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Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation. ispartof: BLOOD vol:141 issue:7 pages:713-724 ispartof: location:United States status: published

We aimed to describe the distribution of gestational age at birth (GAB) to inform the estimation of GAB when clinical or obstetric estimates are not available for perinatal epidemiologic research. We estimated GAB (median, mode, mean, standard deviation) and percentage born at each gestational week in groups based on plurality and other variables for live births in CDC’s US birth data.In 2020, 3,617,213 newborns had birth certificates with nonmissing GAB. Among singletons (3,501,693), median and mode GAB were both 39 weeks. Births with lower median GAB were from women with eclampsia (37 weeks) or receiving intensive care (37 weeks); newborns receiving intensive care (37 weeks); infants with birth weight < 2,500 grams (35 weeks), < 1,500 grams (28 weeks), or < 1,000 grams (25 weeks); and newborns not discharged alive (23 weeks). Among twins (112,633), median GAB was 36 weeks (mode, 37 weeks). Additional noteworthy groups were women with 7-8 (median, 35 weeks) or 0-6 prenatal visits (median, 34 weeks) or aged 15-19 years (median, 35 weeks).Some maternal and infant groups had distinct GAB distributions in the US. This information can be useful in estimating GAB when individual-level clinical estimates are not available.

There is a need to identify new biomarkers of radiation exposure for not only systemic total-body irradiation (TBI) but also to characterize partial-body irradiation and organ specific radiation injury. In the current study, we sought to develop novel biodosimetry models of radiation exposure using TBI and organ specific partial-body irradiation to only the brain, lung or gut using a multivariate proteomics approach. Subset panels of significantly altered proteins were selected to build predictive models of radiation exposure in a variety of sample cohort configurations relevant to practical field application of biodosimetry diagnostics during future radiological or nuclear event scenarios. Female C57BL/6 mice, 8-15 weeks old, received a single total-body or partial-body dose of 2 or 8 Gy TBI or 2 or 8 Gy to only the lung or gut, or 2, 8 or 16 Gy to only the brain using a Pantak X-ray source. Plasma was collected by cardiac puncture at days 1, 3 and 7 postirradiation for total-body exposures and only the lung and brain exposures, and at days 3, 7 and 14 postirradiation for gut exposures. Plasma was then screened using the aptamer-based SOMAscan proteomic assay technology, for changes in expression of 1,310 protein analytes. A subset panel of protein biomarkers which demonstrated significant changes (P0.01) in expression after irradiation were used to build predictive models of radiation exposure using different sample cohorts. Model 1 compared controls vs. all pooled irradiated samples, which included TBI and all organ specific partial irradiation. Model 2 compared controls vs. TBI vs. partial irradiation (with all organ specific partial exposure pooled within the partial-irradiated group), and model 3 compared controls vs. each individual organ specific partial-body exposure separately (brain, gut and lung). Detectable values were obtained for all 1,310 proteins included in the SOMAscan assay for all samples. Each model algorithm built using a unique sample cohort was validated with a training set of samples and tested with a separate new sample series. Overall predictive accuracies of 89%, 78% and 55% resulted for models 1-3, respectively, representing novel predictive panels of radiation responsive proteomic biomarkers. Though relatively high overall predictive accuracies were achieved for models 1 and 2, all three models showed limited accuracy at differentiating between the controls and partial-irradiated body samples. In our study we were able to identify novel panels of radiation responsive proteins useful for predicting radiation exposure and to create predictive models of partial-body exposure including organ specific radiation exposures. This proof-of-concept study also illustrates the inherent physiological limitations of distinguishing between small-body exposures and the unirradiated using proteomic biomarkers of radiation exposure. As use of biodosimetry diagnostics in future mass casualty settings will be complicated by the heterogeneity of partial-body exposure received in the field, further work remains in adapting these diagnostic tools for practical use.

Samples of the carbonaceous asteroid Ryugu were brought to Earth by the Hayabusa2 spacecraft. We analyzed 17 Ryugu samples measuring 1 to 8 millimeters. Carbon dioxide–bearing water inclusions are present within a pyrrhotite crystal, indicating that Ryugu’s parent asteroid formed in the outer Solar System. The samples contain low abundances of materials that formed at high temperatures, such as chondrules and calcium- and aluminum-rich inclusions. The samples are rich in phyllosilicates and carbonates, which formed through aqueous alteration reactions at low temperature, high pH, and water/rock ratios of

Background Functional mitral regurgitation (FMR) is not uncommon in atrial fibrillation (AF) patients. Left atrial (LA) substrate remodeling and corresponding mitral valve annulus dilation has been reported as the most possible cause of FMR. Percutaneous catheter ablation (CA) is an effective treatment for AF. Although significant FMR could be improved by sinus restoration, patients with mitral regurgitation were more likely to experience recurrent AF post ablation, especially those with significant mitral regurgitation. There is no information available on the efficacy of CA for persistent AF in patients with FMR. Purpose The purpose of this study is to investigate the predictors of FMR improvement by CA and to determine the efficacy of substrate and trigger CA for persistent AF in patients with FMR. Methods We prospectively studied 512 consecutive patients admitted for persistent AF ablation from the EARNEST-PVI (Prospective Multicenter Randomized Study of Effect of Extensive Ablation on Recurrence in Patients with Persistent Atrial Fibrillation Treated with Pulmonary Vein Isolation) trial. On admission, enrolled patients were randomly assigned in a 1:1 ratio to pulmonary vein isolation (PVI) or PVI-plus additional ablation (linear ablation or/and CFAE ablation). Of the 512 patients, we studied 94 patients with preoperative echocardiography showing moderate or greater baseline FMR. FMR grades were classified into 5 grades (0/1/2/3/4). The FMR improvement group (FMRI(+)) was defined as a case in which the FMR was improved by two or more grades compared the preoperative echocardiography and the one year follow-up examination. Results Of the 94 patients, 42 were in the PVI group and 52 were in the PVI-plus additional ablation group. There were 30 cases in the FMRI(+) group and 64 cases in the FMRI(−) group. There were no significant baseline differences in age, sinus rhythm maintenance, plasma B-type natriuretic peptide (BNP) level, left ventricular diastolic dimension, or left atrium dimension between the FMRI(+) and FMRI(−) groups. AF duration was significantly shorter in the FMRI(+) group than FMRI(−) groups (5.8±9.4 months vs 12.4±15.4 months, p Conclusions Catheter ablation is a valid option for the treatment of AF in patients with functional MR and additional substrate and trigger ablation were the only independent predictor of FMR improvement. Funding Acknowledgement Type of funding sources: None.

Background Malnutrition is associated with increased mortality risk in patients with acute decompensated heart failure (ADHF). Cardiohepatic interactions have been a focus of attention among heart failure. It was reported that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index provide prognostic information in ADHF patients. However, there is no information available on the long-term prognostic value of the combination of malnutrition and FIB4 index in patients admitted for ADHF. Methods and results We studied 294 patients admitted for ADHF, who were discharged with survival. Nutritional status was evaluated by Geriatric Nutritional Risk Index (GNRI) calculated as follows: 14.89 × serum albumin (g/dl) + 41.7 × BMI/22, and malnutrition was defined as GNRI 2.67. During a mean follow-up period of 4.3±3.3 yrs, 94 patients had all-cause death. At multivariate Cox regression analysis, GNRI and FIB4 index were significantly associated with the total mortality, independently of prior heart failure hospitalization, systolic blood pressure, and serum creatinine level. Patients with malnutrition and abnormal FIB4 index had a significantly higher risk of the total mortality than those with either and none of them (49% vs 32% vs 20%, p Conclusions The combination of malnutrition and FIB4 index might be useful for stratifying ADHF patients at higher risk for the total mortality. Funding Acknowledgement Type of funding sources: None.

Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced HF. On the other hand, systemic inflammation plays a critical role in the outcomes of heart failure, and malnutrition is also associated with poor outcome in heart failure patients It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index × serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. However, there is no information available on the prognostic value of the combination of MPS ratio and ALI in patients with acute decompensated HF (ADHF). Methods and results We studied 219 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. During a follow up period of 5.1±4.2 yrs, 57 had cardiovascular death (CVD). MPS ratio was significantly greater (0.401±0.107 vs 0.346±0.105, p=0.0009) and ALI was significantly smaller (34.2±18.7 vs 52.0±27.1, p0.350 (AUC 0.652 [0.569–0.735]) and smaller ALI Conclusion The combination of MPS ratio and ALI might be useful for stratifying ADHF patients at higher risk for CVD. Funding Acknowledgement Type of funding sources: None.

Background Systemic inflammation plays a critical role in the outcomes of heart failure. Malnutrition is also associated with poor outcome in heart failure patients. It has been recently reported that advanced lung cancer inflammation index (ALI), which is calculated as body mass index × serum albumin / neutrophil to lymphocyte ratio (NLR), is an independent prognostic marker in several types of cancer. However, there is no information available on the prognostic impact of ALI in patients admitted with acute decompensated heart failure (ADHF), especially in comparison with malnutrition. Methods and results We studied 263 ADHF patients discharged with survival. At the discharge, we measured ALI. Malnutrition was assessed by prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a follow up period of 5.1±4.3 yrs, 67 patients had cardiovascular death (CVD). ALI was significantly smaller in patients with than without CVD (32.5±18.2 vs 52.2±30.2, p53.6: HR 5.80 [2.60–12.94]) (48% vs 21% vs 9%, p Conclusion ALI, a systemic inflammation-nutrition index, is more useful prognostic marker than malnutrition in patients admitted with ADHF. Funding Acknowledgement Type of funding sources: None.

Background Sarcopenia and malnutrition are associated with poor clinical outcome in patients with chronic heart failure. However, there is little information available on the prognostic significance of the combination of sarcopenia and malnutrition in patients with acute decompensated heart failure (ADHF), relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods We prospectively studied 543 consecutive ADHF patients who survived to discharge (HFrEF [LVEF Results During a follow-up period of 2.8±1.4 years, 161 patients had all-cause death. Multivariate Cox analysis showed that both FFMI and GNRI were independently associated with all-cause death in both HFrEF (p=0.0064 and p Conclusions Sarcopenia or malnutrition at discharge was associated with all-cause death even in ADHF patients, irrespective of reduced or preserved LVEF. The combination of sarcopenia and malnutrition could provide prognostic information in ADHF patients with reduced LVEF. Funding Acknowledgement Type of funding sources: None. Figure 1

PurposePublications are an important information source for clinicians, researchers, and patients. Key methodological elements must be reported for maximum transparency. We identified key methodological elements necessary for fully understanding pharmacoepidemiological research in pregnancy and quantified the proportion of studies that report these elements in a sample of publications.MethodsKey methodological elements were identified from guidelines from regulatory agencies, literature, and subject-matter knowledge: source of information to determine pregnancy start; mother- or father-infant linkages (process, success rate); unit of analysis; and whether non-live births and fetuses with various anomalies were included in the study population.We conducted a literature review for recent observational studies on medical product utilization or safety during pregnancy and estimated the prevalence of reporting these elements.ResultsData were extracted from a random sample of 100 publications; 8% were published in epidemiology/pharmacoepidemiology journals; 85% were medical product–safety studies.Of included publications, 43% reported the source for determining pregnancy start; 57% reported whether the study population included multifetal pregnancies; 39%, whether it included more than 1 pregnancy per woman; 27%, whether it included fetuses with chromosomal abnormalities; 60%, fetuses with major congenital malformations; and 93%, non-live births. Of the 20 studies with mother-infant linkage, 35% described the process; 21% reported the linkage success rate. Among studies with more than one pregnancy/offspring per woman, 22% reported methods addressing sibling correlation.ConclusionsIn this sample of pregnancy-related pharmacoepidemiology publications, completeness of reporting can be improved. A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.Key points▪Publications on the utilization or safety of medical products in pregnancy (pregnancy pharmacoepidemiology) are fully understandable when all key methodological elements are presented to the reader.▪We identified 17 methodological elements from guidelines, literature, and subject-matter knowledge that we felt were crucial for understanding publications on pregnancy pharmacoepidemiology.▪In a random sample of 100 publications, completeness of reporting varied across elements, with almost perfect reporting on whether non-live births were included in the study population to a 21% completeness on mother-infant linkage success rate.▪A pregnancy-specific checklist would help to increase transparency in the dissemination of study results.

Background Comorbidities are strongly associated with poor clinical outcome in heart failure patients (pts). The Age-adjusted Charlson comorbidity index (ACCI), which is well-known widely used comorbidity index, recently has been used as a robust prognostic model in heart failure pts. On the other hand, AHEAD risk score has been recently reported as a useful long-term risk stratification score in acute decompensated heart failure (ADHF) pts. Recently, a new group of heart failure pts with mid-range ejection fraction (HFmrEF) has been defined, separated from reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). We sought to compare the prognostic value of ACCI and AHEAD score in ADHF pts, relating to HFrEF, HFmrEF and HFpEF. Methods We prospectively studied 410 consecutive ADHF pts (HFrEF [n=143], HFmrEF [n=99] and HFpEF [n=168]) with survival discharge. ACCI contains 19 issues which was weighted according to their potential influence on mortality. AHEAD risk score is a simple index, which is range 0–5; atrial fibrillation, hemoglobin 70 years, creatinine >130 μmol/L, and diabetes mellitus. The endpoint of this study was all cause death (ACD). Results During a follow-up period of 2.4±1.4 years, 119 pts had ACD (42, 29 and 48 pts in HFrEF, HFmrEF and HFpEF, respectively). At univariate Cox analysis, ACCI and AHEAD risk score were significantly associated with ACD in each subgroup. At multivariate Cox analysis, in HFrEF pts, ACCI, but not AHEAD risk score, showed the significant and independent association with ACD. In HFmrEF, both ACCI and AHEAD risk score was significantly and independently associated with ACD and ROC analysis showed AUC of ACCI was greater than that of AHEAD risk score (0.778 [0.683–0.855] vs 0.637 [0.572–0.764], p=0.07). On the other hand, in HFpEF pts, AHEAD risk score, but not ACCI, showed the significant and independent association ACD. Conclusion ACCI provides more prognostic value in HFrEF pts, and AHEAD risk score has more prognostic value in HFpEF pts. In HFmrEF pts, both ACCI and AHEAD score might have prognostic values, although ACCI tends to be more associated with ACD than AHEAD score. Funding Acknowledgement Type of funding source: None

Background The transtubular potassium concentration gradient (TTKG) has been reported to be a marker of renal aldosterone bioactivity, and has been shown to be a surrogate of arterial underfilling in patients with acute decompensated heart failure (ADHF). Moreover, high TTKG at discharge has been shown to be associated with poor prognosis in ADHF patients. Empagliflozin, one of the sodium glucose cotransporter 2 inhibitors, has been shown to reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2D) and cardiovascular disease. However, little is known about the effect of empagliflozin as add-on therapy on TTKG in T2D patients with ADHF. Purpose We sought to elucidate the effect of empagliflozin as add-on therapy on TTKG in T2D patients with ADHF. Methods We enrolled 58 consecutive T2D patients admitted for ADHF. On admission, enrolled patients were randomly assigned in a 1:1 ratio to either empagliflozin add-on therapy (EMPA(+)) or conventional glucose-lowering therapy (EMPA(−)). All patients in EMPA(+) group received empagliflozin (10 mg/day) throughout the study period. Left ventricular ejection fraction (LVEF) was measured at baseline using echocardiography. Body weight and vital signs, such as blood pressure and heart rate, were measured, and blood and urine samples were collected at baseline and 1, 2, 3 and 7 days after randomization. The TTKG was measured using the first morning urine samples collected on each day. TTKG was calculated according to the following equation: TTKG = (Ku/Ks)×(plasma osmolality/urine osmolality), where Ku is urine potassium concentration and Ks is serum potassium concentration, as previously reported. Results Thirty patients were assigned to the EMPA(+) group, and 28 patients were assigned to the EMPA(−) group. There were no significant baseline differences in LVEF, plasma B-type natriuretic peptide (BNP) level, body mass index, or serum creatinine level between the EMPA(+) and EMPA(−) groups. TTKG did not significantly differ between the two groups at baseline. However, seven days after randomization, plasma BNP level was significantly lower in the EMPA(+) group than in the EMPA(−) group (median 227 [IQR 114–381] pg/mL vs 362 [227–554] pg/mL, p=0.0294). Furthermore, TTKG of the EMPA(+) group was significantly lower at 2, 3 and 7 days after randomization (Figure). Conclusions This study demonstrated that empagliflozin as add-on therapy can lower TTKG in T2D patients with ADHF. Figure 1 Funding Acknowledgement Type of funding source: None

Background Malnutrition is one of the most important comorbidities among heart failure (HF) patients, and serum cholinesterase (CHE) has been reported to be a prognostic factor in HF patients. On the other hand, atrial fibrillation (AF) is frequently observed in patients with HF with preserved ejection fraction (HFpEF). However, there is little information available on the prognostic value of nutritional status in HFpEF patients, with and without AF. We sought to clarify the prognostic value of CHE in HFpEF with and without AF and compare it with that of other nutrition indices such as gastric nutritional risk index (GNRI), controlling nutritional status (CONUT), and the prognostic nutritional index (PNI). Methods and results Patients data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study, which is a prospective multicenter observational registry for acute decompensated heart failure patients with left ventricular ejection fraction ≥50% in Osaka. We analyzed 380 patients (median age: 80 [75–87] years, male: 46%) after exclusion of patients with in-hospital death, missing follow-up data, or missing data to calculate nutritional indices. On admission, 155 patients had AF. Laboratory data were obtained at discharge. During a mean follow up period of 1.1±0.6 years, 131 patients had a composite endpoint (CE) of all-cause death and hospitalization for worsening heart failure or cerebrovascular disorder. In multivariate Cox analysis, in patients with AF, CHE was significantly associated with CE independently of age, gender and body mass index after the adjustment with serum albumin, total cholesterol levels and total lymphocyte count, while it was not significantly associated with CE in patients without AF. C-index of CHE (0.708) was higher than that of GNRI (0.555, p=0.0028), CONUT (0.651, p=0.208) and PNI (0.635, p=0.208) in AF patients, while there were no significant differences in those nutritional indices in patients without AF. Kaplan-Meier curve analysis revealed that AF patients with lower CHE ( Conclusions Prognostic value of CHE would be stronger than other nutritional indices in HFpEF patients with AF, while it would be weak in HFpEF patients without AF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnostics K.K.; Fuji Film Toyama Chemical Co. Ltd.

Background The novel nutrition index; triglyceride (TG) × total cholesterol (TG) × body weight (BW) index (TCBI) has been reported to be an easy and useful predictor for patients with coronary artery disease. However, there is no information available on the prognostic value of TCBI in patients with heart failure with preserved LVEF (HFpEF) who admitted with acute decompensated heart failure (ADHF). Methods and results Data were extracted from The Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with Preserved Ejection Fraction (PURSUIT HFpEF) study. PURSUIT-HFpEF study is a prospective multicenter observational study in which collaborating hospitals recorded clinical, echocardiographic, and outcome data of ADHF pts with HFpEF. We enrolled consecutive 757 HFpEF patients who admitted with ADHF from June 2016 to June 2019. TCBI was calculated by the formula; TG × TC × BW / 1000 at the discharge. After we excluded patients with in-hospital death or without sufficient data, we analyzed 419 patients. The primary endpoint was all-cause mortality. During a median follow up period of 1.1 (0.9–1.9) years, 59 patients died. ROC analysis revealed that TCBI at discharge was a fair discriminator for predicting all-cause mortality (AUC 0.676, sensitivity 53%, specificity 78%). Multivariate Cox proportional analysis showed that TCBI (p=0.002) was an independent predictor for all cause death after adjustment with major confounders such as age, gender, NT-proBNP, hemoglobin and serum creatinine level. We divided patients into 4 groups according to quartiles of TCBI. Kaplan-Meier analysis showed a significantly higher risk of all-cause death in relation to the decrease in TCBI. Conclusion TCBI, a simple and novel nutrition index, is a useful and strong long-term prognostic indicator in ADHF patients with HFpEF. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Roche Diagnositics K.K.; Fuji Film Toyoma Chemical Co. Ltd.

Introduction Cather ablation (CA) has been identified as an effective and safe treatment option for patients with atrial fibrillation (AF). One of the serious complications associated AF is cerebral infarction (CI). Recent studies reported that CA was associated with lower incidence of ischemic stroke in patients with AF. However, CA for AF itself has a potential risk of CI. Several previous studies showed that the incidence of silent CI (SCI) assessed by magnetic resonance imaging (MRI) of the brain occurred 5 to 18% during CA for AF. Recently, CA for AF made a remarkable progress in technology. However, there are few information available that the impact of 3-dimensional electroanatomical mapping system on the incidence of SCI. This study aimed to clarify the prevalence and predictors of SCI during CA for AF. Methods We enrolled 893 consecutive patients (male 534, age 71±10 years), who underwent CA for AF and MRI of brain 1 day after the procedure. We collected patients data such as physical examinations, blood sampling, echo cardiography, and CA data. A brain MRI was performed the next day following the procedure to identify any CIs. One-hundred and forty-six of patients used the Rhythmia® mapping system catheter, and the other mapping system such as CARTO or EnSite system used in the remaining 747 patients. Results The MRI depicted acute micro-CIs in 144 (16%) patients, but neither symptoms nor abnormal neurological findings were present in these patients. Patients with SCI had significantly higher prevalence of persistent AF (60 vs 43%, p=0.0002), CHADS2 Score (2 (1–3) vs 1 (1–2), p=0.0001), higher prevalence of previous stroke (19 vs 12%, p=0.02), larger left atrial (LA) diameter (43.2±6.4 vs 41.7±6.5mm, p=0.01), lower left ventricular ejection fraction (LVEF) (59.0±13.2 vs 64.2±11.3%, p≤0.0001), higher B-type natriuretic peptide level (221±236 vs 163±225 pg/dl, p≤0.0001), more Rhythmia® mapping system use (30 vs 8%, p Conclusion Acute SCI occurred about 16% after CA for AF. Rhythmia® mapping system use exhibited a higher incidence of acute SCI after catheter ablation for AF than the other mapping system use. Rhythmia® mapping system use, LVEF, CHADS2 score, and procedure time are associated with SCI relating CA for AF. Funding Acknowledgement Type of funding source: None

Background Diuretics has been reported to have a potential for an activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, leading to a possibility of poor clinical outcome in patients with cardiovascular disease. However, few data are available on clinical impact of diuretics on long-term outcome in patients with acute myocardial infarction (AMI) based on plasma volume status. Methods To address the issue, a total of 3,416 survived patients with AMI who were registered to a large database of the Osaka Acute Coronary Insufficiency Study (OACIS) were studied. Plasma volume status was assessed with the estimated plasma volume status (ePVS) that was calculated at discharge as follows: actual PV = (1 − hematocrit) × [a + (b × body weight)] (a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal PV = c × body weight (c=39 in males and c=40 in females), and ePVS = [(actual PV − ideal PV)/ideal PV] × 100 (%). Multivariable Cox regression analysis and propensity score matching were performed to account for imbalances in covariates. The endpoint was all-cause of death (ACD) within 5 years. Results During a median follow-up period of 855±656 days, 193 patients had ACD. In whole population, there was no significant difference in long-term mortality risk between patients with and without diuretics in both multivariate cox regression model and propensity score matching population. When patients were divided into 2 groups according to ePVS with a median value of 4.2%, 46 and 147 patients had ACD in groups with low ePVS and high ePVS, respectively. Multivariate Cox analysis showed that use of diuretics was independently associated with an increased risk of ACD in low ePVS group, (HR: 2.63, 95% confidence interval [CI]: 1.22–5.63, p=0.01), but not in high ePVS group (HR: 0.70, 95% CI: 0.44–1.10, p=0.12). These observations were consistent in the propensity-score matched cohorts; the 5-year mortality rate was significantly higher in patients with diuretics than those without among low ePVS group (4.7% vs 1.7%, p=0.041), but not among high ePVS group (8.0% vs 10.3%, p=0.247). Conclusion Prescription of diuretics at discharge was associated with increased risk of 5-year mortality in patients with AMI without PV expansion, but not with PV expansion. The role of diuretics on long-term mortality may differ in plasma volume status. Therefore, prescription of diuretics after AMI may be considered based on plasma volume status. Funding Acknowledgement Type of funding source: None

Background Concomitant presence of pulmonary hypertension in heart failure (HF) is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. An increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is reported to be associated with worse clinical outcomes in patients with advanced HF. On the other hand, cardiohepatic interactions have been a focus of attention in HF, and liver dysfunction in HF patients is caused by liver congestion, which is related to liver stiffness. It has been recently shown that liver stiffness assessed by non-invasive fibrosis marker such as Fibrosis-4 (FIB4) index predicts the mortality in HF patients. However, there is no information available on the prognostic value of the combination of MPS ratio and FIB4 index in patients with acute decompensated heart failure (ADHF). Methods and results We studied 238 patients admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. MPS ratio was obtained at the admission. FIB4 index was calculated by the formula: age (yrs) × AST [U/L] / (platelets [103/μL] × √(ALT[U/L])). FIB4 index >2.67 was defined as abnormal, as previously reported. During a follow up period of 5.2±4.4 yrs, 93 patients died. At multivariate Cox analysis, MPS ratio (p=0.01) and FIB4 index (p=0.01) were significantly associated with the total mortality, independently of creatinine level and prior heart failure hospitalization, after the adjustment with hemoglobin, albumin levels and body mass index. The patients with both MPS ratio ≥0.388 (determined by ROC analysis; AUC 0.613 [0.541–0.687]) and abnormal FIB4 index had a significantly increased risk of the total mortality than those with either greater MPS or abnormal FIB4 index and none of them (52% vs 40% vs 28%, p=0.0068, respectively). Conclusion The combination of MPS ratio and FIB4 index might be useful for stratifying ADHF patients at higher risk for the total mortality. Funding Acknowledgement Type of funding source: None

Background Comorbidities are strongly associated with poor clinical outcome in heart failure patients. The Age-adjusted Charlson comorbidity index (ACCI), which is well-known widely used comorbidity index, recently has been used as a robust prognostic model in heart failure patients. On the other hand, Cystatin C, as a novel and important biomarker of renal function, has been recently reported as a useful long-term risk stratification score in heart failure patients. However, there is no information available on the impact of comorbidities on the prognostic value of cystatin-C in patients admitted for acute decompensated heart failure (ADHF). Methods We prospectively studied 458 consecutive ADHF patients with survival discharge. Patients with hemodialysis were excluded. Echocardiography and venous blood sampling were performed just before discharge and serum cystatin-C level was measured. Comorbidity was measured with the Age-adjusted Charlson comorbidity index (ACCI). ACCI was commonly used for the evaluation of the comorbid condition which is weighted and scored, with additional points added for age. The endpoint was all-cause death (ACD). Results During a follow-up period of 2.8±1.5 years, 132 patients had ACD. At multivariate Cox analysis, ACCI (p=0.0015) and cystatin-C level (p=0.0145) were significantly and independently associated with ACD. Patients with high ACCI (≥6: determined by ROC analysis) had a significantly greater risk of ACD (37.2% vs 17.8%, p Conclusions The prognostic value of cystatin-C is not affected by comorbidities and cystatin-C provide prognostic information even in patients admitted for ADHF, irrespective of comorbid burden. All-cause death-free rate in ADHF pts Funding Acknowledgement Type of funding source: None

Background It is widely known that even new-generation drug-eluting stent (DES) induce coronary vasomotion abnormality. On the other hand, recent studies reported that drug-coated balloon (DCB) for native coronary artery was non-inferior to DES in medium term outcomes. However, there is no available information about vasomotion after treatment with DCB. Purpose The aim of this study was to prospectively compare coronary vasomotion in patients treated with DCB versus new-generation DES. Methods Twenty-seven patients were randomly treated with angioplasty with DCB (n=12) versus implantation of bioabsorbable polymer everolimus-eluting stent (BP-EES, n=15) after successful predilation. At 8 months after treatment, endothelium-dependent and -independent vasomotion were evaluated by intracoronary infusion of incremental doses of acetylcholine (for right coronary artery: low-dose 5μg, high-dose 50μg and for left coronary artery: low-dose 10μg, high-dose 100μg) and nitroglycerine (200μg). Mean luminal diameter of the distal segments, beginning 5 mm and ending 15 mm distal to the edge of the treated segment was quantitatively measured by angiography. Results Clinical and procedural characteristics were not different between two groups. Vasoconstriction after acetylcholine infusion was less pronounced in the DCB group than the BP-EES group (low-dose: 4±13% vs −4±14%, p=0.158, high-dose: −2±14% vs −28±30%, p=0.013). The response to nitroglycerin was not different between two groups (17±13% vs 18±24%, p=0.838). Conclusion Vasoconstriction after acetylcholine infusion in the peri-treated region was more pronounced in the BP-EES group than in the DCB group, which suggests that endothelial function of coronary vessel treated by DCB can be more preserved than new-generation DES. Figure 1 Funding Acknowledgement Type of funding source: None

Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with chronic heart failure (CHF). Serial evaluation of cardiac MIBG imaging was shown to be useful for predicting adverse outcome in CHF. However, there was no information available on long-term serial changes of cardiac sympathetic nerve dysfunction after discharge of acute decompensated heart failure (ADHF) hospitalization. Purpose We aimed to clarify the serial change of cardiac MIBG imaging parameter in long-term after discharge of heart failure hospitalization, especially relating to HFrEF (LVEF Methods We studied 112 patients (HFrEF; n=44, HFmrEF; n=23 and HFpEF; n=45) who were admitted for ADHF, discharged with survival and without heart failure hospitalization during follow-up period. All patients underwent cardiac MIBG imaging at the timing of discharge, in 6–12 months and in 18–24 months after discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). The cardiac MIBG washout rate (WR) was calculated from the early and delayed planar images after taking radioactive decay of I-123 into consideration. Results In HFrEF patients, late H/M was significantly improved from discharge to 6–12 months data (1.60±0.24 vs 1.75±0.31, p Conclusion The improvement in cardiac sympathetic nerve dysfunction was observed in patients with HFrEF and HFmrEF, not in HFpEF, after the discharge of acute heart failure hospitalization. Funding Acknowledgement Type of funding source: None

Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with heart failure (HF). Most of the literature on the use of 123I-MIBG imaging is based on planar images in patients with chronic HF and reduced left ventricular ejection fraction (HFrEF), because It is technically challenging to conduct precise 123I-MIBG SPECT analysis in globally denervated heart, which is frequently observed in HFrEF patients. There was no information available on cardiac sympathetic nerve dysfunction evaluated by cardiac MIBG SPECT imaging in acute decompensated HF (ADHF) patients with preserved left ventricular ejection fraction (HFpEF). Purpose We aimed to clarify the prognostic significance of 123I-MIBG SPECT myocardial imaging in ADHF patients with HFpEF. Methods We enrolled 183 patients who were admitted for ADHF with HFpEF, discharged with survival. All patients underwent cardiac MIBG imaging at the timing of discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). We studied 156 patients after excluding 27 patients whose MIBG SPECT reconstruction was difficult due to too low MIBG uptake or extracardiac accumulation interference. SPECT analysis on the delayed image was conducted by using CardioBull, a fully automated software for the quantification of I-123 MIBG SPECT. All of 17 regional tracer uptake were compared with normal control database. A scoring algorithm for the evaluation of low uptake employs a 5-point scoring system as 0–4 for normal, mildly abnormal, moderately abnormal, severe abnormal, and perfusion defect, respectively. The summed severity (SSS) scores were obtained by summing the score for all segments. SSS could range from 0 to 68. The endpoint of this study is cardiac events defined as the composite of unplanned heart failure hospitalization and cardiac death. Results During a mean follow up period of 2.4±1.6 years, 60 patients reached cardiac events. SSS was significantly high in patients with than without cardiac events (20 [10–27] vs 7 [4–16], p10, defined by median) had significantly greater risk of cardiac event (56% vs 21%, Hazard ratio: 3.56 (2.00–6.33, p Conclusion Cardiac MIBG SPECT imaging was useful for risk stratification in ADHF patients with HFpEF. Funding Acknowledgement Type of funding source: None

Background Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure (ADHF). On the other hand, concomitant presence of pulmonary hypertension in heart failure is associated with increased adverse events and may be related to interventricular uncoupling and impaired cardiac efficiency. It has recently been shown that an increased mean pulmonary artery pressure to mean systemic arterial pressure ratio (MPS ratio), a marker of interventricular coupling and efficiency, is associated with worse clinical outcomes in patients with advanced heart failure. However, there is no information available on the long-term prognostic value of the combination of malnutrition and MPS ratio in pts admitted for ADHF. Methods and results We studied 248 pts admitted for ADHF, who underwent right heart catheterization at the admission and were discharged with survival. Malnutrition was assessed by geriatric nutritional risk index (GNRI), prognostic nutritional index (PNI) and controlling nutritional status score (CONUT). During a mean follow-up period of 5.2±4.4 yrs, 62 pts had cardiovascular death (CVD). MPS ratio was significantly greater in pts with than without CVD (0.408±0.114 vs 0.347±0.102, p=0.0001). GNRI and PNI were significantly lower, CONUT was significantly greater in pts with than without CVD. At multivariate Cox regression analysis, GNRI and MPS ratio were significantly associated with CVD, independently of prior heart failure hospitalization, eGFR, and serum sodium level and anemia, although PNI and CONUT showed the association with CVD at unvariate analysis. Pts with malnutrition (GNRI≤median value=96.5) and greater MPS ratio (≥median value=0.346) had a significantly higher CVD risk than those with either and none of them (51% vs 20% vs 12%, p Conclusions The combination of malnutrition and MPS ratio might be useful for stratifying pts at risk for CVD in patients with ADHF. Funding Acknowledgement Type of funding source: None

In an emulsion-counter hybrid experiment performed at J-PARC, a Ξ^{-} absorption event was observed which decayed into twin single-Λ hypernuclei. Kinematic calculations enabled a unique identification of the reaction process as Ξ^{-}+^{14}N→_{Λ}^{10}Be+_{Λ}^{5}He. For the binding energy of the Ξ^{-} hyperon in the Ξ^{-}-^{14}N system a value of 1.27±0.21 MeV was deduced. The energy level of Ξ^{-} is likely a nuclear 1p state which indicates a weak ΞN-ΛΛ coupling.

Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

Background Asymptomatic ulcerative colitis (UC) is increasingly detected by improved screening tests such as the fecal immunochemical test. However, there have been few reports on the difference in the clinical course of UC according to the presence or absence of symptoms at diagnosis. The purpose of this study was to compare the clinical course of UC according to the presence or absence of clinical symptoms at the time of diagnosis. Methods Data were obtained from a retrospective chart review of 64 consecutive patients with UC diagnosed at our hospital between 2014 and 2020. Patients were grouped according to the presence or absence of clinical symptoms at the time of UC diagnosis, and clinical characteristics (age, sex, extent of disease, Mayo Score, endoscopic severity, and hematological findings) at the time of diagnosis were subjected to univariate and multivariate analyses. In the clinical characteristics, propensity score matched analysis was performed, and systemic steroids use, hospitalization within 1 year, and the introduction of therapies for refractory UC were evaluated. Patients with a clinical course of less than 1 year after UC diagnosis, patients intolerant to 5-aminosalicylic acid, patients with carcinoma, pregnant women, and patients under 15 years of age were excluded. Results Eligible patients were 64 UC patients (19 asymptomatic and 45 symptomatic) diagnosed at our hospital during the period of the study. The symptomatic group included 32 cases of bloody stools, 30 cases of diarrhea, 7 cases of abdominal pain, and 4 cases of fever. Multivariate analysis of clinical features at diagnosis showed significant differences in Mayo Score (p=0.003, odds ratio: 3.650, 95% confidence interval: 1.541–8.647) and serum hemoglobin level (p=0.021, odds ratio: 0.367, 95% confidence interval: 0.157–0.859). As a result of propensity score matched analysis, 24 patients (12 asymptomatic, 12 symptomatic) were selected. There were no significant differences in the rates of systemic steroid use (16.7% vs. 16.7%), hospitalization within 1 year (16.7% vs. 8.3%), and the introduction of therapies for refractory UC (16.7% vs. 8.3%) between the two groups (p=1.000 in all items). Conclusion There was no difference in the prognosis of the asymptomatic group compared with the symptomatic group using propensity score matched analysis. The results suggest that asymptomatic UC detected by colonoscopy may be acceptable for follow-up without treatment.