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The infectious propagation of SARS-CoV-2 is continuing worldwide, and specifically, Japan is facing severe circumstances. Medical resource maintenance and action limitations remain the central measures. An analysis of long-term follow-up reports in Japan shows that the infection number follows a unique wavy oscillation, increasing and decreasing over time. However, only a few studies explain the infection wavy oscillation. This study introduces a novel nonlinear mathematical model of the new infection wavy oscillation by applying the macromolecule diffusion theory. In this model, the diffusion coefficient that depends on population density gives nonlinearity in infection propagation. As a result, our model accurately simulated infection wavy oscillations, and the infection wavy oscillation frequency and amplitude were closely linked with the recovery rate of infected individuals. In conclusion, our model provides a novel nonlinear contact infection analysis framework., (© 2022. The Author(s).)

The hypothesis that regional characteristics of the East Asian summer monsoon (EASM) result from the presence of nonlinear coupled features that modulate the seasonal circulation and rainfall at the intraseasonal time scale is advanced in this study. To examine this hypothesis, the authors undertake the analysis of daily EASM variability using a nonlinear multivariate data classifying algorithm known as self-organizing mapping (SOM). On the basis of various SOM node analyses, four major intraseasonal phases of the EASM are identified. The first node describes a circulation state corresponding to weak tropical and subtropical pressure systems, strong upper-level jets, weakened monsoonal winds, and cyclonic upper-level vorticity. This mode, related to large rainfall anomalies in southeast China and southern Japan, is identified as the mei-yu-baiu phase. The second node represents a distinct circulation state corresponding to a strengthened subtropical high, monsoonal winds, and anticyclonic upper-level vorticity in southeast Korea, which is identified as the changma phase. The third node is related to copious rain over Korea following changma, which we name the postchangma phase. The fourth node is situated diagonally opposite the changma mode. Because Korea experiences a dry spell associated with this SOM node, it is referred to as the dry-spell phase. The authors also demonstrate that a strong modulation of the changma and dry-spell phases on interannual time scales occurs during El Niño and La Niña years. Results imply that the key to predictability of the EASM on interannual time scales may lie with analysis and exploitation of its nonlinear characteristics. [ABSTRACT FROM AUTHOR]

In this paper, sequential importance sampling is used to assess the impact of observations on an ensemble prediction for the decadal path transitions of the Kuroshio Extension. This particle-filtering approach gives access to the probability density of the state vector, which allows the predictive power-an entropy-based measure-of the ensemble prediction to be determined. The proposed setup makes use of an ensemble that, at each time, samples the climatological probability distribution. Then, in a postprocessing step, the impact of different sets of observations is measured by the increase in predictive power of the ensemble over the climatological signal during one year. The method is applied in an identical-twin experiment for the Kuroshio Extension using a reduced-gravity shallow-water model. This study investigates the impact of assimilating velocity observations from different locations during the elongated and the contracted meandering states of the Kuroshio Extension. Optimal observation locations correspond to regions with strong potential vorticity gradients. For the elongated state the optimal location is in the first meander of the Kuroshio Extension. During the contracted state it is located south of Japan, where the Kuroshio separates from the coast. [ABSTRACT FROM AUTHOR]

The article examines the association of higher-level functional capacity with the incidence of falls using linear, polynomial, and nonparametric logistic regression models in Japan. The cumulative incidence rate of falls is higher in women that in men, increasing with age. Several studies have showed that disability in activities of daily living and instrumental activities of daily living are risk factors for the incidence of falls among older persons. Moreover, the basis of an understanding of the impact of disabilities in physical functions on the incidence of falls is discussed.

This cross-sectional study aimed to clarify the characteristic gut microbiota of Japanese patients with type 2 diabetes (T2DM) using t-distributed stochastic neighbor embedding analysis and the k-means method and to clarify the relationship with background data, including dietary habits. The gut microbiota data of 383 patients with T2DM and 114 individuals without T2DM were classified into red, blue, green, and yellow groups. The proportions of patients with T2DM in the red, blue, green, and yellow groups was 86.8% (112/129), 69.8% (81/116), 76.3% (90/118), and 74.6% (100/134), respectively; the red group had the highest prevalence of T2DM. There were no intergroup differences in sex, age, or body mass index. The red group had higher percentages of the Bifidobacterium and Lactobacillus genera and lower percentages of the Blautia and Phascolarctobacterium genera. Higher proportions of patients with T2DM in the red group used α-glucosidase inhibitors and glinide medications and had a low intake of fermented soybean foods, including miso soup, than those in the other groups. The gut microbiota pattern of the red group may indicate characteristic changes in the gut microbiota associated with T2DM in Japan. These results also suggest that certain diabetes drugs and fermented foods may be involved in this change. Further studies are needed to confirm the relationships among traditional dietary habits, the gut microbiota, and T2DM in Japan.

When encountering the outbreak and early spreading of COVID-19, the Government of Japan imposed gradually upgraded restriction policies and declared the state of emergency in April 2020 for the first time. To evaluate the efficacy of the countering strategies in different periods, we constructed a SEIADR (susceptible-exposed-infected-asymptomatic-documented-recovered) model to simulate the cases and determined corresponding spreading coefficients. The effective reproduction number R was obtained to evaluate the measures controlling the COVID-19 conducted by the Government of Japan during different stages. It was found that the strict containing strategies during the state of emergency period drastically inhibit the COVID-19 trend. t was obtained to evaluate the measures controlling the COVID-19 conducted by the Government of Japan during different stages. It was found that the strict containing strategies during the state of emergency period drastically inhibit the COVID-19 trend. R was 1.028 which illustrated that the strategies were less effective than the previous state of emergency. Finally, the overall infected population was predicted using combined isolation and testing intensity; the effectiveness and the expected peak time were evaluated. If using the optimized control strategies in the current stage, the spread of COVID-19 in Japan could be controlled within 30 days. The total confirmed cases should reduce to less than 4.2 × 10 t was decreased to 1.1123 and 0.8911 in stages 4 and 5 (a state of emergency in April and May 2020) from 3.5736, 2.0126, 3.0672 in the previous three stages when the containing strategies were weak. The state of emergency was declared again in view of the second wave of massive infections in January 2021. We estimated the cumulative infected cases and additional days to contain the COVID-19 transmission for the second state of emergency using this model. R t was 1.028 which illustrated that the strategies were less effective than the previous state of emergency. Finally, the overall infected population was predicted using combined isolation and testing intensity; the effectiveness and the expected peak time were evaluated. If using the optimized control strategies in the current stage, the spread of COVID-19 in Japan could be controlled within 30 days. The total confirmed cases should reduce to less than 4.2 × 10 5 by April 2021. This model study suggested stricter isolating measures may be required to shorten the period of the state of emergency., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Zhongxiang Chen et al.)

Aims/introduction: To assess the prevalence of diabetic polyneuropathy (DPN)-related sensory symptoms/signs and associated factors in patients with polyneuropathy, considering non-linear effects for numerical variables., Materials and Methods: A cross-sectional survey of patients with type 2 diabetes mellitus from 17 primary care clinics across Japan was carried out. DPN and DPN-related sensory symptoms/signs were diagnosed according to the Diabetic Neuropathy Study Group in Japan criteria., Results: Of the 9,914 patients with type 2 diabetes mellitus in this study, 2,745 had DPN and 1,689 had DPN-related sensory symptoms/signs (61.5% of patients with DPN). There were significant correlations between DPN-related sensory symptoms/signs and smoking status (odds ratio 2.04 for current and 1.64 for former; P < 0.001 and P = 0.002, respectively), sex (odds ratio 0.56 for male/female; P < 0.001) and alcohol consumption (odds ratio 2.02 for former/never; P = 0.004). Based on the non-linear logistic regression model, significant correlations were observed between the presence of DPN-related sensory symptoms/signs and higher systolic blood pressure (SBP), longer diabetes duration, and decreasing age. The logarithm of odds for SBP increased until reaching approximately 130 mmHg, then it plateaued., Conclusions: Some modifiable factors assessed in the large survey database might be associated with DPN-related sensory symptoms/signs, namely smoking, alcohol consumption and SBP. Maintaining SBP <130 mmHg was associated with lower odds of DPN-related sensory symptoms/signs in patients with DPN., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

This article is a comprehensive review of recent studies of the authors on the indication of mental health from biological information contained in pulse waves. A series of studies discovered that the largest Lyapunov exponent (LLE) of the attractor, which is constructed for the time series data from pulse waves, can provide as an effective indicator of mental health. A low level of LLE indicates insufficiency of external adaptability, which is characteristic of dementia and depression sufferers. On the contrary, a continuous high level of LLE indicates excessive external adaptability, and people in this condition tend to resort to violence. With this discovery, real-time display of the LLE, combined with other physiological indexes such as the autonomic nerve balance (ANB), sample entropy, and vascular age, as a reference, can enable people to conduct self-check of mental status. To this end, software development was performed in order to enable users to conduct pulse wave measurement anywhere at any time and display the analytical results in real time during the measurement.

Aims: This study aimed to analyse the effects of genetic polymorphisms in drug transporters and metabolizing enzymes, and clinical laboratory data on the pharmacokinetic parameters of apixaban., Methods: Data were collected from 81 Japanese patients with atrial fibrillation. Pharmacogenomic data were stratified by ABCB1, ABCG2 and CYP3A5 polymorphisms. The pharmacokinetic profile of apixaban was described by a one-compartment model with first-order absorption. Population pharmacokinetic analysis was conducted using a nonlinear mixed effect modelling (NONMEM™) program., Results: The nonlinear relationship between oral clearance (CL/F) of apixaban and creatinine clearance (Ccr) was observed. The population mean of CL/F for a typical patient (Ccr value of 70 ml min -1 ) with the CYP3A5*1/*1 and ABCG2 421C/C or C/A genotypes was estimated to be 3.06 l h -1 . When Ccr values were set to the typical value, the population mean of CL/F was 1.52 times higher in patients with the CYP3A5*1/*1 genotype compared with patients with the CYP3A5*1/*3 or *3/*3 genotype, while the population mean of CL/F was 1.49 times higher in patients with the ABCG2 421C/C or C/A genotype compared with patients with the ABCG2 421A/A genotype. However, no covariates affected the population mean of the apparent volume of distribution (Vd/F) of apixaban. The population mean of Vd/F was estimated to be 24.7 l., Conclusion: The present study suggests that the ABCG2 421A/A and CYP3A5*3 genotypes and renal function are intrinsic factors affecting apixaban pharmacokinetics. These findings may provide useful information for precision medicine using apixaban, to avoid the risk of adverse reactions., (© 2018 The British Pharmacological Society.)

Nonalcoholic fatty liver disease (NAFLD) is closely associated with obesity. Disulfide bond-forming oxidoreductase A-like protein (DsbA-L) is known to be a key molecule in protection against obesity and obesity-induced inflammation. In the present study, we used a modeling and simulation approach in an attempt to develop body mass index (BMI) and BMI-based NAFLD prediction models incorporating the DsbA-L polymorphism to predict the BMI and NAFLD in 341 elderly subjects. A nonlinear mixed-effect model best represented the sigmoidal relationship between the BMI and the logit function of the probability of NAFLD prevalence. The final models for BMI and NAFLD showed that DsbA-L rs1917760 polymorphism, age, and gender were associated with the BMI, whereas gender, patatin-like phospholipase 3 rs738409 polymorphism, HbA1c, and high-density and low-density lipoprotein cholesterol levels were associated with the risk of NAFLD. This information may aid in the genetic-based prevention of obesity and NAFLD in the general elderly population., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: Ethnicity plays a modulating role in atorvastatin pharmacokinetics (PK), with Asian patients reported to have higher exposure compared with Caucasians. Therefore, it is difficult to safely extrapolate atorvastatin PK data and models across ethnic groups. This work aims to develop a population PK model for atorvastatin and its pharmacologically active metabolites specifically for the Japanese population. Subsequently, it aimed to identify genetic polymorphisms affecting atorvastatin PK in this population., Methods: Atorvastatin acid (ATA) and ortho-hydroxy-atorvastatin acid (o-OH-ATA) plasma concentrations, clinical/demographic characteristics and genotypes for 18 (3, 3, 1, 1, 7, 2 and 1 in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes, respectively) genetic polymorphisms were collected from 27 Japanese individuals (taking 10 mg atorvastatin once daily) and analysed using a population PK modelling approach., Results: The population PK model developed (one-compartment for ATA linked through metabolite formation to an additional compartment describing the disposition of o-OH-ATA) accurately described the observed data and the associated population variability. Our analysis suggested that patients carrying one variant allele for the rs2622604 polymorphism (ABCG2) show a 55% (95% confidence interval: 16-131%) increase in atorvastatin oral bioavailability relative to the value in individuals without the variant allele., Conclusion: The current work reports the identification in the Japanese population of a BCRP polymorphism, not previously associated with the PK of any statin, that markedly increases ATA and o-OH-ATA exposure. The model developed may be of clinical importance to guide dosing recommendations tailored specifically for the Japanese.

Although several studies have investigated the effects of temperature on the incidence of infectious gastrointestinal disease in a single city or region, few have investigated variations in this association using nationwide data. We obtained weekly data, gathered between 2000 and 2012, pertaining to infectious gastroenteritis cases and weather variability in all 47 Japanese prefectures. A two-stage analysis was used to assess the nonlinear and delayed relationship between temperature and morbidity. In the first stage, a Poisson regression allowing for overdispersion in a distributed lag nonlinear model was used to estimate the prefecture-specific effects of temperature on morbidity. In the second stage, a multivariate meta-analysis was applied to pool estimates at the national level. The pooled overall relative risk (RR) was highest in the 59.9(th) percentile of temperature (RR, 1.08; 95% CI: 1.01, 1.15). Meta-analysis results also indicated that the estimated pooled RR at lower temperatures (25(th) percentile) began immediately but did not persist, whereas an identical estimate at a higher temperature (75(th) percentile) was delayed but persisted for several weeks. Our results suggest that public health strategies aimed at controlling temperature-related infectious gastroenteritis may be more effective when tailored according to region-specific weather conditions.

Objective: 3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers., Materials and Methods: In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires., Results: After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP., Conclusion: This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.

Background: Ambient ozone (O3) concentration has been reported to be significantly associated with mortality. However, linearity of the relationships and the presence of a threshold has been controversial., Objectives: The aim of the present study was to examine the concentration-response relationship and threshold of the association between ambient O3 concentration and non-accidental mortality in 13 Japanese and Korean cities from 2000 to 2009., Methods: We selected Japanese and Korean cities which have population of over 1 million. We constructed Poisson regression models adjusting daily mean temperature, daily mean PM10, humidity, time trend, season, year, day of the week, holidays and yearly population. The association between O3 concentration and mortality was examined using linear, spline and linear-threshold models. The thresholds were estimated for each city, by constructing linear-threshold models. We also examined the city-combined association using a generalized additive mixed model., Results: The mean O3 concentration did not differ greatly between Korea and Japan, which were 26.2 ppb and 24.2 ppb, respectively. Seven out of 13 cities showed better fits for the spline model compared with the linear model, supporting a non-linear relationships between O3 concentration and mortality. All of the 7 cities showed J or U shaped associations suggesting the existence of thresholds. The range of city-specific thresholds was from 11 to 34 ppb. The city-combined analysis also showed a non-linear association with a threshold around 30-40 ppb., Conclusion: We have observed non-linear concentration-response relationship with thresholds between daily mean ambient O3 concentration and daily number of non-accidental death in Japanese and Korean cities.

Oxcarbazepine is an anti-epileptic drug, which is almost completely metabolized by cytosolic enzymes in the liver to the active 10-monohyroxy metabolite (MHD) following oral administration. The pharmacokinetic (PK) profiles of MHD were evaluated in pediatric epileptic patients and a possible ethnic difference in PK of MHD between Japanese and non-Japanese pediatric patients was assessed. A non-linear mixed effect modeling approach was used to determine the PK of MHD. A one-compartment population model with first-order absorption appropriately described the PK of MHD. No clinically relevant differences were found for using body surface area or weight to explain between-patient variability, therefore the final model included the effects of body weight on apparent clearance (CL/F) and apparent volume of distribution (V/F) of MHD, and in addition, the effect of 3 concomitant anti-epileptic drugs (carbamazepine, phenobarbital and phenytoin) on CL/F of MHD. Inclusion of ethnicity as a covariate in the final model, concluded no ethnic difference with respect to CL/F of MHD between Japanese and non-Japanese patients. Hence, oxcarbazepine can be generally applied using the same dosage and administration for the treatment of partial onset seizures in pediatric patients, regardless of ethnicity., (Copyright © 2014 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background: A frailty index (FI) based on the accumulation of deficits typically has a submaximal limit at about 0.70. The objectives of this study were to examine how population characteristics of the FI change in the Honolulu-Asia Aging Study cohort, which has been followed to near-complete mortality. In particular, we were interested to see if the limit was exceeded., Methods: Secondary analysis of six waves of the Honolulu-Asia Aging Study. Men (n = 3,801) aged 71-93 years at baseline (1991) were followed until death (N = 3,455; 90.9%) or July 2012. FIs were calculated across six waves and the distribution at each wave was evaluated. Kaplan-Meier analyses and Cox proportional hazard models were performed to examine the relationship of frailty with mortality., Results: At each wave, frailty was nonlinearly associated with age, with acceleration in later years. The distributions of the FIs were skewed with long right tails. Despite the increasing mortality in each successive wave, the 99% submaximal limit never exceeded 0.65. The risk of death increased with increasing values of the FI (eg, the hazard rate increased by 1.44 [95% CI = 1.39-1.49] with each increment in the baseline FI grouping). Depending on the wave, the median survival of people with FI more than 0.5 ranged 0.84-2.04 years., Conclusions: Even in a study population followed to almost complete mortality, the limit to deficit accumulation did not exceed 0.65, confirming a quantifiable, maximum number of health deficits that older men can tolerate., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

No prior investigation has considered the effects of state dependence and unobserved heterogeneity on the relationship between regular physical activity (RPA) and latent health stock (LHS). Accounting for state dependence corrects the possible overestimation of the impact of socioeconomic factors. We estimated the degree of the state dependence of RPA and LHS among middle-aged Japanese workers. The 5 years' longitudinal data used in this study were taken from the Longitudinal Survey of Middle and Elderly Persons. Individual heterogeneity was found for both RPA and LHS, and the dynamic random-effects probit model provided the best specification. A smoking habit, low educational attainment, longer work hours, and longer commuting time had negative effects on RPA participation. RPA had positive effects on LHS, taking into consideration the possibility of confounding with other lifestyle variables. The degree of state dependence of LHS was positive and significant. Increasing the intensity of RPA had positive effects on LHS and caused individuals with RPA to exhibit greater persistence of LHS compared to individuals without RPA. This result implies that policy interventions that promote RPA, such as smoking cessation, have lasting consequences. We concluded that smoking cessation is an important health policy to increase both the participation in RPA and LHS.

We previously reported that aging and/or cytochrome P450 2D6 polymorphism are responsible for the interindividual variability in the systemic clearance (CL) and bioavailability (F) of metoprolol. The aim of the present study was to evaluate the residual variability of F of metoprolol in routinely treated Japanese patients and to investigate the intestinal absorption mechanism of the drug using human intestinal epithelial LS180 cells. We first re-analyzed the blood concentration data for metoprolol in 34 Japanese patients using a nonlinear mixed effects model. The oral clearance (CL/F) of metoprolol was positively correlated with the apparent volume of distribution (V/F), suggesting the residual variability of F. The uptake of metoprolol into LS180 cells was significantly decreased by the acidification of extracellular medium pH, and was dependent on temperature and intracellular pH. Furthermore, the cellular uptake of metoprolol was saturable, and was significantly decreased in the presence of hydrophobic cationic drugs such as diphenhydramine, procainamide, bisoprolol, and quinidine. These findings indicate that residual variability of F is one of the causes of the interindividual pharmacokinetic variability of metoprolol, and that the interindividual variability of not only presystemic first-pass metabolism, but also intestinal absorption, may be responsible for the variable F of the drug.

Background: Bepridil is used as an antiarrhythmic drug due to its class I, class III, and class IV electrophysiological properties, but it has serious adverse effects such as QT prolongation and torsade de pointes. Bepridil has complex pharmacokinetic (PK) properties with large interindividual differences in plasma concentrations. The aim of this study was to evaluate the contributing factors to changes in the dose-concentration relationship of bepridil and the risk factors for excessive QT prolongation in patients with paroxysmal or persistent atrial fibrillation (AF)., Methods: A population PK analysis was performed by using NONMEM based on 425 concentration points from 76 patients receiving bepridil. A 1-compartment model approximating an intravenous model was used to examine the interindividual variability of the apparent systematic clearance (CL/F) of bepridil. A population PK-pharmacodynamic analysis was performed using the linear regression., Results: Age was a contributing factor to the CL/F of bepridil in AF patients. The QTc interval increased as the area under the plasma bepridil concentration time curve (AUC) increased. The AUC in patients without a bundle branch block, the baseline QT interval, and the existence of structural heart disease in patients with a bundle branch block were explanatory variables of excessive QTc prolongation (QTc > 500 ms) during bepridil therapy., Conclusions: Using population PK methodology, this study showed that age was a contributing factor to the apparent clearance of bepridil in Japanese patients with AF and that excessive QT prolongation might be related to a larger AUC.

This study evaluated the differences between linear and non-linear modelled heritability estimates of racing performance based on lifetime earnings (LE) and lifetime ranking (LR) in Japanese Thoroughbred racehorses. The heritability estimate (h(2) = 0.25) obtained from a non-linear model based on formal Japan Racing Association ranking was much higher than that obtained from a linear model based on the original trait phenotype (h(2) = 0.11). The linear models showed slightly higher heritability estimates under the trait categorizations than under the original phenotypes, while the non-linear categorical trait models showed much higher heritability estimates than the linear models, especially for binary trait categorizations (h(2) = 0.34) with non-winning and winning horses. The binary trait categorizations were consistent with the case and control classifications in the previous genome-wide association study (GWAS), which identified possible sequence variants on ECA18 that affect racing performance in Japanese Thoroughbred racehorses. Those findings suggested that the different heritability estimates obtained from several trait categorizations would reflect the possible presence of susceptibility gene segregations in the analyzed population, indicating that heritability estimates from non-linear models are useful for the selection of case and control populations in GWAS., (© 2011 Blackwell Verlag GmbH.)

Background and Objectives: Nonlinear measures of heart rate variability (HRV) have gained recent interest as powerful risk predictors in various clinical settings. This study examined whether they improve risk stratification in hemodialysis patients., Design, Setting, Participants, & Measurements: To assess heart rate turbulence, deceleration capacity, fractal scaling exponent (α(1)), and other conventional HRV measures, 281 hemodialysis patients underwent 24-hour electrocardiography between January 2002 and May 2004 and were subsequently followed up., Results: During a median 87-month follow-up, 77 patients (27%) died. Age, left ventricular ejection fraction, serum albumin, C-reactive protein, and calcium × phosphate independently predicted mortality. Whereas all nonlinear HRV measures predicted mortality, only decreased scaling exponent α(1) remained significant after adjusting for clinical risk factors (hazard ratio per a 0.25 decrement, 1.46; 95% confidence interval [95% CI], 1.16-1.85). The inclusion of α(1) into a prediction model composed of clinical risk factors increased the C statistic from 0.84 to 0.87 (P=0.03), with 50.8% (95% CI, 20.2-83.7) continuous net reclassification improvement for 5-year mortality. The predictive power of α(1) showed an interaction with age (P=0.02) and was particularly strong in patients aged <70 years (n=208; hazard ratio, 1.87; 95% CI, 1.38-2.53), among whom α(1) increased the C statistic from 0.85 to 0.89 (P=0.01), with a 93.1% (95% CI, 59.3-142.0) continuous net reclassification improvement., Conclusions: Scaling exponent α(1) that reflects fractal organization of short-term HRV improves risk stratification for mortality when added to the prediction model by conventional risk factors in hemodialysis patients, particularly those aged <70 years.

Objective: Patients with peripheral artery disease (PAD), defined as having low ankle-brachial pressure index (ABI), have increased risk for incident stroke compared with those without PAD. We aimed to reveal whether ABI abnormality, especially high ABI is associated with prevalent silent cerebral infarction (SCI) in type 2 diabetic patients., Methods: We studied 538 Japanese type 2 diabetic patients, 227 women and 311 men, with a mean [±SD] age of 64±11 years. All patients underwent cranial magnetic resonance imaging (MRI). Values of ABI were classified as low (<0.9), normal (0.9≤ and <1.3), and high (1.3≤). Logistic regression model was used to calculate odds ratio and 95% confidence interval (95% CI) for prevalent SCI., Results: The mean ABI among the overall 538 patients was 1.09±0.16. Low and high ABI values were found in 52 (9.7%) and 33 (6.1%) patients, respectively. SCI was detected in 297 (55.2%) patients. The prevalence in patients with low, normal, and high ABI values were 88.5%, 49.7%, and 78.8 (p<0.001), respectively. In the multivariate logistic regression analysis, both patients with high and low ABI were significantly increased risk of prevalent SCI (odds ratio 4.53, 95% CI 1.67-12.34, p=0.003 and odds ratio 3.50, 95% CI 1.50-10.29, p=0.005), independently of other traditional cardiovascular risk factors, than those with normal ABI., Conclusions: Both high and low ABI may be strongly associated with prevalent SCI in Japanese patients with type 2 diabetes., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The prediction of influenza epidemics has long been the focus of attention in epidemiology and mathematical biology. In this study, we tested whether time series analysis was useful for predicting the incidence of influenza in Japan., Methods: The method of time series analysis we used consists of spectral analysis based on the maximum entropy method (MEM) in the frequency domain and the nonlinear least squares method in the time domain. Using this time series analysis, we analyzed the incidence data of influenza in Japan from January 1948 to December 1998; these data are unique in that they covered the periods of pandemics in Japan in 1957, 1968, and 1977., Results: On the basis of the MEM spectral analysis, we identified the periodic modes explaining the underlying variations of the incidence data. The optimum least squares fitting (LSF) curve calculated with the periodic modes reproduced the underlying variation of the incidence data. An extension of the LSF curve could be used to predict the incidence of influenza quantitatively., Conclusions: Our study suggested that MEM spectral analysis would allow us to model temporal variations of influenza epidemics with multiple periodic modes much more effectively than by using the method of conventional time series analysis, which has been used previously to investigate the behavior of temporal variations in influenza data.

Background: The aim of the present study was to clarify the association between waist circumference and all-cause and cardiovascular disease (CVD) mortality risk in relatively lean Japanese subjects., Methods and Results: A total of 3,554 men and 4,472 women who had no history of CVD were examined and their waist circumference measured at baseline. The subjects were aged ≥40 years and were obtained from 3 prospective cohort studies during 1988-1996. Hazard ratios for all-cause and CVD mortality were analyzed over a follow-up period of 14.7 years using a Cox proportional hazards model and penalized spline method, after adjustment for study cohort, age, smoking, alcohol drinking, hypertension, dyslipidemia, and diabetes. Compared with the lowest quintile, the highest quintile of waist circumference in men was associated with a linear reduction in all-cause mortality risk (multivariate-adjusted hazard ratio, 0.73; 95% confidence interval: 0.60-0.89; P for trend=0.001). CVD mortality risk was increased in men aged ≤65 years with a higher waist circumference. This relationship was U-shaped. Waist circumference was not associated with all-cause or CVD mortality risk in women., Conclusions: Waist circumference was associated inversely with increased risk of all-cause death in men, but not in women. Middle-aged men with a greater waist circumference potentially have an increased risk of CVD mortality.

What Is Known and Objective: Optimal use of phenobarbital in the neonatal population requires information regarding the drug's pharmacokinetics and the influence of various factors, such as different routes of administration, on the drug's disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in neonates and infants. This study was conducted to establish the role of patient characteristics in estimating doses of phenobarbital for neonates and infants using routine therapeutic drug monitoring data., Methods: The population pharmacokinetics of phenobarbital was evaluated using 109 serum concentration measurements obtained from routine phenobarbital monitoring of 70 neonates and infants. The data were analysed using the non-linear mixed effects model. A one-compartment pharmacokinetic model with first-order elimination was used. Covariates screened were current total bodyweight (TBW), gestational age, postnatal age (PNA), post-conceptional age, gender and neonates-infants clearance factor (serum concentration of phenobarbital; Conc)., Results and Discussion: The final pharmacokinetic parameters were CL/F (mL/h) = (5.95.TBW (kg) +1.41.PNA (weeks)) Conc (serum phenobarbital concentration >50 μg/mL)(-0.221),Vd/F(L) =1.01.TBW (kg), and F = 0.483 for oral administration and F = 1 was assumed for suppository. Conc(-0.221) is 1 for phenobarbital concentration <50 μg/mL. The important variables for predicting phenobarbital clearance in this study were TBW, PNA and Conc. Phenobarbital clearance increases proportionately with increasing TBW, and an older newborn was expected to have a higher rate of clearance than a younger newborn of equal bodyweight. Moreover, the clearance of phenobarbital decreased nonlinearly with increasing serum concentration of phenobarbital >50 μg/mL (Conc(-0.221) )., What Is New and Conclusion: We developed a new model for neonate and infant dosing of phenobarbital with good predictive performance. Clinical application of our model should permit more accurate selection of initial and maintenance doses to achieve target phenobarbital concentrations in Japanese neonates and infants, thereby enabling the clinician to achieve the desired therapeutic effect. A similar approach can be used to validate our model for use in other neonate and infant populations., (© 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.)

Background: The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug., Objectives: In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM., Methods: In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis., Results: Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linagliptin was well tolerated with no reported serious adverse events or symptoms suggestive of hypoglycemia. Overall, fewer adverse events were reported by patients after linagliptin than after placebo (11 of 55 [20%] vs 6 of 17 [35%])., Conclusions: Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Objectives: The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis., Methods: The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters., Key Findings: The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two-compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms., Conclusions: A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required., (© 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society.)

Objective: The purpose of this study was to explore the possibility of using Lyapunov exponents (LE) to evaluate the voice and speech in cleft palate (CP) patients., Subjects and Methods: Fifty healthy adults (25 males and 25 females) and 17 adult patients (10 males and 7 females) with repaired CP, who had no hypernasality, were enrolled. Five Japanese vowels were recorded at 44.1 kHz. Nasalance scores were measured simultaneously. The first LE was computed for each 1-second interval, and the mean for the first LE from all intervals (mLE(1)) was then calculated. The delay time and embedding dimension were estimated at 13, 40, 34, 27 and 22 points for the vowels /a/, /i/, /u/, /e/ and /o/, respectively, and at 8 points for all vowels., Results: The mLE(1)s for all vowels did not differ between normal males and females. The mLE(1)s for /a/ were significantly higher both in males and females with CP than in normal individuals. The correlation coefficient between the mLE(1)s and nasalance scores for all vowels was not significant for both normal and CP subjects., Conclusion: The LE seemed to be related to pathological disorders of the vocal cords in CP patients, but was independent of resonance parameters., (Copyright © 2010 S. Karger AG, Basel.)

Linezolid (Zyvox), belonging to oxazolidinone antibiotics, is commonly used for the treatment of patients infected with methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Although linezolid has been approved worldwide, the Japanese pharmacokinetic (PK) profile has not been characterized in detail. The objective of this study is to develop a population PK model for linezolid that can be applied to a Japanese population. This population PK model was established based on the 1 Japanese phase III and 4 Caucasian phase II/III studies. A total of 2539 linezolid plasma concentration measurements from 455 patients, aged 18 to 98 years and body weight 30 to 190.5 kg, were used for the analysis. The data were analyzed using nonlinear mixed effects modeling. Body weight (BW), age, ethnicity, and gender were investigated as covariates. The final model was validated by the bootstrap technique. The PK profiles of linezolid were described with a 1-compartment PK model with first-order absorption and first-order elimination. In the final population PK model, BW and age were influential covariates on clearance, and the distribution volume was affected by BW. The present population PK model of linezolid described well the PK profiles in Japanese patients who have lower BW and are relatively older compared with those in the United States/European Union.

Objective: To evaluate the influence of obesity on pharmacokinetics of amiodarone (AMD) using Non-Linear Mixed Effects Modelling (NONMEM) in Japanese patients treated with oral therapy., Method: Serum concentrations of AMD were determined by high performance liquid chromatography. One hundred and fifty-one trough concentrations from 23 patients receiving repetitive oral AMD were collected. Body mass index (BMI) and body fat percentage were measured., Results: Estimates generated using NONMEM indicated that the clearance of AMD was influenced by BMI, age and daily dosage of AMD. The final pharmacokinetic model was CL (L/h) = 0*16 * TBW * 0.53(AGE >or= 65 ) * 0*78(BMI >or= 25) * DD(0.51), V(d) (L) = 10*2 * TBW, where CL is total body clearance, TBW is total body weight (kg), DD (mg/kg/day) is daily dosage of AMD, AGE (years) >or=65 = 1 for patient was 65 years old or over and 0 otherwise, BMI (kg/m(2)) >or=25 = 1 for patient was 25 kg/m(2) or over and 0 otherwise and V(d) is apparent volume of distribution. The clearance of AMD decreased significantly by 22.3% with a BMI higher than 25 kg/m(2). The clearance of AMD also decreased significantly by 46.9% when patient age was more than 65 years., Conclusion: Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD.

Objective: By using a population pharmacokinetic analysis method, we predicted the efficacy of Ceftriaxone (CTRX) based on the pharmacokinetics of CTRX in Japanese adults and the sensitivity of infective organisms to CTRX in 2004. In addition, we clarified the difference in efficacy between once-a-day administration and twice-a-day administration., Methods: The population pharmacokinetic analysis was based on the serum concentrations of CTRX already published by NONMEM. The possible effect of body weight and age on the pharmacokinetics of CTRX was examined using a model which incorporated the change of a specific protein-binding ratio of CTRX. A Monte Carlo simulation was conducted based on the population pharmacokinetic parameters obtained by this analysis, and thereby the time above MIC (TAM) was determined from the MIC values of CTRX administered once at 0.5, 1, and 2 g and twice at 1 g. The efficacy ratio was predicted from the TAM thus obtained., Results: Because the time course of serum concentration of CTRX in adult subjects was fitted to a 2-compartment model and both body weight and age were not incorporated as the covariate, the dosing method by which a fixed amount of CTRX is administered to patients has been thought to be adequate. Based on the efficacy ratio estimated from the MIC of CTRX, we have predicted that the once-a-day administration of CTRX even at 0.5g is effective on various infecting organisms.

Objective: This study aimed to develop a population pharmacokinetic model for high-dose methotrexate (MTX), specifically focusing on the drug urinary excretion process., Methods and Results: Three hundred and forty-eight serum samples and 416 urine samples from 51 Japanese adult patients with malignancies were concurrently fitted into a multi-compartment model using the nonmem program. In the final model, creatinine clearance (CCR, mL/min) and the MTX dose (DOSE10G; 0 when <10 g, 1 when >or=10 g) were the most significant factors that affected the renal clearance (CL(r)) and non-renal clearance (CL(nr)), respectively: CL(r)(L/h) = 5.57 x (CCR/80.0)(0.112), V(1)(L) = 26.9, Q(L/h) = 0.0778, V(2)(L) = 2.27, CL(nr)(L/h) = 0.567 x 3.39(DOSE10G), where V(1) and V(2) are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the inter-compartmental (central-peripheral) clearance. For another nine patients, the model enabled a satisfactory Bayesian estimation using two time-point serum concentrations., Conclusion: The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high-dose MTX to predict and control toxic events.

We examined whether a cusp catastrophe model for binge alcohol consumption by college students that was reported earlier (Smerz & Guastello, 2008) could generalize to another culture. Participants were 130 undergraduates enrolled in economics courses at a private urban Japanese university. They completed the same questionnaire items that were used in the previous US study. For some analyses, a stratified random subsample was taken from the earlier US data that was comparable in number, age, and gender proportions (N = 132). Results for the combined sample showed essentially the same results that were obtained from the US sample: Binge drinking can be modeled as a cusp catastrophe with two stable states of behavior - low to moderate consumption and binge level consumption. The two control parameters were peer influence (bifurcation) and attitude toward alcohol use (asymmetry). The nonlinear models (average R2 = .74) accounted for considerably more variance in binge drinking and other alcohol consumption indices than the comparison linear models (average r2 = .18 ). There were some subtle differences between the two samples of students, however.

Objective: To assess the relationship between depression, reduced heart rate (HR) variability, and altered HR dynamics among patients with end-stage renal disease who are receiving hemodialysis (HD) therapy., Methods: We analyzed the 24-hour electrocardiograms of 119 outpatients receiving chronic HD. HR variability was quantified with the standard deviation of normal-to-normal R-R intervals, the triangular index, and the powers of the high- (HF), low- (LF), very-low (VLF), and ultra-low frequency (ULF) components. Nonlinear HR dynamics was assessed with the short-term (alpha(1)) and long-term (alpha(2)) scaling exponents of the detrended fluctuation analysis and approximate entropy. The depression level was assessed using the Beck Depression Inventory, Second Edition (BDI-II). HR variability and dynamics measurements were compared by gender, diabetes, and depression with adjustment for age and serum albumin concentration., Results: Most indices of HR variability and dynamics were negatively correlated with age, serum albumin concentration, depression score, and were lower in women and patients with diabetes. The alpha(2) was inversely associated with these variables. Depressed men had significantly lower HF, LF, VLF, and marginally lower ULF than nondepressed persons after adjustment for diabetes and other covariates; no difference in depression was observed in women. The alpha(2) showed marginally significant difference in depression independent from gender and diabetes., Conclusions: Among the patients who received HD, depression is associated with reduced HR variability and loss of fractal HR dynamics. However, the influence of depression on HR variability may vary by gender and physiological backgrounds. Further prospective studies are necessary to confirm their association with poor prognosis.

Objective: To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data., Method: The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated., Results: Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%., Conclusion: Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.

The objective of this study was to evaluate the Bayesian predictability of vancomycin (VCM) pharmacokinetics in Japanese pediatric patients using one-compartment population pharmacokinetic (PPK) parameters, which we reported previously. The validity of the PPK model was evaluated by bootstrap method and cross validation method, and the Bayesian predictive performance was examined. The predictive performance of the PPK model for premature patients was also examined. The cross validation method showed the predictability to be acceptable for practical use, especially for predicting trough concentration using other trough data. However, for the external premature patient data, this PPK model did not seem to be adequate. A theoretical approach using a simulation technique was also examined to evaluate the predictive performance. The results suggested that the predictability at the peak was not necessarily good at all sampling times and the predictability at the trough was better when a later time point was used. The optimal sampling time for prediction of VCM concentration in pediatric patients is discussed.

The effects of drug-drug interactions on clonazepam clearance were examined through a retrospective analysis of serum concentration data from pediatric and adult epileptic patients. Patients received clonazepam as monotherapy or in combination with other antiepileptic drugs. A total of 259 serum clonazepam concentrations gathered from 137 patients were used in a population analysis of drug-drug interactions on clonazepam clearance. Data were analyzed using a nonlinear mixed-effects modeling (NONMEM) technique. The final model describing clonazepam clearance was CL = 152 x TBW(-0.181) x DIF, where CL is clearance (ml/kg/h), TBWis total body weight (kg), and DIF (drug interaction factor) is a scaling factor for concomitant medication with a value of 1 for patients on clonazepam monotherapy, 1.18 for those patients receiving concomitant administration of clonazepam and one antiepileptic drug (carbamazepine or valproic acid), and 2.12 x TBW(-0.119) for those patients receiving concomitant administration of clonazepam and more than two antiepileptic drugs. Clonazepam clearance decreased in a weight-related fashion in children, with minimal changes observed in adults. Concomitant administration of clonazepam and carbamazepine resulted in a 22% increase in clonazepam clearance. Concomitant administration of clonazepam and valproic acid resulted in a 12% increase in clonazepam clearance. Concomitant administration of clonazepam with two or more antiepileptic drugs resulted in a 23% to 75% increase in clonazepam clearance.

Objective: Prediction of patient outcome can be useful as an aid to clinical decision making. Many studies, including my own, have constructed predictive multivariate models for outcome following stroke rehabilitation therapy, but these have often required several minutes work with a pocket calculator. The aim is to develop a simple, easy-to-use model that has strong predictive power., Methods: Four hundred sixty-four consecutive patients with first stroke who were admitted to a rehabilitation hospital during a period of 19 mo were enrolled in the study. Sex, age, the stroke type, Functional Independence Measure total score on admission (X), onset to admission interval (number of days from stroke onset to rehabilitation admission), and length of rehabilitation hospital stay (number of days from hospital admission to discharge) were the independent variables. Functional Independence Measure total score at discharge (Y) was the dependent variable., Results: Stepwise multiple regression analysis resulted in the model containing age (P < 0.0001), X (P < 0.0001), and onset to admission interval (P < 0.0001). The equation was: Y = 68.6 - 0.32 (age) + 0.80X - 0.13 (onset to admission interval), a multiple correlation coefficient (R) = 0.82, and a multiple correlation coefficient squared (R2) = 0.68. Simple regression analysis revealed the relation between Xand Y: Y = 0.85X + 37.36, and R = 0.80 R2 = 0.64. In fact, plots of X vs. Ywere nonlinear, but seemed to be able to be linearized by some form of equation. It was found that there is a linear relation between logX and Y. The equation is Y = 106.88x - 95.35, where x = logX, R = 0.84, and R2 = 0.70. The correlation is improved by a regression analysis of a natural logarithmic transformation of X (R = 0.84 vs. R = 0.82)., Conclusion: The results in this study confirm that the simple regression model using a logarithmic transformation of X (R = 0.84) has predictive power over the simple regression model (R = 0.80). This model is well validated and clinically useful.

Hypertension is one of the risk factors for the development of coronary artery disease as well as stroke. The National Nutrition Survey shows that the systolic and diastolic blood pressures of Japanese adults have decreased over time. These trends have plateaued during the last decade. We investigated national trends in blood pressure (BP) levels during these 10 years by plotting the relation between the mean BP levels during year t, BP(t), and those of the following year, BP(t+1). When we plotted the systolic BP levels of Japanese men and women aged 15 to 80 years, the trace revolved clockwise, with cycles of 4 to 5 years. The approximate center of the circular trace corresponding to data for 1985 through 1990 was at 134 mmHg in men and 129 mmHg in women, and the approximate center of a smaller circle was at 135 mmHg in men and 130 mmHg in women, respectively. In addition, with respect to the data for Japanese men in their 60s, the mean systolic BP level decreased linearly from 1982 to 1986, whereas it seemed to generate 4 circles after 1986. The approximate center of the first circle was 146 mmHg in the men. The center of the second circle was 145 mmHg and that of the third circle was 144 mmHg. Plotting of the data for Japanese women of the same age group yielded the same number of circles as the data for men. Our method of documenting changes in the mean BP levels in Japanese adults provided information about a chaotic oscillation that occurred in the populations we studied. The centers of Lorenz-plotted circles may thus provide essential information about trends in the BP levels in these populations.

For the development of a totally implantable ventricular assist system (VAS), we have been developing the vibrating flow pump (VFP), which can generate oscillated blood flow with a relative high frequency (10-50 Hz) for a totally implantable system. In this study, the effects of left ventricular assistance with this unique oscillated blood flow were analyzed by the use of nonlinear mathematics for evaluation as the whole circulatory regulatory system, not as the decomposed parts of the system. Left heart bypasses using the VFP from the left atrium to the descending aorta were performed in chronic animal experiments using healthy adult goats. The ECG, arterial blood pressure, VFP pump flow, and the flow of the descending aorta were recorded in the data recorder during awake conditions and analyzed in a personal computer system through an A-D convertor. By the use of nonlinear mathematics, time series data were embedded into the phase space, the Lyapunov numerical method, fractal dimension analysis, and power spectrum analysis were performed to evaluate nonlinear dynamics. During left ventricular assistance with the VFP, Mayer wave fluctuations were decreased in the power spectrum, the fractal dimension of the hemodynamics was significantly decreased, and peripheral vascular resistance was significantly decreased. These results suggest that nonlinear dynamics, which mediate the cardiovascular dynamics, may be affected during left ventricular (LV) bypass with oscillated flow. The decreased power of the Mayer wave in the spectrum caused the limit cycle attractor of the hemodynamics and decreased peripheral resistance. Decreased sympathetic discharges may be the origin of the decreased Mayer wave and fractal dimension. These nonlinear dynamic analyses may be useful to design optimal VAS control.

Cancer incidence and mortality data from the atomic bomb survivors cohort has been analyzed to allow for the possibility of a threshold dose response. The same dose-response models as used in the original papers were fit to the data. The estimated cancer incidence from the fitted models over-predicted the observed cancer incidence in the lowest exposure group. This is consistent with a threshold or non-linear dose-response at low-doses. Thresholds were added to the dose-response models and the range of possible thresholds is shown for both solid tumor cancers as well as the different leukemia types. This analysis suggests that the A-bomb cancer incidence data agree more with a threshold or non-linear dose-response model than a purely linear model although the linear model is statistically equivalent. This observation is not found with the mortality data. For both the incidence data and the mortality data the addition of a threshold term significantly improves the fit to the linear or linear-quadratic dose response for both total leukemias and also for the leukemia subtypes of ALL, AML, and CML.