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Funding Acknowledgements Type of funding sources: None. Background Right ventricular fractional area change (RVFAC) as right ventricular function is recently referred as an independent predictor of sudden cardiac death (SCD). Light ventricular function is related with SCD and adopted as a criteria of ICD implantation for primary prophylaxis. The purpose of this study was to evaluate the association of RVFAC and appropriate ICD therapy. Methods Consecutive patients who underwent initial ICD implantation for any diseases except for hypertrophic cardiomyopathy and Brugada syndrome and long QT syndrome were retrospectively enrolled from 2012 to 2018. Transthoracic echocardiographic parameters before ICD implantation were evaluated to investigate the association with appropriate ICD therapy. We analyzed RV function of patients undergoing echocardiography one year after implantation. RVFAC was measured by one physician and one echocardiologist. Results In total, 172 patients (60.3±13.6 years, 131 males) including 63 ischemic cardiomyopathy were enrolled. Ninety patients received an ICD as a secondary prophylaxis. Mean LVEF and RVFAC were 38.3±14.3% and 35.8±8.82%, respectively. There was no correlation between RVFAC and LVEF (correlation coefficient =0.274). Regarding appropriate ICD therapy events, the best cut-off value of RVFAC was 34.8%. The odds ratio of low RVFAC was 2.731 (95%CI: 1.456-5.121, P Conclusion RVFAC and RV function improvement may be important to stratify the prognosis of ICD patients.

Increasing food loss and waste (FLW) is a global problem, and efforts are being made to use waste food as potential livestock feed material. The amount of self-supplied feed is lower in Japan than in other countries, and the government recommends FLW use for animal feed. Sake (Japanese rice wine) is a traditional alcoholic beverage. During the sake manufacturing process, large amounts of squeezed solids or "lees" (sake lees) are generated. Sake lees are nutritious and functional, but are prone to spoilage. In this study, we investigated whether sake lees should be mixed with animal feed immediately or after drying. To assess the usefulness of sake lees as a poultry feed ingredient and determine the effect of sake lees on intestinal immunity, we performed a feeding trial with three treatments: a raw sake lees (RSL) diet, dried sake lees (DSL) diet, and control diet. Three-week-old broilers were fed these diets (

Putatively, colostral proteins are partly absorbed and transferred to blood circulation in newborn piglets, which suggests that colostrum ingestion alters the protein composition of their blood. Here, we conducted a pilot study to estimate the changes in the protein composition of piglet blood. Plasma collected from piglets pre- and post-ingestion of colostrum (PreC and PostC) was analyzed by shotgun proteomics. Proteins in colostrum were also analyzed. We identified 393 and 427 proteins in PreC and PostC plasma, respectively, and 596 colostral proteins. Whereas 202 unique proteins were identified in PostC, PreC and PostC commonly shared 225 proteins. By contrast, when compared with PreC, 54 proteins in PostC had their emPAI values increased2-fold. Notably, using plasma samples collected from a separate experiment, the concentrations of growth differentiation factor 8 and haptoglobin were higher in PostC than in PreC, which was validated by ELISA. Approximately 60% of the uniquely identified or highly concentrated proteins in PostC were also found in colostrum, which were likely, at least partly, transferred from colostrum. The present study demonstrated that the protein composition of plasma of newborn piglets drastically changed post-colostrum ingestion, partly due to transfer of colostral proteins.

Background For decades, ICD is a well-established therapy for improving prognosis of structural heart disease with severe cardiac dysfunction, and ICD for primary prophylaxis against sudden cardiac death were routinely provided. However, long-term prognosis and clinical course are different in each individual patient with an ICD, and it is moreover unclear what kind of factors might have influences on their clinical outcomes. Purpose The aim of this study is to clarify long-term prognosis and predictors of future major adverse cardiac events (MACEs) in HFrEF patients with an ICD as primary prophylaxis in Japanese population. Methods We retrospectively analyzed our ICD database. Patients underwent primary prophylactic ICD implantation from 2006 to 2020 at our institute and met the criteria of ICD recommendation of the latest Japanese guideline. Its requirements are receiving optimal medication therapy, symptomatic heart failure (New York Heart Association classification II or greater), and severe cardiac dysfunction (left ventricular ejection fraction (LVEF) is 35% or less). Additionally, prior NSVT is considered Class I ICD recommendation. In the case of ischemic cardiomyopathy (ICM), ICD implantation was done at least 40 days after myocardial infarction and at least 90 days after revascularization. MACEs were defined as composite outcome of cardiovascular death, heart failure hospitalization, and appropriate ICD therapies. Results A total of 148 consecutive patients were enrolled (male, 120 (81%); age, 62.1±11.8 years; LVEF, 23.0±5.86%; left ventricular end-diastolic diameter (LVDd), 67.6±9.26mm; paroxysmal or persistent atrial fibrillation (AF), 38 (26%); NSVT, 113 (76%); use of class III antiarrhythmic drugs, 48 (32%); ICM, 49 (33%); cardiac resynchronization therapy (CRT), 63 (43%)). One hundred twenty patients (81%) were programmed with a shock-only zone over 200 beats per minute. The median follow-up duration was 58.5 months. Among those 148 patients, MACEs were occurred to 60 patients (41%). As a result of dividing all patients into two groups by the occurrence of MACE, LVEF and LVDd were worse in MACE(+) group, whereas, MACE(−) had greater number of co morbidities. The results of cox-regression analysis showed LVDd (HR: 1.07, 95% CI: 1.03–1.12, p Conclusions The incidence of MACEs in patients with an ICD and severe HFrEF was substantially high in this Japanese population. Etiology of ICM, left ventricle size, and AF were the potential risk factors for future MACEs. Funding Acknowledgement Type of funding sources: None.

Background Patients with hypertrophic cardiomyopathy (HCM) are at high risk of lethal arrhythmias, and implantable cardioverter defibrillators (ICD) are widely used for prevention of sudden cardiac death (SCD). Apical HCM is a phenotype variant of HCM, with hypertrophy predominantly affecting apex, that was initially described 30 years ago. Apical HCM patients may have different clinical prognosis compared with other subsets of HCM. In previous studies, apical HCM patients seem to have a more benign prognosis than other types of HCM. However, little is known about the long-term outcomes of apical HCM patients and there are many unclear points. Moreover, there are few reports about the clinical prognosis in apical HCM patients with an ICD. Objective The aim of this study is to identify the difference between the prognosis of apical and the other types of HCM patients with an ICD. Methods We retrospectively analyzed the database of our ICD clinic. All subjects underwent ICD implantation between October 2006 and September 2018. We classified HCM patients into LV outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), apical HCM and other non-obstructive types. We divided all the patients into apical and other types of HCM, and examined their background, incidence of appropriate ICD therapies, hospitalization for heart failure, electrical storm and death. Results A total of consecutive 64 Japanese HCM patients with an ICD (follow-up period, 86±24 months; age, 65±14 years; male sex, 83%; left ventricular ejection fraction, 56±14%; LV max wall-thickness, 19±7mm; LV apical aneurysm, 9.4%; 5-year risk of SCD, 4.4±2.1) were enrolled in this study. We classified them into 14 apical HCM and 50 other types of HCM patients. The clinical characteristics and major clinical events of these patients are shown in the Table 1. During the follow-up periods, there were no significant differences in the incidence of electrical storm, hospitalization for heart failure and death between the 2 groups (p=0.11; p=0.60; p=0.39). Appropriate ICD therapies occurred in 6 of 14 (43%) patients with apical HCM and 5 of 50 (10%) patients with other types of HCM (p=0.010). The risk factors of patients with apical HCM patients are shown in Table 2. Conclusions Appropriate ICD therapy was more prevalent in patients with apical HCM, compared to patients with other types of HCM. Aggressive intervention such as catheter ablation for ventricular tachycardia and ventricular fibrillation may be considered in patients with apical HCM and higher score of 5-year risk of SCD. Further studies are needed to clarify the manifestations and long-term outcome of apical HCM patients. Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. Background Right ventricular fractional area change (RVFAC) as right ventricular function is recently referred as an independent predictor of sudden cardiac death (SCD). The purpose of this study was to evaluate the association of RVFAC and appropriate ICD therapy in order to determine the cut-off value of RVFAC. Methods Consecutive patients who underwent initial ICD implantation for any diseases except for non-dilated phase hypertrophic cardiomyopathy and channelopathy were retrospectively enrolled from 2012 to 2018. Primary endpoint was an initial appropriate ICD therapy. Transthoracic echocardiographic parameters before ICD implantation were evaluated by one physician and one echocardiologist to be validated. Right ventricular dimensions and function were also measured to be analyzed. Results In total, 172 patients (60.3±13.6 years, 131 males) including 63 ischemic cardiomyopathy were enrolled. Ninety patients received an ICD as a secondary prophylaxis. Mean LVEF and RVFAC were 38.3±14.3% and 35.8±8.82%, respectively. There was little correlation between RVFAC and LVEF (correlation coefficient =0.274). Regarding appropriate ICD therapy events, the best cut-off value of RVFAC was 34.8%. The odds ratio of low RVFAC was 2.731 (95%CI: 1.456-5.121, P=0.00174). Secondary prophylactic cohort with low RVFAC showed highest incidence of appropriate ICD therapy as shown in the figure. In multivariate analysis, only low RVFAC is an independent predictor of appropriate ICD therapy (HR: 3.53, 95%CI:1.78- 6.99, P=0.0003). Conclusion Low RVFAC seemed independently associated with increased appropriate ICD therapy.

Funding Acknowledgements Type of funding sources: None. Background Non-sustained ventricular tachycardia (NSVT) is frequent phenomenon in severe heart failure with reduced ejection fraction (HFrEF) patients, and causes any negative impacts on such patients. In the Japanese Circulation Society (JCS) and Japanese Heart Rhythm Society (JHRS) guidelines, NSVT is regarded as a major component of indication for implantable cardioverter defibrillator (ICD) implantation. However, the long-term prognostic significance of NSVT in severe HFrEF is incompletely resolved. Purpose The aim of this study is to investigate the relation between prior NSVT episodes and major adverse cardiac events (MACEs) in HFrEF patients with an ICD as primary prophylaxis. Methods We retrospectively analyzed our ICD database. Patients underwent primary prophylactic ICD implantation from 2007 to 2018 following ICD recommendation of JCS and JHRS guidelines. Patients met the criteria of receiving optimal medication therapy, symptomatic heart failure (New York Heart Association classification II or greater), and severe cardiac dysfunction (left ventricular ejection fraction (LVEF) is 35% or less). In the case of ischemic cardiomyopathy (ICM), implantation of ICD was done at least 40 days after myocardial infarction and at least 90 days after revascularization. Incidence of NSVT episodes were identified through daily electrocardiogram (ECG), Holter ECG or monitor ECG in the hospital. MACEs were defined as composite outcome of cardiovascular death, heart failure hospitalization, and appropriate ICD therapies. Results A total of 148 consecutive patients were enrolled (male, 120 (81%); age, 62.1±11.8 years; LVEF, 23.0±5.86%; left ventricular end-diastolic diameter (LVDd), 67.6±9.26mm; paroxysmal or persistent atrial fibrillation (AF), 38 (26%); NSVT, 113 (76%); use of class III antiarrhythmic drugs, 48 (32%); ICM, 49 (33%); cardiac resynchronization therapy (CRT), 63 (43%)). The median follow-up duration was 58.5 months. As a result of comparison of the Kaplan-Meier curve between NSVT group (n=113) and non-NSVT group (n=35), cardiovascular death, heart failure hospitalization, and appropriate ICD therapy were not statistically different (Figures). Of those, MACEs were occurred to 60 patients (41%). The results of cox-regression analysis showed LVDd (HR: 1.07, 95% CI: 1.03-1.12, p Conclusions In this Japanese population, the long-term prognosis of severe HFrEF patients is considered to be comparable regardless of prior NSVT episodes. However, the incidence of MACEs in patients with severe HFrEF after ICD implantation was substantially high. ICM, left ventricle size, and atrial fibrillation were the potential risk factors for MACEs as the previous reports showed.

We previously reported on the development of left ventricular (LV) structural and functional changes in an aged, female rat model where the effects of ovariectomy and excess weight (stimulated by fructose in water) were also explored. Ovariectomy and/or excess weight led to a prolongation of active relaxation, loss of cardiac output, and LV fibrosis in the setting of preserved ejection fraction. In this follow-up study, we wished to characterize the possible role of LV inflammation, oxidative stress (OS), and cell death in inducing such changes. Four experimental groups were studied: young (3 months old), aged (18 months old), aged + ovariectomy (OVX), and aged + ovariectomy + 10% fructose (OVF). Using conventional histology and immunohistochemistry of myocardium as well as biochemical assays of plasma samples, we document the presence of inflammatory cell aggregates in LV myocardium which are associated to high levels of plasma inflammatory cytokines (IL-1β, TNF-α, IFN-γ, TGF-β1) and OS (carbonyl proteins) in aged, OVX, and OVF vs. young animals. In the inflammatory areas, normal cardiac tissue was substituted by replacement and interstitial fibrosis and M1 macrophages, (as per by CD68 immunostaining) as we all as by co-localization with TGF-β1. We also document increases in plasma troponin I levels, loss of capillary density, cardiomyocyte hypertrophy, and death. Select changes were further aggravated by ovariectomy and/or excess weight. In conclusion, aging in the female rat heart, when compounded with estrogen depletion and excess weight promotes the development of greater levels inflammation, OS, fibrosis, capillary rarefaction, cardiomyocyte hypertrophy, and injury/death. These factors likely play an important role in the development of LV remodeling that leads to the development of a “pre-HFpEF” phenotype. Impact statement The incidence of HFpEF continues to increase and ∼2/3 of the patient population are post-menopausal women. Unfortunately, most studies focus on the use of male animal models of remodeling. In this study, however, using female rats to set a model of pre-HFpEF, we provide insights to possible mechanisms that contribute to HFpEF development in humans that will lead us to a better understanding of the underlying pathophysiology of HFpEF.

Background Atrial fibrillation (AF) is the most common arrhythmia. AF-related stroke tends to be more severe, and the mortality rate is higher compared with stroke without AF. Recent cardiac implantable electronic devices (CIEDs) have led to an improvement in the early detection of AF episodes. Previous studies showed that AF episodes detected by CIEDs are associated with ischemic stroke. However, little is known about the relationship between new-onset AF and ischemic stroke events in Japanese patients with CIEDs who have no prior AF and take no anticoagulant therapy. ESC guidelines for the management of AF recommend the use of CHA2DS2-VASc score as class I to predict the risk of ischemic stroke in patients with AF. However, the validity of the CHA2DS2-VASc and HAS-BLED scores to predict ischemic stroke and major bleeding events in patients without AF remains unclear. Objective The purpose of this study was to identify the incidence of ischemic stroke and major bleeding events in CIEDs patients without AF and assess the validity of CHA2DS2-VASc and HAS-BLED scores in this population. Methods We retrospectively analyzed the database of our CIEDs clinic. Every 6 months, CIEDs were checked using remote monitoring system. We examined the characteristics and incidence of ischemic stroke and bleeding events. In addition, we investigated the relationship between CHA2DS2-VASc and HAS-BLED scores and the incidence of these events. Results We enrolled 620 consecutive patients who were followed up at our CIED clinic. We excluded patients who had a history of AF or had received anticoagulant therapies, 348 patients (follow-up period, 65±58 months; age, 70±16 years; male sex; 64%; defibrillator, 55%) were included in this study. The mean CHA2DS2-VASc and HAS-BLED scores were 2.8±1.5 points and 1.7±1.6 points, respectively. During the follow-up, 23 (6.6%) and 12 (3.4%) of 348 patients had ischemic stroke and major bleeding events, respectively. The incidence of ischemic stroke and major bleeding events stratified by the CHA2DS2-VASc and HAS-BLED scores were shown in Figure 1. Conclusion The risk stratification for ischemic stroke and major bleeding using the CHA2DS2-VASc and HAS-BLED scores is valid in patients without AF. Funding Acknowledgement Type of funding sources: None. Figure 1

Background Prophylactic use of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death (SCD) is widely spread all over the world in patients with hypertrophic cardiomyopathy (HCM). Apical HCM is a phenotype variant of HCM, with hypertrophy predominantly affecting apex, that was initially described 30 years ago. Apical HCM patients may have different clinical prognosis compared with other subsets of HCM. In previous studies, apical HCM patients seem to have a more benign prognosis than other types of HCM. However, little is known about the long-term outcomes of apical HCM and there are many unclear points. Moreover, there are few reports about the clinical prognosis in apical HCM patients with an ICD. Objective The aim of this study is to identify the difference between the prognosis of apical and the other HCM patients with an ICD. Methods We retrospectively analyzed the database of our ICD clinic. All subjects had been implanted with an ICD from October 2006 to August 2017. We classified HCM patients into LV outflow tract obstruction (LVOTO) and midventricular obstruction (MVO), apical HCM and other non-obstructive types. We divided all the patients into apical and other types of HCM, and examined their background, incidence of appropriate ICD therapies, hospitalization for heart failure, electrical storm and death. Results A total of consecutive 62 Japanese HCM patients with an ICD (follow-up period, 86±25 months; age, 67±14 years; male sex, 85%; left ventricular ejection fraction, 57±12%; LV max wall-thickness, 19±5mm; LV apical aneurysm, 9.7%; HCM Risk-SCD, 4.4±3.0) were enrolled in this study. We classified them into 14 apical HCM and 48 other types of HCM patients. The clinical characteristics and major events of these patients are shown in the Figure. During the follow-up periods, there were no significant differences in the incidence of hospitalization for heart failure, electrical storm and death between the 2 groups (p=0.40; p=0.22; p=0.23). Appropriate therapies occurred in 5 of 14 (36%) patients with apical HCM and 4 of 48 (8.3%) patients with other types of HCM (p=0.022). Conclusions Appropriate ICD therapy was more prevalent in patients with apical HCM, compared to patients with other types of HCM. However, the incidences of hospitalization for heart failure, electrical storm and death were not significantly different between two groups. Funding Acknowledgement Type of funding sources: None.

Summary: Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models. Cmpd43 stimulated FPR1/2-mediated signaling, enhanced proresolution cellular function, and modulated cytokines. Cmpd43 increased LV function and reduced chamber remodeling while increasing proresolution macrophage markers. The findings demonstrate that FPR agonism improves cardiac structure and function post-MI. Key Words: agonist, Compound 43, formyl peptide receptor, heart failure, myocardial infarction

Background Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

KEY POINTS Heart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight. No female animal models of early stage remodelling (pre-HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function. In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function. The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis. Excess weight did not markedly aggravate such findings. This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents. ABSTRACT Two-thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18-month-old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n = 8-16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22 months of age, animals were anaesthetized and catheter-based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure-volume loop analysis showed significant (P

Funding Acknowledgements Type of funding sources: None. Aim The purpose of this study was to evaluate the association of RV function and appropriate therapy of ICD.Methods: This study was a single-center retrospective cohort study. Consecutive patients who underwent ICD implantation for any diseases were enrolled except for non-dilated phase hypertrophic cardiomyopathy and channelopathy. Transthoracic echocardiographic parameters including left ventricular ejection fraction (LVEF), RV basal diameter, RV end-diastolic area, and right ventricular fractional area change (RVFAC) were evaluated. RV systolic dysfunction was defined as RVFAC Results In total, 151 patients (60.9 ± 13.6 years, 117 males) consisting of 67 old myocardial infarction, 34 dilated cardiomyopathy, 19 cardiac sarcoidosis, and 31 others were enrolled. Eighty patients received an ICD as a secondary prophylaxis. Mean LVEF and RVFAC were 37.8 ± 13.9% and 33.2 ± 10.8%, respectively. RV systolic dysfunction was present in 86 (57.0%) patients, which was significantly associated with ICD therapy (odds ratio 2.313; 95% confidence interval 1.067-5.014; P = 0.034) according to a univariate analysis. There was no correlation between RVFAC and LVEF (correlation coefficient =0.064). Regarding the subjects LVEF > 35%, RV systolic dysfunction was an independent predictor of ICD therapy in a multivariate analysis. Conclusion RV systolic dysfunction was independently associated with increased ICD therapy despite of relatively preserved LVEF.

Visual Abstract, Highlights • MI leads to ischemic damage of myocardium and activation of inflammatory programs as part of the wound healing response. • Selective activation of FPR2 on macrophages potentiates key cellular activities that enable wound healing. • MI was induced in rodents to study the effects of treatment with BMS-986235, a selective small molecule agonist of FPR2. • BMS-986235 stimulated proresolution macrophage activities, induced neutrophil apoptosis and clearance, improved LV and infarct structure, and preserved cardiac function post MI. • The findings suggest that targeted activation of FPR2 can improve post-MI outcome and may diminish the development of HF., Summary Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.

Objective Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. Design We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. Results We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. Conclusion HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

Background Endovascular therapy (EVT) using self-expandable bare nitinol stent (BNS) has been commonly accepted in patients with symptomatic femoropopliteal (FP) occlusive disease. However, poor clinical outcomes in hemodialysis (HD) patients are major problems. We investigated the impact of HD on clinical outcome after EVT in patients with FP disease. Methods A total of 427 consecutive HD patients undergoing successful EVT with BNS for FP disease were enrolled with 157 non-HD patients as a control group. They were followed-up for 5 years. We collected data on target lesion revascularization (TLR) rate, and limb salvage rate as well as survival rate. Propensity-score matching analysis was performed to investigate the true impact of HD on the outcome. Results Critical limb ischemia was observed in 44.0% of overall population (43.0% in HD group vs. 46.8% in non-HD group, p=0.42). Rates of diabetes (67.1% vs. 58.1%, p=0.045) and coronary artery disease (73.5% vs. 58.3%, p=0.0008) were higher, while age (70±10 years old vs. 76±10 years old, p Conclusion The freedom rate from TLR at 5 years after BNS implantation for FP disease were significantly lower in HD group than in non-HD group, though the limb salvage rate was similar between the groups. The survival rate was consistently lower in HD group compared to non-HD group. HD status had a great impact on TLR and mortality after EVT with BNS in patients with FP disease. Funding Acknowledgement Type of funding source: None

The high resolution statistical data such as the number of households in small areas are indispensable for urban planning, disaster prevention and many kinds of business activities. However, it is difficult to obtain the number of households in small areas because census data are usually aggregated in municipal districts. Techniques for automatically analyzing statistical data, e.g., land cover, population density, and the number of households obtained from satellite/aerial images have been continuously studied. In recent years, many methods using deep learning have been proposed in the related literature. In estimating the number of households, the use of buildings, the number of floors and that of rooms are also important information, but it is difficult to obtain such information from only image analysis using deep learning. This study proposes a method for estimating the number of households in 100 meter grid cells from satellite images using deep learning, and adjusting it using ancillary data obtained from a few statistical datasets. The application of this method to Djakarta shows that the difference between the estimated values and the corresponding values of census is less than 10%.

Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.

We develop a coherent beam splitter for single electrons driven through two tunnel-coupled quantum wires by surface acoustic waves (SAWs). The output current through each wire oscillates with gate voltages to tune the tunnel-coupling and potential difference between the wires. This oscillation is assigned to coherent electron tunneling motion that can be used to encode a flying qubit and is well reproduced by numerical calculations of time evolution of the SAW-driven single electrons. The oscillation visibility is currently limited to about 3%, but robust against decoherence, indicating that the SAW-electron can serve as a novel platform for a solid-state flying qubit., Comment: 5+3 pages, 4+2 figures

Background Global longitudinal strain (GLS) is an echocardiographic marker to detect subclinical left ventricular systolic dysfunction prior to the appearance of reduced left ventricular ejection fraction (LVEF). Reduced GLS identified in patients with maintenance hemodialysis (HD) has been reported to be a predictor of their higher mortality and cardiovascular events. On the other hand, pharmacological stress 13N-ammonia positron emission tomography (13N-NH3-PET) has been an established and reliable imaging modality to evaluate myocardial perfusion expressed as coronary flow reserve (CFR) or maximal stress myocardial blood flow (MBF). CFR and MBF are powerful parameters to detect coronary artery disease and to predict cardiovascular events and mortality. However, association between GLS and those myocardial perfusion parameters are not fully understood. Purpose：The aim of this study was to evaluate the relationship between GLS and the myocardial perfusion parameters of 13N-NH3-PET in HD patients with preserved LVEF. Methods We studied 24 HD patients (mean age 67 years, 67% male) who underwent ATP stress 13N-NH3-PET as well as transthoracic echocardiography including 2-dimensional speckle tracking imaging for suspected ischemic heart disease. Exclusion criteria were as follows: LVEF Results Mean GLS in all patients was -16.2 ± 3.6%. The patients were divided into 2 groups based on GLS: patients with reduced GLS ( Conclusion Reduced GLS was significantly associated MPA. MPA may be one of the major contributors to the reduction in GLS in HD patients with preserved LVEF.

Summary The novel WBN/Kob-Leprfa (fa/fa) congenic rat strain is considered a useful rat model of type 2 diabetes mellitus (T2DM). Accumulating findings suggest that low-grade inflammation is a causative factor in T2DM and that circulating levels of inflammatory cytokines are associated with insulin resistance. However, inflammatory cytokine profiles and their correlations with T2DM development/progression in fa/fa rats have not been studied. In this study, we found that the fa/fa rats had considerably high plasma levels of interleukin (IL)-1α. Abundant cecal IL-1α mRNA expression and cecal inflammation with infiltrating IL-1α-producing macrophages was observed in fa/fa rats. Bone marrow derived macrophages from fa/fa rats expressed high levels of IL-1α upon lipopolysaccharide stimulation. Furthermore, Syphacia muris infection, which delays the onset of T2DM, reduced both plasma and cecal IL-1α levels in fa/fa rats. These results suggest that macrophage infiltration and IL-1α secretion comprise an important part of T2DM development and that S. muris infection inhibits pro-inflammatory cytokine expression in fa/fa rats.

In order to clarify the association between hyperglycemia during the early period after allogeneic stem cell transplantation (allo-SCT) and adverse outcomes, we retrospectively analyzed 563 consecutive patients who underwent allo-SCT at our institute between 2008 and 2015. Patients were categorized into three groups according to mean fasting blood glucose levels on days 0-7 (normoglycemia group

Background Atrial fibrillation (AF) is the most common type of arrhythmia. AF-related stroke tends to be more severe, and the mortality rate is higher compared with stroke without AF. The definition of AF in patients with cardiac implantable electronic devices (CIEDs) is not clear and the appropriate treatment guideline for patients with AF episode has not established yet. Recent CIEDs have led to an improvement in the early detection of AF episodes, especially in patients who are asymptomatic. Previous studies showed that atrial high-rate episodes (AHREs) detected by CIEDs are associated with embolic stroke events. However, little is known about the incidence of AF and stroke events in Japanese patients with CIEDs who have no prior AF and take no anticoagulant. Objective The purpose of this study was to identify the incidence of embolic stroke events in patients with and without AF events detected by CIEDs and examine the risk factors of embolic stroke events. Methods We retrospectively analyzed the database of our hospital. Every 6 months, AF events were checked by CIEDs. AF30 was defined as AF episodes lasting for ≥30 seconds detected by CIEDs. We examined the characteristics and incidence of embolic stroke events and investigated the relationship between AF30 and the incidence of embolic stroke events. Results We enrolled 348 consecutive patients who had no prior AF and took no anticoagulant in this study (follow-up period, 65±58 months; age, 70±16 years; male sex; 64%; defibrillator, 55%). The mean CHADS2 score and CHA2DS2-VASc score were 1.8±1.1 points and 2.8±1.5 points, respectively. The mean HAS-BLED score was 1.7±1.2 points. During the follow-up, 23 of 348 patients (6.6%) had embolic stroke events. Thirteen patients (4.1%/year) and 10 patients (0.63%/year) had embolic stroke events with and without AF30, respectively. The comparison of characteristics among patients with and without embolic stroke events was shown in Table. In multivariate logistic regression analysis, independent predictors for embolic stroke events were new-onset episode of AF30 (odd ratio [OR] 5.3, 95% confidence interval [CI] 2.2–13, P=0.0003) and an enlarged left atrium ≥40mm (OR 3.1, 95% CI 1.2–7.9, P=0.016). Conclusions Embolic stroke events were common in Japanese patients with CIEDs. AF30 and enlarged left atrium were risk factors of embolic stroke events in this population. Therefore, when physicians detect new-onset AF in patients with CIEDs, they should consider a comprehensive assessment of the risk and benefit of prescribing an anticoagulant.

Background/Introduction Dysregulated inflammation following myocardial infarction (MI) can lead to maladaptive infarct healing, myocardial damage and heart failure. Formyl peptide receptor 2 (FPR2) plays an important role in the ligand-dependent regulation of inflammation resolution. Stimulation of resolution via FPR2 activation is hypothesized to preserve left ventricular (LV) structure-function relationships thereby preventing pathological cardiac remodeling, and heart failure. Purpose We evaluated a selective 4-phenylpyrrolidinone FPR2 agonist in rodent MI models by assessing the impact on LV and infarct scar remodeling and cardiac function. Methods The FPR2 agonist was evaluated in phagocytosis, chemotaxis and cytokine response assays. In vivo, following permanent occlusion of the left anterior descending (LAD) artery, C57BL/6 mice or Sprague-Dawley rats were treated with the FPR2 agonist or vehicle; PO gavage, QD. Treatment began 24 hours after occlusion (0.3 and 3 mg/kg) and continued for three days to assess early inflammation or four weeks to evaluate LV and infarct structure and function. Rats subjected to permanent MI were treated 48 hours after occlusion (0.01, 0.1. 1, 10 mg/kg) for six weeks to assess structure-function relationships. A parallel study in rats evaluated compound treatment (0.01, 0.1. 1, 10 mg/kg) following 60 minutes occlusion and reperfusion of the LAD artery. Results The FPR2 agonist enhanced cellular phagocytosis and chemotaxis, and stimulated IL-10 and MCP-1 gene expression in isolated human whole blood. In mice, FPR2 agonist treatment improved survival post MI, reduced LV chamber area and infarct size (26% and 55% vs. vehicle, respectively, P Conclusion(s) Improvements in cardiac structure-function versus vehicle treated animals support the concept that agonism of FPR2 improves post-MI wound healing, limiting adverse post-MI LV remodeling, thereby preserving cardiac function. These preclinical results suggest targeting FPR2 may present an innovative approach towards development of effective drug therapies to prevent heart failure post-MI. Acknowledgement/Funding Bristol-Myers Squibb Company

Background Hypoalbuminemia, a manifestation of protein-energy wasting or malnutrition, is commonly observed in patients with end-stage renal disease (ESRD), and is associated with chronic inflammation and increasing cardiovascular (CV) risk. Recently, C-reactive protein (CRP)/albumin ratio at discharge is reportedly a well-predictor of mortality in severe sepsis or cancer patients. We investigated prognostic value of the CRP/albumin ratio at just starting haemodialysis (HD) therapy for CV morbidity and mortality in patients with ESRD. Methods A total of 1,548 ESRD patients were enrolled and were divided into quartiles according to CRP/albumin levels at initiation of HD; quartile 1 (Q1): 1.84. They were followed up for 10-year after starting HD therapy. Primary endpoint was CV events defined as hospitalization due to CV events such as cardiac disease, stroke and peripheral artery disease and CV death. We also evaluated the incremental value with C-index when CRP alone, albumin alone and the CRP/albumin ratio were added into a model with established risk factors. Results During follow-up period (median: 59 months), 512 cases experienced CV events (33.1%) including 165 cases of CV deaths (10.7%). Kaplan-Meier analysis shows that CV event-free survival rates for 10 years were 63.5%, 53.8%, 47.5% and 31.9% in Q1, Q2, Q3 and Q4, and that CV survival rates were 90.4%, 83.9%, 77.2% and 64.6% in Q1, Q2, Q3 and Q4, respectively (p Conclusion The CRP/albumin ratio, which easily available from daily practice, could strongly stratify the risk of future CV morbidity and mortality in ESRD patients who need HD therapy.

Background Carotid atherosclerosis such as increased intima-media thickness (IMT) is associated with poor cardiovascular outcome. On the other hand, protein-energy wasting (PEW) or malnutrition, currently considered to be due to inflammatory process rather than poor nutritional intake, is highly prevalent in in chronic kidney disease (CKD) patients, particularly those on haemodialysis (HD). We investigated the association of carotid atherosclerosis, PEW and inflammation, and their joint role with prediction of mortality in chronic HD patients. Methods Carotid ultra-sound was performed in a total of 774 CKD patients stably undergoing HD therapy. Carotid atherosclerosis is defined as IMT>0.8mm as median value with hyperechoic plaque. Geriatric nutritional risk index (GNRI) which calculated from serum albumin levels, body weight and height as a surrogate marker of the PEW, and C-reactive protein (CRP) were measured at the same point. Patients were followed-up for 7 years. Results Declined GNRI and elevated CRP levels were independently associated with carotid atherosclerosis [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.93–0.98, p=0.0082 and OR 1.30, 95% CI 1.04–1.64, p=0.019, respectively] accompanied with age (OR 1.03, 95% CI 1.01–1.05, p=0.0024) and hypertension (OR 1.78, 95% CI 1.12–2.91, p=0.013). During follow-up period (median of 67 months), 180 patients (23.3%) died. Carotid atherosclerosis [62.7% vs. 79.3% for 7-year survival rate, hazard ratio (HR) 1.57, 95% CI 1.12–2.16, p=0.0078], GNRI1.1 mg/l as a median value (65.8% vs. 88.6%, HR 2.87, 95% CI 2.00–4.22, p Conclusions Presence of carotid atherosclerosis was closely associated with both declined GNRI and elevated CRP levels in CKD patients on HD. Combination of these predictors was also additively associated with an increasing risk of mortality. These results clearly manifested the so-called malnutrition, inflammation and atherosclerosis (MIA) syndrome in this high-risk population.