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Background There has not been a previous report on the long-term outcomes of those patients who refuse aortic valve replacement (AVR) despite physicians' recommendations.Methods and Results:Among 3,815 consecutive patients with severe aortic stenosis (AS) enrolled in the CURRENT AS registry, the study population comprised 2,005 symptomatic patients, who were subdivided into 3 groups by their treatment strategy and the reasons for conservative strategy (Initial AVR group: n=905; Patient rejection group: n=256; Physician judgment group, n=844). The primary outcome measure was a composite of aortic valve-related death and heart failure hospitalization. Patients in the patient rejection group as compared with those in the physician judgment group were younger, and had less comorbidities, and lower surgical risk scores. The cumulative 5-year incidence of the primary outcome measure in the patient rejection group was markedly higher than that in the initial AVR group, and was similar to that in the physician judgment group (60.7%, 19.0%, and 66.4%, respectively). Conclusions Patient rejection was the reason for non-referral to AVR in nearly one-quarter of the symptomatic patients with severe AS who were managed conservatively. The dismal outcome in patients who refused AVR was similar to that in patients who were not referred to AVR based on physician judgment despite less comorbidities and lower surgical risk scores in the former than in the latter.

There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to a widely varying usage in the real world. The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic venous thromboembolisms (VTEs) in Japan. The present study population consisted of 1549 patients with PEs treated with tissue plasminogen activator (t-PA) thrombolysis (N = 180, 12%) or without thrombolysis (N = 1369). Thrombolysis with t-PA was implemented in 33% of patients with severe PEs, and 9.2% of patients with mild PEs with a wide variation across the participating centers. Patients with t-PA thrombolysis were younger, and less frequently had active cancer, history of major bleeding, and anemia. At 30 days, t-PA thrombolysis as compared to no thrombolysis was associated with similar mortality rates (5.0% vs. 6.9%, P = 0.33), but a lower adjusted mortality risk (OR 0.41; 95% CI 0.18–0.90, P = 0.03), while it was associated with a trend for higher rates of major bleeding (5.6% vs. 2.9%, P = 0.06) and a significantly higher adjusted risk for major bleeding (OR 2.39; 95% CI 1.06–5.36, P = 0.03). In patients with severe PEs, the mortality rates at 30 days were significantly lower in the t-PA thrombolysis group than no thrombolysis group (15% vs. 37%, P = 0.006). In the present real-world VTE registry in Japan, t-PA thrombolysis was not infrequently implemented, not only in patients with severe PEs, but also in patients with mild PEs. A substantial mortality risk reduction might be suggested with t-PA thrombolysis in patients with severe PEs.

The simplified Pulmonary Embolism Severity Index (sPESI) score is a practical score for identification of patients with low-risk pulmonary embolism (PE), although it has not been applied in patients with active cancer. The current study aimed to evaluate the usefulness of the sPESI score in patients with PE and active cancer.The COMMAND VTE Registry is a multicenter registry enrolling consecutive patients with acute symptomatic VTE. The current study population consisted of 368 patients with PE and active cancer. The 30-day clinical outcomes were compared between patients with sPESI score = 1 and patients with sPESI scores ≥ 2.Overall, 37 patients (10%) died during the 30 days after diagnosis. The cumulative 30-day incidences of mortality, and PE-related death, were lower in patients with sPESI score = 1 than in patients with sPESI scores ≥ 2 (6.3% vs 13.1%; log-rank P = .03; and 0.7% vs 3.9%; log-rank P = .046). Among patients with sPESI score = 1, the predominant cause of death was cancer. There were no significant differences in the cumulative 30-day incidence of recurrent VTE and major bleeding between the two groups (3.9% vs 5.6%; log-rank P = .46; and 6.4% vs 4.5%; log-rank P = .45).Among patients with PE and active cancer, patients with sPESI score = 1 had a lower 30-day mortality rate compared with patients with sPESI scores ≥ 2, and they showed very low PE-related mortality risk, although the overall mortality rate remained high because of cancer-related mortality. They also showed relatively high risks for recurrence and major bleeding, suggesting the need for careful follow-up.UMIN Clinical Trials Registry; No.: UMIN000021132; URL: http://www.umin.ac.jp/ctr/index.htm.

Key Points Question Is use of mineralocorticoid receptor antagonist at discharge associated with better outcomes in patients hospitalized for acute decompensated heart failure? Findings In this cohort study of 2068 propensity score–matched Japanese patients hospitalized for acute decompensated heart failure, mineralocorticoid receptor antagonist administered at discharge was statistically significantly associated with a lower risk for the primary composite outcome of mortality or heart failure readmission, although no difference in all-cause death was observed. Meaning Use of mineralocorticoid receptor antagonist at discharge from acute decompensated heart failure hospitalization may be associated with heart failure hospitalization but not with lower mortality., Importance Scarce data are available on the association of mineralocorticoid receptor antagonist (MRA) use with outcomes in acute decompensated heart failure (ADHF). Objective To investigate the association of MRA use with all-cause mortality and hospital readmission in patients with ADHF. Design, Setting, and Participants This cohort study examines participants enrolled in the Kyoto Congestive Heart Failure (KCHF) registry, a physician-initiated, prospective, multicenter cohort study of consecutive patients admitted for ADHF, between October 1, 2014, and March 31, 2016, into 1 of 19 secondary and tertiary hospitals throughout Japan. To balance the baseline characteristics associated with the selection of MRA use, a propensity score–matched cohort design was used, yielding 2068 patients. Data analysis was conducted from April to August 2018. Exposures Prescription of MRA at discharge from the index hospitalization. Main Outcomes and Measures Composite of all-cause death or heart failure hospitalization after discharge. Results Among 3717 patients hospitalized for ADHF, 1678 patients (45.1%) had received MRA at discharge and 2039 (54.9%) did not. After propensity score matching, 2068 patients (with a median [interquartile range] age of 80 [72-86] years, and of whom 937 [45.3%] were women) were included. In the matched cohort (n = 1034 in each group), the cumulative 1-year incidence of the primary outcome was statistically significantly lower in the MRA use group than in the no MRA use group (28.4% vs 33.9%; hazard ratio [HR], 0.81; 95% CI, 0.70-0.93; P = .003). Of the components of the primary outcome, the cumulative 1-year incidence of heart failure hospitalization was significantly lower in the MRA use group than in the no MRA use group (18.7% vs 24.8%; HR, 0.70; 95% CI, 0.60-0.86; P, This cohort study of Japanese participants with acute decompensated heart failure in the Kyoto Congestive Heart Failure study evaluates the association of mineralocorticoid receptor antagonist use with all-cause mortality and hospital readmission.

Fluoropyrimidine has been commonly used not only in unresectable cases of metastatic colorectal cancer, but also in adjuvant therapy. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down more than 80% of standard doses of 5-fluorouracil (5-FU) and capecitabine, an oral prodrug of 5-FU. The lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity which may lead to life-threatening side effects. There have been several published case reports about DPD deficiency in patients with colorectal cancer in Western countries. However, case reports of DPD deficiency in Japanese patients with colorectal cancer are rare because measuring DPD activity is not covered by public medical insurance in Japan, and it is not examined in our daily clinical practice currently. Therefore, we think that it is important to accumulate such case reports for further understanding. This report describes the case of a Japanese patient with colon cancer who experienced severe side effects while taking capecitabine, due to DPD deficiency. A 68-year-old man with ascending colon cancer underwent curative laparoscopic right hemicolectomy. Because final pathologic staging was Stage IIIa, standard adjuvant chemotherapy with capecitabine (3600 mg/body/day, days 1–14, every 3 weeks) was started on postoperative day 50. After 2 weeks, he started to experience Grade 3 diarrhea and was admitted to the hospital on postoperative day 66. On day 70, the patient had Grade 4 febrile neutropenia. Antibiotics and granulocyte-colony-stimulating factor were administered until his blood tests recovered to the normal degree. After 1 week of diarrhea, antidiarrheal agents were administered, and the patient gradually recovered. During the occurrence of diarrhea, specimen cultures were negative for infection. He was discharged on day 21 of the hospital stay. DPD deficiency was suspected, and 2 weeks later the DPD activity of the peripheral blood mononucleocytes was examined. The result was 10.3 U/mg protein which was remarkedly low (reference range 22.6–183.6 U/mg protein), and DPD deficiency was diagnosed. We always must consider the possibility of DPD deficiency in patients who experience severe side effects while taking capecitabine.

Fractional flow reserve (FFR) is an established method for diagnosing physiological coronary artery stenosis. A method for computing FFR using coronary computed tomography (CT) images was recently developed. However, its calculation requires off-site supercomputer analysis. Here, we report the preliminary result of a method using simple estimation of boundary conditions. The lumen boundaries of the coronary arteries were semi-automatically delineated using full width at half maximum of CT number profiles. The computational fluid dynamics (CFD) of the blood flow was performed using the boundary conditions of a fixed pressure at the coronary ostium and flow rates at each outlet. The total inflow at the coronary ostium was estimated based on the uniform wall shear stress hypothesis and corrected using a hyperemic multiplier to gain a hyperemic flow rate. The flow distribution from a parent vessel to the downstream daughter vessels was determined according to Murray's law. FFR estimated by CFD was calculated as FFRCFD = Pd/Pa. We collected patients who underwent coronary CT and coronary angiography followed by invasively measured FFR and compared FFRCFD with FFR. Sensitivity, specificity, and correlations were assessed. A total of 48 patients and 72 arteries were assessed. The correlation coefficient of FFRCFD with FFR was 0.56. The cut-off value was ≤ 0.80, sensitivity was 59.1%, and specificity was 94.0%. CFD-based FFR using simple boundary conditions for on-site clinical computation provided FFRCFD values that were moderately correlated with invasively measured FFR.

BACKGROUND It remains controversial whether sex category is a risk for recurrent venous thromboembolism (VTE) and major bleeding among VTE patients.Methods and Results:The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive acute symptomatic VTE patients from 29 centers in Japan between January 2010 and August 2014. We compared the clinical characteristics and outcomes of men and women. Men accounted for 1,169 (39%) and women 1,858 (61%). Compared with women, men were younger (64.9±14.7 vs. 68.6±15.6 years old, P

AIMS: Prediction of post-intervention fractional flow reserve (FFR) in a diffuse or sequential coronary lesion is difficult due to complex haemodynamic interactions between individual stenoses. Furthermore, the existence of a residual intra-stent pressure gradient makes the prediction difficult. We developed an equation predicting the post-intervention FFR in a diffuse/sequential lesion by considering intra-stent FFR gradient. The present study aims to validate the equation in an in vitro model and in clinical data. METHODS AND RESULTS: In the in vitro experiment, three sequential coronary stenoses were made with a collateral flow. The correlation coefficient of the predicted FFR and the actual post-intervention FFR was 0.99, and the absolute difference was 0.008±0.006 (n=50). In the clinical data analysis, the correlation coefficient was 0.41, and the absolute difference was 0.06±0.05 (n=67). We applied a fixed value of intra-stent FFR gradient and a collateral flow index so that the equation can be used in clinical practice. The correlation coefficient became 0.28 and the absolute difference became 0.06±0.06. CONCLUSIONS: In clinical practice, prediction of post-intervention FFR in a diffuse/sequential lesion is difficult even when residual intra-stent pressure gradient is considered.

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs. Dusp1 and Atm were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.

Background Data are scarce on the role of aortic valve area (AVA) to identify those patients with asymptomatic severe aortic stenosis (AS) who are at high risk of adverse events. We sought to explore the prognostic impact of AVA in asymptomatic patients with severe AS in a large observational database. Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study included 1309 conservatively managed asymptomatic patients with left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on AVA (group 1: AVA >0.80 cm2, N=645; group 2: 0.8 cm2 ≥AVA >0.6 cm2, N=465; and group 3: AVA ≤0.6 cm2, N=199). The prevalence of very severe AS patients (peak aortic jet velocity ≥5 m/s or mean aortic pressure gradient ≥60 mm Hg) was 2.0%, 5.8%, and 26.1% in groups 1, 2, and 3, respectively. The cumulative 5‐year incidence of AVR was not different across the 3 groups (39.7%, 43.7%, and 39.9%; P=0.43). The cumulative 5‐year incidence of the primary outcome measure (a composite of aortic valve–related death or heart failure hospitalization) was incrementally higher with decreasing AVA (24.1%, 29.1%, and 48.1%; P, See Editorial by Tribouilloy et al

There is a paucity of data on patients with deep vein thrombosis (DVT) in upper extremities.The COMMAND VTE Registry is a retrospective multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) in Japan. The current study population included 2498 patients with upper or lower extremities DVT.There were 74 patients (3.0%) with upper extremities DVT and 2424 patients with lower extremities DVT. Patients with upper extremities DVT more often had active cancer (58%) and central venous catheter use (22%). The proportion of concomitant pulmonary embolism at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P 0.001). Discontinuation of anticoagulation therapy was more frequent in patients with upper extremities DVT (63.8% and 29.8% at 1-year, P 0.001). The cumulative 3-year incidence of recurrent VTE was not different between the 2 groups (9.8% and 7.4%, P = 0.43). After adjusting confounders, the risks of upper extremities DVT relative to lower extremities DVT for recurrent VTE remained insignificant (HR 0.94, 95%CI 0.36-2.01, P = 0.89).The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation.

Atlantoaxial instability is a relatively common com- plication in children with Down syndrome. Atlantoaxial rotatory fixation (AARF) is a condition in which the atlantoaxial joint is fixed at the position of rotation deformity accompanied by pain. We report a 10-year-old girl with Down syndrome who developed AARF postoperatively. No symptoms had been present prior to surgery. During anesthesia induction and then surgery, her neck was maintained at rest However, there was intense body movement during extubation. On postoperative day 8, she experi- enced sudden onset of neck pain and neck exercise restrictions, and a neck sprain was thus diagnosed. The symptoms gradually improved with analgesic administration and rehabilitation, but complete recovery was not obtained. Therefore, on postoperative day 23, cervical radiography and computed tomography were performed. These imaging studies revealed AARF. She was given conservative treatment We conclude that preoperative evaluation and peri- operative protection of the cervical spine are important Considering the mental retardation characteristic of Down syndrome, it is essential to diagnose and treat AARF at the earliest possible stage based on careful observation.

The lead authors failed to name two collaborators as co-authors. The authors listed should include: Miss Claudia L. Compean-Gonzalez (ORCID: 0000-0002-2367-8450) and Dr. Giacomo Ceccone (ORCID: 0000-0003-4637-0771). These co-authors participated in VAMAS project A27, provided data that were analyzed and presented in this publication (and supporting information), and reviewed the manuscript before submission.

BackgroundAtrial fibrillation (AF) and renal failure coexist and interact. However, scarce data about association between renal function and clinical outcomes in patients undergoing catheter ablation for AF are available. We sought to evaluate long-term renal function and clinical outcomes after AF ablation.MethodsWe enrolled 791 non-dialysis patients undergoing catheter ablation for AF, and evaluated the incidence of worsening renal function (WRF) after the procedure, defined as >30% decline in estimate glomerular filtration rate.ResultsMean follow-up duration was 5.1±2.5 years. Five hundreds and twenty-six patients (66.5%) were free from recurrent atrial arrhythmias without any antiarrhythmic drugs at the time of final follow-up. Cumulative incidence of WRF was 13.2% at 5-year after procedure, which was significantly higher in patients with recurrent AF compared to those without (21.6% versus 8.7%, P2at baseline. Patients with WRF had significantly higher 5-year incidences of all-cause death, cardiovascular death, heart failure hospitalization, ischemic stroke, and major bleeding compared to those without WRF. After adjustment of baseline differences in the multivariate Cox model, the excessive risks of WRF for all-cause death and heart failure hospitalization remained significant (adjusted HR 3.46, P = 0.002; adjusted HR 3.67, PConclusionsIn AF patients undergoing catheter ablation for AF, arrhythmia recurrence was associated with WRF during follow-up, which was a strong predictor of adverse clinical outcomes.

Kubota and colleagues show that neurons sequester VEGF to prune blood vessels during eye development., Vascular development involves not only vascular growth, but also regression of transient or unnecessary vessels. Hyaloid vasculature is the temporary circulatory system in fetal eyes, which spontaneously degenerates when the retinal blood vessels start to grow. Failure of the hyaloid vessels to regress leads to disease in humans, persistent hyperplastic primary vitreous, which causes severe intraocular hemorrhage and impairs visual function. However, the mechanism underlying the endogenous program that mediates spontaneous regression of the hyaloid vessels is not well understood. In this study, we identify a robust switch triggering this program directed by neurons in mice. Marked up-regulation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) occurs in retinal neurons just after birth via distal-multipotent-mesodermal enhancer, a hemangioblast-specific enhancer of VEGFR2. Genetic deletion of neuronal VEGFR2 interrupts this program, resulting in massive hyaloid vessels that persist even during late postnatal days. This abnormality is caused by excessive VEGF proteins in the vitreous cavity as a result of impairment in the neuronal sequestration of VEGF. Collectively, our data indicate that neurons trigger transition from the fetal to the postnatal circulatory systems in the retina.

An asymptomatic 40-year-old woman with a first-degree atrioventricular block presented a right atrial mass in transthoracic echocardiograms. Transesophageal echocardiograms showed abnormally thickened tissue on the interatrial septum, which extended around the aortic annulus. Multimodality examinations demonstrated lesions in the heart, lungs, liver, and spleen, suggesting sarcoidosis. She was diagnosed with cardiac sarcoidosis after we detected granulomas in a lung specimen. A right atrial mass shrunk following steroid therapy. We should therefore consider the possibility of cardiac sarcoidosis when we see wall thickening and a mass echo in the atrium. These signs may point to an early-phase lesion of cardiac sarcoidosis.

A series of trans/trans and cis/cis fused-bis tetrahydrofuran compounds have been obtained stereoselectively in high yields via a one-pot operation involving the intramolecular haloetherification of (Z,Z)-diene diol 19a and (E,E)-diene disilylether 19d, respectively. This method was subsequently applied to the biomimetic-type synthesis of (±)- and (-)-aplysiallene. The inhibitory activities of these compounds and their bromodiene isomers toward Na(+)/K(+) ATPase were determined in vitro, and gave IC50 values of approximately 15 μM in all cases.

Background: Emergence agitation for pediatric patients after general anesthesia is one of the postoperative complications. The relationship between consciousness at tracheal extubation and emergence agitation is not clear. Aim: The aim of the present study was to determine whether tracheal extubation of anesthetized pediatric patients with heart disease by propofol decreases the incidence of emergence agitation. Settings and Design: This was a retrospective case-control study conducted at a children's hospital. Materials and Methods: Pediatric patients with heart disease aged 0-14 years who underwent cardiac catheterization under general anesthesia by propofol between October 2014 and September 2018 were enrolled. The incidence of emergence agitation by anesthetized extubation was compared with that by awake extubation. Statistical Analysis Used: Logistic regression analysis was performed. Results: Anesthetized extubation was performed in 202 patients and awake extubation was performed in 56 patients. The incidence of emergence agitation was significantly lower in patients who underwent anesthetized extubation than in patients who underwent awake extubation (25.2% vs. 69.6%, P = 0.000). In logistic regression analysis, anesthetized extubation [odds ratio (OR): 0.075, 95% confidence interval (CI): 0.034-0.165, P = 0.000] and older age (OR: 0.808, 95% CI: 0.728-0.897, P = 0.000) were associated with a decreased incidence of emergence agitation, and preoperative anxiety (OR: 2.220, 95% CI: 1.060-4.660, P = 0.03) was associated with an increased incidence of emergence agitation. Conclusions: Tracheal extubation under anesthesia by propofol decreases the incidence of emergence agitation in pediatric patients with heart disease.

The authors investigated the association between intraoperative motor-evoked potential (MEP) changes and the severity of spinal cord infarction diagnosed with magnetic resonance imaging (MRI) to clarify the discrepancy between them, which was observed in patients with postoperative motor deficits after thoracic and thoracoabdominal aortic surgery.A multicenter retrospective study.Motor-evoked potential25% of control values was deemed positive for spinal cord ischemia. The severity of spinal cord infarction was categorized into grades A to D based on previous studies using the most severe axial MRI slices. The associations between MRI grade, MEP changes, and motor deficits were examined using logistic regression.Twenty-three of 1,245 patients (from 1999 to 2013, at 12 hospitals in Japan) were extracted from medical records of patients who underwent thoracic and thoracoabdominal aortic repair, with intraoperative MEP examinations and postoperative spinal MRI.No intervention (observational study).Motor-evoked potential25% of control value was associated significantly with motor deficits at discharge (adjusted odds ratio [OR], 130.0; p = 0.041), but not with severity of spinal cord infarction (adjusted OR, 0.917; p = 0.931). Motor deficit at discharge was associated with severe spinal cord infarction (adjusted OR, 4.83; p = 0.043), MEP25% (adjusted OR, 13.95; p = 0.031), and combined deficits (motor and sensory, motor and bowel or bladder, or sensory and bowel or bladder deficits; adjusted OR, 31.03; p = 0.072) in stepwise logistic regression analysis.Motor-evoked potential25% was associated significantly with motor deficits at discharge, but not with the severity of spinal cord infarction.

We designed and synthesized a novel phenyl C-glycoside analogue of Spliceostatin A, which is potent splicing inhibitor and has anti-cancer activities. We successfully synthesized its right phenyl C-glycoside sugar fragment in shorter steps compared to previous synthetic methods for Spliceostatin A and revealed an appropriate fragment combination with a Julia-coupling reaction. Regarding biological activity, the Ph-C-glycoside analogue of Spliceostatin A showed repressed cell proliferation in three prostate cancer cell lines and suppressed AR-V7 expression.

Copeptin, a surrogate marker of pro-arginine vasopressin, is expected to be a marker in cardiovascular diseases. Its utility for predicting long-term clinical outcomes in heart failure (HF), however, has not been adequately evaluated in daily clinical practice in Japan.To assess the relationship of serum copeptin at admission with long-term clinical outcomes, we evaluated serum copeptin at admission in consecutive 107 patients hospitalized for HF between April 2011 and July 2012. The primary outcome measure was defined as a composite of all-cause death and re-admission for HF (all-cause death/HF).In this study population, median serum copeptin at admission was 15.5 (6.7-32.0)pmol/L. As compared with the low-copeptin group (18pmol/L, N=60), the high-copeptin group (≥18pmol/L, N=47) included more male patients and those with prior myocardial infarction, prior HF, low left ventricular ejection fraction, and chronic kidney disease. During median 4.5 (1.0-5.5) years of clinical follow-up, the cumulative incidence of all-cause death/HF was significantly higher in the high-copeptin than in the low-copeptin group (63.4% versus 33.0% at 1 year, and 85.2% versus 77.2% at 5 years, log-rank p=0.03). After adjusting for confounders, high-copeptin was still an independent predictor for all-cause death/HF [hazard ratio (95% confidence interval): 1.77 (1.04-3.01), p=0.03].Copeptin was suggested as a useful marker for predicting long-term clinical outcomes in patients with HF.

Introduction The optimal surgical management strategy for isolated para-aortic lymph node (PALN) metastases from colorectal cancer (CRC) remains unclear. However, the complication rates for open approaches remain high. In this study, the outcomes of laparoscopic para-aortic lymphadenectomy in patients with clinically suspected PALN metastasis were evaluated. Methods Between April 2013 and April 2018, we performed laparoscopic primary resection and para-aortic lymphadenectomy in 11 patients with advanced colorectal cancer and clinically suspected PALN metastasis. This study was a single-center, retrospective, case series analysis, and the surgical outcomes were reviewed. Results There were no cases of perioperative mortality, and conversion to open surgery was necessary in only one patient (9%) because of invasion into a rib. One patient (9%) required a blood transfusion. Postoperative complications occurred in three patients, and the morbidity rate was 27% (3/11). Pathologically, PALN metastasis was confirmed in five patients (45%), all of whom received postoperative chemotherapy. The median survival time for all patients was 25 months, and one patient died of recurrence at 25 months after the initial surgery. Two other patients were alive with recurrence after 47 and 36 months, and two patients were alive without recurrence after 17 and 2 months. Conclusion Laparoscopic para-aortic lymphadenectomy for advanced colorectal cancer with clinically suspected PALN is technically feasible and may be beneficial in selected patients. It is necessary to investigate the feasibility of this procedure in a future case series, and information regarding true oncologic outcome will require long-term follow-up.

BACKGROUND Patients with concomitant atrial fibrillation (AF) and coronary stenting are at high risk for both cardiovascular and bleeding events. We aimed to evaluate the influence of sex on long-term clinical outcomes in this patient subset.Methods and Results:We identified 1,450 patients with AF and coronary stenting in a patient-level pooled database from 3 Japanese studies, and compared 3-year clinical outcomes between men and women (n=1,075, and n=375, respectively). The cumulative 3-year incidence of all-cause death was significantly higher in women than in men (26.5% vs. 17.2%, log-rank P

Spinal cord ischemic injury is the most devastating sequela of descending and thoracoabdominal aortic surgery. Motor-evoked potentials (MEPs) have been used to intraoperatively assess motor tract function, but it remains unclear whether MEP monitoring can decrease the incidence of postoperative motor deficits. Therefore, we reviewed multicenter medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open surgery and endovascular repair) to assess the association of MEP monitoring with postoperative motor deficits.Patients included in the study underwent descending or thoracoabdominal aortic repair at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery between 2000 and 2013. Using multivariable mixed-effects logistic regression analysis, we investigated whether intraoperative MEP monitoring was associated with postoperative motor deficits at discharge after open and endovascular aortic repair.We reviewed data from 1214 patients (open surgery, 601 [49.5%]; endovascular repair, 613 [50.5%]). MEP monitoring was performed in 631 patients and not performed in the remaining 583 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. Multivariable logistic regression analysis revealed that postoperative motor deficits at discharge did not have a significant association with MEP monitoring (adjusted odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69-1.88; P = .624), but with other factors: history of neural deficits (adjusted OR, 6.08; 95% CI, 3.10-11.91; P.001), spinal drainage (adjusted OR, 2.14; 95% CI, 1.32-3.47; P = .002), and endovascular procedure (adjusted OR, 0.45; 95% CI, 0.27-0.76; P = .003). The sensitivity and specificity of MEP25% of control value for motor deficits at discharge were 37.8% (95% CI, 26.5%-49.5%) and 95.5% (95% CI, 94.7%-96.4%), respectively.MEP monitoring was not significantly associated with motor deficits at discharge.

Aim Many studies have evaluated the risk factors for anastomotic leakage after laparoscopic anterior resection. In this study in order to increase the tightness of anastomoses and prevent bleeding from their staple lines, a linear stapler with pre-attached bioabsorbable polyglycolic acid (PGA) felt was used for rectal transection, and the short-term surgical outcomes were evaluated. Patients and methods A prospective registry of 62 patients with rectosigmoidal or rectal carcinoma who initially underwent laparoscopic anterior resection using PGA felt for rectal transection was reviewed. Results The overall frequency of anastomotic leakage was 1.6% (1/62), and none of the patients developed postoperative staple line bleeding or other adverse events related to the use of PGA felt. Conclusion The frequency of anastomotic leakage was relatively low, and therefore the use of a linear stapler with pre-attached bioabsorbable PGA felt might reduce the risk of adverse events related to anastomosis, especially anastomotic leakage.

Haloacetamides (HAcAms) are nitrogenous disinfection byproducts in drinking water. The profiles of six HAcAms and their formation potentials (FPs) upon chlorination at water purification plant 1 (WPP-1) in September 2016 and at WPP-2 in September 2016 and January 2017 were investigated. HAcAms were removed effectively when they were formed via intermediate chlorination during water purification processes. Removal of total HAcAm-FPs ranged from 50% to 75%. Coagulation/flocculation/sand filtration showed the highest removal of total HAcAm-FPs. As for individual HAcAms, while chlorinated acetamide-FPs were removed, brominated acetamide-FPs, particularly 2,2-dibromoacetamide, remained. The bromine incorporation factors increased during all water purification processes except ozonation and the ozone/hydrogen peroxide process for diHAcAms (2,2-dichloroacetamide, 2-bromo-2-chloroacetamide, and 2,2-dibromoacetamide). The trends in relationships between DOM indices (fractions of dissolved organic matter, ultraviolet absorbance at 260 nm, and fluorescence intensities representing humic-like and tryptophan-like compounds) and total HAcAm-FPs during ozonation and ozone/hydrogen peroxide process were different from those during other processes.

Acute kidney injury (AKI) after cardiopulmonary bypass (CPB) is a well-known postoperative complication. Remifentanil, which is a commonly used ultra-short-acting opioid, has antiinflammatory and sympatholytic effects with improvement of microcirculation. A retrospective study was conducted to clarify the effect of the use of remifentanil during CPB on the incidence of postoperative AKI. Patients who underwent valve surgery while under cardiopulmonary bypass between January 2012 and December 2014 in our hospital were enrolled in this study. The incidences of postoperative AKI were compared in patients who received remifentanil during CPB (group R) and those who did not (group N). Univariate and multivariate regression analyses were performed to determine risk factors for AKI. Eighty patients received remifentanil (group R) and 50 patients did not (group N). The incidences of AKI were not significantly different in group R and group N (51% vs. 36%, P = 0.10). In multivariate regression analysis, age [adjusted odds ratio (OR) 1.048, 95% CI 1.008–1.089, P = 0.017], male gender (adjusted OR 3.101, 95% CI 1.303–7.378, P = 0.011), and use of preoperative calcium channel blockers (adjusted OR 3.240, 95% CI 1.302–8.063, P = 0.011) and diuretics (adjusted OR 2.673, 95% CI 1.178–6.066, P = 0.019) were associated with the incidence of AKI. The use of remifentanil was not associated with AKI (adjusted OR 2.321, 95% CI 0.997–5.402, P = 0.051). The use of remifentanil during CPB did not decrease the incidence of postoperative AKI after cardiac surgery.

The aim of this study was to evaluate the prognostic impact of left ventricular ejection fraction (LVEF) in patients with severe aortic stenosis (AS).The prognostic impact of LVEF in severe AS remains controversial.Among 3,815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the present study population consisted of 3,794 patients after excluding 21 patients without LVEF data. Patients were divided into 4 groups according to LVEF at index echocardiography (50%, 50% to 59%, 60% to 69%, and ≥70%; conservative strategy: n = 388, n = 390, n = 1,025, and n = 800; initial aortic valve replacement strategy: n = 206, n = 170, n = 375, and n = 440). Echocardiographic data were site reported, and there was no echocardiography core laboratory.In the conservative group, the cumulative 5-year incidence of the primary outcome measure (a composite of aortic valve-related death or heart failure hospitalization) was significantly higher in patients with LVEFs 50% and 50% to 59% than in those with LVEFs 60% to 69% and ≥70% (72.3%, 58.4%, 38.7%, and 35.0%, respectively, p 0.001), whereas in the initial aortic valve replacement group, the negative effect of low LVEF was markedly attenuated (20.2%, 20.3%, 17.7%, and 12.4%, respectively, p = 0.03). After adjusting for confounders, LVEF 50% (hazard ratio: 1.82; 95% confidence interval: 1.44 to 2.28; p 0.001) and 50% to 59% (hazard ratio: 1.77; 95% confidence interval: 1.42 to 2.20; p 0.001) but not 60% to 69% (hazard ratio: 1.14; 95% confidence interval: 0.94 to 1.39; p = 0.17) were independently associated with poorer outcomes compared with LVEF ≥70% (reference) in the conservative group. In the initial aortic valve replacement group, the adjusted risk for the primary outcome measure was not significantly different across the 4 LVEF groups.This study demonstrates that survival in patients with severe AS is impaired when LVEF is 60%, and these findings have implications for decision making with regard to the timing of surgical intervention.

Background There are limited data regarding the risk stratification based on peak aortic jet velocity (Vmax) in patients with severe aortic stenosis ( AS ). Methods and Results Among 3815 consecutive patients with severe AS enrolled in the CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry, the study population consisted of 1075 conservatively managed patients with Vmax ≥4.0 m/s and left ventricular ejection fraction ≥50%. The study patients were subdivided into 3 groups based on Vmax (group 1, 4.0 ≤ Vmax AS ‐related events (aortic valve–related death or heart failure hospitalization) was incrementally higher with increasing Vmax (entire population; 38.0%, 49.4%, and 62.8%, P P =0.008; and asymptomatic patients; 29.4%, 38.9%, and 47.7%, P =0.005). After adjusting for confounders, the excess risk of group 2 and group 3 relative to group 1 for AS ‐related events remained significant (hazard ratio, 1.39; 95% CI , 1.07–1.81; P =0.02, and hazard ratio, 1.53; 95% CI , 1.17–2.00; P =0.002, respectively). The effect size of group 3 relative to group 1 for AS ‐related events in asymptomatic patients (N=479) was similar to that in symptomatic patients (N=596; hazard ratio, 1.59; 95% CI , 1.01–2.52; P =0.047, and hazard ratio, 1.67; 95% CI , 1.16–2.40, P =0.008, respectively), and there was no significant overall interaction between the symptomatic status and the effect of the Vmax categories on AS ‐related events (interaction, P =0.88). Conclusions In conservatively managed severe AS patients with preserved left ventricular ejection fraction, increasing Vmax was associated with incrementally higher risk for AS ‐related events. However, the cumulative 5‐year incidence of the AS ‐related events remained very high even in asymptomatic patients with less greater Vmax.

Background Glycosylation is one of the major posttranslational modifications of proteins and it is essential for proteins to obtain normal biological functions. Congenital disorders of glycosylation (CDGs) are very rare genetic disorders that lack enzymes needed for glycosylation. Phosphomannomutase-2 (PMM2)-CDG is the most common type of CDG. CDGs can cause a wide variety of clinical symptoms in almost every organ system. Muscular hypotonia is often present in patients with CDGs and is one of the most notable problems for anesthetic management because the susceptibility to nondepolarizing neuromuscular blocking agents (NMBAs) in patients with CDGs is unknown. Case presentation The patient was a 17-month-old boy who weighed 6.5 kg and was 71 cm tall. He presented for strabismus surgery. He had muscular hypotonia, mental retardation, hepatic dysfunction, mild cerebellar hypoplasia, and some dysmorphic features including inverted nipples and abnormal subcutaneous fat distribution of the hips. Gene analysis revealed a compound heterozygous mutation in the gene encoding PMM2 and the patient was diagnosed as having PMM2-CDG. General anesthesia was performed with sevoflurane, nitrous oxide, and rocuronium. Neuromuscular monitoring was performed during anesthesia using train-of-four (TOF)-Watch® (MSD, Japan). As postoperative analgesia, the surgeon performed sub-Tenon’s anesthesia. We did not use any intravenous analgesic. After completion of the operation, residual rocuronium was competed by administration of sugammadex. The patient gained consciousness and spontaneous breathing was established shortly thereafter, and the trachea was smoothly extubated. He was transported to an inpatient ward and was discharged to his home the next day without any complication. Conclusions We performed safe anesthetic management in a 17-month-old boy with PMM2-CDG using rocuronium under neuromuscular monitoring. A patient with PMM2-CDG may show nearly normal susceptibility to nondepolarizing NMBAs.

The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth. Mice lacking FLRT2 in endothelial cells exhibited embryonic lethality at mid-gestation, with systemic congestion and hypoxia. Although they lacked apparent deformities in the embryonic vasculature and heart, the placental labyrinths of these embryos exhibited aberrant alignment of endothelial cells, which disturbed the feto-maternal circulation. Interestingly, this vascular deformity was related to endothelial repulsion through binding to the UNC5B receptor. Our results suggest that the proper organization of the placental labyrinth depends on coordinated inter-endothelial repulsion, which prevents uncontrolled layering of the endothelium.

This study sought to compare the 2-year outcomes between bioresorbable vascular scaffold (BVS) and everolimus-eluting metallic drug-eluting stent (EES).The occurrence of very late stent/scaffold thrombosis (VLST) of BVS beyond 1 year after implantation is an increasing concern.We conducted a meta-analysis of 24 studies (BVS: n = 2,567 and EES: n = 19,806) reporting the 2-year outcomes of BVS and/or EES to compare the risk of BVS versus EES for stent/scaffold thrombosis (ST) and target lesion failure (TLF) in 7 comparative studies (3 randomized and 4 observational), and to estimate the pooled incidence rates of ST and TLF including additional 17 single-arm studies.In the 7 comparative studies, the risk for VLST between 1 and 2 years was numerically higher in BVS than in EES (odds ratio [OR]: 2.03 [95% confidence interval (CI): 0.62 to 6.71]). The excess risk of BVS relative to EES for ST through 2 years was significant (OR: 2.08 [95% CI: 1.02 to 4.26]). The risk for TLF was neutral between BVS and EES. In the 24 studies, the pooled estimated incidence rates of VLST, and ST through 2 years were higher in BVS than in EES (0.240 [95% CI: 0.022 to 0.608]% vs. 0.003 [95% CI: 0.000 to 0.028]%, and 1.43 [95% CI: 0.67 to 2.41]% vs. 0.56 [95% CI: 0.43 to 0.70]%, respectively). The corresponding rates for TLF were comparable between BVS and EES (1.88 [95% CI: 1.30 to 2.55]% and 1.78 [95% CI: 1.17 to 2.49]% and 7.90 [95% CI: 6.26 to 9.69]% and 7.49 [95% CI: 5.86 to 9.29]%, respectively).In this meta-analysis, BVS as compared with EES was associated with higher risk for VLST between 1 and 2 years and ST through 2 years.

With interest, we read the article by Kikuta et al. [(1)][1] in which they assessed the accuracy of instantaneous wave-free ratio (iFR) pullback measurements for predicting the post-percutaneous coronary intervention iFR in tandem and diffuse coronary disease. They concluded that iFR pullback

Periodontal tissue homeostasis depends on a complex cellular network that conveys cell-cell communication. Gap junctions (GJs), one of the intercellular communication systems, are found between adjacent human periodontal ligament (hPDL) cells; however, the functional GJ coupling between hPDL cells has not yet been elucidated. In this study, we investigated functional gap-junction-mediated intercellular communication in isolated primary hPDL cells. SEM images indicated that the cells were in contact with each other via dendritic processes, and also showed high anti-connexin43 (Cx43) immunoreactivity on these processes. Gap-junctional intercellular communication (GJIC) among hPDL cells was assessed by fluorescence recovery after a photobleaching (FRAP) analysis, which exhibited dye coupling between hPDL cells, and was remarkably down-regulated when the cells were treated with a GJ blocker. Additionally, we examined GJs under hypoxic stress. The fluorescence recovery and expression levels of Cx43 decreased time-dependently under the hypoxic condition. Exposure to GJ inhibitor or hypoxia increased RANKL expression, and decreased OPG expression. This study shows that GJIC is responsible for hPDL cells and that its activity is reduced under hypoxia. This is consistent with the possible role of hPDL cells in regulating the biochemical reactions in response to changes in the hypoxic environment.