Nonischaemic myocardial fibrosis is associated with progressive deterioration of myocardial function and forms the substrate for arrhythmias in atria and ventricles. In the absence of a specific aetiology, its origin is commonly attributed to preceding viral myocarditis. Athletes presenting with ventricular arrhythmias often demonstrate nonischaemic fibrosis on magnetic resonance imaging. Previous translational studies have shown an adverse effect of exercise on the course of acute viral myocarditis. Nevertheless, the effect on myocardial fibrosis development, a frequent and important consequence of viral myocarditis, has not yet been investigated. In the present study, we evaluate for the first time the impact of endurance exercise on longer-term myocardial inflammation, myocardial fibrosis and arrhythmogenicity using a murine viral myocarditis model. Male C57BL/6J mice (11 weeks of age, n=72) were randomly assigned to 8 weeks of treadmill running (EEX) or without exercise (SED). Two weeks into the study (training or control), animals were injected intraperitoneally with either coxsackievirus B3 to induce acute viral myocarditis (CVB) or vehicle (PBS). Exercising myocarditis mice showed lower mortality (11% vs. 27%), albeit without statistical significance (P=0.23). At sacrifice (i.e. 6 weeks after inoculation), prominent myocardial inflammatory infiltration and cardiomyocyte loss was observed in both CVB groups, without difference on semiquantitative histological scoring. Nevertheless, the infiltrating cells in the CVB-EEX group were more often proinflammatory in nature (predominantly iNOS-reactive macrophages and positive CD8+/CD4+ ratio) compared to these in CVB-SED (predominantly arginase-1-reactive macrophages and higher CD4+/CD8+ ratio). In addition, the EEX group showed more haemosiderin-laden macrophages and spindled fibroblasts as signs of organisation. At that time, the majority of virus was cleared from the heart. Treadmill running during myocarditis enhanced development of interstitial fibrosis (with limited or extensive distribution)(82.4% in CVB-EEX vs. 56.3% in CVB-SED; P=0.049) and perivascular and/or interstitial fibrosis with extensive distribution (64.7% & 64.7% in CVB-EEX vs. 50% & 31.3% in CVB-SED; P=0.048). The highest scar counts were observed in CVB-EEX, but the mean count (1.9 vs. 1.2; P=0.19) did not significantly differ between the myocarditis groups. In CVB-EEX, the lesions contained denser and more organised collagen bundles. In vivo electrophysiology studies showed similar ventricular arrhythmia inducibility (P>0.20) and arrhythmia burden (P=0.49) in the myocarditis groups, although the longest arrhythmias and highest cumulative burden occurred in CVB-EEX. Endurance exercise training during viral myocarditis modulates the longer-term inflammatory process and promotes perivascular and interstitial fibrosis development, potentially enhancing ventricular arrhythmogenicity.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Aims Patients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality. Methods and results We used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existing heart disease and in-hospital mortality. A total of 16 511 patients with COVID-19 were included (21.1% aged 66-75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male, and often had other comorbid conditions when compared with those without. Mortality was higher in patients with cardiac disease (29.7%; n= 1545 vs. 15.9%; n= 1797). However, following multivariable adjustment, this difference was not significant [adjusted risk ratio (aRR) 1.08, 95% confidence interval (CI) 1.02-1.15; P = 0.12 (corrected for multiple testing)]. Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure (aRR 1.19, 95% CI 1.10-1.30; P <0.018) particularly for severe (New York Heart Association class III/IV) heart failure (aRR 1.41, 95% CI 1.20-1.64; P < 0.018). None of the other heart disease subtypes, including ischaemic heart disease, remained significant after multivariable adjustment. Serious cardiac complications were diagnosed in <1% of patients. Conclusion Considerable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare during hospitalization. [GRAPHICS] .

AbstractAimsPatients with cardiac disease are considered high risk for poor outcomes following hospitalization with COVID-19. The primary aim of this study was to evaluate heterogeneity in associations between various heart disease subtypes and in-hospital mortality.Method and resultsWe used data from the CAPACITY-COVID registry and LEOSS study. Multivariable Poisson regression models were fitted to assess the association between different types of pre-existent heart disease and in-hospital mortality. 16,511 patients with COVID-19 were included (21.1% aged 66 – 75 years; 40.2% female) and 31.5% had a history of heart disease. Patients with heart disease were older, predominantly male and often had other comorbid conditions when compared to those without. Mortality was higher in patients with cardiac disease (29.7%; n=1545 versus 15.9%; n=1797). However, following multivariable adjustment this difference was not significant (adjusted risk ratio (aRR) 1.08 [95% CI 1.02 – 1.15; p-value 0.12 (corrected for multiple testing)]). Associations with in-hospital mortality by heart disease subtypes differed considerably, with the strongest association for heart failure aRR (1.19 [1.10 – 1.30]; p-value <0.018) particularly for severe NYHA III/IV) heart failure (aRR 1.41 [95% CI 1.20 – 1.64; p-value <0.018]. None of the other heart disease subtypes, including ischemic heart disease, remained significant after multivariable adjustment. Serious cardiac complications were diagnosed in <1% of patients.ConclusionConsiderable heterogeneity exists in the strength of association between heart disease subtypes and in-hospital mortality. Of all patients with heart disease, those with heart failure are at greatest risk of death when hospitalized with COVID-19. Serious cardiac complications are rare.

Background and aims: One of the objectives of the ESC-EORP EUROASPIRE V survey is to determine how well European guidelines on the management of dyslipidaemias are implemented in coronary patients. Methods: Standardized methods were used by trained technicians to collect information on 7824 patients from 130 centers in 27 countries, from the medical records and at a visit at least 6 months after hospitalization for a coronary event. All lipid measurements were performed in one central laboratory. Patients were divided into three groups: on high-intensity LDL-C-lowering-drug therapy (LLT), on low or moderate-intensity LLT and on no LLT. Results: At the time of the visit, almost half of the patients were on a high-intensity LLT. Between hospital discharge and the visit, LLT had been reduced in intensity or interrupted in 20.8% of the patients and had been started or increased in intensity in 11.7%. In those who had interrupted LLT or had reduced the intensity, intolerance to LLT and the advice of their physician were reported as the reason why in 15.8 and 36.8% of the cases, respectively. LDL-C control was better in those on a high-intensity LLT compared to those on low or moderate intensity LLT. LDL-C control was better in men than women and in patients with self-reported diabetes. Conclusions: The results of the EUROASPIRE V survey show that most coronary patients have a less than optimal management of LDL-C. More professional strategies are needed, aiming at lifestyle changes and LLT adapted to the need of the individual patient.

Single molecule magnets comprising rare earth metals are of high interest due to the unquenched orbital moments of the rare earth ions that result in a large energy barrier for magnetization reversal. We investigate the magnetic properties of polynuclear 3d-4f 15-MC-5 metallacrowns using x-ray magnetic circular dichroism of powder samples at a temperature of 7 K in a magnetic field of 7 T. The sum rule analysis reveals element-specific spin and orbital moments. The magnetic moments of the 3d transition metal Ni(II) ions are coupled antiferromagnetically to each other and contribute only little to the total molecular moment. The spin and orbital moments of the rare earth ions are unexpectedly smaller than the ionic values resulting from Hund's rules. We explain the reduction of the orbital magnetic moment by a finite magnetic anisotropy. Considering an energy functional including magnetic anisotropy and Zeeman energy the powder average reveals a magnetic anisotropy of 28 meV (340 K) in the case of Dy(III) and 7 meV (85 K) in the case of Tb(III). The spin moments agree with the ionic value, too, when the expectation values of the dipole operator are considered.

Background Females as well as lower socioeconomic classes are known to have a worse coronary risk factor profile. The aim of this study was to focus on gender differences regarding risk profile and lifestyle factors, as well as the interplay between gender, age and educational level in a large European sample of patients with clinically developed coronary heart disease. Methods Analyses are based on …

Purpose: The Latent Transforming growth factor Binding Protein 2 (LTBP2) was recently discovered in an unbiased proteomics search for novel markers in patients with acute dyspnea. The highest levels of LTBP2 are found in lung tissue and plasma levels of LTBP2 are a powerful predictor of all-cause mortality in patients presenting with acute dyspnea. We evaluated the relationship between plasma levels of LTBP2 and phenotypic changes suggestive for heart failure with preserved ejection fraction (HFPEF) including parameters of neurohormonal activation, Left Ventricular (LV) remodeling and filling pressures as well as exercise capacity. Methods: We studied 136 stable patients with CAD and LVEF≥50% (mean age 68±8 years, 76% men, LVEF 63±8%, 37% in NYHA class II/III). All patients underwent resting echocardiography for evaluation of LVEF and volumes, TDI derived longitudinal systolic and diastolic velocities function and E/E', as well as a six minute walking distance test (6minWD), maximal bicycle spiroergometry (peakVO2 and VE/VCO2 slope, n=104) and blood sampling. A proteomic approach for antibody-free targeted protein quantification based on high-end mass spectrometry was used to measure LTBP2 levels. Results: Levels of LTBP2 were higher in NYHA II/III as compared to NYHA I patients (p<0.05) and were correlated with NT-proBNP levels (r=0.49, p<0.01). ROC analysis showed a comparable modest AUC of 0.61 (p<0.05) for NT-proBNP and 0.60 (p<0.05) for LTBP2 to discern NYHA I versus NYHA II/III patients. LTBP2 levels were correlated with LV volumes (r=-0.38, p<0.01 for LVEDV, r=-0.33, p<0.01 for LVESV) as well as with LV longitudinal systolic velocities (r=-0.35, p<0.01), LV early diastolic velocities (r=-0.31,p<0.01) and E/E' (r=0.28,p<0.01). In linear regression analysis, including age and creatinine, LVESV and E/E' were independent predictors for LTBP2 levels (all p<0.05). Higher levels of LTBP2 were associated with lower 6minWD (r=-0.43, p<0.001), lower peakVO2 (r=-0.38, p<0.001) and higher VE/VCO2 slope (r=0.36, p<0.001). In multiple linear regression analysis including age, creatinine, LVESV and E/E', LTBP2 levels appeared to be an independent predictor for both 6minWD and peakVO2 (p<0.01). Conclusion: In stable patients with CAD and preserved LV function, higher levels of LTBP2 are related to phenotypic changes suggestive for HFPEF including higher neurohormonal activation, adverse LV remodeling with loss of longitudinal function, higher LV filling pressures and a lower exercise capacity. Therefore, the role of LTBP2 in the development, diagnosis and outcome of HFPEF deserves further study.

Purpose: The optimal in-hospital and pre-discharge management of the mainly elderly patients hospitalised for acute Heart Failure (HF) is still a matter of debate. We evaluated the short and long-term effects of the introduction of a HF nurse for the support of the in-hospital management of these patients. The specific tasks of the HF nurse included participation in daily ward rounds, patient counseling and a pre-discharge medication check. Methods: We performed a sequential comparison of all consecutive patients admitted with HF at the department of cardiology during 2 study periods: group 1 (2008-2009) before introduction of the HF nurse (n=388 pts, mean age 78±11 years, 44% women, 43% HFPEF) and group 2 (2010-2011) after introduction of the HF nurse (n=450 pts, mean age 78±11 years, 46% women, 40% HFPEF). Baseline clinical characteristics, hospitalisation duration and in-hospital mortality as well as pre-discharge medication were compared between the 2 groups. All patients were followed for 1 year for the combined end-point of all-cause mortality and rehospitalisation for HF. Results: Baseline characteristics including clinical characteristics, severity of HF and comorbidities were comparable between the two groups. Although in-hospital mortality was comparable (6.7% vs 8.7%, p=0.30) hospitalisation duration was shorter for group 2 (8 days for group 1 (IQ range 6-14) vs 7 days for group 2 (IQ range 5-13), p=0.034). Introduction of the HF nurse resulted also in a significantly higher use of beta-blockers and mineralocorticoid receptor antagonists at discharge (both for all patients as for the HFREF patients in group 2). After 1 year FU, 156 pts (44%) had died or were rehospitalised for HF in group 1 and 88 patients in group 2 (23%, p<0.01). In multivariate Cox regression analysis, introduction of a HF nurse was associated with a 33% (95% CI 11%-50%, p<0.01) reduction of all cause-mortality or rehospitalisation for HF. Conclusion: The introduction of a HF nurse for the support of the in-hospital management of mainly elderly patients admitted with acute HF, was associated with a shorter in-hospital stay, a more frequent use of evidence-based medication at discharge and a significant reduction of the combined endpoint of all-cause mortality and rehospitalisation for HF after 1 year follow-up.

Purpose: Exercise training has been shown to be beneficial in patients with Heart Failure (HF). We evaluated the participation rate in exercise training after hospitalisation for HF as compared to patients hospitalised for Acute Coronary Syndrome (ACS) or cardiac surgery. Training results were compared between these patient populations and clinical characteristics for non-participation in the HF population were investigated. Methods: Between January 2010 and May 2012 we prospectively evaluated patients who were hospitalised for HF (HF group, n=428), ACS (ACS group, n=467) or cardiac surgery (surgery group, n=358) as well as patients who started a cardiac rehabilitation program (REHAB group, n=371). HF patients who participated in exercise training were compared to HF patients who did not participate. Then, the percentage change in peak V02 and 6-Minutes Walking Distance (6MWD) after exercise training was compared between HF patients and patients after ACS or cardiac surgery in the REHAB group. Results: Of the total HF group, only 37 (9%) participated in an exercise training program in contrast to a participation rate of 29% in the ACS group and 56% in the surgery group. HF patients who didn't participate in exercise training were older (79±10 vs 65±10 years, p<0.001) and more frequently female (48% vs 24%, p= 0.005). They had more frequently hypertension (65% vs 49%, p=0.053) and AF on admission (46% vs 19%, p=0.001). Non-participation was also associated with more difficulties with mobility, one out of four was not able to walk independently on discharge (26% vs none p=0.002). In the REHAB group, these 37 HF patients had higher NT-proBNP and lower peakVO2 values at the start of the exercise training as compared to the patients after ACS (n=133) or after cardiac surgery (n=201) (2331±3484 pg/ml vs 652±838 pg/ml vs 804±916 pg/ml, p<0.001 for NT-proBNP and 16.2±4.5 vs 21.7±5.8 vs 17.8±5.3 ml/kg/min, p<0.001 for peakVO2). However, they obtained a similar percentage increase in VO2 max and 6 MWD as compared to the patients after ACS or after cardiac surgery (20% vs 18% vs 21% increase in peak VO2 and 30% vs 28% vs 28% increase in 6MWD). Conclusions: Although the benefits of an exercise training program for heart failure patients is comparable to the benefits obtained in patients after ACS or cardiac surgery, only 9% actually participates after an episode of hospitalisation for acute heart failure. Clinical characteristics which may be a barrier for attending rehabilitation should be the focus of further research in order to increase the participation rate of HF patients in exercise training.

Over the last decades, more and more evidence is accumulated that physical activity (PA) and exercise interventions are essential components in primary and secondary prevention for cardiovascular disease. However, it is less clear whether and which type of PA and exercise intervention (aerobic exercise, dynamic resistive exercise, or both) or characteristic of exercise (frequency, intensity, time or duration, and volume) would yield more benefit in achieving cardiovascular health. The present paper, as the first of a series of three, will make specific recommendations on the importance of these characteristics for cardiovascular health in the population at large. The guidance offered in this series of papers is aimed at medical doctors, health practitioners, kinesiologists, physiotherapists and exercise physiologists, politicians, public health policy makers, and the individual member of the public. Based on previous and the current literature, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding type, volume, and intensity of PA and exercise.

BACKGROUND:Despite the fact that subjects with established coronary heart disease (CHD) are at high risk of further events and deserve meticulous secondary prevention, current audits such as EUROASPIRE show poor control of major risk factors. Ongoing monitoring is required. We present a new risk factor audit system, SURF (Survey of Risk Factor management), that can be conducted much more quickly and easily than existing audit systems and has the potential to allow hospitals of all sizes to participate in a unified international audit system that will complement EUROASPIRE. Initial experience indicates that SURF is truly simple to undertake in an international setting, and this is illustrated with the results of a substantive pilot project conducted in Europe and Asia. METHODS:The data collection system was designed to allow rapid and easy data collection as part of routine clinic work. Consecutive patients (aged 18 and over) with established CHD attending outpatient cardiology clinics were included. Information on demographics, previous coronary medical history, smoking history, history of hypertension, dyslipidaemia or diabetes, physical activity, attendance at cardiac rehabilitation, cardiac medications, lipid and glucose levels (and HbA1c in diabetics) if available within the last year, blood pressure, heart rate, body mass index, and waist circumference were collected using a one-page data collection sheet. Years spent in full time education was added as an additional question during the pilot phase. RESULTS:Three European countries - Ireland (n = 251), Belgium (n = 122), and Croatia (n = 124) - and four Asian countries - Singapore (n = 142), Taiwan (n = 334), India (n = 97), and Korea (n = 45) - were included in the pilot study. The results of initial field testing were confirmed in that it proved possible to collect data within 60-90 seconds per subject. There was poor control of several risk factors including high levels of physical inactivity (41-45%), overweight and obesity (59-78%), and ongoing smoking (15%). There were lower levels of individuals attending cardiac rehabilitation in Asia. More Europeans than Asians reached the low-density lipoprotein cholesterol target of <2.5 mmol/l (66 vs. 59%) reflecting differences in medication usage. However, blood pressure control was superior in Asia, with 71% <140/90 compared with 66% of Europeans (NS). CONCLUSIONS:This phase of SURF has confirmed its ease of use which should allow wide participation and the collection of representative risk factor data in subjects with CHD as well as ongoing data collection to monitor secular trends in risk factor control. Notwithstanding that this is a pilot study, the results suggest that risk factor control, particularly for lifestyle-related measures, is poor in both Europe and Asia.

ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American–Australian–African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association ANDROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor blocker ARISTOTLE : Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation ATHENA : A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d. for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter ATRIA : AnTicoagulation and Risk factors In Atrial fibrillation AVERROES : Apixaban VErsus acetylsalicylic acid (ASA) to Reduce the Rate Of Embolic Stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment AVRO : A prospective, randomized, double-blind, Active-controlled, superiority study of Vernakalant vs. amiodarone in Recent Onset atrial fibrillation b.i.d : bis in die (twice daily) b.p.m. : beats per minute CABANA : Catheter ABlation vs . ANtiarrhythmic drug therapy for Atrial fibrillation CABG : coronary artery bypass graft CAP : Continued Access to Protect AF CHA2DS2-VASc : Congestive heart failure or left ventricular dysfunction Hypertension, Age ≥75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex category (female) CHADS2 : Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke (doubled) CI : confidence interval CRAFT : Controlled Randomized Atrial Fibrillation Trial CrCl : creatinine clearance DAFNE : Dronedarone Atrial FibrillatioN study after Electrical cardioversion DIONYSOS : Randomized Double blind trIal to evaluate efficacy and safety of drOnedarone (400 mg b.i.d.) vs . amiodaroNe (600 mg q.d. for 28 daYS, then 200 mg qd thereafter) for at least 6 mOnths for the maintenance of Sinus rhythm in patients with atrial fibrillation EAST : Early treatment of Atrial fibrillation for Stroke prevention Trial EHRA : European Heart Rhythm Association ECG : electrocardiogram EMA : European Medicines Agency ERATO : Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation EURIDIS : EURopean trial In atrial fibrillation or flutter patients receiving Dronedarone for the maIntenance of Sinus rhythm FAST : atrial Fibrillation catheter Ablation vs . Surgical ablation Treatment FDA : Food and Drug Administration Flec-SL : Flecainide Short-Long trial HAS-BLED : Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly HF-PEF : heart failure with preserved ejection fraction HF-REF : heart failure with reduced ejection fraction HR : hazard ratio HRS : Heart Rhythm Society ICH : intracranial haemorrhage INR : international normalized ratio i.v. : intravenous J-RHYTHM : Japanese RHYTHM management trial for atrial fibrillation LAA : left atrial appendage LoE : level of evidence LVEF : left ventricular ejection fraction MANTRA-PAF : Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation NICE : National Institute for Health and Clinical Excellence NOAC : novel oral anticoagulant NSAID : non-steroidal anti-inflammatory drug NYHA : New York Heart Association OAC : oral anticoagulant or oral anticoagulation o.d. : omni die (every day) PALLAS : Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy PCI : percutaneous coronary intervention PREVAIL : Prospective Randomized EVAluation of the LAA closure device In patients with atrial fibrillation v s. Long-term warfarin therapy PROTECT AF : WATCHMAN LAA system for embolic PROTECTion in patients with Atrial Fibrillation PT : prothrombin time RAAFT : Radio frequency Ablation Atrial Fibrillation Trial RE-LY : Randomized Evaluation of Long-term anticoagulant therapY with dabigatran etexilate ROCKET-AF : Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in atrial fibrillation RRR : relative risk reduction TE : thromboembolism TIA : transient ischaemic attack t.i.d. : ter in die (three times daily) TOE : transoesophageal echocardiogram TTR : time in therapeutic range VKA : vitamin K antagonist Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on …