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Background Radiation-related cardiotoxicity has been refocused nowadays as the follow-up was increased amomg the patients with advanced lung cancer. The early recognition of the occult cardiotoxicity enables the early intervention preventing clinically significant cardiac events or worsening of severity. Purpose We aim to search whether the F-18 fluorodeoxyglucose positron emission tomography (FDG PET) performed immediately after radiotherapy could predict the late cardiac events. Methods We retrospectively enrolled 133 patients with locally advanced, unresectable stage III NSCLC who underwent F-18 fluorodeoxyglucose positron emission tomography (FDG PET) immediately after CCRT for the response evaluation and survived at least for 6 months. Heart was recontoured according to the RTOG 0617 secondary analysis atlas for the dose volume analysis. Standardized uptake values (SUV) of the left ventricular myocardium were measured on FDG PET images. The patients were regularly followed up for the disease progression and complications. The primary end-point was the cardiac events grade ≥2 based on the Common Terminology Criteria for Adverse Events (version 5.0). Results FDG PET was performed at median interval of 11 days after CCRT. Fourty-two patients experienced cardiotoxicity during a median follow-up of 47 months (range, 12 – 123 months). In univariable analysis, mean heart dose, maximum SUV of the left ventricle (LV SUVmax), white blood cell count, and diabetes were associated with the risk of cardiotoxicity. In multivariable analysis, only higher mean heart dose (>11.1 Gy, hazard ratio 3.930 [95% confidence interval 1.933–7.988]; p=0.0002) and higher LV SUVmax (>12.84, 2.189 [1.162–4.124]; p=0.0152) were independently associated with increased risk of cardiotoxicity. In subgroup analyses, LV SUVmax remained predictive of cardiotoxicity among those with higher mean heart dose, but not among those with lower mean heart dose. Conclusion Early FDG PET after CCRT for NSCLC could predict the late cardiac events, especially in patients with high dose cardiac irradiation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): This work was supported by a grant of the Basic Science Research Program through the National Research Foundation funded by the Ministry of Education, Republic of Korea (Principal Investigator: Sang-Geon Cho)

Background Patients with atrial fibrillation (AF) who initiated vitamin K antagonist (VKA) were at highest risk of stroke and bleeding in the first few months of therapy. Understanding of the temporal trend of clinical events in AF patients on non-VKA oral anticoagulant (NOAC) therapy should aid therapeutic decisions. Purpose To evaluate the temporal trend of clinical events in AF patients receiving edoxaban in routine clinical practice in the Global ETNA-AF program. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Thromboembolic, bleeding and death events were analysed separately for the 1st and 2nd year of the follow-up period, using a time-to-first-event estimation of cumulative incidence and annual rate via Kaplan-Meier method. Results A total of 27,617 patients were included in this analysis, 48.6% from Europe and 51.4% from Japan, Korea, and Taiwan. Baseline characteristics were consistent with typical AF population in real world studies (Table 1). Approximately 83% of patients received the recommended edoxaban dose. Annualized rates of ischaemic stroke and major bleeding (ISTH) were lower in the 2nd year than in the 1st year: ischaemic stroke 0.59% (95% CI, 0.50–0.70) vs 0.86% (95% CI, 0.75–0.98), p=0.015; major bleeding 0.87% (95% CI, 0.75–1.00) vs 1.15% (95% CI, 1.02–1.29), p=0.036. The trend toward lower rates of ischaemic stroke and major bleeding in the 2nd year was consistent across regions. All-cause mortality increased slightly from the 1st year to the 2nd year, which was not statistically significant and was not driven by cardiovascular (CV) mortality (Table 2). Conclusion In routine clinical practice in the Global ETNA-AF program, major bleeding and ischaemic stroke rates in >27,000 patients on edoxaban therapy declined from 1st year to 2nd year. Further analyses will investigate whether such trend is influenced by selection for healthier patients over time. Longer follow-up is needed to better understand long-term trends. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Baseline characteristicsTable 2. Annualised clinical event rates

Background The ESC atrial fibrillation management guidelines recommend a risk-based approach to oral anticoagulant (OAC) therapy. How clinical practice aligns with these recommendations is of interest. Purpose To analyse real world data from Global ETNA-AF program in patient groups stratified by stroke and bleeding risk scores according to ESC guidelines. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program evaluating the safety and effectiveness of edoxaban in patients from European and Asian countries. Baseline characteristics and clinical event data at 2-year follow-up were analysed in 4 subgroups defined by CHA2DS2-VASc score (≥3 for female / ≥2 for male [OAC recommended] vs 2 for female / 1 for male [OAC should be considered]) and HAS-BLED score (≥3 [Bleeding risk high] vs Results Of 27,616 patients included in this analysis, 23,152 (83.8%) were in the “OAC recommended” category and 3,539 (12.8%) were in the “OAC should be considered” category. Only 3.3% of patients did not meet ESC guideline criteria for OAC initiation. Among patients with high bleeding risk, 98% were in the “OAC recommended” category. A similar distribution was observed across regions (Table 2). The recommended edoxaban dose was used in the vast majority (>80%) of patients across all risk stratification subgroups. In the “OAC recommended” category, patients with high bleeding risk had higher rates of thromboembolic, bleeding, and death events than those with low bleeding risk. Conclusion Data from routine clinical practice in Global ETNA-AF demonstrate high concordance of edoxaban treatment with ESC guidelines. Edoxaban dose is consistent with label recommendation in the vast majority (>80%) of patients. Clinical event rates were generally low across all risk groups, including acceptable bleeding rates in anticoagulated patients with high bleeding risk. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Table 1. Subgroups as per ESC guidelinesTable 2. Patient characteristics & events

Trials that randomize patients to different “usual care” treatments play a crucial role in helping healthcare systems optimize the delivery of care. Yet, as illustrated by controversies surrounding...

Background Beta-carotene (BC) is a carotenoid which exerts anti-cancer effects in several types of cancer, including colorectal cancer. Epigenetic modifications of genes, such as histone deacetylation and DNA hypermethylation, have also been detected in various types of cancer. To understand the molecular mechanism underlying cancer preventive and therapeutic effects of BC, microRNAs (miRNAs), histone acetylation, and global DNA methylation in colon cancer stem cells (CSCs) were investigated. Methods HCT116 colon cancer cells positive for expression of CD44 and CD133 were sorted by flow cytometry and used in subsequent experiments. Cell proliferation was examined by the MTT assay and self-renewal capacity was analyzed by the sphere formation assay. The miRNA sequencing array was used to detect miRNAs regulated by BC. Histone acetylation levels were measured by the Western blot analysis. mRNA expression of DNA methyltransferases (DNMTs) was examined by qPCR and global DNA methylation levels were determined by enzyme-linked immunosorbent assay. Results Treatment of CD44+CD133+ colon CSCs with BC caused a reduction in both cell proliferation and sphere formation. Analysis of the miRNA sequencing array showed that BC regulated expression of miRNAs associated with histone acetylation. Histone H3 and H4 acetylation levels were elevated by BC treatment. In addition, BC treatment down-regulated DNMT3A mRNA expression and global DNA methylation in colon CSCs. Conclusions These results suggest that BC regulates epigenetic modifications for its anti-cancer effects in colon CSCs.

Impaired skin wound healing in the elderly can lead to medical issues and increased mortality. Although l -histidine and l -carnosine are potent anti-aging amino acids, the wound healing effects of these amino acids in aging remain to be elucidated. Here, we investigated the regenerative potential of l -histidine and l -carnosine in in vitro and in vivo aging models. l -histidine (1 mM), l -carnosine (10 mM), or a combination improved proliferation, migration, senescence, and epithelial-mesenchymal transition (EMT) in d -galactose-induced aged keratinocytes. An in vivo mouse aging model was established with injection of d -galactose (s.c. 500 mg/kg) daily for eight weeks. Supplementation with l -histidine (2 g/L), l -carnosine (2 g/L), or a combination improved collagen and wound healing with EMT markers, E-cadherin, N-cadherin, and MMP-2. These effects were concomitant with reduced circulating levels of corticosterone and increased PI3K/Akt phosphorylation. These results suggest that l -histidine and l -carnosine have the potential to facilitate wound healing in aging skin.

The effect of glass composition, pure silica glass, boron-doped and fluorine-doped silica glasses of inner cladding, in the germano-silicate glass core fibers on optical and mechanical prop...

BackgroundEuthanasia or assisted suicide (EAS) for psychiatric disorders, legal in some countries, remains controversial. Personality disorders are common in psychiatric EAS. They often cause a sense of irremediable suffering and engender complex patient–clinician interactions, both of which could complicate EAS evaluations.MethodsWe conducted a directed-content analysis of all psychiatric EAS cases involving personality and related disorders published by the Dutch regional euthanasia review committees (N = 74, from 2011 to October 2017).ResultsMost patients were women (76%, n = 52), often with long, complex clinical histories: 62% had physical comorbidities, 97% had at least one, and 70% had two or more psychiatric comorbidities. They often had a history of suicide attempts (47%), self-harming behavior (27%), and trauma (36%). In 46%, a previous EAS request had been refused. Past psychiatric treatments varied: e.g. hospitalization and psychotherapy were not tried in 27% and 28%, respectively. In 50%, the physician managing their EAS were new to them, a third (36%) did not have a treating psychiatrist at the time of EAS request, and most physicians performing EAS were non-psychiatrists (70%) relying on cross-sectional psychiatric evaluations focusing on EAS eligibility, not treatment. Physicians evaluating such patients appear to be especially emotionally affected compared with when personality disorders are not present.ConclusionsThe EAS evaluation of persons with personality disorders may be challenging and emotionally complex for their evaluators who are often non-psychiatrists. These factors could influence the interpretation of EAS requirements of irremediability, raising issues that merit further discussion and research.

Introduction As the number of Alzheimer's disease (AD) prevention studies grows, many individuals will need to learn their genetic and/or biomarker risk for the disease to determine trial eligibility. An alternative to traditional models of genetic counseling and disclosure is needed to provide comprehensive standardized counseling and disclosure of apolipoprotein E (APOE) results efficiently, safely, and effectively in the context of AD prevention trials. Methods A multidisciplinary Genetic Testing, Counseling, and Disclosure Committee was established and charged with operationalizing the Alzheimer's Prevention Initiative (API) Genetic Counseling and Disclosure Process for use in the API Generation Program trials. The objective was to provide consistent information to research participants before and during the APOE counseling and disclosure session using standardized educational and session materials. Results The Genetic Testing, Counseling, and Disclosure Committee created a process consisting of eight components: requirements of APOE testing and reports, psychological readiness assessment, determination of AD risk estimates, guidance for identifying providers of disclosure, predisclosure education, APOE counseling and disclosure session materials, APOE counseling and disclosure session flow, and assessing APOE disclosure impact. Discussion The API Genetic Counseling and Disclosure Process provides a framework for large-scale disclosure of APOE genotype results to study participants and serves as a model for disclosure of biomarker results. The process provides education to participants about the meaning and implication(s) of their APOE results while also incorporating a comprehensive assessment of disclosure impact. Data assessing participant safety and psychological well-being before and after APOE disclosure are still being collected and will be presented in a future publication., Highlights • Participants may need to learn their risk for Alzheimer's disease to enroll in studies. • Alternatives to traditional models of apolipoprotein E counseling and disclosure are needed. • An alternative process was developed by the Alzheimer's Prevention Initiative. • This process has been implemented by the Alzheimer's Prevention Initiative Generation Program.

We have performed the first direct measurement of the 83Rb(p,g) radiative capture reaction cross section in inverse kinematics using a radioactive beam of 83Rb at incident energies of 2.4 and 2.7 A MeV. The measured cross section at an effective relative kinetic energy of Ecm = 2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of 84Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted., 6 pages, 4 figures, published in Physical Review Letters

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background Age is a risk factor for ischemic stroke and bleeding in patients with atrial fibrillation (AF). The large dataset from the global prospective, noninterventional ETNA-AF program allows for analysis of the impact of age on clinical events in AF patients treated with edoxaban. Purpose Evaluate the safety and effectiveness of edoxaban by age subgroups and the impact of age on clinical events. Methods Baseline patient characteristics, thromboembolic and bleeding events, and mortality data were collected from patients with 2-year follow-up in ETNA-AF program and analyzed in defined age subgroups. Cox regression analysis was conducted using age as a continuous variable and clinical events as outcome variables. Results A total of 27,617 patients were categorized into four age subgroups: Conclusion Two-year follow-up data from the global ETNA-AF program support the use of edoxaban as a safe and effective treatment for AF patients across all age groups, including the very elderly, in routine clinical care. The impact of age on the risk of ICH was smaller than that of ischemic stroke and major bleeding.

Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Background and Purpose The large global Edoxaban Treatment in routiNe clinical prActice (ETNA)-AF program was designed to assess the safety and effectiveness of edoxaban, complementing randomized clinical trials. Methods ETNA collects data on patient characteristics and clinical events in unselected AF patients treated with edoxaban for stroke prevention, integrating data from prospective, noninterventional studies conducted in Europe, Japan, South Korea, and Taiwan. Results The 2-year follow-up analysis included 27,617 patients, the majority of whom (82.6%) received the recommended dose according to the local label. At baseline, the mean age was 73.6 ± 9.8 years and 58.1% were male. Half of the patients (50.5%) were 75 years or older. The CHA2DS2-VASc score was 3.3 ± 1.5, and the modified HAS-BLED score was 2.4 ± 1.1. The rate of ischemic stroke was 0.74%/yr, major bleeding 1.02%/yr, intracranial hemorrhage 0.29%/yr, and major gastrointestinal (GI) bleeding 0.51%/yr. All-cause mortality was 3.13%/yr, and cardiovascular (CV) mortality 1.45%/yr (see Table). Conclusion The rates of ischemic stroke and major bleeding events remained low globally and across regions during the two-year follow-up period in AF patients treated with edoxaban. Global(N = 27,617) Japan(N = 11,330) Korea/Taiwan(N = 2,870) Europe(N = 13,417) Age, mean (SD) 73.6 (9.8) 74.2 (10.1) 71.6 (9.5) 73.6 (9.5) Gender, male, % 58.1 59.4 60.2 56.6 Weight [kg], median (IQR) 69 (58, 81) 59 (51, 68) 65 (57, 73) 80 (70, 90) CrCL [mL/min], mean (SD) 68.7 (28.4) 63.9 (25.8) 63.4 (23.7) 74.4 (30.5) CHA2DS2-VASc, mean (SD) 3.3 (1.5) 3.5 (1.7) 3.1 (1.4) 3.2 (1.4) Mod. HAS-BLED≠, mean (SD) 2.4 (1.1) 2.4 (1.1) 2.3 (1.1) 2.5 (1.1) Edoxaban 60mg/30mg, % 53.5 / 46.5 27.6 / 72.4 48.8 / 51.2 76.4 / 23.6 2-year clinical events, N (%/year), [95% CI] Major Bleeding (ISTH) 477 (1.02) [0.93; 1.11] 188 (1.09) [0.94; 1.25] 51 (1.00) [0.74; 1.31] 238 (0.97) [0.85; 1.11] Intracranial Hemorrhage 135 (0.29) [0.24; 0.34] 68 (0.39) [0.30; 0.50] 17 (0.33) [0.19; 0.53] 50 (0.20) [0.15; 0.27] Major GI Bleeding 241 (0.51) [0.45; 0.58] 122 (0.70) [0.58; 0.84] 18 (0.35) [0.21; 0.55] 101 (0.41) [0.33; 0.50] Any Stroke 455 (0.97) [0.88; 1.06] 244 (1.41) [1.24; 1.60] 54 (1.06) [0.80; 1.38] 157 (0.64) [0.54; 0.75] Ischemic Stroke 347 (0.74) [0.66; 0.82] 179 (1.03) [0.89; 1.20] 43 (0.84) [0.61; 1.13] 125 (0.51) [0.42; 0.61] Hemorrhagic Stroke 99 (0.21) [0.17; 0.26] 67 (0.39) [0.30; 0.49] 9 (0.17) [0.08; 0.33] 23 (0.09) [0.06; 0.14] All-cause Death 1479 (3.13) [2.98; 3.30] 470 (2.70) [2.46; 2.96] 72 (1.40) [1.09; 1.76] 937 (3.80) [3.56; 4.05] CV Death 684 (1.45) [1.34; 1.56] 140 (0.80) [0.68; 0.95] 26 (0.50) [0.33; 0.74] 518 (2.10) [1.92; 2.29] ≠Excluding labile INR.

Funding Acknowledgements Type of funding sources: None. Introduction Although atrial fibrillation (AF) catheter ablation is effective for rhythm control, in some patients it is hard to maintain sinus rhythm in spite of repeated AF catheter ablation (AFCA) procedures and anti-arrhythmic drugs (AADs). We explored the pre-procedural predictors for poor responders to AFCA and tested whether artificial intelligence (AI) assists the prediction of poor responders in the independent cohort by determining the invasive parameters. Methods Among 1,214 patients who underwent AFCA and regular rhythm follow-up for 56.2 ± 33.8 months (59 ± 11 years, 73.5% male, 68.6% paroxysmal AF), we differentiated 92 poor responders defined as those with sustained AF despite repeat AFCAs, AADs, or electrical cardioversion. Using the Youden index, we identified advanced LA remodeling with lower LA voltage under 1.109mV. AI model, which was derived from development cohort using medical record, was applied to predict LA voltage Results The patients with lower LA voltage under 1.109mV showed significantly poorer rhythm outcomes (Log-rank p Conclusions The patients with advanced atrial remodeling with low LA voltage, which can be predicted by an AI, showed significantly higher recurrence of AF after AFCA with AADs or cardioversion. AI may assist to select these poor responder patients before the AFCA procedure. Abstract Figure.

A novel Monte Carlo technique has been developed to determine lifetimes of excited states in the tens-to-hundreds femtoseconds range in products of low-energy heavy-ion binary reactions, with complex velocity distributions. The method is based on a detailed study of Doppler-broadened $$\gamma $$ γ -ray lineshapes. Its relevance is demonstrated in connection with the $$^{18}\text {O}(7.0\, \text {MeV/u})+\,^{181}\text {Ta}$$ 18 O ( 7.0 MeV/u ) + 181 Ta experiment, performed at GANIL with the AGATA+VAMOS+PARIS setup, to study neutron-rich O, C, N, ... nuclei. Excited states in $$^{17}\text {O}$$ 17 O and $$^{19}\text {O}$$ 19 O , with known lifetimes, are used to validate the method over the $$\sim 20{-}400\,\text {fs}$$ ∼ 20 - 400 fs lifetime-sensitivity range. Emphasis is given to the unprecedented position resolution provided by $$\gamma $$ γ -tracking arrays, which turns out to be essential for reaching the required accuracy in Doppler-shift correction. The technique is anticipated to be an important tool for lifetime investigations in exotic neutron-rich nuclei, produced with intense ISOL-type beams.

To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial.This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision.In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status.Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Euthanasia or assisted suicide (EAS) is permitted in a handful of jurisdictions. But its scope (ranging from being restricted to the end of life to no restrictions save those of autonomy) and its legal basis (ranging from a necessary prerogative of physicians to a human right) vary greatly. The debate over psychiatric EAS (pEAS) needs to be understood within this complex context. This essay addresses one specific aspect: can pEAS be grounded on a basic human right? The author argues against pEAS as grounded on a basic human right by showing that such a view has several implications we ought not accept.

BACKGROUND AND PURPOSE: Accurate radiologic prediction of cavernous sinus invasion by pituitary adenoma remains challenging. We aimed to assess whether 1-mm-slice-thickness MRI with deep learning–based reconstruction can better predict cavernous sinus invasion by pituitary adenoma preoperatively and to estimate the depth of invasion and degree of contact in relation to the carotid artery, compared with 3-mm-slice-thickness MRI. MATERIALS AND METHODS: This single-institution, prospective study included 67 consecutive patients (mean age, 53 [SD, 12] years; 28 women), between January and August 2020, who underwent a combined contrast-enhanced T1-weighted imaging protocol of 1-mm-slice-thickness MRI + deep learning–based reconstruction and 3-mm-slice-thickness MRI. An expert neuroradiologist who was blinded to the imaging protocol determined cavernous sinus invasion using the modified Knosp classification on 1-mm-slice-thickness MRI + deep learning–based reconstruction and 3-mm-slice-thickness MRI, respectively. Reference standards were established by the consensus of radiologic, intraoperative, pathologic, and laboratory findings. The primary end point was the diagnostic performance of each imaging protocol, and the secondary end points included depth of invasion and degree of contact in relation to the carotid artery. RESULTS: The diagnostic performance of 1-mm-slice-thickness MRI + deep learning–based reconstruction (area under the curve, 0.79; 95% CI, 0.69 − 0.89) in predicting cavernous sinus invasion by pituitary adenoma was higher than that of 3-mm-slice-thickness MRI (area under the curve, 0.61; 95% CI, 0.52–0.70; P 270°, 38.8% versus 16.4%, P

Background/Objectives Many jurisdictions use a functional model of capacity with similar legal criteria, but there is a lack of agreed understanding as to how to apply these criteria in practice. We aimed to develop a typology of capacity rationales to describe court practice in making capacity determinations and to guide professionals approaching capacity assessments. Methods We analysed all published cases from courts in England and Wales [Court of Protection (CoP) judgments, or Court of Appeal cases from the CoP] containing rationales for incapacity or intact capacity(n = 131). Qualitative content analysis was used to develop a typology of capacity rationales or abilities. Relationships between the typology and legal criteria for capacity [Mental Capacity Act (MCA)] and diagnoses were analysed. Results The typology had nine categories (reliability: kappa = 0.63): 1) to grasp information or concepts, 2) to imagine/ abstract, 3) to remember, 4) to appreciate, 5) to value/ care, 6) to think through the decision non-impulsively, 7) to reason, 8) to give coherent reasons, and 9) to express a stable preference. Rationales most frequently linked to MCA criterion ‘understand’ were ability to grasp information or concepts (43%) or to appreciate (42%), and to MCA criterion ‘use or weigh’ were abilities to appreciate (45%) or to reason (32%). Appreciation was the most frequently cited rationale across all diagnoses. Judges often used rationales without linking them specifically to any MCA criteria (42%). Conclusions A new typology of rationales could bridge the gap between legal criteria for decision-making capacity and phenomena encountered in practice, increase reliability and transparency of assessments, and provide targets for decision-making support.

Colorectal cancer is presently the third most commonly diagnosed cancer in the United States. In this study, we identified molecular differences between hepatic and non-hepatic metastases in colorectal cancer and evaluated their prognostic significance.We downloaded primary data from the NCBI Gene Expression Omnibus (GSE6988, GSE62321, GSE50760, and GSE28722). To identify the molecular differences, we used the Significance Analysis of Microarray method. We selected nine prognostic genes (SYTL2, PTPLAD1, CDS1, RNF138, PIGR, WDR78, MYO7B, TSPAN3, and ATP5F1) with hepatic metastasis prediction score in colorectal cancer (hereafter referred to as LASSO Score). We confirmed the prognostic significance of the LASSO Score by using Kaplan-Meier survival analysis, multivariate analysis, the time-dependent area under the curve (AUC) of Uno's C-index, and the AUC of the receiver operating characteristic curve at 1-5 years.Survival analysis revealed that a high LASSO Score is associated with a poor prognosis in colorectal cancer patients with hepatic metastases (p = 0). Analysis of C-indices and AUC values from the receiver operating characteristic curve further supported this prediction by the LASSO Score. Multivariate analysis confirmed the prognostic significance of the LASSO Score (p = 1.13e-06).This study reveals the biological mechanisms underlying hepatic metastases in colorectal cancer and will help in developing targeted therapies for colorectal cancer.

The purpose of the present study was to investigate the anti-inflammatory effects of a sugar isomer, leucrose (D-glucopyranosyl-α-(1–5)-D-fructopyranose) in a dextran sulfate sodium (DSS)-induced colitis mouse model and in RAW 264.7 macrophages. Colitis was induced in vivo with administration of two cycles of DSS (2.5%). Two groups of mice received an AIN-93G diet with 25% or 50% of the total sucrose content replaced with leucrose. This leucrose supplementation improved disease activity index (DAI) scores, colon length, histopathological damage, and myeloperoxidase (MPO) activity levels. In addition, the expression of pro-inflammatory mediators and cytokines decreased in the leucrose supplementation groups compared with the DSS alone treatment group. Furthermore, leucrose supplementation increased M2 macrophage polarization. Leucrose treatment suppressed IL-4-induced M2 polarization and increased JAK1/STAT6 phosphorylation in RAW264.7 cells. Taken together, these results indicate that leucrose exerts an anti-inflammatory effect by regulating M2 macrophage polarization via inflammatory cytokines and the JAK1/STAT6 signaling pathway.

Background The prevalence of atrial fibrillation (AF) and the need for appropriate anticoagulation increase with age. The benefit/risk profile of direct oral anticoagulants such as edoxaban in elderly population with AF in regular clinical practice is therefore of particular interest. Purpose Analyses of Global ETNA-AF data were performed to report patient characteristics, edoxaban treatment, and 1-year clinical events by age subgroups. Methods Global ETNA-AF is a multicentre, prospective, noninterventional program conducted in Europe, Japan, Korea, Taiwan, and other Asian countries. Demographics, baseline characteristics, and 1-year clinical event data were analysed in four age subgroups. Results Of 26,823 patients included in this analysis, 50.4% were ≥75 years old and 11.6% were ≥85 years. Increase in age was generally associated with lower body weight, lower creatinine clearance, higher CHA2DS2-VASc and HAS-BLED scores, and a higher percentage of patients receiving the reduced dose of 30 mg daily edoxaban. At 1-year, rates of ISTH major bleeding and ischaemic stroke were generally low across all age subgroups. The proportion of intracranial haemorrhage within major bleeding events was similar across age groups. All-cause mortality increased with age more than cardiovascular mortality. Conclusion Data from Global ETNA-AF support the safety and effectiveness of edoxaban in elderly AF patients (including ≥85 years) in routine clinical care with only a small increase in intracranial haemorrhage. The higher all-cause mortality with increasing age is not driven by cardiovascular causes. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Daiichi Sankyo

Background Persistent atrial fibrillation (PeAF) can change to paroxysmal AF (PAF) after antiarrhythmic drug medication and cardioversion. Purpose We investigated whether electrical posterior box isolation (POBI) may improve rhythm outcome of catheter ablation in those patient group. Methods We prospectively randomized 114 patients with PeAF to PAF (male 75%, 59.8±9.9 years old) to circumferential pulmonary vein isolation (CPVI) alone group (n=57) and additional POBI group (n=57). The primary end-point was AF recurrence after a single procedure, and the secondary end-point was a recurrence pattern, cardioversion rate, and the response to antiarrhythmic drugs (AADs). Results After a mean follow-up of 22.5±9.4 months, the clinical recurrence rate did not significantly differ between the two groups (29.8% vs. 28.1%, p=0.836; log rank p=0.815) The recurrence rate for atrial tachycardias (17.6% vs. 43.8%, p=0.141) was higher in POBI group, but the cardioversion rates (13.5% vs. 8.5%, p=0.434) were not significantly different between two groups. At the final follow-up, sinus rhythm was maintained without antiarrhythmic drug in 52.6% in CPVI group and 59.7% of POBI group (p=0.452). No significant difference was found in the major complication rates between the two groups (5.3% vs. 1.8%, p=0.618), but the total ablation time was significantly longer in the POBI group (4397±842 sec vs. 5337±1517 sec, p Conclusion In patients with persistent AF converted to paroxysmal AF by AAD, the addition of POBI to CPVI did not improve the rhythm outcome of catheter ablation nor influence overall safety. Funding Acknowledgement Type of funding source: None

International audience; Excited states of neutron rich Iodine isotopes 130−134 I above the high spin isomers have been identified using prompt-delayed γ-ray spectroscopy. The Iodine isotopes have been produced as fission fragments of fusion-fission and transfer induced fission of 9 Be(238 U, f) at a beam energy of 6.2 MeV/u. The complete (A, Z) identification was obtained using the large acceptance magnetic spectrometer VAMOS++. The AGATA γ-ray tracking array was used to detect the prompt γ rays while the delayed γ rays (in the time range of 100 ns to 200 µs) from the isomeric states were identified by the EXOGAM segmented Clover detectors, placed behind the focal plane of VAMOS++ spectrometer. The high spin states above the (8 −) isomers in 130,132 I have been populated for the first time and a new isomer in 132 I has been identified. New γ-ray transition has also been assigned to the level structure of 134 I. Prompt transitions above the 19/2 − isomer have been identified in 131,133 I, for the first time. The level structures are interpreted in terms of the systematics of odd-Z nuclei above Z = 50 shell closure and large scale shell model calculations.

Pragmatic clinical trials (PCTs) comparing interventions “within the standard of care” can efficiently yield important real-world evidence for healthcare practice and policymaking. But since PCTs attempt to mimic real-world procedures, any requirements added to the PCTs—even ethical requirements such as informed consent—can compromise the pragmatic nature of the trials. Many therefore treat such PCTs as ethically exceptional and propose that if PCTs compare two standard interventions, by that mere fact they pose no more than minimal risk—making them candidates for waivers of informed consent. This chapter argues that such an approach misunderstands research risks, is dangerous, and is unnecessary. Using a rigorous research analysis model, the chapter argues that instead of discarding the research–treatment distinction, it is better to pragmatically integrate research and clinical ethics.

The genetically encoded voltage indicators, ArcLight and its derivatives, mediate voltage dependent optical signals by intermolecular, electrostatic interactions between neighboring fluorescent proteins (FPs) via proton wires. A random mutagenesis event placed a negative charge on the exterior of the FP resulting in a greater than 10-fold improvement of the voltage-dependent optical signal. Repositioning this negative charge on the exterior of the FP reversed the polarity of voltage-dependent optical signals suggesting the presence of ‘hot spots’ capable of interacting with the negative charge on a neighboring FP thereby changing the fluorescent output. To explore the potential effect on the chromophore state, voltage-clamp fluorometry was performed with alternating excitation at 390 nm followed by excitation at 470 nm resulting in several mutants exhibiting voltage-dependent, ratiometric optical signals of opposing polarities. However, the kinetics, voltage ranges, and optimal FP fusion sites were different depending on the wavelength of excitation. These results suggest that the FP has external, electrostatic pathways capable of quenching fluorescence that are wavelength specific. ArcLight-derived GEVIs may therefore offer a novel way to map how conditions external to the β-can structure can affect the fluorescence of the chromophore and transiently manipulate those pathways via conformational changes mediated by whole cell voltage clamp.Statement of SignificanceArcLight-type GEVIs utilize proton pathways that send charge information outside of the FP to the internal chromophore enabling voltage induced conformational changes to affect fluorescence. These pathways are excitation wavelength specific suggesting that different external positions affect the protonated and deprotonated states of the chromophore.

The genetically encoded voltage indicators ArcLight and its derivatives mediate voltage-dependent optical signals by intermolecular, electrostatic interactions between neighboring fluorescent proteins (FPs). A random mutagenesis event placed a negative charge on the exterior of the FP, resulting in a greater than 10-fold improvement of the voltage-dependent optical signal. Repositioning this negative charge on the exterior of the FP reversed the polarity of voltage-dependent optical signals, suggesting the presence of “hot spots” capable of interacting with the negative charge on a neighboring FP, thereby changing the fluorescent output. To explore the potential effect on the chromophore state, voltage-clamp fluorometry was performed with alternating excitation at 390 nm followed by excitation at 470 nm, resulting in several mutants exhibiting voltage-dependent, ratiometric optical signals of opposing polarities. However, the kinetics, voltage ranges, and optimal FP fusion sites were different depending on the wavelength of excitation. These results suggest that the FP has external, electrostatic pathways capable of quenching fluorescence that are wavelength specific. One mutation to the FP (E222H) showed a voltage-dependent increase in fluorescence when excited at 390 nm, indicating the ability to affect the proton wire from the protonated chromophore to the H222 position. ArcLight-derived sensors may therefore offer a novel way to map how conditions external to the β-can structure can affect the fluorescence of the chromophore and transiently affect those pathways via conformational changes mediated by manipulating membrane potential.

To assess associations between parameters derived from F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and mRNA expression levels of immune checkpoint biomarkers such as programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4) as well as tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) patients.Integrated data were downloaded from Genomic Data Common Data Portal. Clinical, mRNA-seq, and whole exome-seq data of lung adenocarcinoma and squamous cell carcinoma from The Cancer Genome Atlas (TCGA) database were analyzed. TMB was defined as the total number of somatic missense mutations per megabase of the genome examined. Expression levels of PD-1, PD-L1, CTLA4 mRNA and TMB were collected. Correlations between imaging parameters of glucose metabolism and the expression levels of genomic biomarkers from cancers were evaluated. Bonferroni correction (adjusted p0.0027) was applied to reduce type 1 error.Of 31 NSCLC cases, 11 cases were adenocarcinoma (LUAD) and 20 were squamous cell carcinoma (LUSC). In linear regression analysis, texture parameters such as low gray-level run emphasis (LGRE, R2=0.48, p0.0001), short run low gray-level emphasis (SRLGE, R2=0.45, p0.0001) and long run low gray-level emphasis (LRLGE, R2=0.41, p=0.0001) derived from gray-level run length matrix (GLRLM) showed remarkable correlation with PD-L1 mRNA expression. Expression of PD-1, CTLA-4, and TMB failed to show any significant correlation with parameters of the F-18 FDG PET/CT.Texture parameters derived from PET, known to indicate glucose uptake distribution, were correlated with expression of PD-L1 mRNA but not with expression of PD-1, CTLA-4 and TMB. Thus, tumoral heterogeneity could be a surrogate marker for the identification of PD-L1 level in NSCLC.

Direct reprogramming is an efficient strategy to produce cardiac lineage cells necessary for cardiac tissue engineering and drug testing for cardiac toxicity. However, functional maturation of reprogrammed cardiomyocytes, which is of great importance for their regenerative potential and drug response, still remains challenging. In this study, we propose a novel electrode platform to promote direct cardiac reprogramming and improve the functionality of reprogrammed cardiac cells. Nonviral cardiac reprogramming was improved via a three-dimensional spheroid culture of chemically induced cardiomyocytes exposed to a small-molecule cocktail. A micropillar electrode array providing biphasic electrical pulses mimicking the heartbeat further enhanced maturation and electrophysiological properties of reprogrammed cardiac spheroids, leading to proper responses and increased sensitivity to drugs. On the basis of our results, we conclude that our device may have a wider application in the generation of functional cardiac cells for regenerative medicine and screening of novel drugs.