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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]