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Increased intra-individual variability of a variety of biomarkers is generally associated with poor health and reflects physiological dysregulation. Correlations among these biomarker variabilities should then represent interactions among heterogeneous biomarker regulatory systems. Herein, in an attempt to elucidate the network structure of physiological systems, we probed the inter-variability correlations of 22 biomarkers. Time series data on 19 blood-based and 3 hemodynamic biomarkers were collected over a one-year period for 334 hemodialysis patients, and their variabilities were evaluated by coefficients of variation. The network diagram exhibited six clusters in the physiological systems, corresponding to the regulatory domains for metabolism, inflammation, circulation, liver, salt, and protein. These domains were captured as latent factors in exploratory and confirmatory factor analyses (CFA). The 6-factor CFA model indicates that dysregulation in each of the domains manifests itself as increased variability in a specific set of biomarkers. Comparison of a diabetic and non-diabetic group within the cohort by multi-group CFA revealed that the diabetic cohort showed reduced capacities in the metabolism and salt domains and higher variabilities of the biomarkers belonging to these domains. The variability-based network analysis visualizes the concept of homeostasis and could be a valuable tool for exploring both healthy and pathological conditions.

Increased intraindividual variability in several biological parameters is associated with aspects of frailty and may reflect impaired physiological regulation. As frailty involves a cumulative decline in multiple physiological systems, we aimed to estimate the overall regulatory capacity by applying a principal component analysis to such variability. The variability of 20 blood-based parameters was evaluated as the log-transformed coefficient of variation (LCV) for one year’s worth of data from 580 hemodialysis patients. All the LCVs were positively correlated with each other and shared common characteristics. In a principal component analysis of 19 LCVs, the first principal component (PC1) explained 27.7% of the total variance, and the PC1 score exhibited consistent correlations with diverse negative health indicators, including diabetes, hypoalbuminemia, hyponatremia, and relative hypocreatininemia. The relationship between the PC1 score and frailty was subsequently examined in a subset of the subjects. The PC1 score was associated with the prevalence of frailty and was an independent predictor for frailty (odds ratio per SD: 2.31, P  = 0.01) using a multivariate logistic regression model, which showed good discrimination (c-statistic: 0.85). Therefore, the PC1 score represents principal information shared by biomarker variabilities and is a reasonable measure of homeostatic dysregulation and frailty.

In hemodialysis (HD) patients with arteriovenous fistula (AVF), changes in systemic or peripheral tissue circulation occur non-physiologically via the presence of AVF; however, associations between blood flow and tissue oxygenation in the brain and access hand are uncertain. In this study, 85 HD patients with AVF were included and evaluated for changes in flow volume (FV) and regional oxygen saturation (rSO 2 ) in the brain and hands with AVF before and after percutaneous transluminal angioplasty (PTA). Furthermore, we evaluated the factors that determine access hand rSO 2 without stenosis after PTA. Brachial arterial FV increased after PTA (p < 0.001), and carotid FV decreased (p = 0.008). Access hand rSO 2 significantly decreased after PTA (p < 0.001), but cerebral rSO 2 did not significantly change (p = 0.317). In multivariable linear regression analysis of factors associated with access hand rSO 2 , serum creatinine (standardized coefficient: 0.296) and hemoglobin (standardized coefficient: 0.249) were extracted as independent factors for access hand rSO 2 . In conclusion, a decrease in access hand oxygenation and maintenance of cerebral oxygenation were observed throughout PTA. To maintain access hand oxygenation, it is important to adequately manage Hb level and maintain muscle mass, in addition to having an AVF with appropriate blood flow.

Several epidemiological studies have demonstrated associations between variability in a number of biological parameters and adverse outcomes. As the variability may reflect impaired homeostatic regulation, we assessed albumin variability over time in chronic hemodialysis (HD) patients. Data from 1346 subjects who received chronic HD treatment from May 2001 to February 2015 were analyzed according to three phases of HD treatment: post-HD initiation, during maintenance HD treatment, and before death. The serum albumin values were grouped according to the time interval from HD initiation or death, and the yearly trends for both the albumin levels and the intra-individual albumin variability (quantified by the residual coefficient of variation: Alb-rCV) were examined. The HD initiation and death-associated changes were also analyzed using generalized additive mixed models. Furthermore, the long-term trend throughout the maintenance treatment period was evaluated separately using linear regression models. Albumin levels and variability showed distinctive changes during each of the 3 periods. After HD initiation, albumin variability decreased and reached a nadir within a year. During the subsequent maintenance treatment period (interquartile range = 5.2-11.0 years), the log Alb-rCV showed a significant upward trend (mean slope: 0.011 ± 0.035 /year), and its overall mean was -1.49 ± 0.08 (equivalent to an Alb-rCV of 3.22%). During the 1-2 years before death, this upward trend clearly accelerated, and the mean log Alb-rCV in the last year of life was -1.36 ± 0.17. The albumin levels and variability were negatively correlated with each other and exhibited exactly opposite movements throughout the course of chronic HD treatment. Different from the albumin levels, albumin variability was not dependent on chronological age but was independently associated with an individual's aging and death process. The observed upward trend in albumin variability seems to be consistent with a presumed aging-related decline in homeostatic capacity.

Background The levels of many laboratory parameters are associated with the outcomes of dialysis patients, but the significance of their variability has not been well studied. Methods A total of 384 patients receiving stable hemodialysis treatment during 2002 were followed up for mortality until the end of 2013. The within-patient coefficients of variation (CV) were calculated for 13 laboratory parameters from 1 year of data. We defined variability as CV and analyzed the survival of the patients according to the baseline CV values of each parameter by proportional hazard modeling. Results During the 11-year observation period, 125 patients died. Higher CV levels for eight parameters, namely, blood urea nitrogen (BUN), sodium, hemoglobin, creatinine, total protein, albumin, potassium and phosphate, were significantly associated with all-cause mortality. The adjusted hazard ratios for a high BUN-CV (>15 %) and a high Na-CV (>1.3 %) against a lower CV were 1.92 (95 % CI 1.31–2.81) and 1.95 (1.36–2.80), respectively. The increased mortality risk associated with each variability was attributed to excess non-cardiac deaths. The CV values of most parameters were correlated with each other and often exhibited negative associations with age, diabetes, and mobility as well as the levels of hemoglobin, albumin, creatinine, Na, the protein catabolic rate, and the creatinine generation rate. Therefore, a high variability was generally associated with frailty-related adverse prognostic factors. Conclusions The variability of several blood parameters had a significant impact on all-cause and non-cardiac mortality. The levels of the variabilities were most likely related to poor physical conditions of the patients.

The authors' purpose in this study was to assess the interactive effects of stressors, coping with stress, and self-efficacy on depression and anxiety in maintenance hemodialysis (HD) patients. Patients (n = 453) undergoing HD for more than 1 year in Japan were investigated. The regression lines illustrating significant (p < .05) interactions predict that itching HD patients with low self-efficacy will be more depressive and anxious than nonitching patients. In HD patients who report a high degree of emotion-oriented coping, itching patients will he more anxious than nonitching patients. These new findings may lead to the development of specific and focused interventions for depression or anxiety in maintenance HD patients.

Although several studies have reported elevated serum galectin-3 levels in type 2 diabetes mellitus, its association with type 2 diabetes mellitus, in Japan, where obesity is relatively uncommon, remains unclear. We investigated whether serum galectin-3 levels can be a predictive marker for type 2 diabetes mellitus in a Japanese general population. A total of 433 participants who underwent a health check-up in Nagasaki between 2013 and 2014 were enrolled; of these, 307 participants completed follow-up by 2023. Participants were classified into quartiles based on serum galectin-3 levels measured by a sandwich enzyme immunoassay, and multivariate logistic regression analysis was performed. The serum galectin-3 levels were associated with type 2 diabetes mellitus prevalence (P = 0.002) in the regression analysis. Over the 10-year follow-up, the highest galectin-3 quartile had a higher type 2 diabetes mellitus incidence than the lowest galectin-3 quartile (adjusted odds ratio: 5.75; 95% confidence interval: 1.08-30.65). Subgroup analysis stratified by body mass index revealed that each 1-standard deviation increase in serum galectin-3 level was associated with a significantly increased risk of incident type 2 diabetes mellitus in the low body mass index group, but not in the high body mass index group. The serum galectin-3 levels were significantly associated with type 2 diabetes mellitus prevalence and incidence in a general Japanese population, particularly among individuals without obesity. Galectin-3 may be a useful biomarker for identifying individuals at risk of type 2 diabetes mellitus.

Co/Pd magnetic multilayers have been prepared by using a sputtering method. Lattice distances and magnetic hysteresis curves have been measured by X-ray diffraction (XRD) measurements and magnetization measurements using a vibrating sample magnetometer (VSM). The XRD measurements have shown that the samples with thinner Pd layers have shorter lattice distances, and the VSM measurements have shown that the samples of thinner Co and thicker Pd layers are closer to those of perpendicular magnetic anisotropy. We have applied the X-ray magnetic diffraction method to the Co/Pd multilayer for the first time and have succeeded in observing a change in the X-ray diffraction intensities by the reversal of the magnetization direction.

Background Irinotecan plus S-1 (IRIS) is the only oral fluoropyrimidine-based regimen reported to be non-inferior to FOLFIRI and widely used in clinical practice for metastatic colorectal cancer (mCRC) patients. However, the combination of IRIS plus an anti-EGFR agent has not been evaluated previously. This study aimed to investigate the feasibility and efficacy of IRIS with panitumumab as second-line therapy for wild-type KRAS mCRC. Methods Main inclusion criteria were patients with wild-type KRAS mCRC refractory to one prior chemotherapy regimen for mCRC, ECOG PS 0–2, and age ≥20 years. Patients received panitumumab (6 mg/kg) and irinotecan (100 mg/m 2 ) on days 1 and 15 and S-1 (40–60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was the feasibility of the therapy. The secondary endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results A total of 36 patients received protocol treatment in eight centers. Of these, 23 patients (63.9 %) completed protocol treatment, demonstrating achievement of the primary endpoint. The most frequent grade 3/4 toxicities were diarrhea (16.7 %), acne-like rash (13.9 %), and neutropenia (11.1 %). The overall RR was 33.3 % (12/36). Of these patients, five underwent conversion surgery. Median PFS and OS were 9.5 months (95 % CI 3.5–15.4 months) and 20.1 months (95 % CI 16.7–23.2 months), respectively. Conclusion IRIS plus panitumumab has an acceptable toxicity profile and a promising efficacy in patients with previously treated wild-type KRAS mCRC. Accordingly, this regimen can be an additional treatment option for second-line chemotherapy in wild-type KRAS mCRC.

Approximately 10% of patients with reflux esophagitis (RE) are not cured with the standard 8-week q.d. regimen with a proton pump inhibitor (PPI). Thus, b.i.d. dosing is often used in refractory RE (rRE) patients, although there has been no report of endoscopically confirmed healing with b.i.d. dosing of PPIs. This study aimed to assess the efficacy and safety of 8-week therapy with rabeprazole (RPZ) sodium at 20 mg b.i.d. or 10 mg b.i.d. as compared with RPZ at 20 mg q.d. in patients with RE refractory to the standard PPI regimen in Japan. Endoscopically confirmed rRE patients (Los Angeles grade A-D) who had received a standard PPI regimen for at least 8 weeks were randomized in a double-blind manner into groups receiving RPZ at 20 and 10 mg b.i.d. or 20 mg q.d. (control) daily for up to 8 weeks. The primary efficacy endpoint was the rate of endoscopically confirmed healing after week 8. A total of 337 rRE patients treated at 71 sites were randomized. The rate of endoscopically confirmed healing after 8 weeks was significantly higher in those who received RPZ at 20 mg b.i.d. (77.0%, P = 0.003) and 10 mg b.i.d. (78.4%, P = 0.001) as compared with 20 mg q.d. (58.8%), and the rates of resolution of heartburn after week 8 were 80.0%, 74.0%, and 56.4%, respectively. All treatment regimens were well tolerated. Regimens of RPZ at 20 and 10 mg b.i.d. for 8 weeks were more effective than 20 mg q.d. with regard to endoscopically confirmed healing and symptom resolution of RE refractory to a standard PPI regimen.