Multiemission of Ce3+ from a Single Crystallographic Site Induced by Disordering of Ions.

White-light emission with a single activator is an attractive function of phosphors. In this work, we investigated the photoluminescence properties of Ca5.7Y1.3Si7O16.7N3.3, which is a compound denoted as Ca4+xY3-xSi7O15+xN5-x discovered by our group, with Ce-activation using optical measurements and density functional theory (DFT) calculation. Samples showed a tunable emission from purple to white under ultraviolet (UV) light. In this compound, Ca and Y as well as anions are distributed disorderly, and Ca/Y ions occupy two crystallographically distinct sites; those sites are possible sites for Ce substitution. DFT calculation and structural refinement revealed that the tunable emission was generated by Ce at the crystallographically equivalent site but with distinct local structures caused by the disordering of cations and anions. As far as we know, this is the first report about a white-light-emitting phosphor with only Ce activation.

CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

Development and Evaluation of a Novel Software Program, SAKURA-TDM, for Area Under the Concentration-Time Curve-Guided Vancomycin Dosing: A Short Communication.

BACKGROUND: The area under the concentration-time curve (AUC)-guided dosing of vancomycin has been introduced in Japan; however, the optimal dosing method remains controversial. Here, a novel software program was developed for AUC-guided vancomycin dosing and to estimate the theoretical threshold of the steady-state AUC 24 that could reduce the risk of renal injury. METHODS: A single-center, retrospective, observational study was conducted to develop a novel software program (SAKURA-TDM ver.1.0) for AUC-guided dosing. The estimation accuracy of pharmacokinetic parameters determined using SAKURA-TDM was compared with that of clinically available software programs and assessed with Bland-Altman analysis. In addition, theoretical cutoff points of the steady-state AUC 24 and the predicted trough values were estimated using Youden J statistic approach. RESULTS: The estimation accuracy of pharmacokinetic parameters and AUC determined using SAKURA-TDM was comparable to that of other TDM software programs. Of note, despite a good relationship between the predicted AUC 24 and trough values, the correlation between the predicted AUC 24 and measured trough values was not strong. The cutoff values of the steady-state AUC 24 and the predicted trough value for reducing the probability of a measured trough value of >20 mcg/mL were 513.1 mg·h/L and 15.6 mcg/mL, respectively. CONCLUSIONS: We demonstrated the equivalence of the estimated PK parameters between SAKURA-TDM and other TDM software programs available in Japan. Considering the threshold of both trough values and the steady-state AUC and monitoring of the AUC in a non-steady state, it would be possible to reduce the risk of vancomycin-associated renal injury.

Surface defect healing in annealing from nanoporous carbons to nanoporous graphenes.

Nanoporous graphene (NPG) materials have the pronounced electrochemical stability of the seamless graphene structures developed over the 3D space. We revisited the Raman spectra of nanoporous carbons (NPCs) synthesized using θ-/γ-Al2O3 templates and NPGs converted from NPCs by annealing at 1800 °C to identify the type and density of defects. We found that both the NPCs and NPGs mostly consist of single-layered graphene with a few single vacancies and Stone-Wales defects. The density of vacancy defect per hexagon in the graphene sheet is estimated to be 10-2 for NPCs, while the annealing reduced the value to 10-3-10-4 for NPGs. This supports the outstanding chemical and electrochemical stability of the novel porous carbon materials.

Absence of diffusion-weighted imaging abnormalities in a patient with neuronal intranuclear inclusion disease.

INTRODUCTION: Herein, we report a genetically confirmed case of neuronal intranuclear inclusion disease without characteristic subcortical hyperintensities on diffusion-weighted imaging. CASE PRESENTATION: A 75-year-old man was admitted to our hospital with subacute onset of conscious disturbance. Except for gastric cancer, he had no apparent past medical or family history. He presented with transient fever, vomiting, and urinary retention. On admission, no apparent abnormal intensity was detected on diffusion-weighted imaging. The symptoms improved within 10 days, without any medical treatment. Additional inspections were performed under suspicion of neuronal intranuclear inclusion disease. Intranuclear inclusions were found not only from skin biopsy but also from his stomach specimens, which had been resected 6 years previously. Subsequent genetic testing revealed repeat expansion of GGC amplification in NOTCH2NLC. CONCLUSION: Characteristic neuroimaging and skin biopsy findings are important clues for diagnosing neuronal intranuclear inclusion diseases. Nonetheless, confirming a diagnosis is difficult due to the diversity of clinical manifestations and radiological features. Clinicians should suspect neuronal intranuclear inclusion disease in patients with transient encephalitic episodes, even if no abnormalities are detected on diffusion-weighted imaging.

The induced mutant allele flo4-303 confers floury characteristics on the japonica rice cultivar 'Hoshinoko'.

Rice flour is useful as a substitute for wheat flour, however, to obtain fine flour, millers need special milling facilities, which increase the cost of milling. To reduce the milling cost, we developed a floury mutant line by irradiating gamma-rays to dry seeds of the japonica cultivar 'Hoshinoyume'. The line was registered as a new cultivar, 'Hoshinoko'. Genetical analysis of the floury trait was conducted using an F2 population derived from a cross between 'Hoshinoko' and 'Corbetti' (a japonica rice cultivar with normal endosperm), which indicated the involvement of a single recessive gene located near the RM163 marker on the long arm of rice chromosome 5, flanking flo4 identified by Kang et al. (2005). Sequence analysis of flo4 showed a two-bp (CA) insertion in the eighth exon of in 'Hoshinoko' compared to that of 'Hoshinoyume', which led to a frameshift mutation. The CAPS-based genotype of flo4 gene completely correlated to the phenotype of endosperm in two populations. This CAPS marker could be helpful for rice breeders to develop new cultivars harboring floury endosperm of the flo4-303 gene.

Initial responsiveness to darbepoetin alfa and its contributing factors in non-dialysis chronic kidney disease patients in Japan.

BACKGROUND: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) is associated with cardiovascular events and poor renal outcome in patients with chronic kidney disease (CKD). This study aimed to investigate the initial responsiveness to darbepoetin alfa (DA) and its contributing factors using the data from the BRIGHTEN. METHODS: Of 1980 patients enrolled at 168 facilities, 1695 were included in this analysis [285 patients were excluded mainly due to lack of hemoglobin (Hb) values]. The initial ESA response index (iEResI) was defined as a ratio of Hb changes over 12 weeks after DA administration per weight-adjusted total DA dose and contributing factors to iEResI were analyzed. RESULTS: The mean age was 70 ± 12 years (male 58.8%; diabetic nephropathy 27.6%). The median creatinine and mean Hb levels at DA initiation were 2.62 mg/dL and 9.8 g/dL, respectively. The most frequent number of DA administration during 12 weeks was 3 times (41.1%), followed by 4 (15.6%) times with a wide distribution of the total DA dose (15-900 µg). Remarkably, 225 patients (13.3%) did not respond to DA. Multivariate analysis showed that male gender, hypoglycemic agent use, iron supplementation, high eGFR, low Hb, low CRP, low NT-proBNP, and low urinary protein-creatinine ratio were independently associated with better initial response to DA (P = < 0.0001, 0.0108, < 0.0001, 0.0476, < 0.0001, 0.0004, 0.0435, and 0.0009, respectively). CONCLUSIONS: Non-responder to DA accounted for 13.3% of patients with non-dialysis CKD. Iron supplementation, low CRP, low NT-proBNP, and less proteinuria were predictive and modifiable factors associated with better initial response to DA.

Factors associated with long-term care certification in older adults: a cross-sectional study based on a nationally representative survey in Japan.

BACKGROUND: Long-term care (LTC) prevention is a pressing concern in ageing societies. To understand the risk factors of LTC, it is vital to consider psychological and social factors in addition to physical factors. Owing to a lack of relevant data, we aimed to investigate the social, physical and psychological factors associated with LTC using large-scale, nationally representative data to identify a high-risk population for LTC in terms of multidimensional frailty. METHODS: We performed a cross-sectional study using anonymised data from the 2013 Comprehensive Survey of Living Conditions conducted by the Ministry of Health, Labour and Welfare of Japan. Among the 23,730 eligible people aged 65 years or older and those who were not in hospitals or care facilities during the survey, 1718 stated that they had LTC certification. Univariate and multivariate logistic regression analyses were performed to determine the factors associated with LTC certification. RESULTS: Factors positively associated with LTC certification in the multivariate analyses included older age, the interaction term between sex and age group at age 85-89 years, limb movement difficulties, swollen/heavy feet, incontinence, severe psychological distress (indicated by a Kessler Psychological Distress Scale [K6] score ≥ 13), regular hospital visits for dementia, stroke, Parkinson's disease, chronic obstructive pulmonary disease, fracture, rheumatoid arthritis, kidney disease, diabetes and osteoporosis. Factors negatively associated with LTC certification included the presence of a spouse, regular hospital visits for hypertension and consulting with friends or acquaintances about worries and stress. CONCLUSIONS: In summary, we identified the physical, psychological and social factors associated with LTC certification using nationally representative data. Our findings highlight the importance of the establishment of multidimensional approaches for LTC prevention in older adults.

The role of anti-complement factor H antibodies in the development of atypical haemolytic uremic syndrome: a possible contribution to abnormality of platelet function.

Atypical haemolytic uremic syndrome (aHUS) is associated with complement system abnormality, such as production of complement factor H (CFH) autoantibodies. The growing evidence indicates complement overactivation on platelets is intimately involved in aHUS pathogenesis, besides endothelial injury. We here showed plasma from patients with anti-CFH antibodies induced aggregation of washed platelets, while purified anti-CFH antibodies suppressed aggregation. This suggested anti-CFH antibody itself suppressed thrombosis, while other plasma factor including complement factors could overactivate the platelets, leading to aggregation, which augmented the notion the state of complement activation influenced by anti-CFH antibodies is important in the aggregation of platelets in aHUS.

Two-Dimensional Perovskite Oxynitride K2 LaTa2 O6 N with an H+ /K+ Exchangeability in Aqueous Solution Forming a Stable Photocatalyst for Visible-Light H2 Evolution.

Undoped layered oxynitrides have not been considered as promising H2 -evolution photocatalysts because of the low chemical stability of oxynitrides in aqueous solution. Here, we demonstrate the synthesis of a new layered perovskite oxynitride, K2 LaTa2 O6 N, as an exceptional example of a water-tolerant photocatalyst for H2 evolution under visible light. The material underwent in-situ H+ /K+ exchange in aqueous solution while keeping its visible-light-absorption capability. Protonated K2 LaTa2 O6 N, modified with an Ir cocatalyst, exhibited excellent catalytic activity toward H2 evolution in the presence of I- as an electron donor and under visible light; the activity was six times higher than Pt/ZrO2 /TaON, one of the best-performing oxynitride photocatalysts for H2 evolution. Overall water splitting was also achieved using the Ir-loaded, protonated K2 LaTa2 O6 N in combination with Cs-modified Pt/WO3 as an O2 evolution photocatalyst in the presence of an I3 - /I- shuttle redox couple.

Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance.

BACKGROUND: In 2013, eculizumab was approved for treatment of the atypical hemolytic-uremic syndrome (aHUS) in Japan, which was defined as a thrombotic microangiopathy (TMA) excluding Shiga toxin-producing Escherichia coli-HUS and thrombotic thrombocytopenic purpura. Simultaneously, post-marketing surveillance was started to assess its safety and effectiveness. In 2016, Japanese clinical guide redefined terms to limit the use of "aHUS" to complement-mediated HUS only. Accordingly, TMA with other causes was defined as secondary TMA. Here we report the interim analysis of post-marketing surveillance of pediatric patients with aHUS and secondary TMA. METHODS: Pediatric patients treated with eculizumab from approval to 15 March 2017 were included in this observational real-world study. Clinical endpoints of effectiveness were TMA event-free status, complete TMA response, platelet count normalization, and improvement of estimated glomerular filtration rate (eGFR). Adverse reactions to eculizumab were also analyzed. RESULTS: In 27 pediatric patients with aHUS, median age at diagnosis was 4 years. Complement genes' variants were detected in 14 of 21 patients (66.7%). Median time from diagnosis to eculizumab initiation was 2.0 days. TMA event-free status, complete TMA response, platelet normalization, and improvement in eGFR were achieved in 85.2, 36.4, 78.3, and 75.0% of patients, respectively. Three patients with aHUS died. Twenty-four and 10 adverse reactions were reported in 31 aHUS patients and 17 secondary TMA patients, respectively; however, no eculizumab-related death or meningococcal infection was reported. CONCLUSIONS: This interim analysis confirmed that eculizumab is well-tolerated and effective for Japanese pediatric patients with aHUS in a real-world setting.

Safety and effectiveness of eculizumab for adult patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance.

BACKGROUND: Eculizumab has been available for the treatment of atypical hemolytic-uremic syndrome (aHUS) in Japan since 2013. To assess safety and effectiveness of eculizumab in adult aHUS patients in the real-life setting, we performed interim analysis of a post-marketing surveillance mandated by Japanese regulations. METHODS: This study enrolled any patient who was diagnosed with TMA excluding Shiga toxin-producing Escherichia coli-HUS or thrombotic thrombocytopenic purpura based on Japanese clinical guide published in 2013 as inclusion criteria and treated with eculizumab. Although the term aHUS was redefined to denote only complement-mediated HUS in the guide revised in 2016, the patients with TMA caused by other causes (secondary TMA) were included. Patient outcomes and safety were evaluated at 6 months, 12 months, and annually thereafter. RESULTS: Thirty-three patients with aHUS and 27 patients with secondary TMA were enrolled. Median treatment duration of aHUS was 24weeks. Complement genes variants were detected in 11 of 18 patients with aHUS (61.1%). Among the 29 aHUS patients with available baseline data, platelet count (PLT), lactic dehydrogenase and serum creatinine (SCr) improved within 1-month after eculizumab initiation. TMA event-free status, complete TMA response, PLT normalization, and SCr decrease were achieved in 67.9% (19/28), 27.8% (5/18), 56.5% (13/23), and 57.1% (16/28) of patients, respectively. Thirty-three and 11 adverse reactions were observed in patients with aHUS (13/33 patients) and secondary TMA (6/27 patients), respectively. CONCLUSIONS: This interim analysis confirmed the acceptable safety profile and effectiveness of eculizumab for Japanese adult aHUS patients in real-world settings.

Correction to: Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome.

The original article can be found online.

Functional splicing analysis in an infantile case of atypical hemolytic uremic syndrome caused by digenic mutations in C3 and MCP genes.

Pathogenic variants in specific complement-related genes lead to atypical hemolytic uremic syndrome (aHUS). Some reports have indicated that patients with digenic variants in these genes might present severer phenotypes. Upon detecting novel intronic variants, transcriptional analysis is necessary to prove pathogenicity; however, when intronic variants are located in intron 1 and, as a result, no transcript is produced, no appropriate method had been established to reveal the pathogenicity. Recently, the minigene assay was used to assess the pathogenicity of intronic variants. Here, we report an infantile case of aHUS caused by digenic mutations in two different complement-related genes, C3 and MCP. Targeted sequencing detected a known variant in C3 and a novel variant in the intron 1 splicing donor site of MCP. To assess the pathogenicity of this intronic variant, we conducted functional splicing assay using a minigene construct and quantitative PCR analysis of the MCP transcript, revealing the pathogenicity of the intronic variant. In conclusion, the minigene assay revealed the pathogenicity of the intron 1 splicing donor site variant for the first time. This case showed a severe phenotype of infantile-onset aHUS associated with digenic variants in two complement-related genes.

Ce4+-Based Compounds Capable of Photoluminescence by Charge Transfer Excitation under Near-Ultraviolet-Visible Light.

Ce4+-based charge transfer phosphor is not common and has been reported mainly in Sr2CeO4 with an excitation band peaking at ∼290 nm, mismatching with the near-ultraviolet light emitting diodes. Herein, we report a new series of Ce4+-based compounds Sr4.4Ce2.6REZnO12 (RE = Y, La, and Eu) capable of photoluminescence induced by O2--Ce4+ charge transfer excitation under near-ultraviolet-visible light. The crystal structure of Sr4.4Ce2.6EuZnO12 was determined by single crystal X-ray diffraction. The RE = La and Y samples were confirmed to be iso-structure compounds of the RE = Eu sample by powder X-ray diffraction. By introducing highly covalent Zn2+-O2- bonds into the framework, the Ce4+-O2- bonds are lengthened due to the effect of the Ce4+-O2--Zn2+ stretch. The lengthened Ce4+-O2- bond weakens the repulsion of the electrons between Ce4+ and O2-, thereby lowering the charge transfer energy to the visible light region. Incorporation of Eu3+ into the present compounds realized red emission under near-ultraviolet-visible excitation by the O2--Ce4+ charge transfer followed by energy transfer to Eu3+.

Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes. METHODS: We conducted a nationwide epidemiological survey of clinically diagnosed aHUS patients and examined 118 patients enrolled from 1998 to 2016 in Japan. We screened variants of seven genes related to complement and coagulation, as well as positivity for anti-CFH antibodies, and assessed clinical manifestations, laboratory findings, and clinical course. RESULTS: The most frequent genetic abnormalities were in C3 (31%) and the frequency of CFH variants was relatively low (10%) compared to Western countries. The predominant variant in this cohort was C3 p.I1157T (23%), which was related to favorable outcomes despite frequent relapses. A total of 72% of patients received plasma therapy, while 42% were treated with eculizumab. The prognosis of Japanese aHUS patients was relatively favorable, with a total mortality rate of 5.4% and a renal mortality rate of 15%. CONCLUSIONS: The common occurrence of genotype C3, especially the p.I1157T variant was the characteristic of the genetic backgrounds of Japanese aHUS patients that differed from those of Caucasian patients. In addition, the favorable prognosis of patients with the unique C3 p.I1157T variant indicates that understanding the clinical characteristics of individual gene alterations is important for predicting prognosis and determining therapeutic strategies in aHUS.

Rationale and design of oBservational clinical Research In chronic kidney disease patients with renal anemia: renal proGnosis in patients with Hyporesponsive anemia To Erythropoiesis-stimulating agents, darbepoetiN alfa (BRIGHTEN Trial).

BACKGROUND: Renal anemia is an important complication in non-dialysis chronic kidney disease (CKD) patients as well as in dialysis patients. Although recombinant human erythropoietin has dramatically improved prognosis and quality of life in these patients, there have been issues among non-dialysis CKD patients who exhibit hyporesponsiveness to erythropoiesis-stimulating agent (ESA). The causes and definition of ESA hyporesponsiveness, as well as the incidence of renal and cardiovascular disease (CVD) events in such patients, are yet to be clarified. METHODS: This ongoing trial is a multicenter, prospective, observational study of non-dialysis CKD patients with renal anemia. The primary objective is to survey the current realities of the therapy with ESA in Japan and evaluate the correlation between hyporesponsiveness to darbepoetin alfa and CKD progression. The secondary objective is to investigate relationship between ESA hyporesponsiveness and CVD events based on the clinical situation in Japan, and to explore an ESA response index. RESULTS: The subjects consist of CKD patients with estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 who present renal anemia. The target number of registered cases is 2000 patients, based on estimates of incidences of renal and CVD events from past studies. Renal function and CVD events will be observed for 96 weeks after the initiation of darbepoetin alfa administration. Definitions of ESA hyporesponsiveness will also be investigated. CONCLUSION: By clarifying markers and factors involved in ESA hyporesponsiveness and their relationships with renal and CVD events, this ongoing study aims to improve evidence-based therapies for renal anemia in non-dialysis CKD patients.

Multiband Imaging CMOS Image Sensor with Multi-Storied Photodiode Structure †.

We developed a multiband imaging CMOS image sensor (CIS) with a multi-storied photodiode structure, which comprises two photodiode (PD) arrays that capture two different images, visible red, green, and blue (RGB) and near infrared (NIR) images at the same time. The sensor enables us to capture a wide variety of multiband images which is not limited to conventional visible RGB images taken with a Bayer filter or to invisible NIR images. Its wiring layers between two PD arrays can have an optically optimized effect by modifying its material and thickness on the bottom PD array. The incident light angle on the bottom PD depends on the thickness and structure of the wiring and bonding layer, and the structure can act as an optical filter. Its wide-range sensitivity and optimized optical filtering structure enable us to create the images of specific bands of light waves in addition to visible RGB images without designated pixels for IR among same pixel arrays without additional optical components. Our sensor will push the envelope of capturing a wide variety of multiband images.

[Atypical hemolytic uremic syndrome in an elderly patient successfully treated with eculizumab].

Herein, we present an elderly onset case of aHUS successfully treated with eculizumab. An 80-year-old woman with severe anemia, thrombocytopenia, and acute renal dysfunction was admitted to our hospital. A laboratory test revealed steep elevation in the LDH level, and the peripheral blood smear showed erythrocyte fragmentations. Accordingly, we diagnosed thrombotic microangiopathy, and treatment with plasma exchange was immediately initiated. In addition, she required hemodialysis because of rapid impairment of the renal function. After excluding Shiga toxin-producing Escherichia coli infection and malignancy and confirming her ADMTS13 activity above 10%, we diagnosed aHUS, according to the Japanese diagnostic criteria for aHUS. Next, we initiated treatment with eculizumab. Her hematological findings improved 23 days after the starting of eculizumab. In addition, her renal function gradually recovered, and hemodialysis was discontinued. The genetic test for several complement regulatory genes tested negative. The onset of aHUS is reported in children or young adults and is rarely reported in elderly. However, our case suggests the importance of precisely diagnosing aHUS and initiating early administration of eculizumab for improving the outcome even in elderly patients.

Undoped Layered Perovskite Oxynitride Li2 LaTa2 O6 N for Photocatalytic CO2 Reduction with Visible Light.

Oxynitrides are promising visible-light-responsive photocatalysts, but their structures are almost confined with three-dimensional (3D) structures such as perovskites. A phase-pure Li2 LaTa2 O6 N with a layered perovskite structure was successfully prepared by thermal ammonolysis of a lithium-rich oxide precursor. Li2 LaTa2 O6 N exhibited high crystallinity and visible-light absorption up to 500 nm. As opposed to well-known 3D oxynitride perovskites, Li2 LaTa2 O6 N supported by a binuclear RuII complex was capable of stably and selectively converting CO2 into formate under visible light (λ>400 nm). Transient absorption spectroscopy indicated that, as compared to 3D oxynitrides, Li2 LaTa2 O6 N possesses a lower density of mid-gap states that work as recombination centers of photogenerated electron/hole pairs, but a higher density of reactive electrons, which is responsible for the higher photocatalytic performance of this layered oxynitride.