measurements also demonstrate drastic control of the switching stochasticity, which is attributable to controlled segregation of a metastable a-TaO2 phase. The findings provide direct clues for tuning the analog resistive switching characteristics of amorphous metal oxides and developing new functions for future neuromorphic computing.

Supplementary Table 3 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Supplementary Table 1 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Supplementary Table 2 from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

CCR Translation for This Article from Randomized Double-Blind Trial of Sulindac and Etodolac to Eradicate Aberrant Crypt Foci and to Prevent Sporadic Colorectal Polyps

Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer.Experimental design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted.Results: ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed.Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer. Clin Cancer Res; 17(11); 3803–11. ©2011 AACR.

Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine's Clinical Data Warehouse (2004-2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change -1.00 ± 0.23 mmol/L, P 0.001) or serotonin-noradrenaline reuptake inhibitor (SNRI; -1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004-2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58-5.45) and SNRIs (5.66, 4.38-7.31), but not for mirtazapine (1.08, 0.74-1.58), fluvoxamine (1.48, 0.94-2.32), and milnacipran (0.85, 0.45-1.62). Finally, pharmacoepidemiological-pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = -0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.

Stable operations as resistive switching memory were demonstrated in amorphous TaOx (a-TaOx) thin films with very flat surfaces by conductive atomic force microscopy (c-AFM). The a-TaOx thin films fabricated on glass and Nb-doped SrTiO3 substrates by pulsed laser deposition showed high surface flatness with root-mean-square roughness of less than 0.2 nm. The c-AFM observations on the surfaces revealed that the resistive switching in a-TaOx causes almost no change in the topographic structures, and the significant structural deformation appears after the electrical breakdown by longer-range migration of the constituent ions. The possible mechanisms of the resistive switching phenomena were discussed based on the changes in the topographic structures and conduction states.

Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.

The global population is concentrating unprecedentedly into urban areas, raising concerns on global sustainability and human well-being. There also exists a niche trend of migration from urban to rural areas particularly in countries with post-industrial economies. This paper investigated values of migration expressed by the migrants arrived in Hokuto City, a Japanese rural municipality experiencing pervasive population decline but is also a popular destination for migrants from urban areas. Statistical analyses of 868 responses to a Hokuto City's migrant survey between April 2017 and January 2019 identified their common values of migration, i.e., nature, housing and food. In addition to these common values, households with different demographic characteristics had different priorities: employment for singles in ages between 16 and 29; favorable environment for raising children for married couples in their 30s and 40s; not specific or ‘lifestyle’ for migrants in 50s; and staying with or near family for retirees over 60 years. Knowledge of heterogeneity in migrants and of their values, as described herein, will enable targeted policies and public services concerning migration. Widespread acceptance of teleworking after experiencing the COVID-19 pandemic might offer people of working age, particularly in their 20s and younger, a wider range of options of places to work and live, and thus is likely to influence future urban-rural population flow. A more detailed analysis of the region's natural attributes which are central to the values of migration to rural areas, such as Hokuto City, will be useful to inform regional land use planning that is salient to the values of migrants.

Effective policies to halt biodiversity loss require knowing which anthropogenic drivers are the most important direct causes. Whereas previous knowledge has been limited in scope and rigor, here we statistically synthesize empirical comparisons of recent driver impacts found through a wide-ranging review. We show that land/sea use change has been the dominant direct driver of recent biodiversity loss worldwide. Direct exploitation of natural resources ranks second and pollution third; climate change and invasive alien species have been significantly less important than the top two drivers. The oceans, where direct exploitation and climate change dominate, have a different driver hierarchy from land and fresh water. It also varies among types of biodiversity indicators. For example, climate change is a more important driver of community composition change than of changes in species populations. Stopping global biodiversity loss requires policies and actions to tackle all the major drivers and their interactions, not some of them in isolation.

Background The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer. Methods In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given. Results In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies. Conclusion Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable. ClinicalTrials.gov Identifier: NCT02141347 (https://clinicaltrials.gov/ct2/show/NCT02141347)

The aims of the present study were to investigate the effects of fenofibrate and bezafibrate on the risk of development of diabetic retinopathy (DR) in patients with type 2 diabetes and dyslipidemia. Japanese working age patients with type 2 diabetes and dyslipidemia were extracted from the Nihon University School of Medicine Clinical Data Warehouse. These patients were divided into three groups: control group (n=2549), fenofibrate group (n=40), and bezafibrate group (n=135). Multivariate logistic regression analysis was performed to assess the association between fibrates and the development of DR. After adjustment for covariates, fenofibrate showed no association with the risk of DR [adjusted odds ratio (OR), 0.160; 95% CI, 0.021-1.209; p=0.0758]. Bezafibrate also showed no association with the risk of DR (adjusted OR, 0.731; 95% CI, 0.411-1.299; p=0.2855). However, poor control of hemoglobin A1c (HbA1c ≥8.0%; adjusted OR, 3.623; 95% CI, 2.649-4.956; p

The present study was performed to understand the interfacial reaction between Al/Ti bi-layered films and 4H–SiC with various surface orientations and the preferential growth orientation of Ti3SiC2 crystals. To this end, n-type 4H–SiC crystals oriented to the (0001), (1 1 ‾ 00), and (11 2 ‾ 0) surfaces were prepared. The (0001) and (11 2 ‾ 0) surfaces of the p-type 4H–SiC were composed of commercially available p-type 4H–SiC wafers; these surfaces were tilted by 8° from (0001) towards [11 2 ‾ 0] by the dicing and polishing of the wafers. Using the same method, another surface orientation was achieved wherein the surface was tilted by 30° from (11 2 ‾ 0) towards [0001]. Further, Al/Ti bi-layered films were deposited on each SiC substrate, using the radio-frequency magnetron sputtering method, which was followed by the stepwise annealing. The microstructures were examined by X-ray diffractometry and transmission electron microscopy. The Ti3SiC2 phase grew epitaxially in the [11 2 ‾ 0]SiC orientation on the (0001) surface of 4H–SiC. Ti3SiC2 phase did not grow uniformly on the other SiC surfaces that were oriented to (1 1 ‾ 00) or (11 2 ‾ 0). The Ti3SiC2 phase growth was columnar and parallel to (0001)SiC in the [11 2 ‾ 0]SiC orientation on the SiC surface tilted by 30° from (11 2 ‾ 0) towards [0001]. The electrical characteristics of p-type 4H–SiC contact films measured before and after annealing revealed that the characteristics of Al/Ti/(11 2 ‾ 0)4H–SiC were improved after annealing.

Trade-offs in nature’s contributions to people (NCP), particularly in material NCP versus regulating and non-material NCP, continue to rise. Socio-ecological production landscapes and seascapes (SEPLS) represent harmonious human–nature interactions resulting in positive outcomes for both biodiversity and human well-being, thus implying synergies among multiple NCP are possible. In case studies of ten projects selected from biodiversity hotspots under the GEF-Satoyama Project, we investigated whether and how synergies in NCP exist within SEPLS and explored management interventions that enhanced these synergies. Using the responses to an online survey completed by project managers from each project and drawing on project reports, we identified a wide array of NCP deriving from various ecosystems within the project SEPLS. Habitat and food provisions, both attributed to multiple ecosystem types, were key components of the NCP bundles present in the project SEPLS. Among the management options that enhanced NCP in SEPLS were food-centred approaches entailing organic agriculture, eco-labelling, branding and improved agricultural practices. Habitat-centred approaches included participatory biodiversity monitoring, ecosystem restoration, co-management and conservation agreements with landowners. Synergies in NCP were generated by integrating these interventions with enabling governance structures and through community empowerment. If combined with mapping and modelling techniques, identifying NCP bundles in SEPLS from local people’s perspectives as we outlined in this study, would help to better contextualise the analysis of NCP bundles. Such contextualised NCP bundle analyses will help field practitioners understand how to enhance synergies between multiple NCP and the broader conservation community could access untapped NCP knowledge.

Cultural Ecosystem Services (CES) are non-material benefits that are indispensable for the health and well-being of communities. CES are often spatially explicit and fluctuate according to the knowledge, beliefs, and perception of users of the location. Therefore, understanding the spatial patterns of CES perceived by people from different backgrounds is important for decision-makers to carry out proactive landscape planning. In this study, we investigated the differences in the perception of CES between residents and tourists on Ishigaki Island, Japan. The study employed a Public Participation Geographic Information System (PPGIS) approach to spatially present the respective perceptions of residents and tourists regarding six types of CES, namely recreational, therapeutic, educational, spiritual, aesthetic, and historic CES, that are recognized as key contributors to human health and well-being. For data collection, we employed a combination of household-level postal surveys and in-person questionnaire surveys targeting residents (n = 410) and tourists (n = 102), respectively. A series of statistical and spatial analyses was conducted on the survey results to understand the influence of the duration of residence and the frequency of visits in shaping the perceptions of CES, as well as the relationship between perceived CES and land-use types. This included the contribution of protected areas to the delivery of CES. The results showed that the average number of locations indicated by residents was significantly higher than that indicated by the tourists, resulting in density maps with distinct spatial patterns. In particular, the spatial pattern of CES identified by tourists was considerably simpler than that recognized by residents and centered on two popular tourist spots. As per the elements of landscapes and seascapes, the perception of “aesthetic,” “recreational,” “therapeutic,” and “educational” CES by residents was associated with “forest” and “sea” and that of “spiritual” and “historic” was associated with “forest” and “farmland.” In contrast, the CES perception of “recreational,” “educational,” “therapeutic,” “aesthetic,” and “historic” by tourists was associated with “sea” and “forest.” “Spiritual” CES was associated with “forest” and “sea.” Lastly, a higher proportion of “aesthetic” CES locations were identified within protected areas compared to outside the areas. Overall, our findings revealed that residents and tourists perceive and appreciate the numerous CES arising from landscapes and seascapes of the island differently. This indicates a possible trade-off resulting from land or sea developments to the benefit among stakeholders, for example, tourists. Hence, to sustain CES that underpin equitable health and well-being benefits, spatial planning should consider the different perceptions of stakeholders, particularly of residents and tourists, regarding CES types and locations.

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27–0.74; p p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32–0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28–0.68, p p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04–0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.

Effective management of invasive alien species (IAS) requires comprehensive stakeholder engagement and a clear understanding of how people interact with these species. Such interactions are particularly complex in socio-ecological production landscapes and seascapes (SEPLS), where local communities and their environment are highly inter-dependent. We reviewed the scientific literature to determine current views of the positive and negative effects of IAS on local communities in SEPLS, with the goals of better understanding interactions between people and IAS, and devising effective management strategies. Of the 105 IAS investigated in the 57 journal papers we found on the topic, 31 species were reported as being purely undesirable for the local communities, while 30 species were reported as purely desirable, and 44 species were both undesirable and desirable. We found that the instrumental value of IAS often constitutes these desirable effects, and that desirable IAS were likely to invite controversy among stakeholders over its management. A common compromise to address such conflicts was to work with stakeholders for the containment of the IAS, while at the same time to retain or amplify its desirable effects on people to ensure their involvement. In the long-run, however, IAS management in SEPLS cannot be exempted from the need for long-term goals and the strategy leading toward them. Such a strategy should devise practical tools, such as stringent risk assessment and black- and white-listing as well as an option to eradicate or replace highly invasive species that fully takes into account different perspectives about IAS.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10-9). East Asian-specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

We performed a caffeine (N-3-methyl-13C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included 130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath samples were collected from the subjects. The subjects orally ingested 100 mg 13C-caffeine dissolved in distilled water. Subsequently, breath samples were collected in bags every 10 min for a total of 90 min. An analysis of 13CO2 in the expired breath was performed by infrared spectroscopy, and the sum of Δ13CO2 over 90 min (S90m) was calculated. DNA from saliva samples was genotyped using TaqMan® SNP Genotyping for the following genes: cytochrome P4501A2: rs762551, rs2472297, aryl-hydrocarbon receptor (rs4410790), and adenosine A2A receptor (rs5751876). All subjects had the genotype CC in rs2472297 alleles. No significant difference was observed in S90m among the genotypes of rs762551 and rs5751876; however, a significant difference was found in S90m among the genotypes of rs4410790 (C > T). Our findings suggest that the N-3 demethylation of caffeine is dependent on the rs4410790 allele and that CafeBT may be used to determine rs4410790 genotypes.