Human immune responses elicited by an intranasal inactivated H5 influenza vaccine.

Intranasally administered influenza vaccines could be more effective than injected vaccines, because intranasal vaccination can induce virus-specific immunoglobulin A (IgA) antibodies in the upper respiratory tract, which is the initial site of infection. In this study, immune responses elicited by an intranasal inactivated vaccine of influenza A(H5N1) virus were evaluated in healthy individuals naive for influenza A(H5N1) virus. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy vinyl polymer, had a notable impact on the induction of nasal IgA antibody responses but not on serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific Th cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against influenza A(H5N1) viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses.

Off-Site Indoor Localization Competitions Based on Measured Data in a Warehouse.

The performance of indoor localization methods is highly dependent on the situations in which they are used. Various competitions on indoor localization have been held for fairly comparing the existing indoor localization methods in shared and controlled testing environments. However, it is difficult to evaluate the practical performance in industrial scenarios through the existing competitions. This paper introduces two indoor localization competitions, which are named the "PDR Challenge in Warehouse Picking 2017" and "xDR Challenge for Warehouse Operations 2018" for tracking workers and vehicles in a warehouse scenario. For the PDR Challenge in Warehouse Picking 2017, we conducted a unique competition based on the data measured during the actual picking operation in an actual warehouse. We term the dead-reckoning of a vehicle as vehicle dead-reckoning (VDR), and the term "xDR" is derived from pedestrian dead-reckoning (PDR) plus VDR. As a sequel competition of the PDR Challenge in Warehouse Picking 2017, the xDR Challenge for Warehouse Operations 2018 was conducted as the world's first competition that deals with tracking forklifts by VDR with smartphones. In the paper, first, we briefly summarize the existing competitions, and clarify the characteristics of our competitions by comparing them with other competitions. Our competitions have the unique capability of evaluating the practical performance in a warehouse by using the actual measured data as the test data and applying multi-faceted evaluation metrics. As a result, we successfully organize the competitions due to the many participants from many countries. As a conclusion of the paper, we summarize the findings of the competitions.

Clinical Characteristics and Long-Term Outcomes of Rotational Atherectomy　- J2T Multicenter Registry.

BACKGROUND: Rotational atherectomy (RA) is an adjunct tool for the management of heavily calcified coronary lesions during percutaneous coronary intervention (PCI), but the long-term clinical outcomes of RA use remain unclear in this drug-eluting stent era.Methods and Results:This multi-center registry assessed the characteristics and outcomes of patients treated by RA for calcified coronary lesions between 2004 and 2015. Among 1,090 registered patients, mean age was 70±10 years and 815 (75%) were male. Sixty percent of patients had diabetes mellitus and 27.7% were receiving hemodialysis. The procedure was successful in 96.2%. In-hospital death occurred in 33 patients (3.0%), and 14 patients (1.3%) developed definite/probable stent thrombosis. During the median follow-up period of 3.8 years, the incidence of major adverse cardiac events (MACE), defined as all-cause death, acute coronary syndrome, stent thrombosis, target vessel revascularization and stroke, was 46.7%. On multivariable Cox hazard analysis, hemodialysis (HR, 2.08; 95% CI: 1.53-2.86; P<0.0001) and age (HR, 1.03; 95% CI: 1.01-1.04; P<0.0001) were strong independent predictors of MACE. Conversely, statin treatment was associated with lower incidence of MACE (P=0.035). CONCLUSIONS: This study has provided the largest Japanese dataset for long-term follow-up of RA. Although RA in calcified lesions appears feasible with a high rate of procedural success, a high incidence of MACE was observed.

Increased cystatin C levels as a risk factor of cardiovascular events in patients with preserved estimated glomerular filtration rate after elective percutaneous coronary intervention with drug-eluting stents.

Chronic kidney disease (CKD) is an important risk factor for coronary artery disease (CAD) and cardiovascular events. Cystatin C (CysC) has been proposed as a sensitive marker for CKD. However, the predictive value of CysC for cardiovascular events in CAD patients with preserved estimated glomerular filtration rate (eGFR) is unclear. We enrolled 277 consecutive patients undergoing elective percutaneous coronary intervention with sirolimus-eluting stents (SES). Patients with an eGFR ≤60 ml/min/1.73 m(2) were excluded. Serum CysC levels were measured immediately before SES implantation. Major adverse cardiac and cerebrovascular events (MACCE) were defined as cardiovascular death, acute coronary syndrome, stroke, and hospitalization because of congestive heart failure. After a median follow-up of 63 months, 29 patients had MACCE. The subjects were divided into 2 groups based on median serum CysC levels and eGFR (0.637 mg/L and 72.43 ml/min/1.73 m(2), respectively). Kaplan-Meier curves showed that the high CysC group had a significantly higher occurrence of MACCE than the low CysC group (p = 0.006), although a low level of eGFR was not significantly associated with an increased risk for occurrence of MACCE. Multivariate analysis revealed that serum CysC levels were an independent predictor of MACCE [hazards ratio: 1.30 per 0.1 mg/L (1.01-1.63), p = 0.038]. These data suggested that serum CysC level is an independent predictor of MACCE, even in patients with preserved eGFR after elective SES implantation.

Comparison of Clinical and Angiographic Outcomes After Bare Metal Stents and Drug-Eluting Stents Following Rotational Atherectomy.

Few studies have investigated the clinical outcomes of rotational atherectomy (RA) prior to and during the drugeluting stent (DES) era. The goal of this study was to assess the long-term outcome after RA followed by DES and bare metal stent (BMS) implantation in complex calcified coronary lesions and to compare the outcomes among various DESs.This was a single center retrospective observational study. Consecutive 406 patients who underwent elective RA followed by BMS or DES implantation at our institution from 2001 to 2011 were included. This study compared the long-term outcomes after treatment with RA among BMS and 3 different DESs (sirolimus-eluting stent, paclitaxel-eluting stent, and everolimus-eluting stent) implantation.The mean follow-up period was 4.6 years. Patients with DES were older and exhibited more vessel disease, longer lesion length, and smaller vessel size. Patients with BMS had a significantly higher rate of target lesion revascularization, restenosis, and larger late lumen loss than those with DES. Composite events including mortality, ACS, and target vessel revascularization were significantly higher in the BMS-RA group than in the DES-RA group. After adjustment, BMS remained an independent predictor of MACE and ACS plus death in patients treated with RA. However, there were no significant differences in late lumen loss, restenosis rate, and MACE among the 3 DES.The combination of DES-RA has a favorable effect in both the angiographic and clinical outcomes compared with BMS-RA. However, no significant differences in late loss and events rates were observed among the 3 DES groups.

Low high-density lipoprotein cholesterol is a residual risk factor associated with long-term clinical outcomes in diabetic patients with stable coronary artery disease who achieve optimal control of low-density lipoprotein cholesterol.

Diabetes mellitus is recognized an independent risk factor for coronary artery disease (CAD) and mortality. Clinical trials have shown that statins significantly reduce cardiovascular events in diabetic patients. However, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein cholesterol (LDL-C) levels with statin. High-density lipoprotein cholesterol (HDL-C) is an established coronary risk factor that is independent of LDL-C levels. We evaluated the impact of HDL-C on long-term mortality in diabetic patients with stable CAD who achieved optimal LDL-C. We enrolled 438 consecutive diabetic patients who were scheduled for percutaneous coronary intervention between 2004 and 2007 at our institution. We identified 165 patients who achieved target LDL-C <100 mg/dl. Patients were stratified into two groups according to HDL-C levels (low HDL-C group, baseline HDL-C <40 mg/dl; high HDL-C group, ≥40 mg/dl). Major adverse cardiac events (MACE) that included all-cause death, acute coronary syndrome, and target lesion revascularization were evaluated between the two groups. The median follow-up period was 946 days. The rate of MACE was significantly higher in diabetic patients with low-HDL-C who achieved optimal LDL-C (6.9 vs 17.9 %, log-rank P = 0.030). Multivariate Cox regression analysis showed that HDL-C is significantly associated with clinical outcomes (adjusted hazard ratio for MACE 1.33, 95 % confidence interval 1.01-1.75, P = 0.042). Low HDL-C is a residual risk factor that is significantly associated with long-term clinical outcomes among diabetic patients with stable CAD who achieve optimal LDL-C levels.

Impact of red blood cell distribution width on long-term mortality in diabetic patients after percutaneous coronary intervention.

BACKGROUND: Red blood cell distribution width (RDW) is a novel prognostic marker that reflects oxidative stress and chronic inflammation in patients with cardiovascular disease. Diabetes mellitus increases oxidative stress and vascular inflammation, which accelerate atherosclerosis. However, the relationship between RDW and long-term outcome in diabetic patients with coronary artery disease (CAD) is unclear. METHODS AND RESULTS: Subjects comprised 560 consecutive diabetic patients (mean age, 66.6 years; male, 80%) with stable CAD who had undergone elective percutaneous coronary intervention (PCI). Patients were divided into 2 groups according to median RDW at baseline (13.1%): a high RDW group (mean RDW, 14.0%; interquartile range, 13.3-14.2%); and a low RDW group (mean RDW, 12.6%; interquartile range, 12.4-12.9%). All-cause mortality rates were compared between groups. Mean duration of follow up was 3.9 years. Patients with high RDW were more likely to be older, show dyslipidemia and have a lower ejection fraction and decreased hemoglobin level. Twenty-nine patients (5.2%) died during follow up. The cumulative incidence of all-cause death was significantly higher in the high RDW group than in the low RDW group (log-rank P=0.0015). Multivariate analysis identified high RDW as being associated with all-cause mortality (hazard ratio, 2.56; 95% confidence interval, 1.12-6.62; P=0.025). CONCLUSIONS: Increased RDW was significantly associated with increased long-term all-cause mortality in diabetic patients after PCI.

Thymus-derived leukemia-lymphoma in mice transgenic for the Tax gene of human T-lymphotropic virus type I.

Adult T-cell leukemia-lymphoma (ATLL) is a group of T-cell malignancies caused by infection with human T-lymphotropic virus type I (HTLV-I). Although the pathogenesis of ATLL remains incompletely understood, the viral regulatory protein Tax is centrally involved in cellular transformation. Here we describe the generation of HTLV-I Tax transgenic mice using the Lck proximal promoter to restrict transgene expression to developing thymocytes. After prolonged latency periods, transgenic mice developed diffuse large-cell lymphomas and leukemia with clinical, pathological and immunological features characteristic of acute ATLL. Transgenic mice were functionally immunocompromised and they developed opportunistic infections. Fulminant disease also developed rapidly in SCID mice after engraftment of lymphomatous cells from transgenic mice. Flow cytometry showed that the cells were CD4(-) and CD8(-), but CD44(+), CD25(+) and cytoplasmic CD3(+). This phenotype is indicative of a thymus-derived pre-T-cell phenotype, and disease development was associated with the constitutive activation of NF-kappaB. Our model accurately reproduces human disease and will provide a tool for analysis of the molecular events in transformation and for the development of new therapeutics.

Geospatial intelligence system for evaluating the work environment and physical load of factory workers.

This study aimed to assess the effectiveness of methods for evaluating the environmental and physical loads on workers in manufacturing plants, considering their locations. Participants were employees of DENSO CORPORATION's manufacturing facilities, and environmental sensors (for temperature and humidity) and BLE beacons were installed to cover the work area. Questionnaires were completed by the participants twice to assess their thermal comfort and fatigue in the work environment. The results showed that a regression prediction model with an adjusted R-squared of 0.418 for fixed-point temperature and 0.495 for perceived temperature was developed for thermal comfort. No linear relationship was found between environmental factors and fatigue, and a decision tree analysis was conducted. Relative humidity and activity level, along with temperature, were selected as predictor variables. The findings suggest that it is possible to estimate the work environment and workload without adding additional measurement-related burdens or challenges. This highlights the usefulness of the proposed method, which takes into account the environmental distribution throughout the work area rather than relying solely on conventional fixed-point observation data, for assessing workers' exposure to the environment and preventing occupational accidents.Clinical Relevance- The proposed approach, combining indoor localization with environmental status, can estimate the condition of workers and is expected to be a good solution for preventing occupational accidents and enhancing workers' health.

Characterization of neutralizing antibodies in adults after intranasal vaccination with an inactivated influenza vaccine.

The levels and properties of neutralizing antibodies in nasal wash and serum collected from five healthy adults were examined after intranasal administration of an A/Uruguay/716/2007 (H3N2) split vaccine (45 µg hemagglutinin (HA) per dose; five doses, with an interval of 3 weeks between each dose). Prior to the assays, nasal wash samples were concentrated so that the total amount of antibodies was equivalent to about 1/10 of that found in the natural nasal mucus. Vaccination induced virus-specific neutralizing antibody responses, which increased with the number of vaccine doses given. Neutralizing antibodies were produced more efficiently in the nasal passages than in the serum: A ≥4-fold increase in nasal neutralization titres was observed after the second vaccination in four out of five subjects, whereas a rise in serum neutralization titres was observed only after the fifth vaccination. Nasal and serum neutralizing antibodies were mainly found in the polymeric IgA and monomeric IgG fractions, respectively, after gel filtration. Taken together, these results suggest that intranasal administration of an inactivated split vaccine induces high levels of nasal neutralizing antibodies (primarily polymeric IgA) and low levels of serum neutralizing antibodies (primarily monomeric IgG).

Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function--a crossover trial (AGENT).

BACKGROUND: Hypertension is associated with impaired glucose tolerance and insulin resistance. Medical treatment that interferes with various steps in the renin-angiotensin system improves glucose tolerance and insulin resistance. However, it remains unclear if long-acting calcium channel blockers (CCBs) such as azelnidipine and amlodipine affect glucose tolerance and insulin resistance in clinical practice. METHODS: Seventeen non-diabetic patients with essential hypertension who had controlled blood pressure levels using amlodipine (5 mg/day) were enrolled in this study. After randomization, either azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks. At baseline and the end of each CCB therapy, samples of blood and urine were collected and 75 g oral glucose tolerance test (OGTT) was performed. In addition, hematopoietic progenitor cells (HPCs) were measured at each point by flow cytometry and endothelial functions were measured by fingertip pulse amplitude tonometry using EndoPAT. RESULTS: Although blood pressure levels were identical after each CCB treatment, the heart rate significantly decreased after azelnidipine administration than that after amlodipine administration (P < 0.005). Compared with amlodipine administration, azelnidipine significantly decreased levels of glucose and insulin 120 min after the 75 g OGTT (both P < 0.05). Serum levels of high-sensitivity C-reactive protein (P = 0.067) and interleukin-6 (P = 0.035) were decreased. Although endothelial functions were not different between the two medication groups, the number of circulating HPCs was significantly increased after azelnidipine administration (P = 0.016). CONCLUSIONS: These results suggest that azelnidipine treatment may have beneficial effects on glucose tolerance, insulin sensitivity, the inflammatory state, and number of circulating progenitor cells in non-diabetic patients with essential hypertension.

Long-term impact of mild chronic kidney disease in patients with acute coronary syndrome undergoing percutaneous coronary interventions.

BACKGROUND: Accumulating evidence shows that chronic kidney disease (CKD) is an independent risk factor for major adverse cardiac and cerebrovascular events (MACCE) after acute coronary syndrome (ACS). However, it is not known whether mild renal insufficiency affects long-term clinical outcomes. METHODS: This is a post-hoc analysis from the Extended-ESTABLISH trial, which was designed to estimate the impact of renal insufficiency on patients with ACS after percutaneous coronary intervention over the long term. One hundred and eighty patients were divided into three groups based on the estimated glomerular filtration rate (eGFR) at time of ACS: moderate-to-severe CKD, <60 mL/min/1.73 m(2) (n = 31, 17.2%); mild CKD, 60-90 mL/min/1.73 m(2) (n = 100, 55.6%) and non-CKD, ≥90 mL/min/1.73 m(2) (n = 47, 26.1%). The eGFR was calculated using the new Japanese equation. Long-term outcomes were compared over a follow-up period of 1538 ± 707 days. RESULTS: Cumulative incidence rates of MACCE did not significantly differ between groups 1 year after ACS onset (P = 0.384), whereas significant differences appeared during the long-term follow-up (10.6 versus 27.0% versus 35.4% in the non-CKD, mild CKD and moderate-to-severe CKD groups, respectively; log-rank test, P = 0.022). In a multivariate Cox hazard regression model, moderate-to-severe CKD and mild CKD were associated with a higher rate of MACCE after adjusting for confounding variables (hazard ratios = 3.46 and 2.67, respectively; P = 0.043). CONCLUSIONS: The presence of mild CKD at ACS occurrence is associated with a worse outcome in the long term, but not the short term.

Clinical impact of angiographic restenosis after bare-metal stent implantation on long-term outcomes in patients with coronary artery disease.

BACKGROUND: In-stent restenosis (ISR) after bare-metal stent (BMS) implantation is thought to be clinically benign, although this notion remains controversial. The long-term clinical outcomes of ISR with BMS have not been established. METHODS AND RESULTS: Among 983 consecutive patients (1,227 lesions) implanted with a BMS between 1999 and 2004 at the authors' institution, 746 underwent routine follow-up angiography. Angiographic ISR (ISR group) was evident in 215 patients (28.8%) and 136 of them underwent repeat revascularization. The incidence of major adverse cardiac events (MACE), acute coronary syndrome (ACS), target lesion revascularization and all-cause death were evaluated between patients with and without ISR (non-ISR group). Patients in the ISR group were older and more likely to have diabetes. The median follow-up period was 2,031 days. The rates of MACE and ACS were significantly higher in the ISR group compared with the non-ISR group (33.5% vs. 13.7%, P<0.0001 and 11.2% vs. 7.0%, P<0.05, respectively). Multivariate Cox regression analysis demonstrated that ISR was significantly associated with clinical outcomes (adjusted hazard ratio [HR] for MACE, 2.81; 95% confidence interval [CI]: 2.01-3.94, P<0.01; adjusted HR for ACS, 1.84; 95%CI: 1.08-3.13, P<0.05). CONCLUSIONS: ISR with BMS was significantly associated with long-term adverse clinical outcomes. Risk of future cardiovascular events due to ISR must be carefully considered.

Azelnidipine and amlodipine anti-coronary atherosclerosis trial in hypertensive patients undergoing coronary intervention by serial volumetric intravascular ultrasound analysis in Juntendo University (ALPS-J).

BACKGROUND: A previous study reported that amlodipine retarded coronary plaque progression in patients with coronary artery disease. The goal of this multicenter study was to determine which calcium-channel blockers (CCBs) other than amlodipine attenuated the progression of plaque volume (PV) accessed by intravascular ultrasound (IVUS). METHODS AND RESULTS: ALPS-J was a prospective, randomized open-label study conducted at 5 centers. Patients who had hypertension and were scheduled for coronary intervention were enrolled. Subjects were randomly assigned to receive 16 mg/day of azelnidipine or 5mg/day of amlodipine administered for 48 weeks. The primary endpoint was the percent change in coronary PV measured by IVUS. Between 2007 and 2009, 199 patients were enrolled; 115 had evaluable IVUS images at both baseline and after 48 weeks of treatment. Blood pressure significantly reduced to 128/68 mmHg at follow-up. The lipid profiles in the 2 groups were comparable (low-density lipoprotein cholesterol: 97 mg/dl). The %change in PV showed a significant regression of 4.67 and 4.85% in the azelnidipine and amlodipine groups, respectively. The upper limit of the 95% confidence interval of the mean difference in %change PV between the 2 groups (0.18%, 95% confidence interval 4.62 to 4.98%) did not exceed the pre-defined non-inferiority margin of 6.525%. CONCLUSIONS: ALPS-J demonstrated that azelnidipine was not inferior to amlodipine for primary efficacy. In addition to standard medical therapy, dihydropyridine CCBs will retard PV progression in hypertensive patients.

Gender-based outcomes among patients with diabetes mellitus after percutaneous coronary intervention in the drug-eluting stent era.

Diabetes mellitus has a greater effect on mortality rates due to coronary artery disease in women than in men. Although women undergoing coronary intervention in general have a higher frequency of adverse outcomes than men, the effect of gender among diabetic patients on clinical outcomes after percutaneous coronary intervention (PCI) has not been well established in the drug-eluting stent (DES) era. We have investigated the impact of gender on long-term clinical outcome in these high risk populations. We enrolled 404 consecutive patients (74 women and 330 men) with diabetes mellitus who underwent elective PCI (85% with DES). We evaluated the incidence of major adverse cardiac events (MACE), which is a composite of total all-cause death, acute coronary syndrome (ACS), and target lesion revascularization (TLR) during a period of 4 years after coronary intervention. The women were significantly older, more likely to have dyslipidemia, and had significantly higher systolic blood pressure and LDL-C values than men. The use of insulin and angiotensin receptor blockers was more frequent among the women (32.4% versus 21.0%, P = 0.04 and 60.8% versus 39.8%, P < 0.01, respectively). The angiographic profiles of both were comparable. At four-year clinical follow-up, cumulative incidence of MACE was identical between the women and the men (16.2% versus 15.5%, P = 0.90; adjusted HR 1.23, 95% CI 0.61-2.50, P = 0.56). Although the baseline characteristics of the women were worse, clinical outcomes did not significantly differ between women and men among diabetic patients after elective PCI.

Safety and Efficacy of Simultaneous Inoculations of Pneumococcal and Influenza Vaccines in Patients with Coronary Artery Disease.

AIM: Pneumococcal and influenza infections can cause serious morbidity and mortality in patients with cardiovascular diseases. The purpose of this study was to investigate the safety and efficacy of simultaneous inoculations of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and trivalent influenza vaccine (TIV) in patients with coronary artery disease (CAD). METHODS: This was a prospective, randomized, single-blind, placebo-controlled study. A total of 40 patients with CAD were randomly assigned to the TIV＋PPSV23 (simultaneous inoculations of TIV and PPSV23) and TIV＋Placebo (inoculations of TIV and placebo) groups. Primary outcomes were the safety of simultaneous vaccinations and the changing of circulating cardiovascular biomarkers before, at 4-, and at 12-weeks after vaccinations. RESULTS: The baseline characteristics between the two groups were identical. The prevalence of injection-site pain, swelling, and reddening were 47%, 37%, and 37% in the TIV＋PPSV23 group, and 10%, 5%, and 0% in the TIV＋Placebo group, respectively. All reactions were self-limited. Body temperature ＞37.0℃ or serious injection-related reaction was not observed. The levels of white blood cells, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, pentraxin-3, and malondialdehide-modified low-density lipoprotein (LDL), were not significantly different between the two groups before and after vaccinations. The levels of anti-oxidized LDL were significantly and step-wisely decreased from baseline, to 4-, and 12-weeks vaccinations in the both groups. No significant changes of other markers were observed in both groups at each time point. CONCLUSION: Simultaneous inoculations of TIV and PPSV23 were safety in patients with CAD, suggesting that dual vaccinations can be considered even in patients with CAD.

Sex differences in clinical outcomes after rotational atherectomy of calcified coronary stenoses: from multicenter registry.

BACKGROUND: Recent improvements in devices and medications may diminish the risk of adverse events following percutaneous coronary intervention (PCI) in women. However, complex calcified coronary lesions are increasingly being encountered in clinical practice, which remain challenging for contemporary PCI. Rotational atherectomy (RA) of severely calcified lesions is an option that facilitates the technical success of PCI. We aimed to examine sex differences in long-term clinical prognoses after PCI with RA in the drug-eluting stent (DES) era. METHODS AND RESULTS: We evaluated J2T ROTA registry data from 1,090 patients with severely calcified de novo coronary artery stenoses who underwent PCI using RA at 3 hospitals between 2004 and 2015. After excluding patients who received regular hemodialysis, 788 patients, including 570 men and 218 women, were ultimately analyzed. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), which included death, acute coronary syndrome (ACS), and stroke. The women were significantly older, and presented more frequently with chronic kidney disease, ACS, atrial fibrillation, lower body mass indexes, and worse lipid profiles than the men. During the observation period, MACCE occurred in 197 patients (25%) (118 deaths, 29 strokes, and 50 ACS). In the unmatched population, women had a higher MACCE rate than men (hazard ratio: 1.48, [95% confidence interval: 1.07-2.06]). However, sex was not associated with MACCE in the propensity score-matched population. CONCLUSION: In the DES era, differences between sexes were not observed in relation to long-term MACCE in patients undergoing PCI with RA for severely calcified coronary artery stenoses.

Frequent detection of noroviruses and sapoviruses in swine and high genetic diversity of porcine sapovirus in Japan during Fiscal Year 2008.

A molecular biological survey on porcine norovirus (NoV) and sapovirus (SaV) was conducted in Toyama Prefecture, Japan, during fiscal year 2008. Both NoV and SaV were detected from swine fecal samples throughout the surveillance period, indicating that these viruses were circulating in this region. NoV strains detected in this study belonged to three genotypes that are known as typical swine NoVs. Although human NoVs were occasionally detected, it was unclear whether they replicated in pigs. As for SaV, genogroup VII (GVII) and other divergent genogroups were identified in addition to the dominant genogroup, GIII, which is the prototypic porcine SaV. In addition, 3 strains genetically related to human SaV were detected. Two of these 3 strains were closely related to human SaV GV. Our study showed that genetic diversification of porcine SaV is currently progressing in the swine population.

Zymosan enhances the mucosal adjuvant activity of poly(I:C) in a nasal influenza vaccine.

The synthetic double-stranded RNA polyriboinocinic polyribocytidylic acid [poly(I:C)] is a potent mucosal adjuvant in mice immunized intranasally with an inactivated influenza vaccine. In an attempt, to increase the effectiveness of a nasal poly(I:C)-combined vaccine, the effect of zymosan, a cell wall extract from Saccharomyces cervisiae was investigated, on the adjuvant activity of poly(I:C) in BALB/c mice. The addition of zymosan (10 microg) as an adjuvant in mice which were immunized intranasally with a poly(I:C) (1-5 microg)-combined vaccine (1 microg) enhanced the ability of the mice to mount an effective immune response to a lethal dose of influenza virus, and resulted in a synergistic increase in secretory IgA and serum IgG antibody levels. To define the mechanism by which zymosan enhanced the adjuvant activity of poly(I:C), bone marrow-derived dendritic cells (BM-DCs) were cultured in the presence of poly(I:C) and/or zymosan. There was a synergistic increase in cytokine production (TNF-alpha, IL-6, IL-10, and IFN-beta) in BM-DCs, together with an increase in the expression of co-stimulatory molecules (CD86 and CD40) in response to co-treatment with poly(I:C) and zymosan. This synergistic effect on cytokine production was mimicked by co-treatment with poly(I:C) and a Toll-like receptor 2 (TLR2) ligand, which represented one of the components of zymosan. The results of the current study suggest that one of the mechanisms by which zymosan enhances the adjuvant activity of poly(I:C) is through increased cytokine production by DCs involving the synergistic activation of poly(I:C)-induced TLR3- and zymosan-induced TLR2-mediated signaling pathways. J. Med. Virol. 82:476-484, 2010. (c) 2010 Wiley-Liss, Inc.

Induction of cross-protective immunity against influenza A virus H5N1 by an intranasal vaccine with extracts of mushroom mycelia.

The identification of a safe and effective adjuvant that is able to enhance mucosal immune responses is necessary for the development of an efficient inactivated intranasal influenza vaccine. The present study demonstrated the effectiveness of extracts of mycelia derived from edible mushrooms as adjuvants for intranasal influenza vaccine. The adjuvant effect of extracts of mycelia was examined by intranasal co-administration of the extracts and inactivated A/PR8 (H1N1) influenza virus hemagglutinin (HA) vaccine in BALB/c mice. The inactivated vaccine in combination with mycelial extracts induced a high anti-A/PR8 HA-specific IgA and IgG response in nasal washings and serum, respectively. Virus-specific cytotoxic T-lymphocyte responses were also induced by administration of the vaccine with extract of mycelia, resulting in protection against lethal lung infection with influenza virus A/PR8. In addition, intranasal administration of NIBRG14 vaccine derived from the influenza A/Vietnam/1194/2004 (H5N1) virus strain administered in conjunction with mycelial extracts from Phellinus linteus conferred cross-protection against heterologous influenza A/Indonesia/6/2005 virus challenge in the nasal infection model. In addition, mycelial extracts induced proinflammatory cytokines and CD40 expression in bone marrow-derived dendritic cells. These results suggest that mycelial extract-adjuvanted vaccines can confer cross-protection against variant H5N1 influenza viruses. The use of extracts of mycelia derived from edible mushrooms is proposed as a new safe and effective mucosal adjuvant for use for nasal vaccination against influenza virus infection.