Japanese Subjects Research Articles

Higher neutrophil–lymphocyte ratio is associated with depressive symptoms in Japanese general male population

Relationships between the neutrophil–lymphocyte ratio (NLR) and/or the platelet-lymphocyte ratio (PLR) and neuroinflammatory diseases have been reported. Depression is also associated with neuroinflammation. Here, we determined the association between the NLR, PLR, and depressive symptoms. This cross-sectional study is a secondary analysis of the data of the Iwaki Health Promotion Project 2017. We analyzed the characteristics and laboratory data of 1,015 Japanese subjects (597 females, 408 males) including their NLR and PLR values. We assigned the subjects with a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16 to the depressive symptoms group. We performed a multivariate logistic regression analysis to determine whether the NLR and/or PLR were associated with depressive symptoms (CES-D ≥ 16). Two hundred subjects (19.7%; 122 [20.4%] females, 78 [19.1%] males) were assigned to the depressive symptoms group. There were significant differences between the non-depressive symptoms and depressive symptoms groups in the NLR [median (25th to 75th percentile): 1.54 (1.24, 1.97) vs. 1.76 (1.32, 2.37), P = 0.005] and the PLR [median (25th to 75th percentile): 123.7 (102.0, 153.9) vs. 136.8 (107.0, 166.5), P = 0.047] in males, but not in females. The multivariate logistic regression analysis demonstrated that the NLR was significantly associated with depressive symptoms in males (adjusted odds ratio: per 1 increase, 1.570; 95% confidence interval: 1.120–2.220; P = 0.009). In conclusion, our findings indicate that higher NLR may be associated with depressive symptoms in males.

1448-P: Partial Pancreatectomy Increased α-Cell Volume Density, but Not Compensated ß-Cell Volume in Japanese Subjects

In type 2 diabetes, deficit of insulin secretion is often ascribed to the reduction of β-cell volume, implying that regeneration of β-cells could be one of its radical treatments. Hitherto, several models are known to elicit β-cell compensation in rodents. Among them, application of partial pancreatectomy can induce replenishment of β-cell volume in young mice, while it is unclear whether this occurs in humans. In the present study, islet pathology was evaluated using the pancreatic specimens from the patients with pancreatic cancer who underwent repeated (i.e., partial followed by total) pancreatectomy because of its local recurrence after the initial surgery. Ten subjects (5 males and 5 females) at Hirosaki University Hospital or Chiba University Hospital were evaluated. Morphometric analysis was performed on formalin fixed pancreatic sections, in which the quadruple immunostaining for each hormone and the fluorescent immunostaining for ALDH1A3 was conducted. The mean age at the first and second operations was 66.2±and 71.6±5.8 years old, respectively. The mean duration until recurrence was 3.2±2.0 years. There were no significant differences in HbA1c and BMI between first and second preoperation. In morphometrical analysis, α-cell volume in the second surgery was significantly increased compared to the first surgery (p<0.04) , while β-cell volume was comparable. There was a positive correlation between the frequency of conduit glucagon positive cells and islet α-cell volume (r=0.66, p<0.05) . The frequency of ALDH1A3 positive cells were positively correlated with the α-cell/ β-cell ratio in the second surgical specimen (r=0.81, p<0.01) . Taken together, unlike rodents, our results indicate that partial pancreatectomy did not induce replenishment of β-cell volume, but increased α-cell volume in human subjects. As its mechanism, the neogenesis of ductal endocrine cells and/or the transdifferentiation of β-cells to α-cells in the islets may be involved. Disclosure Y.Takeuchi: None. H.Mizukami: None. S.Osonoi: None. K.Kudoh: None. T.Sasaki: None. S.Yagihashi: None.

Rationale and design of a prospective study evaluating population pharmacokinetics and pharmacodynamics of rivaroxaban in Chinese patients with non-valvular atrial fibrillation

IntroductionRivaroxaban is one of the most commonly used non-vitamin K antagonists for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Different individual exposures exist for Asian and non-Asian populations,...

Reaching agreement on contribution behavior in different cultures-a public goods game with representatives in Japan and Germany

We discuss the results of an experimental public good game with group representatives in Germany and Japan, societies with varying levels of individualism. Representatives are permitted to communicate with their constituencies, but not with other representatives. We focus on accountability between representative and his constituency and on the risk taken in the interaction between representatives. We find that in Germany, subjects more readily trust a stranger's cooperativeness, groups reach agreement faster and are quicker to discuss and formulate a strategy in pre-play communication vis-a-vis Japanese subjects, where group formation takes longer. Further, we find a stronger end effect in Germany than in Japan, where the period of play explains much less variance in contribution behavior.Our study contributes to our understanding of intercultural differences in group formation and behavior when small group representatives invest in the public good, with implications for cross-cultural management, negotiation and leadership. Our evidence on between-country differences seems to empirically validate Yuki's (2003) framework for group behavior. We hope that our findings will stimulate further enquiry into human group behavior from a cross-cultural perspective.

0453 Lemborexant Exposure Is Independent of Race

Abstract Introduction Some hypnotic treatments for insomnia require dosing consideration due to exposure differences based on patient characteristics. Lemborexant (LEM) is a dual orexin receptor antagonist approved in multiple countries for the treatment of adult insomnia. LEM is not associated with exposure differences based on sex, age, or BMI that impact dosing. The potential impact of race on exposure was determined in two stand-alone pharmacokinetic (PK) studies and by modeling data from studies comprising the LEM clinical development program, which included healthy subjects and insomnia patients. Methods Study 003 (NCT02039089) was a single-center, multiple-dose, randomized, double-blind, placebo-controlled, parallel-group study in healthy Japanese and White subjects. Study 014 (NCT04555733) was a phase 1, single center, open-label, single and multiple oral dose study in healthy Chinese subjects. Additionally, effect of race on LEM exposure was independently examined as part of a population PK analysis incorporating LEM data from 9 Phase 1 studies (n=407), and Studies 201 (NCT01995838; n=235), 303 (NCT02952820; n=726) and 304 (NCT02783729; n=524) (Lalovic et al., 2020). Plasma concentrations of LEM were quantified from plasma by validated liquid chromatography with tandem mass spectrometry. Adverse events (AE) were recorded. Results Exposure of LEM increased in an approximately dose-proportional manner across the dose range (2.5 mg to 25 mg) in studies 003 and 014. There were no significant exposure differences between Japanese and White subjects following single LEM10 administration on Day 1 in Study 003 (maximum concentration [Cmax] mean[SD], ng/mL: Japanese, 46.5[25.8]; White, 47.3[28.1]; area under the curve from time zero to 24h [AUC0-24] mean[SD], ng·h/mL: Japanese, 231[40.2]; White, 208[83.4]) or when comparing PK data from Chinese subjects in Study 014 following single dose administration on Day 1 (Cmax mean[SD], ng/mL: LEM5, 29.8[12.8]; LEM10, 56.2[16.9]; LEM25, 116[46.8]; AUC0-24 mean[SD], ng·h/mL: LEM5, 106[29.9]; LEM10, 205[35.6]; LEM25, 549[116]) to Japanese and White subjects in Study 003. These results are supported by the cross-study, population PK model-based analysis, indicating no significant clinical or statistical differences in LEM PK attributable to the intrinsic factor race. Conclusion LEM exposure is not significantly affected by race. Therefore, dosing of LEM can be consistent across patient populations from different racial groups. Support (If Any) Eisai Inc.

Metabolic dysfunction-associated fatty liver disease predicts new onset of chronic kidney disease better than fatty liver or nonalcoholic fatty liver disease.

Possible associations of chronic kidney disease (CKD) with fatty liver (FL) and nonalcoholic fatty liver disease (NAFLD) have recently been focused on. Metabolic dysfunction-associated fatty liver disease (MAFLD), defined as FL with overweight/obesity, type 2 diabetes mellitus or metabolic abnormalities, has been proposed as a new feature of chronic liver disease. However, the relationship between MAFLD and new onset of CKD has not been fully addressed. We investigated the associations of FL, NAFLD and MAFLD with the development of CKD, defined as an estimated glomerular filtration rate (eGFR) <60mL/min/1.73 m2 or positive for urinary protein, over a 10-year period in 28 890 Japanese subjects who received annual health examinations. After exclusion of subjects with no data for abdominal ultrasonography and subjects with CKD at baseline, a total of 13 159 subjects (men 8581, women 4578; mean age 48 years) were recruited. The prevalence of FL, NAFLD and MAFLD was 34.6% (men 45.1%, women 15.1%), 32.8% (men 42.7%, women 14.5%) and 32.3% (men 42.4%, women 13.4%), respectively. During the 10-year follow-up period, 2163 subjects (men 1475, women 688) had new onset of CKD. Multivariable Cox proportional hazards model analyses showed that MAFLD [hazard ratio 1.12 (95% confidence interval 1.02-1.26); P=.027] but not FL or NAFLD was an independent risk factor for new onset of CKD after adjustment of age, sex, eGFR, current smoking habit, ischemic heart disease, diabetes mellitus, overweight/obesity, hypertension and dyslipidemia. The addition of MAFLD [continuous net reclassification improvement (NRI) 0.154, integrated discrimination improvement (IDI) 0.0024] to traditional risk factors without metabolic abnormalities significantly improved the discriminatory capacity better than did the addition of FL (NRI 0.138, IDI 0.0018) or NAFLD (NRI 0.132, IDI 0.0017). MAFLD is modestly and independently associated with new onset of CKD and predicts the risk for development of CKD better than FL or NAFLD.

Characterization of Peripheral Blood TCR in Patients with Type 1 Diabetes Mellitus by BD RhapsodyTM VDJ CDR3 Assay.

The sequence of complementarity-determining region 3 of the T-cell receptor (TCR) varies widely due to the insertion of random bases during V-(D)-J recombination. In this study, we used single-cell VDJ sequencing using the latest technology, BD Rhapsody, to identify the TCR sequences of autoreactive T-cells characteristic of Japanese type 1 diabetes mellitus (T1DM) and to clarify the pairing of TCR of peripheral blood mononuclear cells from four patients with T1DM at the single-cell level. The expression levels of the TCR alpha variable (TRAV) 17 and TRAV21 in T1DM patients were higher than those in healthy Japanese subjects. Furthermore, the Shannon index of CD8+ T cells and FOXP3+ cells in T1DM patients was lower than that of healthy subjects. The gene expression of PRF1, GZMH, ITGB2, NKG7, CTSW, and CST7 was increased, while the expression of CD4, CD7, CD5, HLA-A, CD27, and IL-32 was decreased in the CD8+ T cells of T1DM patients. The upregulated gene expression was IL4R and TNFRSF4 in FOXP3+ cells of T1DM patients. Overall, these findings demonstrate that TCR diversity and gene expression of CD8+ and FOXP3+ cells are different in patients with T1DM and healthy subjects.

A high‐performance SNP panel developed by machine‐learning approaches for characterizing genetic differences of Southern and Northern Han Chinese, Korean, and Japanese individuals

Population stratification analyses targeting genetically closely related East Asians have revealed that distinguishable differentiation exists between Han Chinese, Korean, and Japanese individuals, as well as between southern (S-) and northern (N-) Han Chinese. Previous studies offer a number of choices for ancestry informative single nucleotide polymorphisms (AISNPs) to discriminate East-Asian populations. In this study, we collected and examined the efficiency of 1185 AISNPs using frequency and genotype data from various publicly available databases. With the aim to perform fine-scale classification of S-Han, N-Han, Korean, and Japanese subjects, machine-learning methods (Softmax and Random Forest) were used to screen a panel of highly informative AISNPs and to develop a superior classification model. Stepwise classification was implemented to increase and balance the discrimination in the process of AISNP selection, first discriminating Han, Korean, and Japanese individuals, and then characterizing stratification between S-Han and N-Han. The final 272-AISNP panel is an alternative optimization of various previous works, which promises reliable and >90% accuracy in classification of the four East-Asian groups. This AISNP panel and the machine-learning model could be a useful and superior choice in medical genome-wide association studies and in forensic investigations for unknown suspect identity.

Resistant Maltodextrin Intake Reduces Virulent Metabolites in the Gut Environment: A Randomized Control Study in a Japanese Cohort.

In recent years, there have been many reports on the effects of prebiotics on intestinal health. In particular, the consumption of resistant maltodextrin (RMD) has been reported to be beneficial. However, there has been no comprehensive quantification of the effect of RMD on the intestinal environment. Therefore, this study aimed to quantify the effects of RMD on the intestine, especially the intestinal microbiome and metabolome profiles. A randomized, double-blind, and controlled trial was conducted in 29 Japanese subjects, whose hemoglobin A1c (HbA1c) levels are larger than 6% (Clinical trial no. UMIN000023970, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000027589). The subjects consumed RMD or placebo twice per day for 24 weeks. Blood and fecal samples were collected before and after the intake. The intestinal environment was assessed by a metabologenomics approach, involving 16S rRNA gene-based microbiome analysis and mass spectrometry-based metabolome analysis. The intake of RMD increased the levels of Bifidobacterium and Fusicatenibacter and decreased deoxycholate levels. Additionally, intake of RMD lowered the levels of some opportunistic virulent metabolites, such as imidazole propionate and trimethylamine, in subjects with an initially high amount of those metabolites. RMD may have beneficial effects on the gut environment, such as commensal microbiota modulation and reduction of virulence metabolites, which is known as a causative factor in metabolic disorders. However, the effects of RMD partially depend on the gut environmental baseline.

Haplotype phasing of a bipolar disorder pedigree revealed rare multiple mutations of SPOCD1 gene in the 1p36–35 susceptibility locus

BackgroundThe etiology of bipolar disorder (BD) is poorly understood. Considering the complexity of BD, pedigree-based sequencing studies focusing on haplotypes at specific loci may be practical to discover high-impact risk variants. This study comprehensively examined the haplotype sequence at 1p36–35 BD and recurrent depressive disorder (RDD) susceptibility loci. MethodsWe surveyed BD families in Okinawa, Japan. We performed linkage analysis and determined the phased sequence of the affected haplotype using whole genome sequencing. We filtered rare missense variants on the haplotype. For validation, we conducted a case-control genetic association study on approximately 3000 Japanese subjects. ResultsWe identified a three-generation multiplex pedigree with BD and RDD. Strikingly, we identified a significant linkage with mood disorders (logarithm of odds [LOD] = 3.61) at 1p36–35, supported in other ancestry studies. Finally, we determined the entire sequence of the 6.4-Mb haplotype shared by all affected subjects. Moreover, we found a rare triplet of missense variants in the SPOCD1 gene on the haplotype. Notably, despite the rare frequency, one heterozygote with multiple SPOCD1 variants was identified in an independent set of 88 BD type I genotyping samples. LimitationsThe 1p36–35 sequence was obtained from only a single pedigree. The replicate sample was small. Short-read sequencing might miss structural variants. A polygenic risk score was not analyzed. ConclusionThe 1p36–35 haplotype sequence may be valuable for future BD variant studies. In particular, SPOCD1 is a promising candidate gene and should be validated.

A Pharmacokinetic Bioequivalence Study Comparing Different-Strength and -Size Capsules of Isavuconazonium Sulfate in Healthy Japanese Subjects.

Isavuconazonium sulfate is the water‐soluble prodrug of the novel, broad‐spectrum, triazole antifungal agent isavuconazole. A size 0 elongated hard capsule containing 100 mg equivalent of isavuconazole is the currently marketed oral formulation in countries where it is approved. An alternative oral formulation, based on a lower‐strength and smaller‐size capsule, is required for pediatric and adolescent patients, as well as for some adult Japanese patients, especially those with difficulties swallowing larger capsules. This study was conducted to evaluate the bioequivalence of a size 0 elongated capsule containing 100 mg equivalent of isavuconazole and a size 3 capsule containing 40 mg equivalent of isavuconazole, after administration of 200 mg equivalent of isavuconazole (5 size 3 capsules or 2 size 0 elongated capsules) under fasted conditions. Bioequivalence of isavuconazole between the formulations was demonstrated, since point estimates (90%CI) for the ratio of the size 0 elongated capsules vs the size 3 capsules for maximum plasma concentration and area under the plasma concentration–time curve from time 0 to the last quantifiable concentration were within the acceptable range of 0.8 to 1.25. It was confirmed that both formulations were well tolerated, and no new safety signals were observed in healthy Japanese adult male subjects.

Pulse pressure is associated with cognitive performance in Japanese non-demented population: a cross-sectional study

BackgroundGrowing evidence suggests that vascular risk factors, especially hypertension, relate not only to cardiovascular disease but also to cognitive impairment. However, the impact of pulse pressure on cognitive function remains controversial. In this study, we evaluated the associations between pulse pressure and cognitive function in a Japanese health examination cohort using propensity matching analysis.MethodsWe examined 2,546 individuals with a mean age of 60.8 ± 10.3 years who voluntarily participated in health examination. Clinical variables included pulse pressure, and brain magnetic resonance imaging (MRI). We divided the participants into the high and low pulse pressure groups with a pre-defined cut-off value of 65 mmHg and evaluated their physical examination data, cognitive functions including Okabe’s test, Kohs’ test, and silent brain lesions using propensity matching. To clarify whether pulse pressure and blood pressure have different implications for cognitive function, a mediating analysis was also conducted.ResultsFrom the 2,546 subjects, 439 (17.2%) were in the high PP group. The propensity matching algorithm produced 433 pairs of patients with similar propensities. Higher pulse pressure corresponded to lower Okabe and Kohs’ scores (44.3 ± 7.1 vs 42.7 ± 7.5; p = 0.002, 97.9 ± 18.0 vs 95.0 ± 18.1 p = 0.019, respectively). The relationship between pulse pressure and cognitive impairment was not significantly mediated by systolic blood pressure. We observed no significant associations between silent brain lesions and pulse pressure.ConclusionHigh pulse pressure was associated with lower cognitive performance without systolic blood pressure mediation in Japanese subjects without dementia.

Seasonal Variation in Thyroid Function in Over 7,000 Healthy Subjects in an Iodine-sufficient Area and Literature Review.

ContextSeasonal variation in thyroid function, especially serum free triiodothyronine (FT3) and free thyroxine (FT4) levels, in healthy subjects remains unclear.MethodsWe examined thyroid function, including serum FT3 and FT4 levels, in healthy Japanese subjects using data of more than 7,000 health check-up participants and applied the analysis of means with transformed ranks (ANOMTR) to compare each month. In addition, we reviewed reports published in the last 2 decades.ResultsThe median serum thyrotropin (TSH) level was the highest in January (1.61 mIU/L), and the lowest in May (1.16 mIU/L). ANOMTR revealed that serum TSH levels are high in winter and low in summer. Conversely, the median serum FT3 level was higher in July than in other months, and the ANOMTR plot demonstrated serum FT3 levels to be significantly higher in summer and lower in winter. In contrast, serum FT4 levels were more consistent throughout the year, but statistically, those in February and March, October, and November were higher than those in other months. ANOMTR revealed variations in serum FT4 levels to be small through the year but biphasic.ConclusionsTaken together with previous reports, our study demonstrated seasonal changes in the serum TSH levels to be high in winter in the northern hemisphere; however, the serum FT3 differed among countries, and those of Japanese, an iodine-sufficient country, were high in summer. In contrast, FT4 levels were more consistent. These changes should be taken into account to precisely evaluate thyroid function.

Effects of water chestnut (Tarpa bispinosa Roxb.) extract/lutein on fingertip-measured advanced glycation endproduct/carotenoid levels

This pilot study tested the effects of the supplements containing water chestnut extract and carotenoids on antiglycation and carotenoid levels. Twenty Japanese subjects (mean age, 67 ± 7 years; 13 men) ingested 200 mg of Tarpa bispinosa Roxb. extract (containing >50 mg of polyphenols), 20 mg of lutein, and 3 mg of zeaxanthin daily for 3 months. Advanced glycation end product (AGEs) levels were estimated by fingertip skin autofluorescence using the AGEs Sensor; carotenoid levels were estimated by pressure-mediated reflection spectroscopy of the fingertips using the Veggie Meter. Compared to baseline, the mean AGEs score decreased significantly (0.55 ± 0.04 arbitrary units (AU) vs. 0.52 ± 0.07 AU, p = 0.03); the mean carotenoid score increased significantly (256 ± 68 optical density (OD) vs. 302 ± 109 OD, p = 0.02) at 3 months. Blood pressure, body weight, visual acuity, refractive error, and intraocular pressure were equivalent between baseline and 3 months. Compared to baseline, 13 (65%) patients had decreased AGEs scores, and 14 (70%) had increased carotenoid scores at 3 months; 9 (45%) subjects had both decreased AGEs scores and increased carotenoid scores, and two (10%) subjects had an inverse response. Co-administration of water chestnut extract and lutein for 3 months decreased the AGEs and increased the carotenoids estimated in the fingertip skin of humans.

The albumin to globulin ratio is associated with clinical outcome in Japanese patients with ulcerative colitis.

The albumin to globulin ratio (AGR) is a recognized chronic inflammation marker. No evidence regarding the relationship between AGR level and ulcerative colitis (UC) exists. The aim of this study was to evaluate the association between AGR and clinical outcomes among Japanese subjects with UC. The study subjects consisted of 273 Japanese individuals with UC. AGR was divided into 4 categories (low, moderate, high, and very high). The definition of complete mucosal healing (MH) was based on the Mayo endoscopic subscore of 0. Clinical remission (CR) was defined as no rectal bleeding and no abnormally high stool frequency (<3 times per day). The percentage of MH was 26.4%. High AGR and very high AGR were significantly positively correlated with CR (adjusted odds ratio [OR], 5.85; 95% confidence interval [CI], 2.52-14.18 and adjusted OR, 4.97; 95% CI, 2.14-12.04) and complete MH (adjusted OR, 4.03; 95% CI, 1.56-11.51 and adjusted OR, 5.22; 95% CI, 1.97-14.89), respectively after adjustment for confounding factors (P for trend=0.001). Only in the low C-reactive protein (CRP) group (≤0.1 mg/dL), very high AGR was significantly positively correlated with complete MH but not CR (adjusted OR, 4.38; 95% CI, 1.06-21.77; P for trend=0.017). In the high CRP group, no correlation between AGR and complete MH was found. Among Japanese patients with UC, AGR may be independently positively correlated with complete MH. In particular, among UC patients with low CRP, AGR might be a useful complementary marker for complete MH.

Positive Association between Aqueous Humor Hydroxylinoleate Levels and Intraocular Pressure.

We previously proposed the total assessment of hydroxylinoleates (HODEs) by LC-MS/MS after saponification and reduction of the biologic samples as biomarkers to investigate pathogenesis, disease progression, and prognosis. In this study, HODE levels were estimated in aqueous humor (AH) samples from 63 eyes (41 Japanese subjects; 15 men; mean age, 77.3 ± 6.8 years) with primary open-angle glaucoma (POAG) or cataracts. The correlations between intraocular HODE levels and background parameters, including intraocular pressure (IOP), were analyzed to assess the possible involvement of oxidative stress in glaucoma pathology. Univariate analyses showed that linoleic acid (LA) (p = 0.034) and arachidonic acid (AA) (p = 0.0041) levels were associated negatively with age; 13-(Z,E)-HODE (p = 0.018) and 13-(E,E)-HODE (p = 0.021) were associated positively with IOP; 9-(Z,E)-HODE (p = 0.039), 13-(Z,E)-HODE (p = 0.021), totally assessed-HODE (t-HODE, p = 0.023), LA (p = 0.0080), and AA (p = 0.0051) were higher in eyes with glaucoma than cataract. No gender differences were seen. A mixed-effect regression model showed that higher 13-(Z,E)-HODE (p = 0.0040) and higher t-HODE (p = 0.040) were associated with glaucoma rather than cataracts; and higher levels of 13-(Z,E)-HODE/LA (p = 0.043), 13-(E,E)-HODE/LA (p = 0.042), 13-(Z,E)-HODE (p = 0.0054), and 13-(E,E)-HODE (p = 0.027) were associated with higher IOP. Linoleate-derived oxidation products were quantified successfully in AH samples from patients with glaucoma and cataracts. A free radical oxidation mechanism can be associated with IOP elevation, while enzymatic oxidation may be involved, specifically, in the pathogenesis of POAG.

Detection of five common variants of ABO gene by a triplex probe-based fluorescence-melting-curve-analysis

Current studies have suggested that the ABO blood group system is associated with several clinical conditions. For large-scale genotyping of ABO alleles, we developed a triplex fluorescence melting curve analysis (FMCA) to determine five single nucleotide variants (SNVs), c.261delG, c.796C>A, c.802G>A and c.803G>C and c.1061delC, responsible for common ABO phenotypes using dual-labeled self-quenched (TaqMan) probes in a single tube. We accurately determined c.796C>A, c.802G>A, and c.803G>C genotypes using a FAM-labeled probe, c.261delG using a CAL Fluor Orange 560- labeled probe, and c.1061delC using a Cy5-labeled probe. The present genotyping results of five SNVs in 214 subjects of the 1000 Genomes Project were in full agreement with those of the database sequence. The predicted ABO phenotypes using combinations of these five SNVs by this method in 288 Japanese subjects were in complete agreement with those by hemagglutination assay, although we did not find any A2 (alleles containing c.1061delC) or O.02 (alleles containing c.802G>A) alleles. The present triplex probe-based FMCA is a valid and credible method for a considerably accurate large-scale determination of ABO allele genotypes and estimation of phenotypes.

Typing of the Gut Microbiota Community in Japanese Subjects.

Gut microbiota are involved in both host health and disease and can be stratified based on bacteriological composition. However, gut microbiota clustering data are limited for Asians. In this study, fecal microbiota of 1803 Japanese subjects, including 283 healthy individuals, were analyzed by 16S rRNA sequencing and clustered using two models. The association of various diseases with each community type was also assessed. Five and fifteen communities were identified using partitioning around medoids (PAM) and the Dirichlet multinominal mixtures model, respectively. Bacteria exhibiting characteristically high abundance among the PAM-identified types were of the family Ruminococcaceae (Type A) and genera Bacteroides, Blautia, and Faecalibacterium (Type B); Bacteroides, Fusobacterium, and Proteus (Type C); and Bifidobacterium (Type D), and Prevotella (Type E). The most noteworthy community found in the Japanese subjects was the Bifidobacterium-rich community. The odds ratio based on type E, which had the largest population of healthy subjects, revealed that other types (especially types A, C, and D) were highly associated with various diseases, including inflammatory bowel disease, functional gastrointestinal disorder, and lifestyle-related diseases. Gut microbiota community typing reproducibly identified organisms that may represent enterotypes peculiar to Japanese individuals and that are partly different from those of indivuals from Western countries.

Efficacy and Safety of IncobotulinumtoxinA in the Treatment of Lower Limb Spasticity in Japanese Subjects.

ObjectiveTo confirm the efficacy and safety of incobotulinumtoxinA (Xeomin®, Merz Pharmaceuticals GmbH; total dose 400 U) in Japanese subjects with lower limb (LL) poststroke spasticity using the Modified Ashworth Scale spasticity score for the plantar flexors (MAS-PF).MethodsThis phase III study (Japic clinical study database No. CTI-153030, 7 October 2015) included a double-blind, 12-week main period (MP) in which 208 subjects were randomized to receive one injection cycle of incobotulinumtoxinA 400 U (n = 104) or placebo (n = 104) in the pes equinus muscles, and an open-label extension (OLEX) that enrolled 202 subjects who received three injection cycles, 10–14 weeks in duration (the last cycle was fixed at 12 weeks). Changes in MAS-PF for incobotulinumtoxinA vs. placebo from baseline to Week 4 of the MP and to the end-of-cycle visits in the OLEX were evaluated.ResultsThe area under the curve for the change in MAS-PF was statistically significantly greater with incobotulinumtoxinA vs. placebo in the MP (mean: −7.74 vs. −4.76; least squares mean: −8.40 vs. −5.81 [p = 0.0041]). In the OLEX, mean changes in MAS-PF from baseline to end-of-study showed continued improvement with repeated injections. No new safety concerns were observed with the incobotulinumtoxinA treatment. Its efficacy and safety were consistent regardless of the length of the injection cycle interval in the OLEX.ConclusionThis study demonstrated that incobotulinumtoxinA (total dose 400 U) is an effective and a well-tolerated treatment for LL spasticity in Japanese subjects using flexible injection intervals of 10–14 weeks.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

Background and ObjectiveAMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects.MethodsThis was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg.ResultsFollowing oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity.ConclusionAMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-022-00386-3.