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Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (PAF). PFA can be performed "cryo-style" using fluoroscopy only, or additional pre- and post-ablation high-density 3D bipolar voltage maps can be performed to assess lesion formation and acute pulmonary vein isolation. We compared 6-month outcome after PFA using fluoroscopy only (X-ray) vs. PFA guided by 3D mapping (3D). Methods In PAF patients, PVI in conscious sedation using a steerable sheath and a pentaspline over-the-wire basket and flower PFA catheter was performed. In a subset of patients, pre- and post-ablation high-density bipolar voltage 3D maps (Carto 3D) were performed. Procedural parameters, acute success, in-hospital safety and arrhythmia recurrence were assessed over 6-month follow-up. Efficacy was evaluated by freedom from a ≥ 30-sec. recurrence of AF/atrial flutter (AFL)/atrial tachycardia (AT). Follow-up included 7-day Holter ECGs and/or telephonic interviews at days 90 and 180 after ablation. Results This study included a total of 101 patients (mean age: 65±10 years; 42% female) in whom 6-month follow-up data were available. There were no selection criteria for the use of 3D mapping. Pre- and post-ablation high-density maps were performed in 34/101 (34%) of patients. Mean CHA2DS2-VASc-score was 2,1±1,6. Median duration since first AF diagnosis was 21 [3-60] months. Skin-to skin procedure time was 56±20 in the X-ray group vs. 118±22 min in the 3D group, respectively (p Conclusions PVI using PFA with or without 3D mapping system resulted in a similar 6-month atrial arrhythmia recurrence rate and safety profile. Procedure and fluoroscopy times were significantly shorter in the fluoroscopy only group.

Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (PAF). Only a few small clinical studies have been published on the mid- and long-term outcome. Here, we present the one-year clinical outcomes of PFA in PAF. Methods In PAF patients, PVI in conscious sedation using a steerable sheath and a pentaspline over-the-wire basket and flower PFA catheter was performed. In a subset of patients, pre- and post-ablation high-density bipolar voltage 3D maps using a pentaspline diagnostic cathter were performed. Procedural parameters, acute success, in-hospital safety and arrhythmia recurrence were assessed during one-year follow-up. Efficacy was evaluated by freedom from a ≥ 30-sec. recurrence of AF/atrial flutter (AFL)/atrial tachycardia (AT). Follow-up included 7-day Holter ECGs and/or telephonic interviews at days 90, 180 and 360 days after ablation. Results This study included a total of 108 patients (mean age 65±10 years; 44% female). Mean CHA2DS2-VASc-score was 2,3±1,7. Mean duration since first AF diagnosis was 45±63 months. Pre- and post-ablation high-density maps were performed in 36/108 (33%) of patients. Skin-to skin procedure time was 78±36 min. Fluoroscopy time and dose area product were 19±8 min and 5,56±4,64 Gy.cm2, respectively. Left atrial dwell time of the PFA catheter was 27±11 min. Acute PVI rate was 100% of PVs using PFA only. Primary adverse events occurred in 3,7% of patients (1 groin hematoma, 2 pericardial tamponades, 1 acute stroke with lethal outcome). No patients were lost during FU. During a mean FU of 346±64 days, 88 of 107 patients (82%) remained free of any symptomatic or documented AF/AFL/AT episode after a single procedure. After the 90-day blanking period, in 19 (18%) patients at least one episode of AF/AFL/AT was documented. In 14/107 (13%) patients, after 216±102 days a re-do procedure was performed. In 7/107 (7%) patients, PV reconduction was seen. In 5/107 (5%) patients, during re-do procedure clinical or induced typical or atypical flutter was treated in presence of durable PV isolation. In the remaining 2/107 (2%) patients, only clinical right atrial typical flutter was treated and no left atrial mapping was performed. Conclusions PVI using PFA in patients with a relatively long history of PAF results in a low one-year atrial arrhythmia recurrence rate. The success rate may be reduced due to the long duration since first AF diagnosis and the initial experience with PFA by the operators. PV reconduction rate during re-do procedure in a limited number of patients was 7%. There was a reasonable safety profile and it improved significantly over the course of time, indicating that the learning curve could have negatively influenced the incidence of complications. Figure: Kaplan-Meier analysis of freedom from atrial arrhythmias, including any AF/AFL/AT episode exceeding 30 sec. Not including the 3-month blanking period.

Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (AF). It is also used as off-label therapy for persistent AF. Only a few small clinical studies have been published on the mid- and long-term outcome. We present data on methods, efficacy and safety on routine clinical use of pulsed field ablation for pulmonary vein isolation in patients with atrial fibrillation. Methods In patients with AF, PVI in conscious sedation using a steerable sheath and a pentaspline over-the-wire basket and flower PFA catheter was performed. In a subset of patients, pre- and post-ablation high-density bipolar voltage 3D maps using a pentaspline diagnostic catheter were performed. Procedural parameters, acute success and in-hospital safety were assessed. Results A total of 5 operators treated 304 patients (mean age 67 years (range 32-85), female 42%, mean BMI 28 kg/m2 (range 20-42), mean CHA2DS2-VaSc score of 2 (range 0-7), first-time ablation 100%, paroxysmal/persistent/longstanding persistent AF 47/17/36%, respectively. Mean duration since first AF diagnosis was 79 months (range 0-332). Most procedures were performed under deep conscious sedation using propofol and midazolam, without intubation (99%). Pre- and post-ablation high-density maps were performed in 27% of cases. Mean procedure time was 75 min. (range 23–245). Mean left atrial dwell time of the PFA catheter was 25 min. (range 8-98). Fluoroscopy time and dose area product were 18 min. (range 6-50) and 5,74 Gy.cm2 (range 0,40-36,50), respectively. Pulmonary vein isolation (PVI) was successful in 100%. There were no phrenic nerve palsies or esophageal complications. Major complications (2,6%) were pericardial tamponade (2,0%) and stroke (0,7%); one of these strokes was lethal (0,3%). Minor complications (1,0%) were vascular access related (0,7%) and transient ischemic attack (TIA) (0,3%). Conclusions In a large, single center cohort of unselected patients, initial experience with de novo PFA for PVI in patients with AF seems to be fast and effective. There were no PFA-specific complications, but the frequency of catheter complications (tamponade, stroke) in this relatively old patient population with a relatively long history of AF demonstrates that there is still room for improvement. The number of complications improved significantly over the course of time, indicating that the learning curve could have negatively influenced the incidence of complications.

Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (PAF). Only very limited data on learning curves after implementing this new technique in clinical practice exist. We present data from our experience with learning curves using pulsed field ablation for atrial fibrillation. Methods In patients with paroxysmal or persistent AF, PVI in conscious sedation using a steerable sheath and a pentaspline over-the-wire basket and flower PFA catheter was performed. No 3D mapping system was used. Total procedure time, left atrial (LA) dwell time, time from first to last ablation and fluoroscopy time were analysed over the course of time. First and last chronological tertiles of each parameter were compared for statistical significance. Results This study included a total of 147 patients (mean age: 66±10 years; 41% female). Mean CHA2DS2-VASc-score was 2,4±1,5. The procedures were performed by 4 operators (3 certified EP specialists and 1 EP fellow) in random teams of 2 operators. Median skin-to skin procedure time was 47 [40;61] min. There was a statistically significant decrease between the first and last tertiles: 53 [44;68] vs. 46 [41;54] min (p Conclusions The introduction of a novel pulsed field ablation system for pulmonary vein isolation used by 4 operators leads to a significant decrease in total procedure time, LA dwell time and fluoroscopy time over the course of time, demonstrating streamlining of the ablation procedure as a whole. Time from first to last ablation remains constant, this is probably due to the standardized protocol of the ablation itself.

Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (PAF). A few small clinical studies and registries have reported an initial clinical success rate of approx. 80% after 1 year. Here, we present the results from re-do ablation after PVI using PFA for AF. Methods In symptomatic AF patients, re-do ablation in conscious sedation using a contact force sensing catheter and 45W RF energy was performed. In all patients, pre- and post-ablation high-density bipolar voltage 3D maps using a pentaspline diagnostic catheter were performed. Procedural parameters and acute success were assessed. Results Eighteen patients (age 67 years; 17% female; 56% PAF) from a total of 304 patients (age 67 years; 42% female; 47% PAF) (6%) treated with PFA as initial AF therapy underwent a re-do ablation 212 days after the index procedure. Mean CHA2DS2-VASc-score was 1,7 in the re-do group vs. 2,5 in the index procedure group. Mean duration since first AF diagnosis and BMI were not significantly different. In 12/18 (67%) patients, reconnection of at least 1 PV was found (LSPV 2x; LIPV 4x; RSPV 2x; RIPV 2x, left carina 4x; right carina 2x). All reconnected PVs were successfully reisolated. In 11/18 (61%) of patients, an atrial flutter (AFL) or tachycardia (AT) was identified (roof 5x; mitral isthmus 5x; anterior/septal 3x; cavotricuspid isthmus 5x). In 5/12 (42%) of patient with reconnection of at least 1 PV, AT/AFL occurred. In contrast, in all 6 patients (100%) with persistently isolated PVs AT/AFL occurred. All tachycardias were successfully ablated. Conclusions Re-do ablation rate after PFA for AF was relatively low (6%), involving mostly male patients. PV reconnection rate was 67%, site of PV reconnection was predominantly left-sided. In 61%, predominantly left-sided AT/AFL occurred. Notably, in all patients with persistently isolated PVs AT/AFL was observed.

Funding Acknowledgements Type of funding sources: None. Background Pulsed field ablation (PFA) has recently been introduced as a novel routine ablation technology for paroxysmal atrial fibrillation (PAF). It is also used as off-label therapy for persistent AF. PFA can be performed "cryo-style" using fluoroscopy only, or additional pre- and post-ablation high-density 3D bipolar voltage maps can be performed to assess lesion formation and acute pulmonary vein isolation. We compared acute outcome after PFA using fluoroscopy only (X-ray) vs. PFA guided by 3D mapping (3D). Methods In patients with AF, PVI in conscious sedation using a steerable sheath and a pentaspline over-the-wire basket and flower PFA catheter was performed. In a subset of patients, pre- and post-ablation high-density bipolar voltage 3D maps (Carto 3D) were performed. Procedural parameters, acute success and in-hospital safety were assessed. Results A total of 4 operators treated 218 patients (mean age 66 years (range 35–86), female 43%, mean BMI 28 kg/m2 (range 20-42), mean CHA2DS2-VaSc score of 2,5 (range 0-7), first-time ablation 93%, paroxysmal AF/persistent AF/re-do 72/21/7%). Mean duration since first AF diagnosis was 42 months (range 1-336). Most procedures were performed under deep conscious sedation without intubation (99%). There were no selection criteria for the use of 3D mapping. Pre- and post-ablation high-density maps were performed in 28% of cases. Skin-to skin procedure time was 54±22 in the X-ray group vs. 123±35 min in the 3D group, respectively (p Conclusions In a large, single center cohort of unselected patients, PVI using PFA with or without 3D mapping system resulted in a similar acute outcome and safety profile. Procedure and fluoroscopy times were significantly shorter in the fluoroscopy only group. There were no PFA-specific complications, but the frequency of catheter complications in this relatively old patient population demonstrates that there is still room for improvement.

m6A mRNA methylation controls cardiomyocyte function and increased overall m6A levels are a stereotyping finding in heart failure independent of the underlying etiology. However, it is largely unknown how the information is read by m6A reader proteins in heart failure. Here we show that the m6A reader protein Ythdf2 controls cardiac function and identified a novel mechanism how reader proteins control gene expression and cardiac function. Deletion of Ythdf2 in cardiomyocytesin vivoleads to cardiac hypertrophy, reduced heart function, and increased fibrosis during pressure overload as well as during aging. Similarly,in vitrothe knockdown of Ythdf2 results in cardiomyocyte growth and remodeling. Mechanistically, we identified the eucaryotic elongation factor 2 as a major target of Ythdf2 using cell type specific Ribo-seq data. Our study expands our understanding on the regulatory functions of m6A methylation in cardiomyocytes and how cardiac function is controlled by the m6A reader protein Ythdf2.

Recent investigations on a novel multi-regime burner (MRB) configuration showed significant deviations in the CO flame structure compared to the limiting cases of premixed and non-premixed flames. However, a prior analysis revealed that major species and temperature are captured by both limiting cases (Butz et al., Combust. Flame, 2019 [1]). In the present work, large eddy simulations using an artificial thickened flame approach and tabulated chemistry are performed for the MRB configuration. Simulation results are compared to experimental Raman/Rayleigh/CO-LIF and PIV measurements, confirming the applicability of the modeling approach. Further, simulation results are consistent with the aforementioned prior analysis. Special attention is paid to predicting CO by analyzing the conditional flame structure and the effects of local residence time. This combined CO and residence time analysis reveals that local convective and diffusive transport processes should be resolved simultaneously with the unsteady flow, instead of being tabulated. Substantial improvements in CO are achieved when local transport is considered.

Gradient free regime identification (GFRI) is applied to 1D Raman/Rayleigh/LIF measurements of temperature and major species from the intermediate velocity case of the Sydney piloted inhomogeneous jet flame series to better understand the structure of reaction zones and the downstream evolution of multi-regime characteristics. The GFRI approach allows local reaction zones to be detected and characterized as premixed, dominantly premixed, multi-regime, dominantly non-premixed, or non-premixed flame structures, based on flame markers (mixture fraction, chemical mode, and heat release rate) derived from the experimental data. The statistics of chemical mode zero-crossings, which mark premixed reaction zones, and the relative populations of flame structures are shown to be sensitive to the state of mixing in the near field of the flame and to the level of local extinction farther downstream. Multi-regime structures, where premixed and non-premixed reaction zones occur in close proximity and both contribute to overall heat release, account for nearly half the total population at streamwise locations within the first several jet diameters. There is a rapid transition within the near field whereby the relative population of non-premixed and dominantly non-premixed structures grows from 0.05 to nearly 0.5, and the population of premixed and dominantly premixed structures decreases correspondingly as fluid entering the reaction zone becomes progressively fuel-rich. Local extinction and re-ignition bring a resurgence in premixed-type structures, many of which occur at fuel-lean conditions. There are also modest populations of multi-regime structures, having chemical mode zero-crossings at lean conditions, which would not exist in a fully burning jet flame.

In this work, the flame structures of the recent Darmstadt turbulent premixed/stratified flame series with 20% volume fraction H2 addition (Schneider et al., PCI, 2019) are analyzed using flamelet tabulated manifolds. Three different methane/hydrogen flames (MHFs) with increasing complexity are studied. The effects of differential diffusion, stretch and stratification on the applicability of the flamelet model are investigated in detail. Specifically, to investigate the differential diffusion effects, three different modeling approaches are considered, in which the diffusion fluxes are calculated using the multi-component (MC), mixture-averaged (MA) and unity Lewis number (Le1) approaches. To investigate stretch effects, a strained premixed flamelet (SPF) model is proposed, in which the flame’s internal response to stretch is characterized with an additional tabulation coordinate. A double-conditioning analysis is conducted for different flame series. The dataset is conditioned on both the local equivalence ratio and local stratification to analyze the coupling effects of stratification and differential diffusion on the flame structure. Overall, the flamelet predictions are consistent with the experimental findings for all flames.

BACKGROUND: Persistent airflow limitation (PAL) occurs in a subset of patients with asthma. Previous studies on PAL in asthma have included relatively small populations, mostly restricted to severe asthma, or have no included longitudinal data. The aim of this post-hoc analysis was to investigate the determinants, clinical implications, and outcome of PAL in patients with asthma who were included in the ATLANTIS study.METHODS: In this post-hoc analysis of the ATLANTIS study, we assessed the prevalence, clinical characteristics, and implications of PAL across the full range of asthma severity. The study population included patients aged 18-65 years who had been diagnosed with asthma at least 6 months before inclusion. We defined PAL as a post-bronchodilator FEV1/forced vital capacity (FVC) of less than the lower limit of normal at recruitment. Asthma severity was defined according to the Global Initiative for Asthma. We used Mann-Whitney U test, t test, or χ2 test to analyse differences in baseline characteristics between patients with and without PAL. Logistic regression was used for multivariable analysis of the associations between PAL and baseline data. Cox regression was used to analyse risk of exacerbation in relation to PAL, and a linear mixed-effects model was used to analyse change in FEV1 over time in patients with versus patients without PAL. Results were validated in the U-BIOPRED cohort.FINDINGS: Between June 30, 2014 and March 3, 2017, 773 patients were enrolled in the ATLANTIS study of whom 760 (98%) had post-bronchodilator FEV1/FVC data available. Of the included patients with available data, mean age was 44 years (SD 13), 441 (58%) of 760 were women, 578 (76%) were never-smokers, and 248 (33%) had PAL. PAL was not only present in patients with severe asthma, but also in 21 (16%) of 133 patients with GINA step 1 and 24 (29%) of 83 patients with GINA step 2. PAL was independently associated with older age at baseline (46 years in PAL group vs 43 years in non-PAL group), longer duration of asthma (24 years vs 12 years), male sex (51% vs 38%), higher blood eosinophil counts (median 0·27 × 109 cells per L vs 0·20 × 109 cells per L), more small airway dysfunction, and more exacerbations during 1 year of follow-up. Associations between PAL, age, and eosinophilic inflammation were validated in the U-BIOPRED cohort, whereas associations with sex, duration of asthma, and risk of exacerbations were not validated.INTERPRETATION: PAL is not only present in severe disease, but also in a considerable proportion of patients with milder disease. In patients with mild asthma, PAL is associated with eosinophilic inflammation and a higher risk of exacerbations. Our findings are important because they suggest that increasing treatment intensity should be considered in patients with milder asthma and PAL.FUNDING: Chiesi Farmaceutici and Dutch Ministry of Economic Affairs and Climate Policy (by means of the public-private partnership programme).

International audience; Interactions between premixed and non-premixed reaction zones can lead to complex mixed combustion regimes, here denoted as multi-regime combustion, which pose challenges to many conventional combustion modeling approaches. Such conditions occur in most practical combustors and can originate from partial premixing, mixture inhomogeneities/stratification, hot product recirculation, or local flame extinction and re-ignition. Therefore, novel equations are derived for modeling multi-regime combustion which are formulated with respect to a twodimensional composition space spanned by mixture fraction and reaction progress variable. Contrary to previous works, the dependency of the progress variable on the mixture fraction is considered in the new model. This is achieved by splitting the progress variable gradient into an aligned and an orthogonal component with respect to the mixture fraction gradient and the latter is used to define the second coordinate. In the theory that follows, a balance equation for the progress variable on mixture fraction iso-surfaces is formulated. Using this balance equation together with the orthogonal coordinate system, the transformation of species and temperature equations to the 2D composition space yields a novel set of equation without so-called cross-terms. This is advantageous since cross-terms obtained with previous approaches lack a general closure and it is uncertain if it exists at all. Furthermore, the approach allows to naturally distinguish between non-premixed and premixed combustion regimes, auto ignition, and it covers multi-regime combustion characteristics. The theory is validated and discussed by means of a fully resolved solution of a laminar triple flame using detailed chemistry. At first, regions which exhibit premixed, non-premixed or multi-regime combustion characteristics are identified. The triple flame solution then serves as a database from which all relevant theoretical relations are post-processed and validated. In comparison to budgets of conventional 1D flamelet equations for premixed and non-premixed combustion it is shown that only the full set of transport terms considered in the 2D equations accurately balances chemical source terms everywhere in the triple flame, especially in regions where

To study combustion fundamentals of complex fuels under well-defined boundary conditions, a novel Temperature Controlled Jet Burner (TCJB) system is designed that can stabilise both gaseous or pre-vaporised liquid fuels. In a first experimental exploratory study, piloted turbulent jet flames of pre-vaporised methanol, ethanol, 2-propanol and 2-butanol mixtures are compared to methane/air as a reference fuel. Complementary one-dimensional laminar flame calculations are used to provide flame parameters for comparison. Blow-off and flame length as global flame characteristics are measured over a wide range of equivalence ratios. For fuel rich conditions, blow-off limits correlate well with extinction strain rate calculations. Differing flame lengths from lean to rich conditions are explained partly by different flame wrinkling that is assessed using planar laser-induced fluorescence imaging of the hydroxyl radical (OH-PLIF). A study of Lewis-number effects indicates that they have substantial influence on flame wrinkling. Lean alcohol/air flames, opposed to methane/air, have a Lewis-number greater than unity. This impedes curvature development, which promotes relatively large flame lengths. In contrast, across stoichiometric conditions, all alcohol/air mixture Lewis-numbers decrease significantly. At such conditions, alcohol/air flames show alike or even larger wrinkling compared to methane/air flames. However, quantitatively, the differences in flame length and wrinkling observed among the flames can neither be explained alone by Lewis-number differences, nor other global mixture parameters available from 1D laminar flame calculations. This study shall therefore emphasise the need for more detailed experimental analyses of the full thermochemical state of laminar and turbulent flames fuelled with complex fuels.

RATIONALE: Recent guidelines consider chronic cough to be a unique clinical entity with different phenotypes. We aimed to investigate them in a general population and to describe prevalence, distribution, and characteristics of these phenotypes within the Austrian general population.METHODS: From the LEAD study, a longitudinal observational population-based cohort, data from questionnaires and spirometry of 10,057 adult participants was analysed. Chronic cough was defined as coughing nearly every day during the last 12 months for at least 3 months (>12 weeks).RESULTS: The prevalence of chronic cough was 9% and increased with age. We found no sex predominance but a female preponderance (68%) in never smokers. A presumable cause was identified in 85% of which more than half (53.9%) had two phenotypes, 36.9% belonged to one only and 9.2% to three or more. Regarding the distribution of phenotypes, 40.8% were current smokers, 32.6% had an ACE inhibitor intake, 18.2% GERD, 17.6% asthmatic cough, 9.7% UACS and 28.3% other diseases associated with chronic cough. 15% had unexplained chronic cough with no identifiable phenotype. Current smoking, low socioeconomic status, obesity, COPD and obstructive sleep apnea were associated factors with chronic cough.CONCLUSION: Chronic cough is common among adults in Austria and highly prevalent in the older population. Most participants can be phenotyped with simple questionnaire-based assessment and can therefore potentially receive specific treatment without intensive clinical workup.

In practical applications, partial premixing of fuel and oxidizer, as well as recirculation of combustion products, result in complex combustion scenarios where multi-regime effects arise and a numerical representation of local reaction zones by purely premixed or purely non-premixed flame structures may not hold. Here, a novel burner system is introduced to investigate the fundamental characteristics of multi-regime combustion and to provide a basis for validating numerical models. This multi-regime burner (MRB) is specifically designed to produce flames with multi-regime characteristics while maintaining well-defined boundary conditions. Thermochemical data from Raman/Rayleigh/CO-LIF scattering experiments are provided for two selected operating conditions. The experimental investigation focuses on the overall flame structure by examining radial profiles of temperature and mixture fraction, as well as scatter plots of temperature, CH4, and CO versus mixture fraction. In order to assess the relative importance of different flame regimes, the gradient-free regime identification (GFRI) approach is extended to allow for an automated classification of local reaction zone structures. Classification criteria are defined, based on the ratio of local heat release rate peaks associated with premixed and non-premixed reaction zones located in close spatial proximity, and an automated process is implemented to classify 1D Raman/Rayleigh sample lines as premixed, dominantly premixed, multi-regime, dominantly non-premixed, or non-premixed flame zones. The importance of different flame zones, indicated by their population fractions, are found to evolve with downstream distance and show distinct differences between the two selected flames. Further, a prior analysis is used to test the applicability of 1D flame structure assumptions for the underlying combustion regime.

Obtaining information about burning characteristics and flame structures by analyzing experimental data is an important issue for understanding combustion processes and pursuing combustion modeling approaches. It has been shown that Raman/Rayleigh measurements of major species and temperature can be used to approximate the local heat release rate and the chemical explosive mode, and that these results are sufficiently accurate for a qualitative assessment of the relative importance of different heat release zones within the same overall flame structure in laminar and mildly turbulent partially premixed flames [1] , [2] . The present study uses data from direct numerical simulation (DNS) to extend and quantify the understanding of the approximation method with respect to premixed and stratified-premixed flames with significant turbulence–chemistry interaction (high Karlovitz number). The accuracy of the approximation procedure is assessed as previously applied, using just major species and temperature, as well as with the OH radical included as an additional experimentally accessible species. The accuracy of the local chemical explosive mode and the local heat release rate results from the approximation are significantly improved with OH included, yielding quantitative agreement with the DNS results. Further, a global sensitivity analysis is applied to identify the sensitivity of the heat release rate and chemical explosive mode to experimental uncertainties imprinted upon the DNS data prior to the approximation procedure.

Premixed flame characteristics play a crucial role in most advanced combustion applications, such as gas turbines, aircraft combustors or internal combustion engines. The laminar burning velocity is one key parameter to determine the stabilisation and propagation of premixed flames. This study examined the influence of high pressures on the laminar burning velocity of biofuels and the correlation between laminar burning velocity and pressure. The investigated biofuels were pure ethanol as the state-of-the-art surrogate, pure iso-butanol as a possible alternative and several blends of ethanol/iso-octane. Due to the usage of two methods to measure the laminar burning velocity – the Heat Flux burner and the closed combustion vessel – a comparison was added for atmospheric conditions. The measured laminar burning velocities were conducted for equivalence ratios from 0.7 to 1.3, a pressure range from 1 bar(a) to 15 bar(a) and 373 K. The results were further compared to existing numerical mechanisms and literature data. The numerical mechanisms reveal prediction performances in the range of 0.2 cm/s (0.4%) and 5.2 cm/s (16.2%) for dedicated mechanisms and equivalence ratios between 0.9 and 1.1. The two methods show deviations of the laminar burning velocities between 2.3 cm/s (4.9%) and 6.7 cm/s (11.4%).

Understanding and quantifying the relative importance of premixed and non-premixed reaction zones within turbulent partially premixed flames is an important issue for multi-regime combustion. In the present work, the recently-developed method of gradient-free regime identification (GFRI) is applied to instantaneous 1D Raman/Rayleigh measurements of temperature and major species from two turbulent lifted methane/air flames. Local premixed and non-premixed reaction zones are identified using criteria based on the mixture fraction, the chemical explosive mode, and the heat release rate, the latter two being calculated from an approximation of the full thermochemical state of each measured sample. A chemical mode (CM) zero-crossing is a previously documented marker for a premixed reaction zone. Results from the lifted flames show strong correlations among the mixture fraction at the CM zero-crossing, the magnitude of the change in CM at the zero-crossing, and the local heat release rate at the CM zero-crossing compared to the maximum heat release rate. The trends are confirmed through a comparable analysis of numerical simulations of two laminar triple flames. These newly documented trends are associated with the transition from dominantly premixed flame structures to dominantly non-premixed flames structures. The methods introduced for assessing the relative importance of local premixed and non-premixed reactions zones have potential for application to a broad range of turbulent flames.

International audience; A combustion regime identification based on convolutional neural networks (CNNs) is developed using the recently proposed gradient-free regime identification (GFRI) approach applied to two turbulent CH 4 /air jet flames featuring multi-regime characteristics. The training and the subsequent application of the CNN rely on the processing of one-dimensional Raman/Rayleigh line measurements of species mass fractions and temperature (CNN input). The combustion regime index is then readily predicted at every point along the measured line (CNN output). For training the neural network, the combustion regime index is first determined using the GFRI method (Hartl et al., 2018) based on the chemical explosive mode analysis (CEMA). Six classes of combustion regimes, including premixed (P), dominantly premixed (DP), multi-regime (MR), dominantly non-premixed (DNP), non-premixed (NP), and lean back-supported (LBS), are well detected by the trained CNN, with a pixel-wise accuracy of more than 85% for burner operating conditions unseen during training (different free-stream equivalence ratios). The quasi instantaneous neural network response provides a perspective towards real-time global combustion regime identification for pollutants emission control. From the results, it is also concluded that introducing physical insight, by combining advanced experimental (Raman/Rayleigh line measurements) and numerical analysis (GFRI), allows for reducing the amount of data needed to train neural networks.

Laminar dimethyl ether (DME) coflow jet flames, defined by different levels of partial premixing in the fuel stream, provide canonical test cases for studying conditions in between perfectly premixed and non-premixed characteristics. This work investigates the structure of DME/air flames and the evaluation of suitable flamelet modeling approaches. Three laminar, partially premixed DME/air flames are studied using fully resolved numerical simulations and the flamelet/progress variable (FPV) approach. The flame structure of the partially premixed DME/air flames is discussed and selected slices are compared to each other as well as to Raman/Rayleigh data. Overall, the experimental data is well predicted and the local flame structure is represented by the fully resolved simulations. In the context of the FPV approach, an a priori analysis of the underlying tabulated manifold is carried out. Lookup tables based on strained counterflow flames were identified as the most suitable candidate for the fully coupled FPV simulations of all three partially premixed DME/air flames. The FPV results are further compared a posteriori to the fully resolved simulation data. The flame structure of the partially premixed DME/air flames was reproduced and good results were obtained for the temperature and the species mass fractions. This numerical investigation contributes to the understanding of local flame structures in partially premixed DME/air flames and has the potential to support model selection in complex combustion processes.

Current methods for combustion regime characterization, such as the flame index, rely on 3D gradient information that is not accessible with available experimental techniques. Here, a method is proposed for reaction zone detection and characterization, which can be applied to instantaneous 1D Raman/Rayleigh line measurements of major species and temperature as well as to results of laminar and turbulent flame simulations, without the need for 3D gradient information. Several derived flame markers, namely the mixture fraction, the heat release rate, and the chemical explosive mode, are combined to detect and characterize premixed versus non-premixed reaction zones. The methodology is developed and evaluated using fully resolved simulation data from laminar flames. The fully resolved 1D simulation data are spatially filtered to account for the difference in spatial resolution between experiment and simulation. Then, starting from just temperature and major species, a constrained homogeneous constant pressure, constant temperature reactor calculation gives an approximation of the full thermochemical state at each sample location along the line. Finally, the chemical explosive mode and the heat release rate are calculated from this approximated state and compared to those calculated directly from the simulation data. As a further test, experimental uncertainty is superimposed onto the filtered numerical data to produce a Raman/Rayleigh equivalent state before running the constrained homogeneous reactor, and results are again compared. After successful tests using the numerical data, the approach is applied to Raman/Rayleigh line measurements from laminar counterflow flames and a mildly turbulent lifted flame. The results confirm that the reaction zones can be reliably detected and characterized using experimental data. Furthermore, the relative importance of premixed and non-premixed reaction zones within the same flame can be qualitatively assessed as demonstrated in the results.

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

A detailed reaction mechanism for ethanol combustion was developed for describing ignition, flame propagation, and species concentration profiles with high accuracy. Starting from a modified version of the ethanol combustion mechanism of Saxena and Williams (Proc. Combust. Inst. 2007, 31, 1149–1156) and adopting the H2/CO base chemistry from the joint optimized hydrogen and syngas combustion mechanism of Varga et al. (Int. J. Chem. Kinet. 2016, 48, 407–422), an optimization of 54 Arrhenius parameters of 16 important elementary C1/C2 reactions was performed using several thousand direct and indirect measurement data points as well as the results of theoretical determinations of reaction rate coefficients. The final optimized mechanism was compared to 16 reaction mechanisms that have been used for the simulation of ethanol combustion with respect to the accuracy in reproducing the available experimental data, including measurements of ignition delay times in shock tubes (444 data points in 39 data sets) and rapid compression machines (20/3), laminar burning velocity measurements (1011/124), and species profiles measured using flow reactors (1750/23), jet-stirred reactors (398/6) and shock tubes (8871/14). In addition to providing best fitted values for 54 Arrhenius parameters, the covariance matrix of the optimized parameters was calculated, which provides a description of the temperature-dependent ranges of uncertainty for each of the optimized rate coefficients.

The effect of different degrees of plastic deformation on the frequency dependence of coercive field and losses in NO Fe–(3 wt%)Si was investigated measuring hysteresis loops on a ring-shaped core over a frequency range of 0.5–1000 Hz. The investigation was performed under sinusoidal and triangular external field $H(t)$ . Although $H(t)$ induce a similar quasi-sinusoidal magnetic induction (similar hysteresis loops), the loop area is smaller for that measured by triangular applied field resulting in smaller magnetic losses. The coercive field and the total losses of all samples increase with increasing frequency; however, the influence of frequency becomes gradually smaller with plastic deformation. The total losses that increase due to plastic deformation at low frequencies become at high frequencies smaller in deformed samples than in an undeformed material. A similar behavior was found in the frequency dependence of the coercivity. Due to a periodic quasi-sinusoidal $B(t)$ , the losses were analyzed using the concept of loss separation. While the quasi-static (hysteresis) loss increases, classical and excess losses decrease with increasing deformation.

The frequency dependence of the hysteresis loop of high-pressure torsion treatment (HPT)-deformed Fe75Al25, industrial steel Fe–3wt%Si, bulk Fe–3wt%Si plates, and nanocrystalline VP800 was measured on ring-shaped samples. Applying a sinusoidal or triangular $H(t)$ delivers a strong frequency dependence of the losses. A sinusoidal or triangular $B(t)$ reduces the total loss [this reduction is larger for triangular $B(t)$ ] and the dependence of loss on frequency becomes smaller. Our results are discussed in terms of Bertotti’s loss separation model. For HPT-deformed Fe75Al25, the total loss $W$ linearly varies with the square root of frequency when a triangular $H(t)$ is applied; however, no significant change in the total loss was found for a triangular induction $B(t)$ up to 500 Hz. The hysteresis, classical, and excess loss values of the Fe–3wt%Si steel plates are different from those of bulk Fe–3wt%Si for all $H(t)$ and $B(t)$ shapes due to different microstructures. In nanocrystalline VP800, the contribution of classical eddy current loss to the total core loss is very small due to high resistivity and small ribbon thickness.

This document is a revision of the guideline for diagnosis and treatment of COPD that replaces the version from 2007. A multitude of recent reports regarding risk factors, diagnosis, assessment, prevention and pharmacological as well as non-pharmacological treatment options made a major revision mandatory. The new guideline is based on the GOLD document taking into account specifics in Germany and Austria.Das vorliegende Dokument ist eine Neufassung und Aktualisierung der Leitlinie zur Diagnostik und Therapie von Patienten mit COPD, die die bisherige Version aus dem Jahr 2007 ablöst. Die Fülle an neuen Erkenntnissen zu Risikofaktoren, Diagnostik, Schweregradeinschätzung, Prävention und medikamentösen sowie nicht medikamentösen Therapiemaßnahmen machten eine umfassende Überarbeitung erforderlich. Die neue Leitlinie baut auf das GOLD-Dokument unter Berücksichtigung von Besonderheiten in Deutschland und Österreich auf.

Partial oxidation (POX) reactors are characterized by different reaction regimes: the near burner zone is mainly governed by the mixing of the initially non-premixed reactants and by the fast oxidation zone, while the post-flame zone is mainly governed by the slow reforming reactions under almost fully premixed conditions. Advanced turbulence–chemistry interaction models are required to describe different regimes in POX reactors. This work investigates the use of the flamelet/progress variable (FPV) approach in laminar and turbulent POX reactors. The FPV approach allows different times and length scales to be captured, using a progress variable to describe the advancement of the reactions in reacting mixtures. The solution of the chemical reactions is generally separated from the solution of the flow and mixing by pre-calculating solutions of one-dimensional canonical flames. The solution of the chemistry is stored in look-up tables and linked to the solution of the flow using the mixture fraction and the progress variable scalars. In this work, different methods for generating the flamelet look-up tables are analyzed for a laboratory reference laminar POX flame. The results are compared to the direct numerical simulation with the goal of identifying the most suitable flame structure for tabulation in POX systems. These results are then used to build a FPV table. Finally, a pilot-scale high-pressure POX reactor was investigated and the numerical results are validated using the measured composition of the syngas at the exit of the reactor.

In the present study the flame structure of a piloted partially-premixed dimethyl ether flame (DME-D), which is based on the Sydney/Sandia piloted jet burner flame series, is investigated using an LES-flamelet-progress variable approach (LES-FPV). Simulation results are used together with a comprehensive experimental data set including multi-scalar measurements of temperature and major species from Raman/Rayleigh scattering, intermediate species CH2O and OH from laser induced fluorescence (LIF) and velocity data from particle image velocimetry (PIV). The comparison between numerical and experimental data includes the mean and the root mean square (RMS) radial profiles for velocity, mixture fraction, temperature and mole fractions of major species at different downstream locations. Furthermore, species distributions conditioned on the experimentally accessible mixture fraction are compared and differences between DME and methane flames are discussed. In addition to this comparison, the computation of CH2O-LIF and OH-LIF signals as well as the effective Rayleigh cross-section was incorporated into the flamelet-progress variable approach. The filtered and time-averaged numerical results are then directly compared with the corresponding experimental signals at different axial positions. The characteristic separation of instantaneous CH2O and OH fields, which was previously observed in simultaneous LIF measurements, is discussed and analyzed based on the underlying flamelet structures. Finally, modeling assumptions from the experimental post-processing for the effective Rayleigh cross-section, which were introduced to account for the experimentally inaccessible intermediate hydrocarbons, are evaluated using the detailed species composition from the numerical simulations.

Flame structure look-up table generating strategies, e.g. the flamelet-progress variable approach, are based on the definition of a suitable progress variable. This variable is usually obtained from a linear combination of the species’ mass fractions contained in the system. The most important issue is the unique mapping between the progress variable and the independent variable, e.g. space or time. This is ensured by claiming the monotonicity of the progress variable. For simple fuel-oxidiser compositions, this can be performed by analysing the flame structure. However, in the case of complex chemical systems, finding such a progress variable is a non-trivial task, since a lack of monotonicity in the main species mass fractions often exists. In this article it is investigated how a valid progress variable can be found by an automated procedure. Some recent investigations use the fact that finding a monotonous progress variable is equivalent to solving a constrained optimisation problem. The new approach is to construct an algorithm to find a valid progress variable, which is also optimal in the sense that the gradients of the tabulated quantities are minimized. This leads to smoother data and reduces the interpolation effort when reading from the table. The method solves a nonlinear optimal control problem, where the monotonicity of the progress variable is ensured as an inequality constraint by using a genetic algorithm. Finally the performance of the new algorithm is evaluated for homogeneous reactor calculations and laminar diffusion flamelet look-up tables.

The substitution of gasoline with bio-ethanol is an intended way to reduce the climate impact of the traffic sector. To extend the knowledge of fundamental flame properties of ethanol/iso-octane flames and improve the numerical predictions for the effect of ethanol blending in internal combustion engines, measurements of the laminar burning velocity of established blend ratios of ethanol and iso-octane were carried out and compared to existing numerical mechanisms. The measurements were carried out with the Heat Flux burner, with thermocouples of type E at the burner plate, which was adapted with an evaporation unit based on direct vaporization to investigate the liquid fuels. The preheating temperature ranges from 298 K to 373 K and the pressure is atmospheric. First measurements of the laminar burning velocity of ethanol/air and iso-octane/air flames were carried out for validating the system. A good agreement with available literature data could be achieved for the investigated equivalence ratios from 0.7 to 1.4. Furthermore laminar burning velocities of different iso-octane/ethanol/air blends, namely E10, E24, E40 and E85, are presented. Through variation of the preheating temperatures (298 K, 323 K, 348 K and 373 K) the temperature dependency could be analyzed. The uncertainty analysis of the measurements has been revealed. Numerical simulations were carried out using different chemical mechanisms for ethanol/air flames, iso-octane/air flames as well as various fuel blends and preheating temperatures and are compared to the experimental data. The agreement is evaluated through a classification of the discrepancy between both.

Combustion of lean and ultra-lean synthetic H 2 /CO mixtures that are highly diluted in inert gases is of great importance in several fields of technology, particularly in the field of post combustion for combined heat and power (CHP) systems based on fuel cell technology. In this case H 2 /CO mixtures occur via hydrocarbon reforming and their complete conversion requires efficient, compact and low emission combustion systems. In order to design such systems, knowledge of global flame properties like the laminar burning velocity, is essential. Using the heat flux burner method, laminar burning velocities were experimentally determined for highly N 2 diluted synthetic H 2 and H 2 /CO mixtures with low calorific value, burning with air, at ambient temperature and atmospheric pressure. Furthermore, numerical 1-D simulations were performed, using a series of different chemical reaction mechanisms. These numerical predictions are analysed and compared with the experimental data.

In March 2010, the European Respiratory Society funded a pilot audit programme of the process and outcomes of hospital care for patients admitted with exacerbations of COPD and on the organisation of care at hospital level. Originally it was intended to involve just five countries in this pilot scheme but such was the enthusiasm from national societies that 13 participated in the data collection programme. In March 2012, ERS published a document containing the results at national level for 19,021 cases entered into the audit database and subsequently site specific data has been distributed to each of the 422 hospitals that participated as shown in figure 1. Figure 1 Hospitals participating in the European COPD Audit. These data are unique in that they have been collected by clinicians prospectively identifying cases then recording in hospital care processes and patient outcomes at 90 days after admission date. In order to collect the data, many individuals had to use their time and skills but the success of the data collection is testimony to the enthusiasm of clinicians to better understand the quality of care delivered in their own institutions. The results are salutary and deserve our attention. In essence, they describe a standard of care with significant variation in adherence to guideline standards both within countries and between them. Arterial blood gases are taken on admission in only 12% cases in one country ranging to 96% in another whilst antibiotics are given to only 54% cases in country A yet 95% in country B. Unsurprisingly, outcomes vary equally widely with median length of stay at national level varying 5–15 days. At this stage in the data analysis, it is not possible to say why this occurs and there may be a number of explanations. There are certainly significant differences in case mix between …

Respiratory diseases place considerable burden on society and are among the leading causes of mortality worldwide. Within the European Union, these diseases account for 17% of male and 10% of female deaths [1]. In monetary terms, the European Lung Foundation (ELF)/European Respiratory Society (ERS) estimates economic burden at approximately €102 billion or €118 per capita [2]. It is concluded that failure to diagnose, treat or manage respiratory diseases, results not only in higher treatment costs, but also impacts upon quality of life and well-being for the patient. Subspecialty training and career development of the young respiratory specialist has been identified as a fundamental aspect of delivering quality care and strengthening respiratory medicine. Moreover, as adult respiratory specialists increasingly seek opportunities abroad, the harmonisation of standards to train specialists in respiratory medicine across Europe becomes crucial. Working towards consistent criteria for respiratory medicine, ERS, since 1990, continues to produce consensus statements and clinical practice guidelines on issues related to this field of medicine. In 2005, as part of the mission to advance the practice of the specialty, the HERMES (Harmonised Education in Respiratory Medicine for European Specialists) project was born to provide a shared framework for the training and certification of adult respiratory specialists across countries. Justification for the project grew from results of a number of surveys carried out by ERS [3] confirming the stark differences of medical educational programmes and lack of homogeneity of syllabus, curriculum and exit criteria for training of adult respiratory specialists. Within the HERMES model, a process of establishing consensus standards for training largely follows four key phases (fig. 1) with the goal of developing collective documentation and activities. To date, three of the phases have been published and delivered by the HERMES Task Force, and are available in …

We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.

Corrosiveness of enamel surfaces of Smartbleach®, Opus White®, Opalescense Xtra Boost® and a gel containing titanium dioxide (TiO2) particles, activated either by a frequency doubled neodymium: yttrium–aluminum–garnet (Nd:YAG) laser (532 nm) or a diode laser (810 nm) was evaluated by environmental scanning electron microscopy (ESEM). Changes in teeth color shades and the pH were also evaluated. Each bleaching agent was laser activated for 30 s and removed after 1 min or 10 min. This procedure was repeated up to four times, the bleaching agent receiving a maximum application time of 40 min, with total irradiation times of 0.5 min to 2 min of laser activation. The results of the pH measurements showed that only Smartbleach® was in the alkaline pH range, whereas the other three were acidic. The surface effects were unrelated to the pH of the bleaching agents. With the exception of Opus White®, no severe alterations on the enamel surface were detected. Although short application times were chosen, improved changes in brightness of up to ten steps on the Vitapan® classical shade guide were detected.