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Background: Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data., Methods: The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity., Results: Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9 months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6 months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4 + (p = 0.015) and CD8 + (p = 0.017) T cells and a lower CD8 + /Foxp3 + ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression., Conclusions: The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors., (© 2024. Society of Surgical Oncology.)

To investigate the effect of heart rate and virtual monoenergetic image (VMI) on coronary stent imaging in dual-source photon-counting detector computed tomography (PCD-CT). A dynamic cardiac phantom was used to vary the heart rate at 50 beats per minute (bpm), 70 bpm, and 90 bpm. Five types of stents (4.0 mm, 3.5 mm, 3.0 mm, 2.75 mm, and 2.5 mm diameter) were scanned at three different locations and reconstructed VMI at 70 keV. In addition, 50% stenosis was assessed for 3.0 mm and 4.0 mm stents. To assess in-stent stenosis, 40 keV, 70 keV, and 100 keV images were compared. Measurable lumen and contrast to noise ratio (CNR) from lumen to stenosis were evaluated quantitatively. A-4-point scale was used for the qualitative image quality of in-stent stenosis. The measurable lumen had no significant differences among heart rates in patent stents (p = 0.55). In-stent stenosis, the residual lumen was significantly larger in 40 keV [27.5% (20.8-32.3%)] than in 70 keV [11.5% (10.0-23.0%), p < 0.05] and 100 keV [0% (0-5.2%), p < 0.05]. The CNR was higher in 40 keV [12.5 (7.5-18.2)] than in 70 keV [5.3 (2.9-7.7), p < 0.05] and 100 keV [1.3 (0.5-2.7), p < 0.05]. The image quality was better in 40 keV (3.4 ± 0.7) than in 70 keV [(2.6 ± 0.8), p < 0.05] and 100 keV [(1.3 ± 0.4), p < 0.05]. Dual-source PCD-CT maintains a measurable lumen even at high heart rates. Adjusting the VMI can be helpful in visualizing the in-stent stenosis., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Low body weight and advanced age are among the best predictors of osteoporosis. Osteoporosis Self-Assessment Tool (OST) values are calculated by a simple formula [(body weight in kilograms - age in years) × 0.2] to identify patients at increased risk of osteoporosis. In our recent single-center study, we demonstrated an association between OST and poor outcomes in postmenopausal women after transcatheter aortic valve replacement (TAVR). We aimed to investigate the impact of osteoporotic risk in men with aortic stenosis who underwent TAVR in a large cohort. In this multi-center study, 1,339 men who underwent TAVR between April 2010 and July 2023 were retrospectively analyzed. Women were excluded from the present study. All patients were deemed appropriate for TAVR after a review by a multidisciplinary team. Baseline characteristics of patients were compared by dividing patients into three tertiles, based on the OST value: ≤ - 6.16, - 6.16 to - 4.14, and - 4.14 < for tertiles 1, 2, and 3, respectively. Primary endpoint was all-cause mortality after TAVR. Tertile 1 (patients with the lowest OST values) included older patients with smaller body mass index, lower hemoglobin and albumin levels. In addition, they had greater clinical frailty scale, slower 5-meter walk test, weaker hand grip strength, and more cognitive impairment, indicating increased frailty. They were more severely symptomatic, with lower ejection fractions, smaller aortic valve areas, and more tricuspid regurgitation than were patients in the other two groups. Multivariate analysis revealed that OST tertiles 3 was associated with decreased risk of all-cause mortality (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90), compared with OST tertile 1 as a reference. For OST tertiles 1, 2, and 3, the estimated 1-year survival rates of all-cause mortality post-TAVR were 83.6% ± 1.9%, 91.1% ± 1.4%, and 93.1% ± 1.3%, respectively, (log-rank, p < 0.001).　In conclusions, in men as same as women, osteoporotic risk assessed by OST values was overlapped with increased frailty. The simple OST formula was useful for predicting all-cause mortality in patients undergoing TAVR in large registry datasets., (© 2024. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Purpose: To investigate the relationship between interstitial lung abnormalities (ILAs) and mortality in patients with esophageal cancer and the cause of mortality., Materials and Methods: This retrospective study investigated patients with esophageal cancer from January 2011 to December 2015. ILAs were visually scored on baseline CT using a 3-point scale (0 = non-ILA, 1 = indeterminate for ILA, and 2 = ILA). ILAs were classified into subcategories of non-subpleural, subpleural non-fibrotic, and subpleural fibrotic. Five-year overall survival (OS) was compared between patients with and without ILAs using the multivariable Cox proportional hazards model. Subgroup analyses were performed based on cancer stage and ILA subcategories. The prevalences of treatment complications and death due to esophageal cancer and pneumonia/respiratory failure were analyzed using Fisher's exact test., Results: A total of 478 patients with esophageal cancer (age, 66.8 years ± 8.6 [standard deviation]; 64 women) were evaluated in this study. Among them, 267 patients showed no ILAs, 125 patients were indeterminate for ILAs, and 86 patients showed ILAs. ILAs were a significant factor for shorter OS (hazard ratio [HR] = 1.68, 95% confidence interval [CI] 1.10-2.55, P = 0.016) in the multivariable Cox proportional hazards model adjusting for age, sex, smoking history, clinical stage, and histology. On subgroup analysis using patients with clinical stage IVB, the presence of ILAs was a significant factor (HR = 3.78, 95% CI 1.67-8.54, P = 0.001). Subpleural fibrotic ILAs were significantly associated with shorter OS (HR = 2.22, 95% CI 1.25-3.93, P = 0.006). There was no significant difference in treatment complications. Patients with ILAs showed a higher prevalence of death due to pneumonia/respiratory failure than those without ILAs (non-ILA, 2/95 [2%]; ILA, 5/39 [13%]; P = 0.022). The prevalence of death due to esophageal cancer was similar in patients with and without ILA (non-ILA, 82/95 [86%]; ILA 32/39 [82%]; P = 0.596)., Conclusion: ILAs were significantly associated with shorter survival in patients with esophageal cancer., (© 2024. The Author(s).)

Despite guideline-based recommendation of the interchangeable use of instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) to guide revascularization decision-making, iFR/FFR could demonstrate different physiological or clinical outcomes in some specific patient or lesion subsets. Therefore, we sought to investigate the impact of difference between iFR and FFR-guided revascularization decision-making on clinical outcomes in patients with left main disease (LMD). In this international multicenter registry of LMD with physiological interrogation, we identified 275 patients in whom physiological assessment was performed with both iFR/FFR. Major adverse cardiovascular event (MACE) was defined as a composite of death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The receiver-operating characteristic analysis was performed for both iFR/FFR to predict MACE in respective patients in whom revascularization was deferred and performed. In 153 patients of revascularization deferral, MACE occurred in 17.0% patients. The optimal cut-off values of iFR and FFR to predict MACE were 0.88 (specificity:0.74; sensitivity:0.65) and 0.76 (specificity:0.81; sensitivity:0.46), respectively. The area under the curve (AUC) was significantly higher for iFR than FFR (0.74; 95%CI 0.62-0.85 vs. 0.62; 95%CI 0.48-0.75; p = 0.012). In 122 patients of coronary revascularization, MACE occurred in 13.1% patients. The optimal cut-off values of iFR and FFR were 0.92 (specificity:0.93; sensitivity:0.25) and 0.81 (specificity:0.047; sensitivity:1.00), respectively. The AUCs were not significantly different between iFR and FFR (0.57; 95%CI 0.40-0.73 vs. 0.46; 95%CI 0.31-0.61; p = 0.43). While neither baseline iFR nor FFR was predictive of MACE in patients in whom revascularization was performed, iFR-guided deferral seemed to be safer than FFR-guided deferral., (© 2024. The Author(s).)

Background: This study aims to compare patency rates of the 0- and 30-s (sec) balloon dilation time in hemodialysis (HD) patients with restenosis after percutaneous transluminal angioplasty (PTA)., Methods: The patients who underwent PTA within 6 months for failed arteriovenous fistula at the forearm were randomly assigned the 0-s or 30-s dilation time group. Effect of dilation time on the 3- and 6-month patency rates after PTA was examined., Results: Fifty patients were enrolled in this study. The 3-month patency rate in the 30-s dilation group was better than that in the 0-s dilation group (P = 0.0050), while the 6-month patency rates did not show a significant difference between the two groups (P = 0.28). Cox's proportional hazard model revealed that 30-s of inflation time (hazard ratio 0.027; P = 0.0072), diameter of the proximal (hazard ratio 0.32; P = 0.031), and dilation pressure (hazard ratio 0.63; P = 0.014) were associated with better 3-month patency. Dilation pressure between previous and present PTA did not differ in the 0-s (P = 0.15) and 30-s dilation groups (P = 0.16). The 6-month patency rate of the present PTA in the 30-s dilation group was higher than that of the previous PTA (P = 0.015). The visual analog scale did not differ between the two groups (P = 0.51)., Conclusion: The presenting data suggest that 30-s dilation potentially results in a better 3-month patency rate than 0-s dilation in HD patients with restenosis after PTA., (© 2024. The Author(s).)

Purpose: To predict solid and micropapillary components in lung invasive adenocarcinoma using radiomic analyses based on high-spatial-resolution CT (HSR-CT)., Materials and Methods: For this retrospective study, 64 patients with lung invasive adenocarcinoma were enrolled. All patients were scanned by HSR-CT with 1024 matrix. A pathologist evaluated subtypes (lepidic, acinar, solid, micropapillary, or others). Total 61 radiomic features in the CT images were calculated using our modified texture analysis software, then filtered and minimized by least absolute shrinkage and selection operator (LASSO) regression to select optimal radiomic features for predicting solid and micropapillary components in lung invasive adenocarcinoma. Final data were obtained by repeating tenfold cross-validation 10 times. Two independent radiologists visually predicted solid or micropapillary components on each image of the 64 nodules with and without using the radiomics results. The quantitative values were analyzed with logistic regression models. The receiver operating characteristic curves were generated to predict of solid and micropapillary components. P values < 0.05 were considered significant., Results: Two features (Coefficient Variation and Entropy) were independent indicators associated with solid and micropapillary components (odds ratio, 30.5 and 11.4; 95% confidence interval, 5.1-180.5 and 1.9-66.6; and P = 0.0002 and 0.0071, respectively). The area under the curve for predicting solid and micropapillary components was 0.902 (95% confidence interval, 0.802 to 0.962). The radiomics results significantly improved the accuracy and specificity of the prediction of the two radiologists., Conclusion: Two texture features (Coefficient Variation and Entropy) were significant indicators to predict solid and micropapillary components in lung invasive adenocarcinoma., (© 2024. The Author(s).)

Feline morbillivirus (FeMV) was identified for the first time in cats in 2012 in Hong Kong. Although its association with chronic kidney disease in cats has attracted the attention of researchers, its clinical significance as an acute infection has not been reported. Previously, we reported FeMV detection using next-generation sequence-based comprehensive genomic analysis of plasma samples from cats with suspected acute febrile infections. Here, we conducted an epidemiological survey to detect FeMV by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using blood samples from cats in Japan. FeMV was detected in 32/102 blood samples (31.4%) from cats with suspected acute viral infections. Most of the FeMV-positive cats had clinical findings consistent with acute viral infections, including fever, leukopenia, thrombocytopenia and jaundice. No FeMV was detected in healthy cats or clinically ill cats that visited veterinary hospitals. Phylogenetic analysis classified FeMV L genes into various FeMV subtypes. We also necropsied a FeMV-positive cat that died of a suspected acute infection. On necropsy, FeMV was detected in systemic organs, including the kidneys, lymph nodes and spleen by qRT-PCR and immunohistochemical staining. These results suggest that FeMV infections may cause acute symptomatic febrile infections in cats. A limitation of this study was that the involvement of other pathogens that cause febrile illnesses could not be ruled out and this prevented a definitive conclusion that FeMV causes febrile disease in infected cats. Further studies that include experimental infections are warranted to determine the pathogenicity of FeMV in cats., (© 2023. The Author(s).)

There have been no studies comparing clinical outcomes of physiology-guided revascularization in patients with unprotected left main coronary disease (ULMD) between percutaneous coronary intervention (PCI) vs. coronary artery bypass grafting (CABG). The aim of this study was to assess the long-term clinical outcomes between PCI and CABG of patients with physiologically significant ULMD. From an international multicenter registry of ULMD patients interrogated with instantaneous wave-free ratio (iFR), we analyzed data from 151 patients (85 PCI vs. 66 CABG) who underwent revascularization according to the cutoff value of iFR ≤ 0.89. Propensity score matching was employed to adjust for baseline clinical characteristics. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, and ischemia-driven target lesion revascularization. The secondary endpoints were the individual components of the primary endpoint. Mean age was 66.6 (± 9.2) years, 79.2% male. Mean SYNTAX score was 22.6 (± 8.4) and median iFR was 0.83 (IQR 0.74-0.87). After performing propensity score matching analysis, 48 patients treated with CABG were matched to those who underwent PCI. At a median follow-up period of 2.8 years, the primary endpoint occurred in 8.3% in PCI group and 20.8% in CABG group, respectively (HR 3.80; 95% CI 1.04-13.9; p = 0.043). There was no difference in each component of the primary event (p > 0.05 for all). Within the present study, iFR-guided PCI was associated with lower cardiovascular events rate in patients with ULMD and intermediate SYNTAX score, as compared to CABG. State-of-the-art PCI vs. CABG for ULMD. Study design and primary endpoint in patients with physiologically significant ULMD. MACE was defined as the composite of all-cause death, non-fatal myocardial infarction, and target lesion revascularization. The blue line denotes the PCI arm, and the red line denotes the CABG arm. PCI was associated with significantly lower risk of MACE than CABG. CABG: coronary artery bypass grafting; iFR: instantaneous wave-free ratio; MACE: major adverse cardiovascular events; PCI: percutaneous coronary intervention; ULMD: unprotected left main coronary artery disease., (© 2023. The Author(s).)

Background: The effect of dialytic modality at the start of renal replacement therapy on prognosis is controversial., Methods: This multicenter, prospective cohort study included patients undergoing incident hemodialysis (HD) (n = 646) and peritoneal dialysis (PD) (n = 72). We excluded patients who lacked complete data for 3 months. One-to-one propensity score (PS) matching was performed before between-group comparison of survival rates (Kaplan-Meier method and log-rank test) and identification of factors affecting prognosis (Cox proportional-hazards regression analysis)., Results: We enrolled 621 and 71 patients undergoing HD and PD, respectively (overall mean ± standard deviation age: 74 ± 13 years); 20% had cardiovascular disease (CVD). The median follow-up period was 41 (interquartile range 24-66) months. Following PS matching, we analyzed 65 patients undergoing HD and PD each. The 5-year overall survival rates did not differ between the groups (P = 0.97). The PD group exhibited a better CVD-related survival rate (P = 0.03). PD yielded adjusted hazard ratios for all-cause and CVD-related mortality of 0.99 (95% confidence interval [CI] 0.49-1.99, P = 0.97) and 3.92 (95% CI 1.05-14.7, P = 0.04), respectively. Age (P < 0.001) and the use of a central venous catheter (CVC) at dialytic initiation (P = 0.02) were independent risks for all-cause mortality; whereas, only the use of a CVC (P = 0.01) was an independent risk for CVD-related mortality., Conclusion: Although no differences were observed in overall survival, CVD-related survival may be better with dialytic initiation with PD than with HD., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: The association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and stroke in Japanese hemodialysis (HD) outpatients is unclear. Therefore, in this study, we investigate whether high NT-proBNP levels are associated with future stroke events in this population., Methods: This was a multicenter prospective observational study with post hoc analysis. Baseline NT-proBNP levels were measured at the first HD session of the week and classified into tertiles (first tertile: < 2255 pg/mL; second tertile: ≥ 2255 and < 5657 pg/mL; third tertile: ≥ 5657 pg/mL). Overall hospitalization-free survival rates were compared using the Kaplan-Meier method. The association between NT-proBNP level and hospitalization for stroke was assessed using the multivariate Cox proportional hazards models., Results: During a 5-year follow-up of 1,229 patients, 103 (8.4%) were hospitalized and 23 (1.9%) died from stroke. The hospitalization-free survival rate for ischemic stroke was lowest in the third tertile (P < 0.01). The crude hazard ratio (HR) of hospitalization was higher in the third tertile compared with the first tertile for both ischemic stroke (HR: 3.92; 95% confidence interval [CI] 2.08-7.37; P < 0.01) and hemorrhagic stroke (HR: 3.75; 95% CI 1.35-10.43; P = 0.01). On multivariate Cox hazard analysis, the adjusted HRs for ischemic stroke were higher in the third tertile. The hospitalization-free survival rates for hemorrhagic stroke and the adjusted HRs did not differ significantly., Conclusions: Elevated NT-proBNP level was associated with hospitalization for ischemic stroke, suggesting that NT-proBNP level is a valid biomarker for predicting hospitalization for ischemic stroke in HD outpatients., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Background: Liver regeneration after liver resection plays an important role in preventing posthepatectomy liver failure. In this study, we aimed to evaluate and compare the impact of laparoscopic liver resection (LLR) and open liver resection (OLR) on liver regeneration., Methods: Patients who underwent curative anatomical liver resection for hepatocellular carcinoma, cholangiocellular carcinoma, and colorectal liver metastases at our institution between January 2010 and December 2018 were included in this study. The patients were divided into the OLR and LLR groups. Preoperative liver volume (PLV), future remnant liver volume, resected liver volume (RLV), liver volume at 1 month after the surgery, and liver volume at 6 months after the surgery were calculated. The liver regeneration rate was defined as the increase in the rate of RLV, and the liver recovery rate was defined as the rate of return to the PLV., Results: The study included 72 patients. Among them, 43 were included in the OLR group and 29 were included in the LLR group. No differences were observed in the baseline characteristics and surgical procedures between the two groups. Moreover, no significant difference was observed in the liver regeneration rate at 1 month after the surgery (OLR vs. LLR: 68.9% vs. 69.0%, p = 0.875) and at 6 months after the surgery (91.8% vs. 93.2%, p = 0.995). Furthermore, the liver recovery rates were not significantly different between the two groups at 1 month after the surgery (90.3% vs. 90.6%, p = 0.893) and at 6 months after the surgery (96.9% vs. 98.8%, p = 0.986)., Conclusion: Liver regeneration after liver resection is not affected by the type of surgical procedure and both laparoscopic and open procedures yield similar regeneration and recovery rates., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A few previous clinical studies have shown that chloride (Cl) contributes to the progression and development of hypertension or proteinuria. Therefore, we aimed to determine whether hyperchloremia is associated with hypertension or proteinuria in patients with chronic kidney disease (CKD) and to define the relationships between the reduction in serum Cl concentration associated with CKD treatment and improvements in hypertension and/or proteinuria., Methods: We performed a retrospective observational study of new or referred patients with CKD who had hyperchloremia, moderate proteinuria, renal dysfunction, and hypertension. Patients taking medication for metabolic acidosis or with a history of dialysis were excluded. The participants' systolic and diastolic blood pressure (BP), serum sodium (Na) and Cl concentrations, and urinary protein (UP) concentration were measured at baseline and after 1 month of CKD treatment., Results: Fifty-one patients with CKD were included in the study. Their serum Cl concentration independently correlated with sBP and UP at baseline (P = 0.022 and P = 0.033, respectively). After 1 month's CKD treatment, their serum Na and Cl concentrations, sBP, and UP were significantly lower. The change in sBP during the month (ΔsBP) correlated with the change in serum Cl (ΔCl) (P = 0.012) but not with the change in serum Na. Multivariate analysis showed that ΔsBP was independently associated with ΔCl (P = 0.029)., Conclusions: Hyperchloremia is an independent predictor of hypertension and proteinuria for patients with CKD., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

In-stent restenosis (ISR) remains the primary concern after a percutaneous coronary intervention (PCI) and is considered to be associated with worse clinical outcomes. However, comparative data on ISR and de novo lesions are rare. Therefore, we aimed to compare PCI-related clinical outcomes between patients with de novo lesions and those with ISR lesions. We undertook a retrospective analysis of patients who had undergone a PCI between 2013 and 2020. The incidences of major adverse cardiac and cerebrovascular events (MACCE) and all-cause death over a 2-year follow-up period were evaluated. In total, 1538 patients were enrolled and divided into two groups: a de novo lesions group (n = 1258, 81.8%) and an ISR lesions group (n = 280, 18.2%). Patients in the ISR lesions group were significantly older, with a higher prevalence of hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease than those in the de novo lesions group. Kaplan-Meier curves showed no significant between-group differences in the incidence of MACCE (log-rank, p = 0.93) and all-cause death (p = 0.09). After adjustment for other covariates, PCIs for ISR lesions were not found to be significantly associated with MACCE (hazard ratio [HR], 1.10; 95% confidential interval [CI] 0.49-2.49; p = 0.81) and all-cause death (HR, 0.58; 95% CI 0.26-1.31; p = 0.19). PCIs for ISR lesions were not associated with worse clinical outcomes compared with PCIs for de novo lesions., (© 2021. Japanese Association of Cardiovascular Intervention and Therapeutics.)

Background: The association between N-terminal pro brain natriuretic peptide (NT-proBNP) level and long-term mortality in Japanese hemodialysis patients has not been fully assessed., Methods: This prospective, multicenter study included 1428 hemodialysis outpatients. Baseline NT-proBNP levels were measured at the first hemodialysis session of the week and participants were followed for 5 years. The areas under the curve were calculated from receiver operating characteristic curves. Groups determined by quartiles of baseline NT-proBNP level were assessed by the Kaplan-Meier method and log-rank test. The association between NT-proBNP level and mortality was assessed using multivariate Cox proportional hazards models., Results: During the 5-year follow-up, we observed 370 deaths and 256 censored cases. The areas under the curve of pre-hemodialysis NT-proBNP for all-cause mortality and cardiovascular disease mortality after 1 year were 0.75 and 0.78, respectively, and significantly greater than the areas under the curve at the 3- and 5-year follow-up. Cut-off values for all-cause mortality and cardiovascular disease mortality after 1 year were 4550 and 5467 ng/L, respectively (sensitivity: 82% and 81%; specificity: 59% and 64%). Kaplan-Meier survival analysis showed that the group with pre-hemodialysis NT-proBNP ≥ 8805 ng/L had increased all-cause mortality (P < 0.001) and cardiovascular disease mortality (P < 0.001). Finally, multivariate Cox analysis showed that NT-proBNP level was associated with all-cause mortality (P < 0.001) and cardiovascular disease mortality (P = 0.004) independently from other clinical parameters., Conclusion: NT-proBNP is a useful marker to predict both all-cause and cardiovascular disease mortality in hemodialysis patients., (© 2021. Japanese Society of Nephrology.)

The physiological pattern of coronary artery disease as determined by pressure-wire (PW)-pullback is important for decision-making of revascularization and risk stratification of patients. However, it remains unclear whether inter-observer differences in interpreting PW-pullback data are subject to the expertise of physicians. This study sought to investigate the subjectivity of this assessment among non-experts. Expert interventional cardiologists classified 545 PW-pullback traces into physiologically focal or physiologically diffuse disease pattern. Defining expert-consensus as the reference standard, we evaluated ten non-expert doctors' classification performance. Observers were stratified equally by two ways: (i) years of experience as interventional cardiologists (middle-level vs. junior-level) and (ii) volume of institutions where they belonged to (high-volume center vs. low-volume center). When judged against the expert-consensus, the agreement of non-expert observers in assessing physiological pattern of disease (focal or diffuse) ranged from 69.1 to 85.0% (p for heterogeneity < 0.0001). There was no evidence for a moderating effect of years of experience; the pooled accuracy of middle-level doctors was 78.8% (95% confidential interval [CI] 72.8-84.7%) vs. 79.1% for junior-level doctors (95% CI 75.9-82.2%, p = 0.95 for difference). On the other hand, we observed a significant moderating effect of center volume. Accuracy across non-experts in high-volume centers was 82.7% (95% CI 80.3-85.1%) vs. 75.1% for low-volume centers (95% CI 71.9-78.3%, p = 0.0002 for difference). Interpretation of PW-pullback by non-expert interventional cardiologists was considerably subjective.

Previous reports showed that GuideLiner (GL) and Guidezilla (GZ) can accommodate bulky and multiple devices beyond the official profiles. However, feasibility of kissing balloon technique (KBT) through these devices is unknown. The tested devices included 7Fr-GL/GZ and respective three types of 2.5 mm semi-compliant (SC) and non-compliant (NC) balloons: conventional model (CM), tapered-tip model (TM) and latest model (LM). First, three experienced operators attempted to advance all 21 combinations of the 2 balloons through GL/GZ on the guidewires and assessed the crossability in 3 grades: easy, difficult and impossible. Second, the only balloon combinations graded as easy by all operators were tested in the polyurethane-made bifurcation model which required KBT following cross-over stenting. Within the total of 42 device combinations, only one balloon combination of double LM-NC balloons was classified as easy in both GL/GZ by consensus opinion of the operators. While two combinations of LM-SC and LM-SC/NC balloons were classified as difficult in both GL/GZ, all four combinations of LM-SC/NC and CM/TM-NC balloons were classified as difficult only in GL. Other 32 combinations were all classified as impossible. In the bifurcation model, the combination of double LM-NC balloons using GL achieved KBT while the same balloon combination with GZ failed. The feasibility of KBT using child-catheter is highly dependent on the device characteristics. The combination of latest small-profile NC balloons through GL could be clinically applicable.

For the revascularization of patients with clinical and anatomical complexities, several technical skills are often required. However, the prognostic effect of complex percutaneous coronary intervention (C-PCI) on the clinical outcomes is not well known. The aim of this study was to investigate the relationship between the C-PCI and mid-term clinical outcomes. We assessed 1062 patients who underwent PCI with newer-generation drug-eluting stent and stratified the patients according to whether they had complex PCI (C-PCI, n = 358) or non-complex PCI (non-C-PCI, n = 704). C-PCI was defined as a procedure with at least 1 of the following features: 3 vessels treated, ≥ 3 stents per vessel implanted, ≥ 3 lesions treated, use of a 2-stent technique, the total stent length per vessel > 60 mm, chronic total occlusion, unprotected left main coronary artery stenting, and rotational atherectomy use. All-cause death and major adverse cardiac and cerebrovascular events (MACCE; cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke) were evaluated. The median follow-up period was 1.9 (0.8-3.0) years. The baseline SYNTAX score was significantly higher in the C-PCI group than in the non-C-PCI group [20 (14-27) vs. 10 (6-17), p < 0.001]. Kaplan-Meier analysis showed that the cumulative incidences of all-cause death (log-rank p = 0.12) and MACCE (log-rank p = 0.64) did not differ between the two groups. On multivariable Cox analysis, C-PCI did not adversely affect the clinical outcomes. Despite a high rate of anatomically complex coronary lesions, the patients who underwent C-PCI had comparable "hard" clinical outcomes with those of non-C-PCI.

Background: Albuminuria and estimated glomerular filtration rate (eGFR) are clinically measured to evaluate the severity of chronic kidney disease (CKD). The aim of our study was to clarify the association between clinical parameters, including albuminuria and eGFR, and the risk of incident CKD in a nondiabetic population with normal range of albuminuria and eGFR., Methods: A 10-year follow-up, retrospective cohort study involving 317 Japanese men (mean age, 42 years) with eGFR ≥ 90 mL/min/1.73 m 2 and urine albumin-to-creatinine ratio (UACR) < 30 mg/gCr was performed. Participants were free of diabetes mellitus. Multivariate logistic regression approaches were used to assess independent predictors of the incidence of CKD., Results: Twenty-nine (9%) participants developed CKD (eGFR < 60 mL/min/1.73 m 2 and/or UACR ≥ 30 mg/gCr) through 10 years of follow-up. At the baseline examination, age, blood pressure, UACR, and eGFR were higher in participants who developed CKD than in those without CKD. After adjustment for confounders, high-normal albuminuria (P < 0.001) and hypertension (P = 0.045) were associated with an increased incidence of CKD. From receiver-operating characteristic curves, UACR ≥ 7.0 mg/gCr was defined as high-normal albuminuria. Logistic regression analysis also showed that, in addition to presence of hypertension, UACR ≥ 7.0 mg/gCr was identified as an independent risk of incident CKD within 10 years after adjustment for age, body mass index, smoking status, and dyslipidemia [UACR: odds ratio (OR) 17.36 (95% CI 6.16-48.93, P < 0.001)]., Conclusion: High-normal albuminuria and hypertension are associated with incident CKD in a nondiabetic population with normal-range UACR and eGFR.

Resveratrol, a phytoalexin present in grapes and other edible foods, has been reported to have beneficial effects against various diseases including cancer. We previously reported that resveratrol and its derivative, caffeic acid-adducted resveratrol, selectively inhibit the three-dimensional (3D) proliferation of a human colorectal cancer cell line, HCT116 with activating KRAS mutation. Herein, we demonstrated that a novel compound, ferulic acid-bound resveratrol, also represses the 3D proliferation of HCT116 cells. We observed that resveratrol conjugated to two ferulic acids represses the 3D proliferation of HCT116 cells more strongly than resveratrol and resveratrol conjugated to one ferulic acid. Resveratrol conjugated to two ferulic acids also inhibited the 3D proliferation of MCF7 human breast cancer cells. We further uncovered that the resveratrol derivative increases the mRNA level of the tumor suppressor p15, a CDK inhibitor that functions as a brake of cell proliferation in HCT116 cells. These results imply that the resveratrol derivative represses 3D proliferation via increasing p15 expression in HCT116 cells.

Purpose: It is unclear whether hypomagnesemia is an independent risk factor or innocent bystander for mortality in maintenance hemodialysis (MHD) patients. Thus, we studied associations between hypomagnesemia and all-cause as well as cardiovascular (CV) mortality in MHD patients., Methods: Baseline clinical characteristics and coronary artery calcium score (CACS) of 353 Japanese MHD patients were reviewed. Three-year survival rate and mortality risk factors were assessed., Results: Median (interquartile range) age, dialysis vintage, serum magnesium (Mg), serum albumin and CACS of the subjects were 68 (60-78) years, 75 (32-151) months, 2.4 (2.2-2.7) mg/dl, 3.6 (3.3-3.8) g/dl, and 1181 (278-3190), respectively. During the 3-year period, 91 patients died. Kaplan-Meier overall 3-year survival rates were 59.0% in in patients with Mg < 2.4 mg/dl (n = 136) and 82.3% in patients with Mg ≥ 2.4 mg/dl (n = 217), (P < 0.0001). In Cox regression models not incorporating serum albumin, Mg < 2.4 mg/dl was significantly associated with 3-year all-cause death, independent of age, dialysis vintage, average ultrafiltration, Log (CACS + 1), warfarin use, serum potassium, high-sensitivity C-reactive protein (hsCRP), phosphate, uric acid, and intact parathyroid hormone [Hazard ratio (HR) 95% confidence interval (CI): 2.82 (1.31-6.29), P = 0.0078], and CV death, independent of age, dialysis vintage, Log (CACS + 1), warfarin use, serum hsCRP, and uric acid [HR (95% CI): 4.47 (1.45-16.76), P = 0.0086]. Nevertheless, associations of Mg < 2.4 mg/dl with all-cause and CV mortality were all absent in models that included serum albumin., Conclusions: Hypomagnesemia is not an independent risk factor for mortality but is associated with malnutrition in MHD patients.

Background: The definition of sepsis was updated to sepsis-3 in February 2016. Currently, direct hemoperfusion therapy using the polymyxin B-immobilized fiber cartridge (PMX-DHP) is widely performed to treat sepsis and septic shock. However, the prognostic factors of PMX-DHPs in patients with sepsis using the new definition are unclear. We retrospectively assessed prognostic factors in patients who had received PMX-DHP therapy for sepsis and septic shock., Methods: We included 71 patients with severe infection who underwent PMX-DHP treatment from January 2006 to August 2015 in this study. Participants were re-evaluated according to the criteria of sepsis-3. The patients were divided into two groups based on having survived (n = 59) or not survived (n = 12) for 28 days after PMX-DHP treatment. Clinical data before and after PMX-DHP treatment were compared between the two groups., Results: Non-survivors showed a lower Glasgow Coma Scale (GCS) score before PMX-DHP treatment compared with 28-day survivors [12 (6-14) vs 14 (12-15), P < 0.01]. Furthermore, pH after the first PMX-DHP session was significantly lower in non-survivors than in survivors (7.28 ± 0.23 vs 7.39 ± 0.06, P = 0.03). Multivariate logistic regression analysis showed that only lower pH after the first PMX-DHP session was a predictor of 28-day mortality independent of age, sex, GCS score, and mean arterial pressure (odds ratio per pH of 0.01, 0.93; 95% confidence interval, 0.83-0.99; P = 0.02)., Conclusion: The pH after the first PMX-DHP session is an independent risk factor for mortality in patients receiving PMX-DHP for sepsis and septic shock.

Background: High-normal albuminuria is an important risk factor for incident chronic kidney disease in diabetic populations, in contrast to an uncertain association in nondiabetic populations. This study aimed to reveal the relationship between high-normal albuminuria and incident chronic kidney disease in a Japanese nondiabetic population., Methods: A 10-year follow-up retrospective cohort study was performed involving 1378 Japanese men (mean age 44 ± 5.3 years) without chronic kidney disease and diabetes mellitus. Chronic kidney disease was diagnosed as either estimated glomerular filtration rate < 60 mL/min/1.73 m 2 or a urine albumin-to-creatinine ratio ≥ 30 mg/g., Results: At baseline, age, estimated glomerular filtration rate, and the presence of hematuria, hypertension, and dyslipidemia were independently associated with the albumin-to-creatinine ratio. Among the 1378 participants, 185 (13.4%) fulfilled diagnostic criteria for chronic kidney disease over the 10-year follow-up period. Median annual estimated glomerular filtration rate decline showed a deterioration with increasing quartiles of baseline albumin-to-creatinine ratio (P = 0.004). Participants who had a baseline albumin-to-creatinine ratio in the highest quartile (5.9-28.9 mg/g) were more likely to develop micro- or macroalbuminuria (odds ratio: 16.23, 95% confidence interval 6.56-54.03), chronic kidney disease (odds ratio: 2.48, 95% confidence interval 1.64-3.82), and hypertension (odds ratio 2.06, 95% confidence interval 1.30-3.31), but not diabetes mellitus compared with those who had an albumin-to-creatinine ratio in the lowest quartile (1.3-3.6 mg/g) after adjustment for potential confounders., Conclusions: High-normal albuminuria was associated with incident chronic kidney disease in this Japanese nondiabetic male population.

Resveratrol is a polyphenolic compound in many edible foods including grapes, peanuts, and berries. Several studies have revealed the beneficial effects of resveratrol against various diseases such as heart disease, diabetes, obesity, neurological disorders, and cancer. A recent study showed that resveratrol inhibits the proliferation of HCT116 human colorectal cancer cells in three-dimensional culture (3DC) via induction of luminal apoptosis in HCT116 cell spheroids. In this study, we showed that a novel compound, caffeic acid-adducted resveratrol, has a stronger inhibitory effect on the growth of HCT116 cell spheroids in 3DC than resveratrol. It showed almost the same inhibitory efficacy as 5-fluorouracil, a conventional anticancer drug. We further showed that the resveratrol derivative did not affect the growth of HKe3 cell spheroids derived from HCT116 cells by disruption of the activating mutant KRAS gene. These results suggest that the resveratrol derivative inhibits the growth of HCT116 cell spheroids via inhibition of an oncogenic KRAS-mediated signaling pathway.

Background: Renal fibrosis is a common pathological feature of the progression of chronic kidney disease. Although valproic acid (VPA) has been recently shown to induce autophagy, the effect of VPA-induced autophagy on renal fibrosis remains unknown. We, therefore, investigated whether VPA-induced autophagy suppresses renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO)., Methods: Male C57BL/6 mice were divided into five groups (n = 8 per group): (1) sham group; (2) vehicle group; (3) VPA-treated group; (4) 3-methyladenine (3-MA; autophagy inhibitor)-treated group; and (5) VPA plus 3-MA-treated group. Mice underwent UUO and the kidneys were studied after 5 days. We also investigated the effect of VPA-induced autophagy on α-smooth muscle actin (α-SMA) in transforming growth factor (TGF)-β1-stimulated rat kidney fibroblasts and epithelial cells., Results: VPA attenuated renal fibrosis and induced autophagy in UUO mice, while 3-MA increased renal fibrosis and suppressed autophagy. In addition, the anti-fibrotic effect of VPA was diminished by 3-MA in UUO mice. In rat kidney fibroblasts and epithelial cells, VPA suppressed TGF-β1-stimulated α-SMA expression and induced autophagy. In contrast, 3-MA enhanced α-SMA expression while inhibiting autophagy. Furthermore, the combined use of VPA and 3-MA treatments increased the expression of α-SMA compared with VPA treatment alone in TGF-β1-stimulated rat kidney fibroblasts and epithelial cells, which was accompanied by the inhibition of autophagy., Conclusion: These findings suggest that VPA may be a candidate drug for the treatment of renal fibrosis through the induction of autophagy.

Background: High glucose (HG) induces production of transforming growth factor-beta1 (TGF-β1), but the mechanism remains elusive. The aim of this study was to determine the gene(s) involved in HG-induced TGF-β1 production in human peritoneal mesothelial cells (HPMCs)., Methods: Microarray analysis was performed following a 3-h preincubation of HPMCs in 4 or 0.1% glucose medium. Transcriptional genes were selected using Gene Ontology analysis for biological processes, including regulation of transcription and DNA-dependent. The effects of small interfering RNA (siRNA) treatments on the up-regulation of TGF-β1 mRNA were assessed by quantitative real-time polymerase chain reaction (qPCR). Finally, enzyme-linked immunosorbent assay (ELISA) was performed to determine which gene(s) contribute to the production of TGF-β1 protein in the medium., Results: Microarray analysis revealed that the expression of 51 genes increased by more than 3-fold. Gene ontology analysis identified 13 genes for further study. qPCR confirmed mRNA amplification for 9 of the 13 genes. Furthermore, HG-induced up-regulation of TGF-β1 mRNA was attenuated by the siRNA of 4 genes: MDS1 and EVI1 complex locus (MECOM), FBJ murine osteosarcoma viral oncogene homolog B (FOSB), FBJ murine osteosarcoma viral oncogene homolog (FOS) and activating transcription factor 3 (ATF3). ELISA showed that siRNA treatment of FOS, but not MECOM, FOSB or ATF3, suppressed the increase of TGF-β1 protein in the medium., Conclusions: FOS is a downstream effector of HG stimulation in HPMCs that contributes to TGF-β1 production, suggesting that blocking FOS expression may be a therapeutic target for peritoneal fibrosis.

Background: Chronic kidney disease patients share clinical and pathological features with the general aging population. Increased oxidative DNA damage, accumulation of cell cycle-arrested cells and decreased Klotho expression are assumed to be age-related factors that are reportedly linked to kidney disease. This study sought to determine the association between these age-related factors and renal damage in patients with IgA nephropathy (IgAN)., Methods: We performed a cross-sectional analysis of 71 patients who were diagnosed with IgAN by renal biopsy. Expression of 8-hydroxydeoxyguanosine (8-OHdG, a marker of oxidative DNA damage), p16 (a marker of cell cycle-arrest) and Klotho (an anti-aging protein) were evaluated by immunohistochemical staining of renal biopsy samples. We correlated the changes in expression of these markers with Lee's pathologic grades and the Oxford classification. We also investigated the independent association between these markers and interstitial fibrosis using multiple linear regression analysis., Results: 8-OHdG and p16 increased but Klotho decreased with progression of pathologic grade. Expression of 8-OHdG and p16 increased with the deterioration of mesangial hypercellularity and segmental glomerulosclerosis. In addition, p16 increased but Klotho decreased with progression of tubular atrophy/interstitial fibrosis. In univariate regression analysis, age, body mass index, systolic blood pressure, urinary protein excretion and expression of 8-OHdG, p16 and Klotho showed significant correlations with interstitial fibrosis. Multivariable regression analyses revealed that aging, increased renal expression of p16 and decreased expression of Klotho were independently correlated with interstitial fibrosis., Conclusions: The age-related factors might play important roles in the development of IgAN.

Channelrhodopsins have become a focus of interest because of their ability to control neural activity by light, used in a technology called optogenetics. The channelrhodopsin in the eukaryote Chlamydomonas reinhardtii (CrChR-1) is a light-gated cation channel responsible for motility changes upon photo-illumination and a member of the membrane-embedded retinal protein family. Recent crystal structure analysis revealed that CrChR-1 has unique extended modules both at its N- and C-termini compared to other microbial retinal proteins. This study reports the first successful expression of a ChR-1 variant in Escherichia coli as a holoprotein: the ChR-1 variant lacking both the N- and C-termini (CrChR-1&#95;82-308). However, compared to ChR-1 having the extended modules (CrChR-1&#95;1-357), truncation of the termini greatly altered the absorption maximum and photochemical properties, including the pKa values of its charged residues around the chromophore, the reaction rates in the photocycle and the photo-induced ion channeling activity. The results of some experiments regarding ion transport activity suggest that CrChR-1&#95;82-308 has a proton channeling activity even in the dark. On the basis of these results, we discuss the structural and functional roles of the N- and C-terminal extended modules in CrChR-1.

Background: Combination therapy of aliskiren and an angiotensin II receptor blocker (ARB) has been reported to be effective for reducing the level of proteinuria. However, it remains unclear whether this combination therapy contributes to suppression of kidney disease progression. The aim of this study was to investigate the effect of aliskiren on hard renal endpoints, when added to an ARB, in patients with advanced chronic kidney disease (CKD)., Methods: The study design was a prospective, randomized open-label design. 83 CKD patients (52 men and 31 women) were enrolled and assigned randomly to an aliskiren add-on group (n = 42) or control group (n = 41). Entry criteria included elevated serum creatinine ≥ 1.5 mg/dl, urine protein excretion (≥ 1+ on urine dipstick test), and hypertension. All participants were treated with an ARB. The follow-up period was 12 months. 12 participants were withdrawn during the study period and the study was terminated in January 2012 as a consequence of the results of the interim analysis of the ALTITUDE study., Results: Nine patients in the aliskiren group and seven patients in the control group started dialysis. Doubling of the serum creatinine level occurred in one patient in the control group. A Cox proportional hazards test showed that dual blockade of the renin-angiotensin-aldosterone system with aliskiren and ARB was not associated with improvement in hard renal endpoints., Conclusion: We conclude that aliskiren add-on therapy to an ARB may not give any benefit and, therefore, should not be recommended in CKD patients.

Background: Low serum testosterone levels have been recently linked to endothelial dysfunction, arterial stiffness, and worse outcomes in male hemodialysis patients. We tested the hypothesis that low serum testosterone levels are also associated with atherosclerosis risk factors in postmenopausal women undergoing hemodialysis., Methods: We measured serum testosterone in 115 confirmed postmenopausal ethnically Japanese women undergoing hemodialysis with mean age of 68.1 ± 10.6 years and median dialysis vintage of 73 months. The severity of atherosclerosis was evaluated by carotid intima-media thickness (cIMT) and cardio-ankle vascular index (CAVI). In addition, we also included a control cohort of 32 age-matched postmenopausal women without chronic kidney disease., Results: Serum testosterone was significantly lower in women undergoing hemodialysis than in age-matched controls. Women undergoing hemodialysis who had undetectable testosterone concentration presented higher cIMT and higher CAVI than women undergoing hemodialysis with testosterone concentration above detection limits (P < 0.05 for all). Multiple logistic regression analyses confirmed the independence of these associations., Conclusion: Serum testosterone levels in postmenopausal women undergoing hemodialysis are abnormally low and associated with features of atherosclerosis.

Background: When diagnosing hypertension (HT) it is essential to determine not only the level of raised blood pressure (BP), but also how the condition relates to organ damage. The best time to measure BP for diagnosing HT in patients on hemodialysis (HD) remains unclear., Methods: A total of 100 HD patients (mean age 63.8 years, 60 males) were studied. Left ventricular hypertrophy (LVH) was detected by echocardiography and BP monitored for 1 week at 20 different times in the morning and night, before and after dialysis. We also checked for masked HT, i.e., patients with weekly morning HT, but not pre-dialysis HT., Results: Average BP for the week was 141.9 ±19.0/79.6 ± 10.6 mmHg, with 68 patients classified as hypertensive. Average morning BP was 144.6 ± 19.8/81.7 ± 11.3 mmHg, and 71 patients had weekly morning HT. In addition, 62 patients had LVH and 51 patients had relative morning HT. Multiple logistic analyses showed that LVH was associated with weekly morning HT, morning HT on HD and non-HD days, average HT, and relative morning HT. However, evening, pre-dialysis, and post-dialysis HT showed no association with LVH. Masked HT was found in 20 % of patients. If HT had been diagnosed using only pre-dialysis BP, 20 of the 71 patients with weekly morning HT would not have been detected., Conclusion: Morning BP is useful for detecting LVH in HD patients. Monitoring of morning BP may be superior to measurements taken at other times for diagnosing HT.

Background: It is important to observe the flow pattern of dialysate when evaluating dialyzer function and developing the most appropriate design. We investigated dialysate flow through two polysulfone membrane dialyzers (TS-UL [Toray Medical] and APS-S [Asahi Medical]) by computed tomography (CT), with barium sulfate as the contrast medium. We also performed a clinical comparison of these two dialyzers., Methods: For the in vitro experiment, after confirming the steady-state flow of mock blood (xanthan gum solution; 200 ml/min) and dialysate (500 ml/min), fresh dialysate, containing 5% (w/v) barium sulfate was perfused, and longitudinal CT scans of the dialyzer were obtained. Then the concentration of barium sulfate was measured (in Hounsfield units) in three fixed regions of interest. For the in vivo experiment, 12 patients on stable hemodialysis who had been using the APS-S for more than 1 month were switched to the TS-UL for 1 month and changes in various parameters were assessed., Results: The distribution of dialysate was homogeneous on CT scans of the TS-UL, but not on scans of the APS-S. The dialysate concentration curves for the three regions of interest were similar with the TS-UL, but not with the APS-S. Clearance of urea nitrogen and albumin loss were both significantly higher with the TS-UL than with the APS-S. The decrease in alpha 1-microglobulin was larger with the TS-UL than with the APS-S, but not significantly., Conclusions: Clearance of substances over a wide range of molecular weights was higher with the TS-UL than with the APS-S, and differences in the design of the dialysate compartment may have been involved in this feature.