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Presepsin (P-SEP) is a specific biomarker for sepsis. Monocytes produce P-SEP by phagocytosing neutrophil extracellular traps (NETs). Herein, we investigated whether M1 macrophages (M1 MΦs) are the primary producers of P-SEP after NET phagocytosis. We co-cultured M1 MΦs and NETs from healthy participants, measured P-SEP levels in the culture medium supernatant, and detected P-SEP using western blotting. When NETs were co-cultured with M1 MΦs, the P-SEP level of the culture supernatant was high. Notably, we demonstrated, for the first time, the intracellular kinetics of P-SEP production by M1 MΦs via NET phagocytosis: M1 MΦs produced P-SEP intracellularly 15 min after NET phagocytosis and then released it extracellularly. In a sepsis mouse model, the blood NET ratio and P-SEP levels, detected using ELISA, were significantly increased (p < 0.0001). Intracellular P-SEP analysis via flow cytometry demonstrated that lung, liver, and kidney MΦs produced large amounts of P-SEP. Therefore, we identified these organs as the origin of M1 MΦs that produce P-SEP during sepsis. Our data indicate that the P-SEP level reflects the trend of NETs, suggesting that monitoring P-SEP can be used to both assess NET-induced organ damage in the lungs, liver, and kidneys during sepsis and determine treatment efficacy. [ABSTRACT FROM AUTHOR]

For novel immuno‐oncology therapies, the primary purpose of a dose‐finding trial is to identify an optimal dose (OD), defined as the tolerable dose having adequate efficacy and immune response under the unpredictable dose–outcome (toxicity, efficacy, and immune response) relationships. In addition, the multiple low or moderate‐grade toxicities rather than dose‐limiting toxicities (DLTs) and multiple levels of efficacy should be evaluated differently in dose‐finding to determine true OD for developing novel immuno‐oncology therapies. We proposed a generalized Bayesian optimal interval design for immunotherapy, simultaneously considering efficacy and toxicity grades and immune response outcomes. The proposed design, named gBOIN‐ETI design, is model‐assisted and easy to implement to develop immunotherapy efficiently. The operating characteristics of the gBOIN‐ETI are compared with other dose‐finding trial designs in oncology by simulation across various realistic settings. Our simulations show that the gBOIN‐ETI design could outperform the other available approaches in terms of both the percentage of correct OD selection and the average number of patients allocated to the OD across various realistic trial settings. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (− 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60–80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP. Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017). [ABSTRACT FROM AUTHOR]

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection. [ABSTRACT FROM AUTHOR]

Background: Young‐onset dementia (YOD) community care requires personalised approaches. Yet, the specific details of YOD consultations are unclear. This study explored how initial consultations correlate with client profiles. Methods: Data from regional YOD helplines were used to analyze the main characteristics of people living with YOD or who had concerns about the possibility of YOD (n = 132). Among several categorical variables, the following were used for analysis: age group, sex, type of living arrangement, employment status, presence of dementia, and content of the consultation. To identify groups of items that frequently occur together, strongly connected rules were identified using association rule analysis with the a priori algorithm. To focus on the characteristics of clients, rules related to client characteristics were extracted based on the type of consultation. Results: A total of 51 rules were identified for the consultations. These rules fell into two categories: (1) consultations for medical matters, which mainly involved employed individuals with undiagnosed dementia, and (2) other consultations on daily life or work, which mainly involved individuals diagnosed with dementia and were characterised by the influence of sex. These rules indicate the importance of medical involvement in confirming the diagnosis and specific individualised care following diagnosis for people living with YOD. Conclusion: Clients with or without a dementia diagnosis were consulted differently in the YOD helplines. Before receiving a diagnosis, medical matters were the main theme of consultations, whereas after receiving a diagnosis, adjustments to daily life or work were the main themes. The results of this study suggest that the needs of people living with YOD and the services they require may vary depending on their backgrounds. [ABSTRACT FROM AUTHOR]

Introduction: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population. Methods: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset. Results: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98–4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< − 0.5 g/dL/week; OR 3.73; 95% CI 1.68–8.27) as compared to stable hemoglobin levels (≥ − 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04–3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71–8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%. Conclusions: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article. Trial Registration: NCT02278341, NCT02273726, NCT02052310, NCT02174731. Plain Language Summary: Roxadustat is an oral treatment for patients with anemia, or low hemoglobin levels, due to chronic kidney disease. Thromboembolic events are caused by a blood clot blocking blood vessels, and they have occurred in clinical trials of roxadustat. This analysis evaluated risk factors for thromboembolic events in patients receiving roxadustat to treat anemia of chronic kidney disease who are on dialysis. Two different statistical approaches were used to investigate risk factors for thromboembolic events that occurred before and after 12 weeks of roxadustat treatment. We found that rapid improvement of anemia after starting roxadustat treatment may be associated with an increased risk of thromboembolic events occurring in the first 12 weeks of treatment. In contrast, severe anemia or worsening of anemia was associated with an increased risk of thromboembolic events after week 12. Low iron levels in the blood or greater decline of available iron in the blood from baseline were also detected as risk factors for the events after week 12, suggesting that iron supplementation is important in patients who are iron-deficient. Moreover, thromboembolic events were also associated with older age (≥ 65 years), Black race, high levels of inflammation, and having had a previous thromboembolic event or having a history of cardiovascular disease or diabetes. Some risk factors, such as iron status and hemoglobin levels, can be changed after beginning roxadustat treatment and should be monitored and modified, as needed. [ABSTRACT FROM AUTHOR]

Introduction: Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan. Methods: Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters. Results: Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36–37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52–25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23–15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07–33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82–33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< − 2 fL; adjusted OR 5.55; 95% CI 1.73–17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events. Conclusion: In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article. Trial Registration: NCT02780726, NCT02952092, NCT02780141, NCT02779764. Plain Language Summary: Roxadustat is an oral medicine that treats anemia in patients with chronic kidney disease (CKD). Thromboembolic events, or blood vessels blocked by a blood clot, have occurred in clinical trials of roxadustat. This study explored potential factors that may be related to thromboembolic events in roxadustat-treated patients with anemia of CKD on dialysis before and after week 12. This study found that hemodialysis (vs peritoneal dialysis), advanced age (older than 65 years), short amount of time on dialysis (less than 4 months), previous history of thromboembolic events, and not receiving iron therapy were risk factors for thromboembolic events before week 12. Iron deficiency and high roxadustat dose were risk factors for thromboembolic events after week 12. When iron status was also considered, we did not find that roxadustat dose was related to thromboembolic events. A different model found that increased levels of transferrin, a protein that transports iron, from baseline and decreased mean corpuscular volume, or smaller red blood cells, increased the risk of thromboembolic events. Patients with anemia of CKD on dialysis may benefit from more intentional monitoring and management of iron while receiving roxadustat. [ABSTRACT FROM AUTHOR]

The primary objective of an oncology dose‐finding trial for novel therapies, such as molecularly targeted agents and immune‐oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure‐efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings. [ABSTRACT FROM AUTHOR]

One of the primary objectives of an oncology dose‐finding trial for novel therapies, such as molecular‐targeted agents and immune‐oncology therapies, is to identify an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. These new therapeutic agents appear more likely to induce multiple low or moderate‐grade toxicities than dose‐limiting toxicities. Besides, for efficacy, evaluating the overall response and long‐term stable disease in solid tumors and considering the difference between complete remission and partial remission in lymphoma are preferable. It is also essential to accelerate early‐stage trials to shorten the entire period of drug development. However, it is often challenging to make real‐time adaptive decisions due to late‐onset outcomes, fast accrual rates, and differences in outcome evaluation periods for efficacy and toxicity. To solve the issues, we propose a time‐to‐event generalized Bayesian optimal interval design to accelerate dose finding, accounting for efficacy and toxicity grades. The new design named "TITE‐gBOIN‐ET" design is model‐assisted and straightforward to implement in actual oncology dose‐finding trials. Simulation studies show that the TITE‐gBOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment while having comparable or higher performance in the percentage of correct OD selection and the average number of patients allocated to the ODs across various realistic settings. [ABSTRACT FROM AUTHOR]

Dose‐finding trials play a key role in the entire drug development process to determine optimal doses for regulatory approval. We address confirmatory efficacy testing for individual dose–placebo comparisons in the context of a dose‐finding trial designed with multiple comparison procedures–modeling (MCP–Mod). An extension of the MCP–Mod, called closed MCP–Mod, has been proposed to carry out the MCP–Mod in conjunction with pairwise dose‐placebo comparisons; however, an issue associated with the misspecification of candidate dose–response models remains. We consider another way to combine the MCP–Mod and the individual dose‐placebo comparisons using serial gatekeeping procedures with fixed sequence, Holm, Hochberg, and step‐down Dunnett procedure. The method controls the family‐wise error rate in the strong sense and is simple enough to be implemented by existing software. Simulation studies suggested that the serial gatekeeping procedure was comparable with the closed MCP–Mod in terms of statistical power to detect the efficacy of at least one dose, and both methods were capable of pursuing the efficacy claim rather than just establishing the dose–response signal with less than a 20% increase in sample size when assuming monotonic dose–response shapes. The serial gatekeeping procedure would have advantages in the simplicity of implementation and ease of interpretation. The dose‐finding trials aiming to declare the dose–response signal, as well as the efficacy of individual doses, would be worth considering as an option to accelerate the drug development program in certain situations. [ABSTRACT FROM AUTHOR]

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in patients with non-dialysis-dependent (NDD) CKD evaluated disease state–related parameters among patients with and without diabetes mellitus who received roxadustat. In the 1517-CL-0310 study (NCT02988973), roxadustat was noninferior to darbepoetin alfa for change in average hemoglobin levels at Weeks 18–24 from baseline who received roxadustat. Methods: Patients enrolled in the 1517-CL-0310 study who received roxadustat were included in this post hoc analysis. Hematologic (hemoglobin, reticulocyte/erythrocyte ratio, mean corpuscular volume [MCV], and mean corpuscular hemoglobin [MCH]), iron-related (ferritin, total iron-binding capacity, transferrin, ceruloplasmin, and hepcidin), metabolic (HbA1c, glycated albumin, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), and renal (eGFR) parameters were summarized descriptively by visit through Week 52. Results: Among 201 included patients, 105 (52.2%) and 96 (47.8%) were in the Diabetes and No Diabetes subgroups, respectively. There were no clinically meaningful differences through Week 52 for most hematologic, iron-related, metabolic, or renal parameters between patients in the Diabetes and No Diabetes subgroups. MCV and MCH remained lower and HbA1c and glycated albumin remained higher in patients in the Diabetes subgroup through Week 52. Both subgroups experienced a similar benefit from roxadustat in maintaining hemoglobin levels in the target range of 10–12 g/dL. Conclusion: Roxadustat maintained hemoglobin levels in the target range with similar clinical parameters irrespective of diabetes mellitus presence at baseline. [ABSTRACT FROM AUTHOR]

Pegfilgrastim, a pegylated form of granulocyte colony‐stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on‐body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer‐controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6‐mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living. [ABSTRACT FROM AUTHOR]

Background: BEC-producing Clostridium perfringens is a causative agent of foodborne gastroenteritis. It was first reported in 2014, and since then, several isolates have been identified in Japan and the United Kingdom. The novel binary ADP-ribosylating toxin BEC, which consists of two components (BECa and BECb), is encoded on a plasmid that is similar to pCP13 and harbours a conjugation locus, called Pcp, encoding homologous proteins of the type 4 secretion system. Despite the high in vitro conjugation frequency of pCP13, its dissemination and that of related plasmids, including bec-harbouring plasmids, in the natural environment have not been characterised. This lack of knowledge has limited our understanding of the genomic epidemiology of bec-harbouring C. perfringens strains. Results: In this study, we determined the complete genome sequences of five bec-harbouring C. perfringens strains isolated from 2009 to 2019. Each isolate contains a ~ 3.36 Mbp chromosome and 1–3 plasmids of either the pCW3-like family, pCP13-like family, or an unknown family, and the bec-encoding region in all five isolates was located on a ~ 54 kbp pCP13-like plasmid. Phylogenetic and SNP analyses of these complete genome sequences and the 211 assembled C. perfringens genomes in GenBank showed that although these bec-harbouring strains were split into two phylogenetic clades, the sequences of the bec-encoding plasmids were nearly identical (>99.81%), with a significantly smaller SNP accumulation rate than that of their chromosomes. Given that the Pcp locus is conserved in these pCP13-like plasmids, we propose a mechanism in which the plasmids were disseminated by horizontal gene transfer. Data mining showed that strains carrying pCP13-like family plasmids were unexpectedly common (58/216 strains) and widely disseminated among the various C. perfringens clades. Although these plasmids possess a conserved Pcp locus, their 'accessory regions' can accommodate a wide variety of genes, including virulence-associated genes, such as becA/becB and cbp2. These results suggest that this family of plasmids can integrate various foreign genes and is transmissible among C. perfringens strains. Conclusion: This study demonstrates the potential significance of pCP13-like plasmids, including bec-encoding plasmids, for the characterisation and monitoring of the dissemination of pathogenic C. perfringens strains. [ABSTRACT FROM AUTHOR]

Multiple imputation is a promising approach to handle missing data and is widely used in analysis of longitudinal clinical studies. A key consideration in the implementation of multiple imputation is to obtain accurate imputed values by specifying an imputation model that incorporates auxiliary variables potentially associated with missing variables. The use of informative auxiliary variables is known to be beneficial to make the missing at random assumption more plausible and help to reduce uncertainty of the imputations; however, it is not straightforward to pre‐specify them in many cases. We propose a data‐driven specification of the imputation model using Bayesian lasso in the context of longitudinal clinical study, and develop a built‐in function of the Bayesian lasso imputation model which is performed within the framework of multiple imputation using chained equations. A simulation study suggested that the Bayesian lasso imputation model worked well in a variety of longitudinal study settings, providing unbiased treatment effect estimates with well‐controlled type I error rates and coverage probabilities of the confidence interval; in contrast, ignorance of the informative auxiliary variables led to serious bias and inflation of type I error rate. Moreover, the Bayesian lasso imputation model offered higher statistical powers compared with conventional imputation methods. In our simulation study, the gains in statistical power were remarkable when the sample size was small relative to the number of auxiliary variables. An illustration through a real example also suggested that the Bayesian lasso imputation model could give smaller standard errors of the treatment effect estimate. [ABSTRACT FROM AUTHOR]

Nearly half of the human genome consists of repetitive sequences such as long interspersed nuclear elements. The relationship between these repeating sequences and diseases has remained unclear. Gene trapping is a useful technique for disrupting a gene and expressing a reporter gene by using the promoter activity of the gene. The analysis of trapped genes revealed a new genome element—the chromosome‐specific clustered trap (CSCT) region. For any examined sequence within this region, an equivalent was found using the BLAT of the University of California, Santa Cruz (UCSC) Genome Browser. CSCT13 mapped to chromosome 13 and contained only three genes. To elucidate its in vivo function, the whole CSCT13 region (1.6 Mbp) was deleted using the CRISPR/Cas9 system in mouse embryonic stem cells, and subsequently, a CSCT13 knockout mouse line was established. The rate of homozygotes was significantly lower than expected according to Mendel's laws. In addition, the number of offspring obtained by mating homozygotes was significantly smaller than that obtained by crossing controls. Furthermore, CSCT13 might have an effect on meiotic homologous recombination. This study identifies a transcriptionally active CSCT with an important role in mouse development. [ABSTRACT FROM AUTHOR]

Roxadustat is an oral hypoxia‐inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis‐stimulating agents (ESAs). This post‐hoc analysis of a Japanese, double‐blind, randomized, phase 3 study in hemodialysis‐dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA‐resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high‐sensitivity C‐reactive protein (hs‐CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight‐adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight‐adjusted AAD/6W relative to within‐arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P =.089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs‐CRP was not significant (estimated slope, −0.494; P =.814); a trend toward increased DA doses was observed with increasing EoT hs‐CRP (estimated slope, 2.973; P =.075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs. [ABSTRACT FROM AUTHOR]

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. Methods: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18–24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. Results: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses. Discussion/Conclusion: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients. [ABSTRACT FROM AUTHOR]

Mixotrophic plants obtain carbon by their own photosynthetic activity and from their root-associated mycorrhizal fungi. Mixotrophy is deemed a pre-adaptation for evolution of mycoheterotrophic nutrition, where plants fully depend on fungi and lose their photosynthetic activity. The aim of this study was to clarify mycorrhizal dependency and heterotrophy level in various phenotypes of mixotrophic Pyrola japonica (Ericaceae), encompassing green individuals, rare achlorophyllous variants (albinos) and a form with minute leaves, P. japonica f. subaphylla. These three phenotypes were collected in two Japanese forests. Phylogenetic analysis of both plants and mycorrhizal fungi was conducted based on DNA barcoding. Enrichment in 13C among organs (leaves, stems and roots) of the phenotypes with reference plants and fungal fruitbodies were compared by measuring stable carbon isotopic ratio. All plants were placed in the same clade, with f. subaphylla as a separate subclade. Leaf 13C abundances of albinos were congruent with a fully mycoheterotrophic nutrition, suggesting that green P. japonica leaves are 36.8% heterotrophic, while rhizomes are 74.0% heterotrophic. There were no significant differences in δ13C values among organs in both albino P. japonica and P. japonica f. subaphylla, suggesting full and high mycoheterotrophic nutrition, respectively. Among 55 molecular operational taxonomic units (OTUs) detected as symbionts, the genus Russula was the most abundant in each phenotype and its dominance was significantly higher in albino P. japonica and P. japonica f. subaphylla. Russula spp. detected in P. japonica f. subaphylla showed higher dissimilarity with other phenotypes. These results suggest that P. japonica sensu lato is prone to evolve mycoheterotrophic variants, in a process that changes its mycorrhizal preferences, especially towards the genus Russula for which this species has a marked preference. [ABSTRACT FROM AUTHOR]

Purpose: A Bayesian confidence propagation neural network (BCPNN) is a signal detection method used by the World Health Organization Uppsala Monitoring Centre to analyze spontaneous reporting system databases. We modify the BCPNN to increase its sensitivity for detecting potential adverse drug reactions (ADRs). Method: In a BCPNN, the information component (IC) is defined as an index of disproportionality between the observed and expected number of reported drugs and events. Our proposed method adjusts the IC value by borrowing information about events that have occurred in drugs defined as similar to the target drug. We compare the performance of our method with that of a traditional BCPNN through a simulation study. Results: The false positive rate of the proposed method was lower than that of the traditional BCPNN method and close to the nominal value, 0.025, around the true difference in ICs between the target drug and similar drugs equal to 0. The sensitivity of the proposed method was much higher than that of the traditional BCPNN method in case in which the difference in ICs between the target drug and similar drugs ranges from 0 to 2. When applied to a database managed by Japanese regulatory authority, the proposed method could detect known ADRs earlier than the traditional method. Conclusions: The proposed method is a novel criterion for early detection of signals if similar drugs have the same tendencies. The proposed BCPNN tends to have higher sensitivity when the true difference is greater than 0. [ABSTRACT FROM AUTHOR]

The mixed effect models for repeated measures (MMRM) analysis is sometimes used as a primary analysis in longitudinal randomized clinical trials. The SE for the treatment effect in the MMRM analysis is usually estimated by assuming the orthogonality of the fixed effect and variance-covariance parameters, which is the orthogonality property of a multivariate normal distribution, because of default settings of most standard statistical software. However, this property might be lost when analysis models are misspecified and/or data include missing values with the mechanism of being missing at random. In this study, we investigated the effect of the assumption of the orthogonality property on the estimation of the SE for the MMRM analysis. From simulation and case studies, it was shown that the SE with the assumption of orthogonality property had nonnegligible bias, especially when the analysis models assuming heteroscedasticity between treatment groups were applied. We also introduce the SAS code for the MMRM analysis without assuming the orthogonality property. Assuming the orthogonality property in the MMRM analysis would lead to invalid statistical inference, and it is necessary to be careful when applying the MMRM analysis with most standard software. [ABSTRACT FROM AUTHOR]

S-Allyl-L-cysteine sulfoxide (ACSO) is an odour precursor in garlic bulbs. One plausible pathway for the biosynthesis of ACSO involves S−2-carboxypropyl glutathione produced from glutathione and methacrylic acid via valine or from γ-glutamyl cysteine. The elimination of glycine and glutamic acid from S−2-carboxypropyl glutathione produces S-2-carboxypropyl cysteine, which is converted to S-allyl cysteine by decarboxylation and oxidation. S-Allyl cysteine is also biosynthesized via the elimination of glutamic acid from γ-glutamyl S-allyl cysteine by γ-glutamyl transpeptidase. The sulfur oxidation of S-allyl cysteine by flavin-containing monooxygenase forms ACSO. When cells are damaged by slicing or grating, ACSO in the cytoplasm or cytoplasmic vesicle is immediately converted to allylsulfenic acid, pyruvic acid, and ammonia by alliinase (C-S lyase), which is located in the vacuoles of vascular bundle sheath cells. Two molecules of allylsulfenic acid form diallyl thiosulfinate (allicin), which exhibits potent antimicrobial activity. Allicin eventually yields garlic odour compounds, such as diallyl disulfide (DADS) and diallyl trisulfide (DATS). Although these sulfides are known to exert various physiological functions, their strong odour limits their use in foods. On the other hand, ACSO is water-soluble and odourless and enhances sweet, salty, and umami tastes, characteristics of which are desirable for food additives. Upon consumption, ACSO is primarily absorbed from the small intestine in the intact form, but is also partly decomposed to allylsulfenic acid, pyruvic acid and ammonia. Allylsulfenic acid is then further converted to DADS and diallyl monosulfide (DAS). ACSO has numerous in vivo functions, such as the prevention of diabetes, myocardial ischaemia, hepatic injury, platelet aggregation and blood ethanol elevation. Although some of these effects may be attributed to its metabolites, ACSO itself contributes to many of these physiological functions. [ABSTRACT FROM AUTHOR]

Multiple imputation is a promising approach for handling of missing data. One uncertainty in applications of the multiple imputation to randomized controlled trials with longitudinal data is whether the imputation should be carried out across all subjects simultaneously or by treatment group separately, which leads to two different strategies for building imputation procedures and/or models. Indeed, it has not been sufficiently addressed and well-documented how the two imputation strategies work in the analysis of the longitudinal data. We consider situations in the presence of heteroscedasticity between treatment groups and conducted extensive simulation studies to examine how the choice of imputation strategy had impacts on the estimation of treatment effects under an assumption of missing at random mechanism. The choice of analysis model was also assessed. The simulation studies suggested that in the presence of heteroscedasticity, the separate imputation by treatment group was robust enough to provide unbiased and precise estimation of the treatment effects; in contrast, the simultaneous imputation, which is frequently used in applications, led to serious biases and poor coverage probabilities of 95% confidence interval for the treatment effects. The heteroscedasticity should be dealt with in more careful manners for the longitudinal data analysis, and if it could be the case in hand, we recommend using the separate imputation by treatment group, as well as applying unequal variance analysis methods for complete data with imputed values. The methods were illustrated with data from two real examples of pediatric research and mental health research. [ABSTRACT FROM AUTHOR]

The use of radical ions as reactive intermediates can complement polarity‐driven and neutral radical‐driven reactions in synthetic organic chemistry. The present study revealed that the reactivity of enol ether radical cations can be simply tuned by addition/removal of a methyl group, allowing development of unique substitution pattern‐selective olefin cross‐couplings. Anodically generated enol ether radical cations selectively add to appropriately substituted alkenes to afford the corresponding cycloadducts in good‐to‐excellent yields. Competition experiments using alkenes possessing two differently substituted double bonds clearly demonstrated the unique reactivity of the enol ether radical cations. [ABSTRACT FROM AUTHOR]

Longitudinal binary data are commonly encountered in clinical trials. Multiple imputation is an approach for getting a valid estimation of treatment effects under an assumption of missing at random mechanism. Although there are a variety of multiple imputation methods for the longitudinal binary data, a limited number of researches have reported on relative performances of the methods. Moreover, when focusing on the treatment effect throughout a period that has often been used in clinical evaluations of specific disease areas, no definite investigations comparing the methods have been available. We conducted an extensive simulation study to examine comparative performances of six multiple imputation methods available in the SAS MI procedure for longitudinal binary data, where two endpoints of responder rates at a specified time point and throughout a period were assessed. The simulation study suggested that results from naive approaches of a single imputation with non-responders and a complete case analysis could be very sensitive against missing data. The multiple imputation methods using a monotone method and a full conditional specification with a logistic regression imputation model were recommended for obtaining unbiased and robust estimations of the treatment effect. The methods were illustrated with data from a mental health research. [ABSTRACT FROM AUTHOR]

Our study evaluated the effects on the prefrontal cortex, especially the inferior frontal gyrus (IFG), of people when touching and stroking a real or soft toy cat, using functional near infrared spectroscopy. Thirty under-graduate students (10 males, 20 females) were recruited and performed three tactile tasks with a real cat and a soft toy cat using their right hand. They also filled in the Self-Assessment Manikin (SAM), to measure their emotional responses, and the NEO-Five Factor Inventory, to assess their personalities. During the tactile interactions with the real cat, the integral values of oxygenated hemoglobin in the left IFG of the females were significantly greater than in the males. The valence scores of the SAM after the real cat-associated tasks in females were significantly higher than after the toy cat-associated tasks. Additionally, the number of times the females stroked the real cat was significantly positively correlated with the activation levels of the left IFG and the valence scores of the SAM. The activation levels of the left IFG in females were also positively correlated with neuroticism when stroking the real cat. Thus, in females, especially those with higher levels of neuroticism, touching/stroking the cat improved their mood. The effects of interacting with a cat may be different between the genders. [ABSTRACT FROM PUBLISHER]

Statistical simulations in medical and biological research are usually conducted with normal random numbers. However, in many cases, the distributions of real data in medical fields are usually right skewed. The conclusions led by simulations with the misspecified model might be misleading because of a gap between real data's distribution and theoretical one. In this paper, we provide the simulation procedure for right skewed data based on reparameterized, easily interpretable parameters of the Box-Cox transformation model which includes multivariate distributions and regression models. We also show that the provided procedure is widely applicable to real world based on laboratory data, and then we provide parameter vector sets obtained by reparameterized parameter estimates that would cover almost all situations in which the distributions of data were right skewed and unimodal. [ABSTRACT FROM AUTHOR]

Umpolung is a classic and central concept in synthesis that produces a reversal of the normal reactivity of the molecules under study. The most straightforward method for umpolung involves an electron transfer reaction. The present study describes bidirectional access to radical cation Diels-Alder reactions by electrocatalysis. The radical cation either of trans-anethole or 9-methylanthracene could trigger the reaction, which was confirmed unambiguously through the use of silica-gel-supported substrates. [ABSTRACT FROM AUTHOR]

Background: In a random effects meta-analysis model, true treatment effects for each study are routinely assumed to follow a normal distribution. However, normality is a restrictive assumption and the misspecification of the random effects distribution may result in a misleading estimate of overall mean for the treatment effect, an inappropriate quantification of heterogeneity across studies and a wrongly symmetric prediction interval.Methods: We focus on problems caused by an inappropriate normality assumption of the random effects distribution, and propose a novel random effects meta-analysis model where a Box-Cox transformation is applied to the observed treatment effect estimates. The proposed model aims to normalise an overall distribution of observed treatment effect estimates, which is sum of the within-study sampling distributions and the random effects distribution. When sampling distributions are approximately normal, non-normality in the overall distribution will be mainly due to the random effects distribution, especially when the between-study variation is large relative to the within-study variation. The Box-Cox transformation addresses this flexibly according to the observed departure from normality. We use a Bayesian approach for estimating parameters in the proposed model, and suggest summarising the meta-analysis results by an overall median, an interquartile range and a prediction interval. The model can be applied for any kind of variables once the treatment effect estimate is defined from the variable.Results: A simulation study suggested that when the overall distribution of treatment effect estimates are skewed, the overall mean and conventional I 2 from the normal random effects model could be inappropriate summaries, and the proposed model helped reduce this issue. We illustrated the proposed model using two examples, which revealed some important differences on summary results, heterogeneity measures and prediction intervals from the normal random effects model.Conclusions: The random effects meta-analysis with the Box-Cox transformation may be an important tool for examining robustness of traditional meta-analysis results against skewness on the observed treatment effect estimates. Further critical evaluation of the method is needed. [ABSTRACT FROM AUTHOR]

Unactivated alkenes were previously found to be effective carbon nucleophiles for anodic cycloadditions in lithium perchlorate/nitromethane electrolyte solution. Herein, 7Li NMR analysis and calorimetric studies clearly illustrate that the entropic effect is essential for these anodic cycloadditions, which has led to the successful screening of novel effective electrolytes. [ABSTRACT FROM AUTHOR]

Bixalomer, a metal-free, nonabsorbable phosphate binder, is approved in Japan to treat hyperphosphatemia in dialysis patients. Bixalomer is effective and has a favorable safety profile in predialysis patients with hyperphosphatemia. This study examined the long-term effectiveness and safety of bixalomer in predialysis patients with hyperphosphatemia. This was a 48-week, multicenter, open-label, phase 3 study in Japanese predialysis patients with hyperphosphatemia. Patients received bixalomer at an initial dose of 1500 mg/day, which was titrated to a maximum of 7500 mg/day depending on patients' serum phosphorus responses to bixalomer. A total of 105 patients received bixalomer treatment, and 39 completed the study. The most common reason for discontinuation was initiation of dialysis. Mean serum phosphorus concentrations decreased from 5.15 mg/dL at baseline to 4.67 mg/dL at Week 12 and then fluctuated slightly around this level until it reached 4.58 mg/dL at Week 48. The proportion of total patients achieving the target serum phosphorus concentration (≥2.5 to <4.6 mg/dL) increased after treatment to a maximum of 66.2% at Week 20 and subsequently decreased to 51.3% by Week 48. Most adverse events (AEs) occurred in the first 12 weeks of treatment. The incidence of AEs did not increase with long-term treatment. Common AEs reported included nasopharyngitis (29.5%), constipation (19%), and upper respiratory tract inflammation (12.4%). These findings suggest that long-term treatment with bixalomer is effective, well tolerated, and has no new safety concerns. Bixalomer may be an alternative treatment option for the long-term management of hyperphosphatemia in patients with chronic kidney diseases. [ABSTRACT FROM AUTHOR]

Currently, calcium- or metal-containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non-calcium, metal-free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double-blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4-week pre-investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (-0.78 [-0.98, -0.57] mg/dL) versus placebo (0.20 [-0.00, 0.41] mg/dL); mean difference: -0.98 (-1.27, -0.69), P < 0.001. At end of treatment, 57.5% of bixalomer-treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor-23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug-related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo ( P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option. [ABSTRACT FROM AUTHOR]

Astaxanthin is a carotenoid pigment and has been shown to be an effective inhibitor of oxidative damage. We tested the hypothesis that astaxanthin intake would attenuate immobilization-induced muscle atrophy in rats. Male Wistar rats (14-week old) were fed for 24 days with either astaxanthin or placebo diet. After 14 days of each experimental diet intake, the hindlimb muscles of one leg were immobilized in plantar flexion position using a plaster cast. Following 10 days of immobilization, both the atrophic and the contralateral plantaris muscles were removed and analyzed to determine the level of muscle atrophy along with measurement of the protein levels of CuZnsuperoxide dismutase (CuZn-SOD) and selected proteases. Compared with placebo diet animals, the degree of muscle atrophy in response to immobilization was significantly reduced in astaxanthin diet animals. Further, astaxanthin supplementation significantly prevented the immobilization-induced increase in the expression of CuZn-SOD, cathepsin L, calpain, and ubiquitin in the atrophied muscle. These results support the postulate that dietary astaxanthin intake attenuates the rate of disuse muscle atrophy by inhibiting oxidative stress and proteolysis via three major proteolytic pathways. [ABSTRACT FROM AUTHOR]

When some trials provide individual patient data (IPD) and the others provide only aggregate data (AD), meta-analysis methods for combining IPD and AD are required. We propose a method that reconstructs the missing IPD for AD trials by a Bayesian sampling procedure and then applies an IPD meta-analysis model to the mixture of simulated IPD and collected IPD. The method is applicable when a treatment effect can be assumed fixed across trials. We focus on situations of a single continuous outcome and covariate and aim to estimate treatment-covariate interactions separated into within-trial and across-trial effect. An illustration with hypertension data which has similar mean covariates across trials indicates that the method substantially reduces mean square error of the pooled within-trial interaction estimate in comparison with existing approaches. A simulation study supposing there exists one IPD trial and nine AD trials suggests that the method has suitable type I error rate and approximately zero bias as long as the available IPD contains at least 10% of total patients, where the average gain in mean square error is up to about 40%. However, the method is currently restricted by the fixed effect assumption, and extension to random effects to allow heterogeneity is required. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The VerifyNow P2Y12 test is a whole-blood, light transmission-based optical detection assay that measures adenosine diphosphate-induced platelet aggregation in a cartridge containing fibrinogen-coated beads. The usefulness of this device to assess the effect of clopidogrel on platelet function was recently highlighted for predicting cardiovascular (CV) events. We therefore performed a meta-analysis to analyze whether adverse clinical outcomes of patients with CV disease increase in association with high on-treatment platelet reactivity (HPR) using the VerifyNow P2Y12 test. We also investigated the effect of the CYP2C19*2 polymorphism on the occurrence of CV events among clopidogrel-treated patients. Relevant studies were searched for in the PubMed database and Cochrane Central Register of Controlled Trials database, and selected if they included data about platelet function assessed using the VerifyNow P2Y12 test or CYP2C19*2 polymorphism in clopidogrel-treated patients with CV disease, and the occurrence of CV events within 6-12 months. In our meta-analysis, 4817 subjects from eight studies and 5307 subjects from seven studies were included for review of platelet function and CYP2C19*2 polymorphism, respectively. Overall, 2237 (46.4%) patients had HPR and these patients had significantly higher odds of CV events compared to patients without HPR (odds ratio(OR) = 3.05, 95% confidence interval: 2.33-3.98, p < 0.001). Heterogeneity among studies was not significant (Cochran's Q-test, p = 0.80 and I2 = 0%). In the secondary investigation, 1926 (36.3%) patients had at least one CYP2C19*2 allele. Heterogeneity in the OR of the CV events between the CYP2C19*2 allele carriers and non-carriers was observed among the seven studies (Cochran's Q-test, p = 0.01 and I2 = 56.5%), and the range of the ORs among the seven studies was 0.58-16.6. In conclusion, HPR assessed by VerifyNow P2Y12 test was associated with increased adverse clinical outcomes of clopidogrel-treated patients with CV disease. [ABSTRACT FROM AUTHOR]

Recently, the frequency of use of bone substitute materials for the purpose of bone augmentation has increased in implant treatment, but bone formation with bone substitute materials alone is limited. Calcification of bone in the body progresses as Ca2+, H2PO4-, and HPO42- in the body form hydroxyapatite (HA) crystals. In this study, therefore, we prepared a biphasic bone substitute with biological activity to promote bone formation by inducing precipitation and growth of HA crystals on the surface of a bone substitute and evaluated it. Biphasic bone substitute granules were prepared by immersing HA granules in a supersaturated calcium phosphate solution prepared by mixing five medical infusion solutions, the precipitate was analyzed, and the biological activities of biphasic HA granules were evaluated in vitro and in vivo. As a result, the precipitated calcium phosphate crystals were identified as low crystalline HA. On the surface of the HA granules, low-crystalline HA grew markedly as needle-shaped crystals and significantly promoted cell proliferation and bone differentiation. In animal experiments, biphasic HA granules had a significantly higher bone mineral density, new bone volume ratio, and new bone area ratio. Therefore, it suggests that biphasic hydroxyapatite is a useful bone substitute for bone augmentation in dental implant treatment. [ABSTRACT FROM AUTHOR]

The combination of the garlic-derived amino acid, S-allyl-l-cysteine sulfoxide (ACSO), and ornithine or arginine on CCl4-induced hepatic injury was examined. After investigating the effectiveness of the mixture of ACSO and ornithine or arginine in preventing hepatic injury in vivo, an extract rich in ACSO and ornithine was prepared by converting arginine in garlic to ornithine by arginase from Hypsizygus marmoreus (buna-shimeji), after screening the productivity of ornithine among 12 kinds of mushrooms. Co-administration of ACSO with ornithine or arginine suppressed the increase in aspartate transaminase, alanine transaminase, and thiobarbituric acid reactive substance, and the decrease in glutathione S-transferase and cytochrome p450 2E1 activities after CCl4 injection more effectively than a single administration of ACSO. All extracts prepared from garlic and buna-shimeji with low and high contents of ACSO and arginine or ornithine significantly suppressed CCl4-induced hepatic injury in rats. Considering that ACSO is tasteless, odourless, and enhances taste, and ornithine has a flat or sweet taste and masks bitterness, the extract rich in ACSO and ornithine from garlic and buna-shimeji could be considered a potential antioxidant food material that can be added to many kinds of food to prevent hepatic injury. [ABSTRACT FROM AUTHOR]

Alcohol is usually consumed with meals, but chronic consumption is a leading cause of alcoholic liver diseases. We investigated if shiitake extracts with a high lentinic acid content (Shiitake-H) and without lentinic acid (Shiitake-N) could suppress the elevation in plasma ethanol concentrations by accelerating ethanol metabolism and preventing ethanol absorption from the gut. Shiitake-H and Shiitake-N suppressed the elevation in concentrations of ethanol and acetaldehyde in plasma, and promoted the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the liver. However, these effects of Shiitake-H were more prominent than those of Shiitake-N. Furthermore, Shitake-H promoted ADH and ALDH activities in the stomach. We also examined the change in plasma ethanol concentration by injecting Shiitake-H or Shiitake-N into the ligated loop of the stomach or jejunum together with an ethanol solution. Shiitake-H suppressed the absorption of ethanol from the stomach and jejunum. In conclusion, Shiitake-H accelerates ethanol metabolism in the stomach and liver and inhibits ethanol absorption in the stomach and jejunum indicating that lentinic acid is a functional component in shiitake. [ABSTRACT FROM AUTHOR]

Hydrochloric acid (HCl)-treated wheat protein (HWP) is widely used in various products, including foods, cosmetics and shampoos. Recently, immediate hypersensitivity towards facial soap containing HWP has been reported. HCl treatment of protein causes hydrolysis not only of main-chain amide bonds (peptide-bond hydrolysis) but also of side-chain ones (deamidation). We have already reported that gliadin, the main allergen in wheat, reduces allergenicity and increases digestibility by deamidation, indicating that deamidation and peptide-bond hydrolysis are effective to reduce the allergenicity of wheat protein. However, transdermally administered HWP is assumed to induce sensitization to orally administered wheat protein even in those who have been taking wheat products daily before sensitization. The present study was conducted to examine which structural change is responsible for the induction of cutaneous sensitization by comparing the allergenicity of deamidated and/or peptide-bond-hydrolyzed wheat gliadin. Because we have developed a deamidation method without causing peptide-bond hydrolysis, only deamidated wheat gliadin is available. Therefore, after deamidated-only, hydrolyzed-only, and deamidated and hydrolyzed gliadins were transdermally administered to mice for several weeks, the corresponding gliadin was intraperitoneally administered and allergenicity was evaluated. Transdermal administration of deamidated and hydrolyzed gliadin induced severe allergic reaction, while that of deamidated-only and hydrolyzed-only gliadin showed almost no allergic response. This result indicates that both deamidation and peptide-bond hydrolysis are necessary to increase the allergenic potency of transdermally administered wheat gliadin. [ABSTRACT FROM AUTHOR]

S-Allyl-l-cysteine sulfoxide (ACSO) is a precursor of garlic-odor compounds like diallyl disulfide (DADS) and diallyl trisulfide (DATS) known as bioactive components. ACSO has suitable properties as a food material because it is water-soluble, odorless, tasteless and rich in bulbs of fresh garlic. The present study was conducted to examine the preventive effect of ACSO on hepatic injury induced by CCl4 in rats. ACSO, its analogs and garlic-odor compounds were each orally administered via gavage for five consecutive days before inducing hepatic injury. Then, biomarkers for hepatic injury and antioxidative state were measured. Furthermore, we evaluated the absorption and metabolism of ACSO in the small intestine of rats and NF-E2-related factor 2 (Nrf2) nuclear translocation by ACSO using HepG2 cells. As a result, ACSO, DADS and DATS significantly suppressed the increases in biomarkers for hepatic injury such as the activities of aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH), and decreases in antioxidative potency such as glutathione (GSH) level and the activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx). We also found ACSO was absorbed into the portal vein from the small intestine but partially metabolized to DADS probably in the small intestine. In in vitro study, ACSO induced Nrf2 nuclear translocation in HepG2 cells, which is recognized as an initial trigger to induce antioxidative and detoxifying enzymes. Taken together, orally administered ACSO probably reached the liver and induced antioxidative and detoxifying enzymes by Nrf2 nuclear translocation, resulting in prevention of hepatic injury. DADS produced by the metabolism of ACSO in the small intestine might also have contributed to the prevention of hepatic injury. These results suggest potential use of ACSO in functional foods that prevent hepatic injury and other diseases caused by reactive oxygen species (ROS). [ABSTRACT FROM AUTHOR]

Background: Clinical testing was required to verify the effect of linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS‐C) in Japan. Methods: This was a randomized, double‐blind, placebo‐controlled (Part 1) and long‐term, open‐label extension (Part 2) study of linaclotide at 60 hospitals and clinics in Japan. Patients with IBS‐C diagnosed using Rome III criteria (n = 500) were randomly assigned to linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12‐week treatment period followed by open‐label treatment with linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. Key Results: Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. Conclusions and Inferences: This study suggests that a linaclotide dose of 0.5 mg is effective and safe for IBS‐C patients in Japan. Linaclotide has been approved in western countries for IBS with constipation (IBS‐C) at a dose of 0.29 mg. A previous phase II trial in Japan reported that 0.5 mg/d of linaclotide was the most effective dose in IBS‐C patients. This phase III trial in IBS‐C patients in Japan revealed that 0.5 mg/d of linaclotide was effective on global improvement (A), complete spontaneous bowel movement (B), and abdominal pain/discomfort with enough safety. [ABSTRACT FROM AUTHOR]

Inhibiting starch hydrolysis into sugar could reduce postprandial blood glucose elevation and contribute to diabetes prevention. Here, both buckwheat and wheat albumin that inhibited mammalian α-amylase in vitro suppressed blood glucose level elevation after starch loading in vivo, but it had no effect after glucose loading. In contrast to the non-competitive inhibition of wheat α-amylase inhibitor, buckwheat albumin acted in a competitive manner. Although buckwheat α-amylase inhibitor was readily hydrolysed by digestive enzymes, the hydrolysate retained inhibitory activity. Together with its thermal stability, this suggests its potential use in functional foods that prevent diabetes. [ABSTRACT FROM AUTHOR]

Background: The biological aging of titanium (Ti) surface is a time‐dependent degradation of the osteoconductivity, lead to a decrease in the biomechanical strength of the bone–Ti integration. To overcome the aging, ultraviolet light (UV) has been shown to changing the physicochemical properties of Ti surface from hydrophobic to hydrophilic for removal of the surface hydrocarbons without altering the surface topography. However, expensive special equipment was required for UV photo‐functionalization. Aim/Hypothesis: In this study, we focused on electrolyzed deoxidized and ionized water (S – 100) which can easily remove contamination such as carbon without special equipment. The aim of this study is to investigate the influence S‐100 treatment on the recovery of the biological activity of the aged Ti surface. Material and Methods: We prepared mirror polished Ti‐6Al‐4V discs. All the discs cleaned using an ultrasonic cleaner in acetone, ethanol, and double distilled water for 10 minutes each. And then the prepared Ti discs were aged by storing in the clean‐bench at a room temperature for 1 and 4 weeks. After the aging, we divided the Ti disks into two groups. Half of the discs immersed in S‐100 for 3 minutes and the remaining half of the discs immersed in saline water for 3 minutes as a control group. The contact angle on the disc surface were measured by digital contact angle measuring device. The chemical composition of the surface analyzed by X‐ray photoelectron spectroscopy (XPS). As a protein adsorption assay, the discs were immersed into 500 μL of bovine serum albumin (1 mg/mL). After incubating for 24 hours, the amount of protein quantified using a micro plate reader at 595 nm. MC3T3‐E1 cell were cultured on the control and S‐100 treated disks for 24 hours, the cell growth were observed with a fluorescence microscope. Results: Fig. 1 shows the contact angle. The dropping 0.5 μL DDW were formed hemispheric droplets with a contact angle of approximately 65.2 degree on the 4‐week aged control surfaces, indicating that the surfaces were hydrophobic (Fig. 2). In contrast, water droplets on the surface treated with S‐100 were spread immediately, and the contact angle was approximately 18.7 degree. Even on the 1‐week aged surface, the contact angle on the S‐100 treatment significantly decreased and changed to a hydrophilic surface. In XPS analysis, a decrease in C1s was observed on the surface treated with S‐100 in all periods. On the other hand, O1s and Ti increased by S‐100 treatment. The results of protein adsorption on the Ti surface, there were no significant difference between the S‐100 treated surface and the control surface. However, the proliferation of osteoblastic cells on the S‐100 treated surface were higher than on the control surface in 4‐week of culture. Conclusions and Clinical Implications: In this study, we compared the biological activity of untreated and S‐100 treated Ti alloys surface. Aged Ti disks were immersed for only 3 minutes could easily improve the reduction of the surface energy due to carbon attached to the Ti surface. As a result, the hydrophobic Ti surface were changed to hydrophilic, and then the proliferation of osteogenic cells were accelerated. S‐100 treatment suggested that the new bone formation on the Ti surface promotes at early stage of osseointegration. [ABSTRACT FROM AUTHOR]