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Background: The Global Limb Anatomic Staging System (GLASS) has been widely used to evaluate patients with chronic limb-threatening ischemia (CLTI). As end-stage kidney disease (ESKD) is a well-known CLTI risk factor, we aimed to determine whether patients on hemodialysis (HD) have a worse limb prognosis than those without ESKD, considering the same GLASS background., Methods: The data of 445 patients who underwent surgical and/or endovascular revascularization procedures for lower extremity ischemia were retrospectively collected in our division between 2005 and 2018. The major amputation rate and amputation-free survival (AFS) were compared between HD and non-HD patients., Results: Among the 215 (48%) patients receiving HD, 58 limbs required major amputation (27% limb loss rate). Among the non-HD group, the limb loss rate was 13% (P < 0.0001). The overall AFS was significantly worse in patients receiving HD than those not (P < 0.0001). The AFS was significantly worse in HD patients when comparing GLASS-standardized subgroups., Conclusions: Patients with CLTI who were receiving HD had a worse limb prognosis than those not receiving, even when considering the same GLASS classification. Furthermore, there is a need for an ideal guideline focused on ESKD-directed peripheral artery disease., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: The influence of changes in alcohol consumption on newly developed metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. We investigated the influence of alcohol consumption on newly developed MAFLD in both sexes., Methods: This observational cohort study included 4071 patients who underwent more than two health check-ups between 2015 and 2020 over an interval of more than a year. Generalised estimating equations were used for analyses., Results: At baseline, the rates of drinking and MAFLD between men and women were 72.5% versus 41.7% and 42.2% versus 22.1%, respectively. At the most recent stage, the rates of an increase in alcohol consumption for men and women were 13.3% and 8.7%, respectively, and 311/1192 (26.1%) men and 155/1566 (9.9%) women had newly developed MAFLD. The odds ratio (OR) for drinking in patients with newly developed MAFLD was 0.863 (men) (95% confidence interval [CI], 0.676-1.102, p = 0.237) and 1.041 (women) (95% CI, 0.753-1.439, p = 0.808); the OR for women who drank 140-279.9 g/week was 2.135 (95% CI, 1.158-3.939, p < 0.05) and that for all drinking categories among women was >1. Several non-invasive fibrosis scores were significantly associated with the quantity of alcohol consumption in patients with newly developed MAFLD (p < 0.005)., Conclusions: Alcohol consumption had no significant protective effect against newly developed MAFLD in both sexes, regardless of quantity. Conversely, alcohol consumption ≥140 g/week was a risk factor for newly developed MAFLD in women. The development of liver fibrosis with increased alcohol intake should be considered in patients with MAFLD., Competing Interests: Conflicts of interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal disease caused by mutations in AGXT that lead to the deficiency of alanine:glyoxylate aminotransferase (AGT). AGT is a liver pyridoxal 5'-phosphate (PLP)-dependent enzyme that detoxifies glyoxylate inside peroxisomes. The lack of AGT activity results in a build-up of glyoxylate that is oxidized to oxalate, then culminating in hyperoxaluria often leading to kidney failure. Most pathogenic mutations reduce AGT specific activity because of catalytic defects, improper folding, mistargeting to mitochondria, reduced intracellular stability, dimerization, and/or aggregation. Administration of pyridoxine (PN), a precursor of PLP, is a therapeutic option available for PH1 patients carrying responsive genotypes through the ability of the coenzyme to behave as a chaperone. Here, we report the clinical and biochemical characterization of the novel mutation c.1093G > T (p.Gly365Cys) identified in a Japanese patient. In silico studies predict that the p.Gly365Cys mutation causes a steric clash resulting in a local rearrangement of the region surrounding the active site, thus possibly affecting PLP binding and catalysis. Indeed, the purified p.Gly365Cys mutant displays proper folding but shows an extensive decrease of catalytic efficiency due to an altered PLP-binding. When expressed in AGXT1-KO HepG2 cells the variant shows reduced specific activity and protein levels in comparison with wild type AGT that cannot be rescued by PN treatment. Overall, our data indicate that the mutation of Gly 365 induces a conformational change at the AGT active site translating into a functional and structural defect and allow to predict that the patients will not be responsive to vitamin B6, thus supporting the usefulness of preclinical studies to guide therapeutic decisions in the era of precision medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Type III endoleaks after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs) with the Endologix unibody endograft remain a major concern, despite fabric, system, and instructional updates. The purpose of this study was to examine real-world outcomes of repairing AAAs using the current version of the AFX2 main body in combination with an aortic cuff, specifically focusing on type III endoleaks and morphological changes of the endograft., Methods: We recruited facilities in Japan that used AFX2 combined with an aortic cuff for at least five cases between April 2017 and March 2018. A total of 175 cases in 24 facilities were analyzed. Patients' background information, including anatomic factors, operative findings, device component variations, and midterm outcomes at 3 years after the EVAR were collected. The data on computed tomography scans from cases registered as types I and III endoleaks and migration from each institute were sent to our department for verification., Results: The mean patient age was 74.6 ± 8.1 years, and 48 cases (27%) were saccular aneurysms. The mean fusiform and saccular AAA diameters were 50.5 ± 5.8 mm and 43.5 ± 8.9 mm, respectively. No in-hospital deaths occurred. Data at 3 years, including computed tomography images, of 128 cases were analyzed. Overall survival, freedom from aneurysm-related mortality, and freedom from reintervention rates at 3 years were 85.8%, 99.3%, and 87.3%, respectively. There were three, one, and three cases of types I, IIIa, and IIIb endoleaks without sac dilatations, respectively. Among five migration cases, one case of aortic cuff migration presented as a type Ia endoleak, and four cases demonstrated sideways displacement, one of which presented as a type IIIa endoleak. The sac regression and enlargement rates at 3 years were 41.4% and 20.5% in the fusiform group and 44.2% and 16.7% in the saccular group, respectively. The proximal neck diameter slightly increased from 20.8 ± 2.7 mm before the EVAR to 22.2 ± 4.6 mm after the repair., Conclusions: Midterm outcomes of the AFX2 used in combination with an aortic cuff were acceptable, considering the rates of types I and III endoleaks. However, there were cases of sideways displacement that could cause future type IIIa endoleaks. When the AFX2 is used in combination with an aortic cuff, close surveillance for endograft deformations and subsequent adverse events, including type III endoleaks, is needed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double-blind, placebo-controlled study, we randomly assigned (2:1) 35 participants with PH1 (n = 29) or PH2 (n = 6) with eGFR ≥30 mL/min/1.73 m 2 to subcutaneous nedosiran or placebo once monthly for 6 months. The area under the curve (AUC) of percent reduction from baseline in 24-hour urinary oxalate (Uox) excretion (primary endpoint), between day 90-180, was significantly greater with nedosiran vs placebo (least squares mean [SE], +3507 [788] vs -1664 [1190], respectively; difference, 5172; 95% CI 2929-7414; P < 0.001). A greater proportion of participants receiving nedosiran vs placebo achieved normal or near-normal (<0.60 mmol/24 hours; <1.3 × ULN) Uox excretion on ≥2 consecutive visits starting at day 90 (50% vs 0; P = 0.002); this effect was mirrored in the nedosiran-treated PH1 subgroup (64.7% vs 0; P < 0.001). The PH1 subgroup maintained a sustained Uox reduction while on nedosiran, whereas no consistent effect was seen in the PH2 subgroup. Nedosiran-treated participants with PH1 also showed a significant reduction in plasma oxalate versus placebo (P = 0.017). Nedosiran was generally safe and well tolerated. In the nedosiran arm, the incidence of injection-site reactions was 9% (all mild and self-limiting). In conclusion, participants with PH1 receiving nedosiran had clinically meaningful reductions in Uox, the mediator of kidney damage in PH., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Objective: This study was conducted to investigate the types of conversational agents (CA) that can help address questions and concerns ("lay topics" [LTs])., Methods: We analyzed audio recordings of telephone consultations with 100 breast cancer patients and their families. (1) We identified the content and mode of expression of LTs about breast cancer raised during actual telephone consultations. (2) We checked for the presence of clue information (CI) that can help patients resolve their LTs., Results: None of the 805 LTs of the 100 callers were the same. Treatment-related questions occurred in 70 of the 100 consultations. CIs were present in 52.5% of the LTs., Conclusion: The results suggest that chatbots (a type of CA) that offer CIs are more feasible than chatbots that answer each question directly in cancer consultations. Moreover, it is difficult to answer questions directly because preparing answers to all LTs in a breast cancer consultation is challenging owing to LT differences. Therefore, preparing high-quality CIs focused on treatments is required., Practice Implications: An increasing number of cancer patients are seeking information to resolve their LTs. CAs can help supplement the limited human resources available if they are supplied with appropriate CIs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Patients with perforated colorectal cancer (PCRC) experience higher recurrence rates than those with non-perforated tissue. We identified the promoting factors of stage II PCRC recurrence after R0 surgery., Method: This retrospective observational study included patients treated for colorectal cancer at a single facility between 2007 and 2016, and compared the clinicopathological features of patients with perforating versus non-perforating stage II tumors who underwent R0 resection, while focusing on recurrences., Results: Thirty-two and 112 patients (predominantly men) with perforating and non-perforating tumors, respectively, were included. The perforated group had significantly higher proportions of T4 tumors than the non-perforated group (44% vs. 15%). The perforated group had significantly lower numbers of resected lymph nodes than the non-perforated group (6 vs. 17). Seven of 17 patients with follow-up data in the perforated group experienced recurrence (41%), versus 19 of 104 in the non-perforated group (18%). In the non-perforated group, male sex (89% vs. 60%, p = 0.030), T4 stage (32% vs. 9%, p = 0.029), and fewer resected lymph nodes (12.5 vs. 18.6, p = 0.003) were significantly associated with recurrence; however, no such influences on recurrence were observed in the perforated group. The recurrence sites in the perforated group were mostly local (6 patients, 86%). Conversely, recurrences in the non-perforated group were mostly distant; 8 of 19 patients (42%) had liver metastasis and 1 (5%) had lung metastasis., Conclusion: Patients with stage II PCRC experienced higher recurrence rates regardless of clinicopathological features and had high local recurrence rates indicating possible local tumor cell dispersal owing to perforation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Overuse of pyrrolidinophenones (PPs) is known to cause damage to vascular and central nervous systems, but little is known about its effect on brain endothelial barrier function. In this study, we found that exposure to 4'-iodo-α-pyrrolidinononanophenone (I-α-PNP), one of the most potently cytotoxic PPs, at sublethal concentrations decreases trans-endothelial electrical resistance and increases paracellular permeability across a monolayer of human brain microvascular endothelial cells. Treatment with I-α-PNP also elevated the production of superoxide anion. Furthermore, the treatment reduced the expression and plasma membrane localization of a tight junction protein claudin-5 (CLDN5), which was almost restored by pretreatment with an antioxidant N-acetyl-l-cysteine. These results indicate that I-α-PNP treatment may down-regulate the plasma membrane-localized CLDN5 by elevating the production of reactive oxygen species (ROS). The treatment with I-α-PNP increased the nuclear translocation of Forkhead box protein O1 (FoxO1), an oxidative stress-responsive transcription factor, and pretreating with a FoxO1 inhibitor ameliorated the decrease in CLDN5 mRNA. In addition, I-α-PNP treatment up-regulated the expression and secretion of matrix metalloproteinase-2 (MMP2) and MMP9, and the addition of an MMP inhibitor reversed the degradation of CLDN5 by I-α-PNP. Moreover, I-α-PNP treatment facilitated the activation of 26S proteasome-based proteolytic activity and pretreatment with an inhibitor of 26S proteasome, but not autophagy, suppressed the CLDN5 degradation by I-α-PNP. Accordingly, it is suggested that the down-regulation of CLDN5 by exposure to I-α-PNP is ascribable to suppression of the gene transcription due to FoxO1 nuclear translocation through ROS production and to acceleration both of the MMPs (MMP2 and MMP9)- and 26S proteasome-based proteolysis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: We evaluated the effectiveness of an original simulation training system in improving the suturing performance of medical students using a previously developed web application for scoring suturing performance., Methods: Medical students were recruited for this study and trained on vascular graft anastomosis. Prosthetic grafts were anastomosed and evaluated after orientation, and after 1 hr and 10 hr after training. Vascular surgeons were recruited as controls. Using a previously developed web application, suturing performance was evaluated on the basis of procedural time, coefficient of variation of bite (length of a stitch across the graft), coefficient of variation of pitch (interval between stitches), and skewness (symmetry of the angles between stitches)., Results: Forty-eight medical students and 10 vascular surgeons were recruited. After 1 hr of training, only the students' procedural time improved. After 10 hr of training, all scores improved compared with those in the first trial, and all students' scores except procedural time were statistically similar to those of the vascular surgeons., Conclusions: Ten-hour training improved all factors, including bite, pitch, skewness, and time. Our simple and inexpensive training system and web application for calculating anastomosis scores can be a useful open educational resource., (Copyright © 2022. Published by Elsevier Inc.)

Background: The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS., Methods: Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety., Results: Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months., Conclusion: For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival., (Copyright © 2022 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

In this study, we newly synthesized four α-pyrrolidinononanophenone (α-PNP) derivatives [4'-halogenated derivatives and α-pyrrolidinodecanophenone (α-PDP)], and then performed the structure-cytotoxicity relationship analyses. The results showed the rank order for the cytotoxic effects, α-PNP < α-PDP < 4'-fluoro-α-PNP < 4'-chrolo-α-PNP < 4'-bromo-α-PNP < 4'-iodo-α-PNP (I-α-PNP), and suggest that cytotoxicities of 4'-halogenated derivatives were more intensive than that of elongation of the hydrocarbon chain (α-PDP). We also surveyed the apoptotic mechanism of I-α-PNP in brain microvascular endothelial (HBME) cells that are utilized as the in vitro model of the blood-brain barrier. HBME cell treatment with I-α-PNP facilitated the apoptotic events (caspase-3 activation, externalization of phosphatidylserine, and DNA fragmentation), which were almost completely abolished by pretreating with antioxidants. In addition, the immunofluorescent staining revealed the enhanced production of hydroxyl radical in mitochondria by the I-α-PNP treatment, inferring that the I-α-PNP treatment triggers the apoptotic mechanism dependent on the enhanced ROS production in mitochondria. The treatment with I-α-PNP increased the production of cytotoxic aldehyde 4-hydroxy-2-nonenal and decreased the amount of reduced glutathione. Additionally, the treatment decreased the 26S proteasome-based proteolytic activities and aggresome formation. These results suggest that decrease in the antioxidant properties is also ascribable to HBME cell apoptosis elicited by I-α-PNP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: An ideal urban network system for improving regional acute myocardial infarction (AMI) outcomes should be geographically balanced and uniform according to regional population in performance of participating hospitals. The objective of our study is to evaluate whether there is a major difference in risk-adjusted in-hospital mortality between the Tokyo Cardiovascular Care Unit (CCU) network hospitals, which cover the whole population of large cities., Methods: The study subjects were all AMI patients without cardiac arrest on arrival admitted to the Tokyo CCU network hospitals from 2009 to 2017. Risk-adjusted in-hospital mortality rates (RAMRs) were compared between the categories of each hospital-level factor. A hospital-level multivariable linear regression was modeled to analyze the association between RAMRs and hospital-level factors. A funnel plot was constructed by plotting RAMRs against hospital volumes., Results: From 2009 to 2017, there were 42,123 hospitalizations for AMI in Tokyo CCU network hospitals (n=72, as of December, 2017). There were no significant differences in RAMRs in the comparison of hospital backgrounds. Each hospital background was not significantly associated with the RAMR. Considering the 99% CI in funnel plots, only five hospitals (7.2%) were located outside the control limits., Conclusions: There was no major difference in the RAMRs between the participating hospitals within the Tokyo CCU network, despite the different hospital backgrounds., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: The purpose of this study was to evaluate the factors associated with asymptomatic splenic artery aneurysm (SAA) dilatation., Methods: Among patients with SAA admitted to our department from 2001 to 2018, 70 lesions in 59 patients were selected and analyzed retrospectively. There were no cases of rupture or pregnancy in the follow-up period. We defined egg-shell appearance as SAA with >75% calcification of the outer shell. We measured the dilatation rate (mm/year) and evaluated the comorbidity and anatomical factors using univariate and multiple linear regression models. Post-hoc multiple linear regression models were fitted to evaluate the possible interactions., Results: The mean age was 61.4 years (range 35-85 years), and the initial aneurysm diameter was 15.1 mm (range 3-47 mm). The mean dilatation rate was 0.26 mm/year (range 0-3.2 mm/year) during the follow-up period (average 4.6 years). Univariate analysis revealed that, portal hypertension (PHT) (P = 0.0003), egg-shell appearance (P = 0.007), and aneurysm diameter > 20 mm (P = 0.05) were significantly associated with the dilatation rate. Multivariate analysis revealed that egg-shell appearance was found to be an independent inverse risk factor of dilatation rate (P = 0.006). The multivariate analysis, including interaction terms, revealed a stronger effect of PHT and diameter >20 mm in cases with no egg-shell appearance (P = 0.08 and P = 0.05 for interactions, respectively)., Conclusions: The egg-shell appearance of SAA was an independent inverse risk factor affecting the SAA dilatation rate. The dilatation rates in the case of PHT and diameter >20 mm were restricted in the presence of the egg-shell appearance., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

We developed a highly sensitive and accurate differential method for analyzing chiral and achiral carboxylic acids in Japanese commercial beers, using ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), based on chiral derivatization combining three isotopic chiral reagents: 12 C-DMT-3(S)-Apy, 13 C 2 -DMT-3(S)-Apy, and d 6 -DMT-3(S)-Apy. By combining these reaction solutions and analyzing the resulting mixture, simultaneous comparative analyses of the three samples could be achieved while offsetting the matrix effects on the samples. Using this approach, it was possible to differentiate the beers according to the type (draft, low-malt, and non-alcoholic), manufacturer, and storage conditions (temperature and storage period), based on the concentrations of carboxylic acids in the beers. Furthermore, we identified α-ketoglutaric acid as a new marker for determining the storage condition of Japanese beers. The proposed method would provide insights into the identification of markers in various fields, such as in biological samples, as well as food and beverages., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: High thymidine kinase 1 (TK1) activity increases the incorporation of trifluridine (FTD) into DNA; thus, FTD antitumor activity is likely to increase in patients with high tumoral TK1 activity. To date, no established predictive biomarker to indicate the clinical benefit of FTD/tipiracil (TPI) has been identified. We aimed to determine the relationship between TK1 expression and FTD/TPI efficacy in refractory metastatic colorectal cancer., Patients and Methods: Individual patient data from 2 randomized placebo-controlled trials were analyzed. We measured TK1 protein expression in tumor tissue samples and its relationship with FTD/TPI clinical efficacy using overall survival (OS), progression-free survival, and disease control rate., Results: This study comprised 329 patients (FTD/TPI, 224; placebo, 105). FTD/TPI significantly improved OS versus placebo in the high-expression (cutoff ≥ 15%) TK1 group (median OS, 7.8 vs. 6.8 months; hazard ratio = 0.65; 95% confidence interval, 0.46-0.93; P = .018). The low-expression (cutoff < 15%) TK1 group experienced a smaller OS benefit (9.3 vs. 7.4 months; hazard ratio = 0.88; 95% confidence interval, 0.63-1.23; P = .45). For patients who received placebo, the high-expression TK1 group had a slightly worse prognosis than the low-expression TK1 group. The tendency of FTD/TPI efficacy concerning progression-free survival and disease control rate was not similar to that concerning OS between groups., Conclusion: Patients with high TK1 expression showed an improvement in OS when treated with FTD/TPI. Further investigations are warranted to confirm this relationship., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Coronary artery vasospasm (CS) can be identified as either a diffuse type or focal type; however, the difference in endothelial characteristics between these spasm types remains unclear. The features of coronary intima associated with diffuse spasm and focal spasm using coronary angioscopy (CAS) were evaluated and the optical coherence tomography (OCT) findings were compared., Methods: CAS and/or OCT observational analysis was performed in 55 patients (mean age: 61.4 years, 31 men) who had acetylcholine-provoked CS (diffuse CS, 31 patients; focal CS, 24 patients). The yellowness of the intima, presence of thrombus in CAS, and intimal characteristics based on the OCT results were evaluated., Results: CAS showed more atherosclerotic yellow plaques at the focal spasm segment than at the diffuse spasm segment (p=0.032). Moreover, there were more thrombi at the focal spasm segment (p=0.039). In addition, OCT results revealed that the intima area, maximum intima thickness, and lipid content in the focal CS group were larger than the diffuse CS group (4.22±1.67mm 2 vs. 3.45±2.36mm 2 ; 0.71±0.29mm vs. 0.53±0.30mm; 55.9% vs. 32.0%, p<0.001, respectively)., Conclusions: These results indicate that the presence of atherosclerotic plaques at the spasm site is likely to be related to the occurrence of a focal vasospasm. This may support the difference of features between focal CS and diffuse CS and contribute to precise treatment for each spasm type., (Copyright © 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: We evaluated images of patients undergoing a thoracic endovascular aortic repair procedure using two reference points as a means for differentiating stent graft migration from aortic elongation. Conventional standards define migration of a stent graft as an absolute change in the distance from the distal graft ring to a distal landmark ≥10 mm compared with a baseline measurement. Aortic elongation occurs over time in both healthy individuals and patients with aortic disease. Aortic elongation in patients with stent grafts may result in increased distal thoracic aortic lengths over time. False-positive stent graft migration would be defined when these patients meet the standard definition for migration, even if the stent has not moved in relation to the elongating aorta., Methods: This retrospective study evaluated the aortic length of 23 patients treated with the conformable GORE TAG thoracic endoprosthesis (W. L. Gore & Associates, Flagstaff, Ariz) in three clinical trials (dissection, traumatic injury, and aneurysm). Patients who met the standard definition for migration were selected. A standardized protocol was used to measure aortic centerline lengths, including the innominate artery (IA) to the most distal device ring, the IA to the celiac artery (CA), and the distal ring to the CA. Baseline lengths obtained from the first postoperative image were compared with length measurements obtained from the first interval at which they met the standard definition for migration. The conventional standards for migration using a single reference point were compared with the use of dual reference points., Results: Of the 23 patients with endograft changes, 20 were deemed to have aortic elongation rather than true migration. The remaining three patients were deemed to have migration on the basis of the IA to distal ring position compared with the IA to CA length change. The IA to CA interval length change was markedly greater in those with elongation compared with migration (23.8 ± 8.4 mm vs -3.5 ± 5.4 mm, respectively; P < .05). The distal ring to CA interval length change was greater in patients showing elongation rather than migration (18.5 ± 6.6 mm vs -9.8 ± 5.4 mm, respectively; P < .05). The distance between the IA and distal ring was similar for elongation and migration., Conclusions: These results highlight the dynamic changes that can occur in the aorta as a natural consequence of age. Employing two landmarks can account for these changes and proves to be an important factor, among others, in the differentiation of aortic elongation from true stent graft migration., (Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Glucagon-like peptide-1 (GLP-1) is thought to inhibit development of aortic atherosclerosis and plaque formation. However, whether GLP-1 stabilizes fully developed atherosclerotic plaque or alters the complicated plaque composition remains unclarified., Methods: Ten Watanabe heritable hyperlipidemic (WHHL) rabbits were divided into GLP-1 receptor agonist treatment group and control group. After confirmation of atherosclerotic plaques in brachiocephalic arteries by iMap intravascular ultrasound (iMAP-IVUS), GLP-1 receptor agonist lixisenatide was administered to WHHL rabbits at 30 nmoL/kg/day for 12 weeks by osmotic pump. An equal volume of normal saline was administered in a control group. After evaluation by iMAP-IVUS at 12 weeks, brachiocephalic arteries were harvested for pathological histological analysis., Results: iMAP-IVUS analysis revealed larger fibrotic plaque components and smaller necrotic and calcified plaque components in the GLP-1 group than in the control group; %fibrotic area: 66.30 ± 2.06% vs. 75.14 ± 2.62%, p < 0.01, %necrotic area: 23.25 ± 1.87% vs. 16.17 ± 2.27%, p = 0.02, %calcified area: 2.15 ± 0.24% vs. 1.00 ± 0.18%, p < 0.01), indicating that GLP-1 receptor agonist might modify plaque composition and increase plaque stability. Histological analysis confirmed that GLP-1 receptor agonist treatment improved smooth muscle cell (SMC)-rich plaque with increased fibrotic content. Furthermore, plaque macrophage infiltration and calcification were significantly reduced by GLP-1 receptor agonist treatment; %SMC area: 6.93 ± 0.31% vs. 8.14 ± 0.48%, p = 0.02; %macrophage area: 9.11 ± 0.80% vs. 6.19 ± 0.85%, p < 0.01; %fibrotic area: 54.75 ± 1.63% vs. 69.60 ± 2.12%, p = 0.02; %calcified area: 3.25 ± 0.67% vs. 0.75 ± 0.15%, p = 0.02)., Conclusions: GLP-1 receptor agonist inhibited plaque progression and promoted plaque stabilization by inhibiting plaque growth and modifying plaque composition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Surgical site infections (SSIs) are a significant burden to patients and health care systems. This retrospective study evaluates the observed rates of SSI after our institution implemented chlorhexidine gluconate-impregnated (CHG) cloth as a preoperative antiseptic preparation in elective vascular surgery., Methods: Between March 2011 and January 2012, we reviewed 250 patients who underwent elective vascular surgery who used the CHG cloth preoperatively. Their rate of SSIs was compared with 252 control patients who received the CHG shower preoperatively during the preintervention period. Urgent and emergent cases were excluded. The primary outcome measured was SSI within 30 days of index operation., Results: There was no baseline difference in mean age, gender distribution, smoking status, diabetes, chronic obstructive pulmonary disease, and the number of patients with body mass index >40 between the cohorts. There was no difference in the overall rate (5.6% vs. 5.6%, P = 1.00) and type of SSIs between the 2 groups, but the control group trended toward deeper infections (4 deep incisional and 2 organ space vs. none and 1, respectively). The control group also had more dirty or infected wound categories (10 vs. 21.4%, P < 0.01) and more perioperative antibiotic errors and hypothermia (P < 0.02)., Conclusions: There was no observed difference in SSI rates before and after implementation of the CHG as the preoperative method of skin decontamination in our retrospective case-control cohorts., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The association between the incidence of contrast-induced nephropathy (CIN) and subsequent clinical outcomes is unclear in Japan. We evaluated the association between CIN and cardiovascular and renal events after cardiac catheterization., Methods: The CINC-J multicenter prospective cohort study examined 853 patients undergoing cardiac catheterization from 27 hospitals. CIN was defined as increase in serum creatinine (SCr)≥0.5mg/dL or ≥25% from baseline between 48 and 72h after exposure to contrast. Major adverse cardiovascular and cerebrovascular events (MACCE) included all-cause deaths, non-fatal myocardial infarction, acute decompensated heart failure (ADHF), and stroke. Renal events included newly-required hemodialysis and increase of SCr≥2× from baseline., Results: During follow-up periods (477±214days), CIN, MACCE, and renal events occurred in 44 (5.2%), 71 (8.3%), and 26 (3.0%) patients, respectively. Kaplan-Meier analysis showed that CIN yielded increasing risk for MACCE, ADHF, newly-required hemodialysis, and renal events. In multivariable Cox proportional hazards analysis, age (HR: 1.03; 95% CI, 1.00-1.07; P=0.0425), anemia (HR: 1.94; 95% CI, 1.08-3.61; P=0.0264), and diabetes mellitus (HR: 1.86; 95% CI, 1.10-3.21; P=0.0119) were independent predictors of MACCE, whereas CIN (HR: 7.78; 95% CI, 3.23-17.9; P=0.0005) and SCr (HR: 2.09; 95% CI, 1.56-2.73; P=0.0006) were independent predictors of renal events. Compared to subjects without both anemia and CIN as the reference, those with both were high risk for MACCE (HR: 3.97; 95% CI, 1.25-10.6; P=0.0218)., Conclusion: CIN was a significant predictor of subsequent renal events after cardiac catheterization. CIN and anemia were associated with increased risk for worse long-term clinical outcome, especially when both were present., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-Kras G12D , Ptf1a-cre model. Delivery of RCAS viruses encoding β-catenin S37A and WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-β-catenin S37A or RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P<.05). Ectopic expression of active β-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the β-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/β-catenin signaling pathway in pancreatic cancer cells. Nuclear β-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P<.01). Knockdown of CYR61 in a β-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) is a prospective, observational registry study evaluating the safety of sorafenib and treatment practices in hepatocellular carcinoma patients. This large global database allowed for assessment of the use and tolerability of sorafenib in patients with liver dysfunction., Methods: Baseline characteristics and medical/treatment history were collected in patients for whom a decision to treat with sorafenib had been made. Adverse event, dosing, and outcomes data were collected during follow-up., Results: In the overall safety population (n=3202), 1968 patients (61%) had Child-Pugh A status and 666 (21%) had Child-Pugh B. The majority of Child-Pugh A (72%) and Child-Pugh B (70%) patients received an initial sorafenib dose of 800mg, consistent with the label, and dose reduction rates were 40% and 29%, respectively. The type and incidence of adverse events were generally consistent across Child-Pugh subgroups. The incidence of drug-related adverse events leading to discontinuation was similar between Child-Pugh A and Child-Pugh B patients (17% and 21%). In the intent-to-treat population (n=3213), median overall survival (months [95% confidence interval]) was longer in Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 [4.6-6.3])., Conclusions: In clinical practice, the safety profile of sorafenib appeared to be consistent across Child-Pugh A and Child-Pugh B patients. Findings suggest sorafenib may be safely used in some Child-Pugh B patients and indicate the importance of careful patient evaluation when making treatment decisions., Lay Summary: The GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study is a large prospective registry of patients with liver cancer who were treated with sorafenib. The aims were to evaluate the safety and tolerability of sorafenib among those in which the liver was not functioning properly. The study showed that the safety profile of sorafenib was consistent across patients with preserved liver function and those in which the liver was not functioning properly, and therefore, suggesting that sorafenib may be a valid treatment for some patients with liver impairment., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The majority of patients who undergo coronary arteriography are discharged from the hospital on the day of the procedure or on the following day. The aim of this study is to investigate whether the change in serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) on the day following cardiac catheterization can predict the development of contrast-induced nephropathy (CIN)., Methods: This is a multicenter prospective observational study, which consists of 860 patients who underwent cardiac catheterization. We measured SCr and eGFR before cardiac catheterization, on the following day, and 48-72h post-procedure. Definition of CIN is changes in SCr ≥0.5mg/dL or ≥25% from baseline 48-72h after contrast exposure., Results: CIN occurred in 40 patients. SCr levels significantly increased from a baseline of 1.55±1.08mg/dL to 1.79±1.26mg/dL on the following day in patients with CIN (p<0.0001), but significantly decreased from a baseline of 1.21±0.65mg/dL to 1.18±0.61mg/dL on the following day in those without CIN (p<0.0001). eGFR significantly decreased from a baseline of 47.3±28.3mL/min/1.73m 2 to 40.6±26.7mL/min/1.73m 2 on the following day in patients with CIN (p<0.0001), but significantly increased from a baseline of 53.1±22.0mg/dL to 53.6±21.2mg/dL on the following day in those without CIN (p=0.0236). Receiver operating characteristic curve analysis indicated that SCr change ≥0.1mg/dL [area under the curve (AUC)=0.852, sensitivity 72.5%, specificity 86.1%] and eGFR change ≤-1.1mL/min/1.73m 2 (AUC=0.789, sensitivity 85.0%, specificity 64.9%) were the best cut-off values for predicting CIN. Multivariate logistic regression showed that a change in SCr ≥0.1mg/dL [odds ratio (OR), 29.3; 95% confidence interval (CI), 10.8-96.2] and change in eGFR ≤-1.1mL/min/1.73m 2 (OR, 69.7; 95% CI, 13.3-952) were powerful independent predictors of CIN., Conclusions: Changes in SCr and eGFR on the day following cardiac catheterization predict the development of CIN., (Copyright © 2016. Published by Elsevier Ltd.)

Background & Aims: The presence of portal vein tumor thrombosis (PVTT) in patients with hepatocellular carcinoma (HCC) is regarded as indicating an advanced stage, and liver resection (LR) is not recommended. The aim of this study was to evaluate the survival benefit of LR for HCC patients with PVTT through the analysis of the data from a Japanese nationwide survey., Methods: We analyzed data for 6474 HCC patients with PVTT registered between 2000 and 2007. Of these patients, 2093 patients who underwent LR and 4381 patients who received other treatments were compared. The propensity scores were calculated and we successfully matched 1058 patients (66.1% of the LR group)., Results: In the Child-Pugh A patients, the median survival time (MST) in the LR group was 1.77years longer than that in the non-LR group (2.87years vs. 1.10years; p<0.001) and 0.88years longer than that in the non-LR group (2.45years vs. 1.57years; p<0.001) in a propensity score-matched cohort. A subgroup analysis revealed that LR provides a survival benefit regardless of age, etiology of HCC, tumor marker elevation, and tumor number. The survival benefit was not statistically significant only in patients with PVTT invading the main trunk or contralateral branch. In the LR group, the postoperative 90-day mortality rate was 3.7% (68 patients)., Conclusions: As long as the PVTT is limited to the first-order branch, LR is associated with a longer survival outcome than non-surgical treatment., Lay Summary: The presence of portal vein tumor thrombosis in patients with hepatocellular carcinoma is regarded as indicating an advanced stage, and liver resection is not recommended. We performed a multicenter, nationwide study to assess the survival benefit of liver resection in hepatocellular carcinoma patients with portal vein tumor thrombosis using propensity score-based matching. As long as the portal vein tumor thrombosis is limited to the first-order branch, liver resection is associated with a longer survival outcome than non-surgical treatment., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Although high-throughput biological technologies have been producing a vast amount of multi-omics data regarding cancer genomics and several disease susceptible genes have been reported, many of these genes are likely to be irrelevant for the cancer process because only one feature of the tumor pathway could be focused on. By identifying 'CpG core', which was extracted from CpG sites in genomic DNA by our newly developed method, we performed integrated analysis using gene expression and DNA methylation profiles of 116 colorectal cancer samples. First, based on gene expression values, colorectal cancer samples were divided into three clusters (Cluster-1, -2, and -3) by k-means clustering. The 5-year overall survival rates of colorectal cancer patients were 74.8%, 29.2%, and 29.4% in Cluster-1, -2, and -3, respectively, and the prognosis of Cluster-2 was significantly poorer than that of the other two clusters owing to liver metastasis (P < 0.001). Second, each cluster was divided into two subgroups based on methylation status, and the 5-year overall survival rate of Cluster-1H (36.8%) was significantly shorter than that of Cluster-1L (96.1%) due to the accumulation of aberrant DNA methylation (P = 0.014). Third, network-based analysis using expression and methylation profiles demonstrated that nucleoporin family genes were downregulated in Cluster-2 and that the PTX3 gene was highly methylated in Cluster-1H. These combined data indicate that integrated analysis can identify disease characteristics that would be missed using single comprehensive analysis, and that multiple pathways would play pivotal roles in the liver metastasis of colorectal cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab., Patients and Methods: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396., Results: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months., Conclusion: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC., Clinical Trials Number: UMIN000001396., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Sortilin is involved multilaterally in the development of atherosclerosis. Here, we examine the release of soluble sortilin (sSortilin) from platelets and assess the association between circulating levels of sSoritlin and atherothrombosis such as coronary artery disease (CAD)., Methods and Results: sSortilin levels measured in healthy subjects were higher in serum than in plasma (38.4 ± 8.7 vs. 15.8 ± 2.9 ng/mL; p < 0.0001). Platelets were shown to contain both membrane-bound sortilin and its soluble form lacking the cytoplasmic tail. Stimulation of platelet-rich plasma with collagen induced sSortilin release concomitantly with platelet aggregation, and the release was suppressed by aspirin. In clinical evaluation, plasma sSortilin was detected at significantly higher levels in cardiovascular risk patients with hypertension, dyslipidemia, and/or diabetes without CAD (non-CAD, 18.7 ± 3.3 ng/mL) than in patients with CAD under aspirin therapy (17.1 ± 3.6 ng/mL; p < 0.01) or in healthy controls (16.8 ± 2.9 ng/mL; p < 0.01). In these patients, plasma sSortilin levels were significantly correlated with platelet counts (rs = 0.33; p = 0.0085) and showed significant positive associations with cardiovascular risk factors: low-density lipoprotein cholesterol (rs = 0.37; p = 0.0023), triglycerides (rs = 0.28; p = 0.023), and serum uric acid (rs = 0.30; p = 0.017) in non-CAD, and γ-glutamyltransferase (rs = 0.43; p = 0.020) and high-sensitivity C-reactive protein (rs = 0.33, p = 0.0022) in CAD., Conclusion: Elevated plasma sSortilin levels may be associated with in vivo platelet activation and could be a risk factor for atherothrombosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In patients with ST-elevation acute myocardial infarction (STEMI), reperfusion therapy limits infarct size, but can directly evoke myocardial reperfusion injury. Activation of the Na(+)/H(+) exchanger (NHE) plays an important role in reperfusion injury. TY-51924, a novel NHE inhibitor, significantly reduced infarct size in animal studies and was well tolerated in early-phase clinical trials. This study aim was to evaluate the efficacy and safety of TY-51924 in patients with STEMI., Methods: In this multicenter, randomized, double-blind, placebo-controlled Phase II trial, 105 patients with first anterior STEMI undergoing primary percutaneous coronary intervention (pPCI) were randomly assigned to receive an intravenous infusion of either TY-51924 or placebo. Primary endpoints were myocardial salvage index (MSI) as determined by single photon emission computed tomography (SPECT) 3-5 days after pPCI and safety up to 7 days., Results: Baseline characteristics were similar in the two groups. MSI 3-5 days after pPCI (0.200 vs. 0.290, p=0.56), 3 months after pPCI (0.470 vs. 0.500, p=0.76), and the incidences of side effects did not differ between the two groups as a whole. However, on post hoc analysis of 52 patients with a large area at risk (AAR) (≥38%) and no antegrade coronary flow, MSI by SPECT at 3 months after pPCI was significantly higher in TY-51924 group (0.450 vs. 0.320, p=0.03). TY-51924 did not adversely influence hemodynamics., Conclusions: TY-51924 did not improve MSI or increase side effects as a whole. However, TY-51924 is potentially cardioprotective in the presence of a large AAR and no antegrade coronary flow., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: In myocardial ischemia-reperfusion injuries, the involvement of the Na(+)/H(+) exchanger (NHE) is considered to be one of the pathogenic mechanisms following reperfusion. TY-51924 is a novel hydrophilic NHE inhibitor with a lower risk of central neurotoxicity than previous NHE inhibitors. This open-label, dose-escalating study was undertaken to investigate the safety, efficacy, and pharmacokinetics of TY-51924 in patients with ST-elevation myocardial infarction (STEMI)., Methods: Consent was obtained from a total of 30 patients with first anterior STEMI. After 12 patients were determined to be ineligible, the remaining 18 patients, each of whom was undergoing primary percutaneous coronary intervention (pPCI), received TY-51924 intravenously up to 10, 20, or 30mg/kg as the low-, medium-, or high-dose groups, respectively (n=6 in each group). The primary endpoints were safety (up to 7 days) and plasma drug concentration. The myocardial salvage index (MSI) was measured by (201)Tl/(123)I-beta-methyl-p-iodophenyl pentadecanoic acid single photon emission computed tomography (SPECT) 3-5 days after pPCI., Results: No side effects were observed. Plasma drug concentrations increased dose-dependently, and were subsequently eliminated rapidly. MSIs were 0.118, 0.335, and 0.192 in the low-, medium-, and high-dose groups, respectively. In additional analysis, the combined MSIs in the medium- and high-dose groups were significantly higher than those in the low-dose group, in patients with a longer time from symptom onset to reperfusion (p=0.0247)., Conclusions: No side effects were observed even at the highest dose with this novel hydrophilic NHE inhibitor. Therefore, TY-51924 is thought to be safe in patients with STEMI, even at the highest dose. Potential cardioprotective effects of intravenous TY-51924 might be expected based on the results obtained for the MSIs using SPECT at 20-30mg/kg. However, further large-scale, double-blind, placebo-controlled clinical studies are required to confirm the efficacy and safety implied in the current study., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: To examine the effects of pitavastatin on atherosclerotic plaque in Watanabe heritable hyperlipidemic (WHHL) rabbits using serial in vivo tissue-characterizing intravascular ultrasound., Methods: A total of 11 WHHL rabbits of 10-12 weeks of age were divided into two groups, control and pitavastatin-administered groups. A total of 29 atherosclerotic plaque segments from control group and 43 plaque segments from the pitavastatin group were serially imaged by 40MHz intravascular ultrasound in vivo with a tissue characterization software (iMAP™, Boston Scientific, Natick, MA, USA) at the baseline and the follow-up (16th week)., Results: The level of low-density lipoprotein cholesterol was significantly decreased in pitavastatin group. During the follow-up period, plaque area was significantly increased in the control group, whereas it was not significantly changed in the pitavastatin group. The fibrotic, necrotic, and necrotic plus lipidic areas were significantly increased in the control group, while no significant change was revealed for tissue profile in pitavastatin group. The change in the percent areas of fibrotic and lipidic plus necrotic tissues were significantly different between the two groups especially in the superficial half portion of plaque., Conclusions: These data indicate that pitavastatin could attenuate atherosclerotic plaque formation and that it could stabilize the plaque in WHHL rabbits. Considering the fact that these were observed even with a high follow-up level of cholesterol, these data might come from the pleiotropic effects of pitavastatin., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Breast cancer is one of the most fearful diseases due to its increasing worldwide prevalence. A number of screening tests has been employed including clinical examinations and mammography. However, another screening method, which is a simple, not embarrassing, and low cost, is highly desired. Based on these findings, we are currently investigating the determination of polyamines including their acetylated structures for the diagnosis of breast cancer patients. We established a diagnostic approach to breast cancer patients based on the ratios of polyamines in saliva by a UPLC-MS/MS analysis., Methods: Twelve polyamines including their acetylated form were labeled with DBD-F, separated by a reversed-phase chromatography and detected by a Xevo TQ-S tandem mass spectrometer., Results: Eight polyamines (e.g., SPM, CAD, Ac-SPM, N1-Ac-SPD, N8-Ac-SPD) strongly correlated with the cancer patients. A simple 1-order equation was developed for the discrimination of the breast cancer patients and healthy persons (Y=0.5XSPM-3XAc-SPM-0.15XSPD-3.5XN8-Ac-SPD+0.5XN1-Ac-SPD+0.04XCAD). The concordance rate of the breast cancer patients and the healthy persons by the equation was 88% and 76% on the training set, respectively, whereas those on the validation set was both 88%. The score Y in the equation tended to correlate with the cancer stage of the patients and increased with the more serious conditions. The determination of polyamines in the saliva after the cancer patient operations was also performed to identify the concentration change before and after the surgical treatment. The discriminant analysis using 6 polyamines (i.e., N8-Ac-SPD, N1-Ac-SPD, CAD, DAc-SPD, PUT, and Ac-PUT), which were the most influenced molecules derived from the ROC analysis, was performed using the relative percentage. Both the sensitivity and specificity indicated nearly 80% from the ROC analysis result using the ratio of N8-Ac-SPD/(N1-Ac-SPD+N8-Ac-SPD)., Conclusion: The discrimination equation appears to be useful for the diagnosis of breast cancer patients. Furthermore, the ratio of N8-Ac-SPD/(N1-Ac-SPD+N8-Ac-SPD) may be adopted as an index of the health status after the surgical treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: To assess aortic arch morphology and aortic length in patients with dissection, traumatic injury, and aneurysm undergoing TEVAR, and to identify characteristics specific to different pathologies., Method: This was a retrospective analysis of the aortic arch morphology and aortic length of dissection, traumatic injury, and aneurysmal patients. Computed tomography imaging was evaluated of 210 patients (49 dissection, 99 traumatic injury, 62 aneurysm) enrolled in three trials that received the conformable GORE TAG thoracic endoprosthesis. The mean age of trauma patients was 43 ± 19.6 years, 57 ± 11.7 years for dissection and 72 ± 9.6 years for aneurysm patients. A standardized protocol was used to measure aortic arch diameter, length, and take-off angle and clockface orientation of branch vessels. Differences in arch anatomy and length were assessed using ANOVA and independent t tests., Results: Of the 210 arches evaluated, 22% had arch vessel common trunk configurations. The aortic diameter and the distance from the left main coronary (LMC) to the left common carotid (LCC) were greater in dissection patients than in trauma or aneurysm patients (p < .001). Aortic diameter in aneurysm patients was greater compared with trauma patients (p < .05). The distances from the branch vessels to the celiac artery (CA) were greater in dissection and aneurysm patients than in trauma patients (p < .001). The take-off angle of the innominate (I), LCCA, and left subclavian (LS) were greater, between 19% and 36%, in trauma patients than in dissection and aneurysm patients (p < .001). Clockface orientation of the arch vessels varies between pathologies., Conclusions: Arch anatomy has significant morphologic differences when comparing aortic pathologies. Describing these differences in a large sample of patients is beneficial for device designs and patient selection., (Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Mechanical circulatory support (MCS) leads to favorable changes in the failing heart at the molecular, cellular, and structural levels. However, myocardial recovery leading to device explantation is rare. We reasoned that the multicenter United Network for Organ Sharing (UNOS) registry might provide insights into clinical predictors and outcomes of the recovery process., Methods: The MCS device data set of the UNOS registry was queried for patients with long-term continuous-flow left ventricular assist devices (CF-LVADs) that were explanted for heart transplantation or indication of recovery. Analysis was restricted to adult patients (≥18 years old) who were listed for an initial heart transplantation. Patients with CF-LVADs that were explanted because of recovery were compared with patients with CF-LVADs who underwent transplantation., Results: We identified 594 patients with HeartMate II devices and 92 patients with HeartWare devices. Duration of support was on average 500.4 ± 325.3 days. In 34 (5.0%) patients, devices were explanted secondary to myocardial recovery. Univariate predictors of recovery in patients with long-term LVADs included younger age (40 years vs 53 years), female sex, lower body mass index (25.7 kg/m(2) vs 27.9 kg/m(2)), non-ischemic etiology (91% vs 59%), lack of implantable cardioverter defibrillator at the time of listing (44% vs 79%), and lower serum creatinine (0.97 mg/dl vs 1.28 mg/dl) (all p < 0.05). In the post-explantation period, freedom from death or transplantation was 66% at 1 year., Conclusions: The incidence of recovery on device support is low in the current MCS era and limited to a select cohort of predominantly young patients with non-ischemic myopathy. Given the high incidence of disease recurrence, patients should be closely followed after device explantation., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Poly(ε-caprolactone) (PCL) is a ductile, bioabsorbable polymer that has been employed as a blend partner for poly(L-lactic acid) (PLLA). An improvement of the material strength and impact resistance of PLLA/PCL polymer blends compared to pure PLLA has been shown previously. To use numerical simulations in the design process of new components composed of the PLLA/PCL blend, a constitutive model for the material has to be established. In this work, a constitutive model for a PLLA/PCL polymer blend is established from the results of compressive tests at high and low strain rates at three different temperatures, including the body temperature. Finite element simulations of the split Hopkinson pressure bar test using the established constitutive model are carried out under the same condition as the experiments. During the experiments, the changes in the diameter and thickness of the specimens are captured by a high-speed video camera. The accuracy of the numerical model is tested by comparing the simulation results, such as the stress, strain, thickness and diameter histories of the specimens, with those measured in the experiments. The numerical model is also validated against an impact test of non-homogenous strains and strain rates. The results of this study provide a validated numerical model for a PLLA/PCL polymer blend at strain rates of up to 1800 s(-1) in the temperature range between 22°C and 50°C., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chiral metabolites are found in a wide variety of living organisms and some of them are understood to be physiologically active compounds and biomarkers. However, the overall analysis of chiral metabolomics is quite difficult due to the high number of metabolites, the significant diversity in their physicochemical properties, and concentration range from metabolite-to-metabolite. To solve this difficulty, we developed a novel approach for chiral metabolomics fingerprinting and chiral metabolomics extraction, which is based on the labeling of a pair of enantiomers of chiral derivatization reagents (i.e., DMT-(S,R)-Pro-OSu and DMT-3(S,R)-Apy) and precursor ion scan chromatography of the derivatives. The multivariate statistics is also required for this strategy. The proposed procedures were evaluated by the detection of a diagnostic marker (i.e., d-lactic acid) using the saliva of diabetic patients. This method was used for the determination of biomarker candidates of chiral amines and carboxyls in Alzheimer's disease (AD) brain homogenates. As the results, l-phenylalanine (L-Phe) and l-lactic acid (L-LA) were identified as the decreased and increased biomarker candidates in the AD brain, respectively. Therefore, the proposed approach seems to be helpful for the determination of non-target chiral metabolomics possessing amines and carboxyls., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A novel triazine-type chiral derivatization reagent, i.e., (S)-2,5-dioxopyrrolidin-1-yl-1-(4,6-dimethoxy-1,3,5-triazin-2-yl) pyrrolidine-2-carboxylate (DMT-(S)-Pro-OSu), was developed for the highly sensitive and selective detection of chiral amines and amino acids by UPLC-MS/MS analysis. The enantiomers of amino acids were easily labeled with the reagents at room temperature within 40 min in an alkaline medium containing triethylamine. The diastereomers derived from proteolytic amino acids, except serine, were well separated under isocratic elution conditions by reversed-phase chromatography using an ODS column (Rs=1.2-9.0). DL-Serine was separated by use of an ADME column which has relatively higher polar surface than the conventional ODS column. The characteristic product ions, i.e., m/z 195.3 and m/z 209.3, were detected from all the diastereomers by the collision-induced dissociation of the protonated molecule. A highly sensitive detection on the amol-fmol level was obtained from the selected reaction monitoring (SRM) chromatogram. The chiral amines (e.g., adrenaline and noradrenaline) labeled with DMT-(S)-Pro-OSu were also well separated and sensitively detected by the present procedure. The method using DMT-(S)-Pro-OSu was used for the determination of DL-amino acids in the human saliva from healthy volunteers. Various L-amino acids were identified in the saliva. Furthermore, D-alanine (D-Ala) and D-proline (D-Pro) were also detected in relatively high concentrations (>5%). The ratio was higher in male saliva than in female saliva. However, the difference in the ratio of D-Ala for one day was not very high and the effect of foods and beverage seemed to be negligible. Based on the results using L-Ala-d3, the D-Ala in saliva seemed to be produced due to the racemization with some enzymes such as racemase. The racemization reaction was reversible, i.e., D-Ala-d3 was also racemized to L-Ala-d3 in saliva. Thus, care should be taken during the analysis of DL-amino acids in saliva. The present method using DMT-(S)-Pro-OSu may be applicable for the determination of chiral amine metabolomics, because the resulting derivatives produce the same product ions without relation to the compounds and show highly sensitive detection in the SRM mode of MS/MS. Consequently, DMT-(S)-Pro-OSu seems to be a useful chiral derivatization reagent for the determination of amines and amino acids in biological samples., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Early and definitive diagnosis of Alzheimer's disease (AD) can lead to a better and more-targeted treatment and/or prevention for patients. In the diagnostic biomarkers of AD, the blood sample represents a more non-invasive, inexpensive and acceptable sources for repeated measurements than the cerebrospinal fluid. In this study, the fingerprinting metabolomics was proposed for the challenge of the blood-based diagnosis of defined AD by hydrophilic interaction liquid chromatography mass spectrometry (HILIC/MS). These plasma samples were selected from postmortem specimens based on these pathological examinations. Firstly, we compared these HILIC columns for the non-targeted metabolic assay using pooled plasma. The principal component analysis plot of these seven columns was performed using the repeatability of these chromatograms, and can be used to visualize trends in data sets by three-dimensional dispersion, contributory standard deviation and the number of detections. Based on these results, TSK-Amide 80 and TSKgel-NH₂ columns are used as a reliable HILIC/MS assay of blood-based AD metabolomics that showed metabolic profiling of the AD pathology in MS chromatograms that ranged from 1182 to 2284 compounds. A total of 54 peaks were evaluated in order to identify useful ion signal candidates using an orthogonal partial least-squares-discriminant analysis. These peaks were then specifically analyzed using the HILIC-tandem MS assay by a receiver operating characteristic curve and linear discriminant analysis for the diagnosis of the defined AD. The fingerprinting metabolomics can overcome the limitations of previous challenging blood-based diagnosis of AD, and directly evaluates the specific comparative statistical values from the raw data., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The limited availability of reconstruction materials can often make it difficult to treat defects in the esophagus caused by necrosis of the transplanted intestinal tissue after cervicothoracic esophagus reconstruction. We were forced to perform flap reconstruction on a patient who suffered necrosis due to impeded blood flow of the transplanted intestinal tract after twice conducting cervicothoracic esophagus reconstruction with an intestinal tract flap. The procedure we performed was esophagus reconstruction using a pectoralis major myocutaneous flap that had been expanded with a tissue expander due to the small volume of tissue available to perform the reconstruction. This case suggested that esophagus reconstruction with a skin flap using a tissue expander should be considered as a possible treatment choice when performing reconstruction of the cervicothoracic esophagus, which requires stable blood flow and a large amount of tissue., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: It is well recognized that low-density lipoprotein cholesterol (LDL-C)-lowering therapy is effective for primary and secondary prevention of cerebrovascular/cardiovascular disease. Ezetimibe, an inhibitor of the Niemann-Pick C1-Like 1 cholesterol transporter, is a relatively new drug for LDL-C-lowering therapy in addition to statins. However, comparison between an aggressive LDL-C-lowering therapy with a combination of statin and ezetimibe versus a standard LDL-C-lowering therapy with statin alone is still unclear in terms of their effects on stabilization and volume regression of coronary plaque. The ZIPANGU (Ezetimibe clinical investigation for the regression of intracoronary plaque evaluated by angioscopy and ultrasound) study is aimed at comparing these two types of therapy based on indices of plaque characteristics using non-obstructive coronary angioscopy and intravascular ultrasound., Methods: The study is a multi-center, prospective, randomized, open-label, blinded-endpoint trial. Through a centralized enrollment method, patients will be allocated to either monotherapy with atorvastatin alone or to combination therapy with atorvastatin (maximum: 20mg/day) and ezetimibe (10mg/day). The target LDL-C level will be <100mg/dL for the monotherapy group and <70mg/dL for the combination therapy group. At the baseline and the follow-up period of 9 months, non-obstructive coronary angioscopy and intravascular ultrasound will be performed to compare the changes in plaque color and volume between the two groups., Conclusions: The ZIPANGU study will clarify whether combination therapy with statins and ezetimibe is better for stabilizing coronary plaque as secondary prevention than monotherapy by statins alone. The study will give new insights into lipid-lowering guidelines in Japan., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)