Advanced ultrasound methods in assessment of carotid plaque instability: a prospective multimodal study.

BACKGROUND: A significant proportion of ischemic strokes are caused by emboli from atherosclerotic, unstable carotid artery plaques. The selection of patients for endarterectomy in current clinical practice is primarily based on the degree of carotid artery stenosis and clinical symptoms. However, the content of the plaque is known to be more important for stroke risk. Intraplaque neovascularization (IPN) has recently emerged as a possible surrogate marker for plaque instability. Neo-microvessels from the adventitial vasa vasorum grow into the full thickness of the vessel wall in an adaptive response to hypoxia, causing subsequent intraplaque haemorrhage and plaque rupture. Conventional ultrasound cannot detect IPN. Contrast-enhanced ultrasound and Superb Microvascular Imaging (SMI), have, however, shown promise in IPN assessment. Recent research using Shear Wave Elastography (SWE) has also reported reduced tissue stiffness in the artery wall (reduced mean Young's modulus) in unstable compared to stable plaques. The purpose of this study is to identify unstable carotid artery plaques at risk of rupture and future ischemic stroke risk using multimodal assessments. METHODS: Forty five symptomatic and 45 asymptomatic patients > 18 years, with > 50% carotid stenosis referred to Oslo University Hospital ultrasound lab will be included in this on-going project. Patients will undergo contrast enhanced ultrasound, SMI, carotid-MRI and PET-(18F-FDG). Contrast enhanced ultrasound will be analyzed semi-quantitatively (5-levels visual classification) and quantitatively by plotting time-intensity curve analyses to obtain plaque peak contrast enhancement intensity. Plaques removed at carotid endarterectomy will be assessed histologically and the number of microvessels, areas of inflammation, granulation, calcification, lipid and fibrosis will be measured. DISCUSSION: This multimodality study will primarily provide information on the clinical value of advanced ultrasound methods (SMI, SWE) for the detection of unstable carotid artery plaque in comparison with other methods including contrast-enhanced ultrasound, carotid-MRI and PET-(18F-FDG) using histology as the gold standard. Secondly, findings from the methods mentioned above will be related to cerebrovascular symptoms, blood tests (leukocytes, CRP, ESR, lipoproteins and inflammatory markers) and cardiovascular risk factors at inclusion and at 1-year follow-up. The overall aim is to optimize detection of plaque instability which can lead to better preventive decisions and reduced stroke rate.

Dosage dependent hormonal counter regulation to combination therapy in patients with left ventricular dysfunction.

UNLABELLED: The present study attempts to assess the efficacy combination therapy for heart failure. Genuine dose-response studies on combination therapy are not available and published studies involved adding one drug on top of 'usual treatment'. Sixteen different dosage combinations of trandolapril and bumetanide was tested in a double blind, double placebo-controlled, randomized, multiple cross-over study in a 16 times six balanced incomplete Latin square design. Patients reported optimal quality of life on the sub maximal dose bumetanide. Bumetanide decreased left ventricular function and increased heart rate and plasma noradrenaline in a dose dependent manner. Doses of bumetanide of more than 0.5 mg, given twice daily significantly decreased the quality of life and increased diuresis. Weight loss was maximal on 0.5 mg bumetanide twice daily. Trandolapril significantly reduced systolic blood pressure with the maximal effect at 0.5 mg daily. Both drugs significantly increased renin concentration with a significant potentiating interaction. It was not possible to detect beneficial effects of combination therapies. The optimal dosage of Bumetanide appeared to be 0.5 mg twice daily based on its effect on quality of life and weight loss. Estimated by the reduction in systolic blood pressure the optimal dosage of Trandolapril appeared to be 0.5 mg once daily. CONCLUSIONS: It appears that patients should be given less than the usually recommended dosages. Patients may be treated with a low dose loop diuretic, if signs of water retention are present or if symptomatic relief is desired.

Investigation and management of severe hyponatraemia in a hospital setting.

AIMS: To evaluate the assessment and management of severe hyponatraemia in a large teaching hospital. METHODS: Inpatients with serum sodium <125 mmol/l were identified prospectively from a laboratory database over a six month period. Notes were examined and data extracted. Case notes were carefully reviewed retrospectively by a consultant endocrinologist with regard to accuracy of the diagnosis and the appropriateness of investigations and management. RESULTS: 104 patients with a serum sodium <125 mmol/l were identified. Mean (SD) age was 69 (14), 52% were female, mean hospital stay was 16 (12) days, and overall mortality 27%. Adequate investigations were rarely performed. Only 28 (26%) had plasma osmolality measured, 29 (27%) urine osmolality, 11 (10%) urinary sodium, 8 (8%) plasma cortisol, and 2 (2%) a short Synacthen test. Comparing the "ward" and "specialist review" diagnoses, there were significant discrepancies for "no cause found" (49% v 27%, p<0.001), alcohol (6% v 11% p<0.01), and syndrome of inappropriate antidiuresis (20% v 32%, p = 0.001). Treatment was often illogical with significant management errors in 33%. These included fluid restriction and intravenous saline given together (4%) and fluid restriction in diuretic induced hyponatraemia (6%). Mortality was higher in the group with management errors (41% v 20% p = 0.002). CONCLUSION: Severe hyponatraemia is a serious condition, but its investigation and evaluation is often inadequate. Some treatment patterns seem to be arbitrary and illogical, and are associated with higher mortality.

Different effects of calcium antagonist and beta-blocker therapy on left-ventricular diastolic function in ischemic heart disease. A direct comparison of the impact of mibefradil and atenolol.

OBJECTIVE: To compare the effect of a calcium antagonist and a beta-blocker on left-ventricular diastolic function in patients with ischemic heart disease. METHODS: 138 patients with chronic stable angina pectoris were randomized in a multicenter, double-blind trial to treatment with either mibefradil or atenolol for 6 weeks (50 mg once daily for 2 weeks followed by 100 mg once daily for 4 weeks). The ratio between early (E) and late (A) diastolic mitral flow velocities (E/A), the E wave deceleration time (DT) and the left ventricular isovolumetric relaxation time (IRT) were measured by Doppler echocardiography as parameters of left-ventricular diastolic function initially, after 4 and after 6 weeks of treatment. RESULTS: Mibefradil did not change the E/A ratio significantly (+4%, NS), while atenolol treatment resulted in a significant increase in the E/A ratio (+20%, p < 0.001). Mibefradil treatment, on the other hand, resulted in a significant decrease (-8%, p < 0.001) in IRT, while atenolol treatment did not change IRT. Neither mibefradil nor atenolol treatment changed DT significantly. CONCLUSIONS: Both mibefradil and atenolol treatment significantly improves echocardiographic indices of left-ventricular diastolic function in patients with chronic stable angina. However, they affect different parameters and thus apparently act through different mechanisms.

Effect of ramipril on mitral regurgitation secondary to mitral valve prolapse.

Ramipril 10 mg/day reduced regurgitation in chronic mitral regurgitation secondary to mitral valve prolapse in patients with sinus rhythm.

Effects of amlodipine and isosorbide dinitrate on exercise-induced and ambulatory ischemia in patients with chronic stable angina pectoris.

This study was designed to compare once-daily administration of 5-10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina.

Metoprolol abolishes exercise-induced left ventricular dysfunction in patients with silent ischemia.

Left ventricular systolic function is reduced during episodes of silent ischemia in patients with coronary artery disease (CAD). Left ventricular ejection fraction (LVEF) is increased at least 5 absolute percent during exercise in most normal subjects; however, in patients with CAD, LVEF often remains unchanged or decreases. The anti-ischemic effect of beta-adrenergic receptor blockade is well documented, including a reduction of exercise-induced electrocardiographic ST depressions; however, the effect of these drugs on left ventricular volume changes during exercise in patients with silent ischemia is unknown. The aim of this study was to evaluate the effect of a cardio-selective beta-blocking agent, metoprolol, on rest and exercise LVEF in patients with silent ischemia, using radionuclide cardiography. Fifteen patients with silent ischemia completed a double-blind, placebo-controlled crossover study at rest and during submaximal exercise. LVEF remained unchanged during exercise in the placebo phase (56% to 58%; p = NS), but even though LVEF tended to decrease 56% during rest after metoprolol versus 52% after placebo (p = NS), the LVEF increase from rest to exercise resembled a normal LVEF response, 52% to 58% (p = 0.005). Exercise-induced electrocardiographic ST depressions were also reduced during metoprolol treatment. In patients with silent ischemia, the exercise-induced change in LVEF rises significantly during metoprolol treatment. The mechanism may be a reduction in myocardial ischemia as indicated by a reduction in ischemic electrocardiographic findings.

Pre- and afterload reduction in chronic mitral regurgitation: a double-blind randomized placebo-controlled trial of the acute and 2 weeks' effect of nifedipine or isosorbide dinitrate treatment on left ventricular function and the severity of mitral regurgitation.

1. The acute effect and effect of 14 days' treatment with isosorbide dinitrate (ISDN) and nifedipine (NIF) was evaluated by radionuclide cardiography in patients with chronic mitral regurgitation and sinus rhythm. 2. In 23 patients with clinically stable disease blood pressure was lowered by 15% and left ventricular volume was reduced by 16-20% after 20 mg sublingual ISDN causing combined pre- and afterload reduction. Afterload reduction alone induced by 10 mg NIF resulted in an acute 9% decrease in left ventricular endsystolic volume, whereas forward stroke volume increased by 30%, and regurgitation fraction tended to decrease. No haemodynamic effects could be detected after 14 days' treatment with 20 mg ISDN orally twice daily (preload reduction), whereas 20 mg NIF twice daily (afterload reduction) caused an increase in forward stroke volume (18%) and a decrease in both regurgitant volume (20%) and regurgitation fraction (22%) without affecting blood pressure or heart rate. 3. ISDN and NIF have beneficial acute haemodynamic effects in patients with chronic mitral regurgitation probably due to their pre- and afterload reducing properties. The reduction in regurgitation induced by NIF appears to be sustained after 14 days therapy.

Influence of gender on short- and long-term mortality after acute myocardial infarction. TRACE study group.

The aim of this study was to assess differences in short- and long-term mortality between male and female patients with acute myocardial infarction (AMI). The study population consisted of 6,676 consecutive patients admitted alive with an enzyme-confirmed AMI to 27 Danish hospitals from 1990 to 1992. Five patients were excluded because of missing information. Female patients (n = 2,170) were on average 5 years older than male patients (n = 4,501, p <0.001), had lower body mass index, and more often had diabetes, hypertension, and congestive heart failure. Left ventricular systolic function was the same for men and women. Women received thrombolytic therapy less often. The 1-year mortality for female patients was 28 +/- 1% and for men 21 +/- 1% (p <0.001). The unadjusted risk ratio associated with male gender in a proportional-hazards model was 0.76 (95% confidence intervals [CI] 0.70 to 0.83). Adjustment for age removed the importance of gender, and the risk ratio associated with male gender was 1.06 (95% CI 0.97 to 1.2, p = 0.2). An introduction of further variables in the model did not change this. Subdividing mortality into 6-day, 30-day, and late mortality demonstrated a significantly increased mortality in women in the short-term (6 and 30 days), with a risk ratio in men of 0.58 (95% CI 0.42 to 0.81) and 0.80 (95% CI 0.65 to 0.99), respectively. From day 30 onward there was an increased mortality in men with a risk ratio of 1.16 (95% CI 1.03 to 1.31, p = 0.01). Thus, women admitted alive to the hospital with an AMI have an increased long-term mortality that is explained by their older age. However, short-term mortality in women seems to increase independently of other risk factors, but is later followed by an increase in mortality in men.

Impact of immediate and delayed myocardial scintigraphy on therapeutic decisions in suspected acute myocardial infarction.

Early myocardial scintigraphic imaging has become technically feasible in patients admitted to hospital with suspected acute myocardial infarction. After prompt injection of 99mTc-sestamibi, subsequent scintigraphic imaging of perfused myocardium can be performed. During a 5-month period, 237 patients were admitted to the coronary care unit of a district hospital on suspicion of acute ischaemic syndrome, and injection of 99mTc-sestamibi for the performance of myocardial scintigraphy was carried out in 134 patients, on average 2 h after onset of symptoms. The investigation was repeated in 126 patients, on average 18 h after the injection. Three planar views were taken in the coronary care unit with a mobile gamma camera. The prevalence of acute myocardial infarction was 53%. The predictive value at the first scintigraphic imaging for a positive or negative test for myocardial infarction 54% and 56%, respectively. Even exclusion of patients with a previous infarction did not increase the diagnostic validity. The predictive value of a negative test, 77%, at the second scintigraphy was still insufficient to make immediate therapeutic decisions. Myocardial scintigraphy performed early, on suspicion of acute myocardial infarction, cannot therefore be used routinely as a diagnostic test prior to intervention in unselected patients because some 90% of this patient group have myocardial perfusion defects.

Mitral regurgitation determined by radionuclide cardiography: dependence on posture and exercise.

OBJECTIVES: To evaluate dependence of posture and exercise on the degree of mitral regurgitation using combined first pass and equilibrium radionuclide cardiography. DESIGN: 24 patients with clinically stable chronic mitral regurgitation and sinus rhythm were studied by first pass list mode and simultaneous multigated frame mode equilibrium radionuclide cardiography using red cells labelled with technetium-99m. RESULTS: When patients changed posture from supine to sitting upright, left ventricular volumes decreased considerably. Regurgitation tended to increase in patients with valve prolapse but decreased in patients with ischaemic heart disease and dilated cardiomyopathy. During submaximal bicycle exercise cardiac output increased without dilatation of the left ventricle. The increase in left ventricular forward stroke volume was more pronounced than that in the total stroke volume, leading to a considerable decrease in the regurgitant flow through the mitral valve. The repeatability and observer variability of radionuclide determination of regurgitation was acceptable, with limits of agreement within about 10%. CONCLUSIONS: Change in posture induces a normal haemodynamic response in most patients with chronic mitral regurgitation; the effect of posture on regurgitation depends on the underlying disease. Mild to moderate exercise causes no deterioration in the severity of regurgitation.

[Ultrasonically guided pericardiocentesis]. / Ultralydvejledt draenage af perikardiehulen.

Ultrasonically guided pericardiocentesis was performed on 25 occasions in 23 consecutive patients. Incipient cardiac tamponade was present in 22 patients and the procedure was performed for diagnostic purposes in one patient. In 21 cases, 5.7 French pig-tail catheters were employed and 1.2 mm lumbar puncture needles in four cases. In 19 out of 22 patients (86%) with incipient cardiac tamponade the ultrasonically guided pericardiocentesis was considered successful. In one patient, the catheter was misplaced in the right atrium, one patient developed pyopericardium and one patient developed transient tachycardia. In two cases, no material could be obtained. Ultrasonically guided pericardiocentesis is preferable to "blind" puncture and the procedure should be carried out by physicians with experience in interventional ultrasound.

Reliability of first-pass radionuclide determination of cardiac output in the upright position at rest and during exercise.

The reliability of non-invasive determination of cardiac output using first-pass radionuclide cardiography at rest and during exercise in the upright position was evaluated in 20 patients with coronary artery disease. Cardiac output values ranged from 2.97 to 5.99 l/min at rest and from 5.08 to 10.82 l/min during exercise. Cardiac output results obtained by the radionuclide method were compared with those derived from the thermodilution technique performed simultaneously. The mean difference between the two techniques was 0.02 l/min at rest and -0.34 l/min during exercise; the limits of agreement (mean +/- 1.96 SD) were -1.29 to 1.33 l/min and -1.97 to 1.29 l/min, respectively, indicating an acceptable level of agreement. A high reproducibility of the radionuclide technique was found, with a mean difference between determinations by two observers of 0.03 l/min at rest and 0.21 l/min during exercise, the corresponding limits of agreement being -0.75 to 0.81 l/min and -0.79 to 1.21 l/min, respectively. With the aid of a variance component analysis of two determinations by each of four observers, 95% confidence intervals of +/- 10% at rest and +/- 12% during exercise were computed for the radionuclide cardiac output measurements. The observer variation was most pronounced for the part of the cardiac output determination related to measurement of left ventricular equilibrium activity during exercise. First-pass radionuclide cardiography is a reliable method for determination of cardiac output in cardiac patients at rest and during exercise in the upright position.

Magnesium substitution in acute ischaemic heart syndromes.

It has recently been suggested that intravenous infusion of magnesium may reduce mortality and the incidence of serious arrhythmias in patients with ischaemic heart disease and acute myocardial infarction. In the present double-blind, placebo-controlled study, 298 patients with suspected acute myocardial infarction were randomized to receive either intravenous magnesium chloride (80 mmol.24 h-1) or placebo. Infusions were started immediately after admission to the coronary care unit. One hundred and fifty patients received magnesium and 148 the placebo. Ischaemic heart disease was diagnosed in 244 patients. Acute myocardial infarction was observed among 83 patients in the magnesium group and 79 in the placebo group. Both treatment groups were comparable regarding sex, age, clinical status, previous cardiac disease and medication. Serum magnesium was significantly raised during magnesium infusion compared to placebo (P less than 0.01). Fatal events were only observed among patients with myocardial infarction, but neither the in-hospital mortality (magnesium: 12.1%; placebo 10.1%) nor the mortality after a follow-up period of 245 days (median observation time) was affected by magnesium substitution. Magnesium infusion was accompanied by a significantly increased incidence of atrioventricular conduction disturbances. The results suggest that patients suffering from acute ischaemic heart syndromes do not benefit from intravenous magnesium supplementation.

[Prognosis in early and late ventricular fibrillation after acute myocardial infarction]. / Prognosen ved tidlig og sen ventrikelflimmer efter akut myokardieinfarkt.

Of 413 patients with in-hospital ventricular fibrillation complicating acute myocardial infarction 281 had early (less than 48 hours post infarction) ventricular fibrillation and 132 had late ventricular fibrillation. In-hospital and longterm prognoses were not influenced by time of ventricular fibrillation, but advanced age and signs of reduced left ventricular function were found to be independent significant risk factors for short and longterm prognoses.

Prognosis of late versus early ventricular fibrillation in acute myocardial infarction.

To determine the prognosis of late ventricular fibrillation (VF) after acute myocardial infarction (AMI), the length of the monitoring period after AMI was extended. All patients in this series were continuously monitored in a coronary care unit to ensure observation of all VF within 18 days of AMI. From 1977 to 1985, 4,269 patients were admitted with AMI and 413 (9.6%) had in-hospital VF. Of these 281 (6.8%) had early VF (less than 48 hours after AMI) and 132 (3.2%) had late VF (greater than or equal to 48 hours after AMI). In-hospital mortality was 50 and 54% for early and late VF, respectively (p = 0.31). Kaplan-Meier survival analysis showed better survival after discharge for patients with early versus late VF (p = 0.009) but this difference was fully explained by the presence of heart failure. Survival analysis showed the same prognosis after 1, 3 and 5 years for early and late VF, when VF was not associated with heart failure. When VF was associated with heart failure (secondary VF) early VF had a greater mortality than late VF after 2 and 5 years. Logistic regression analysis showed that heart failure (relative risk 1.9 [1.1 to 3.1]) and cardiogenic shock (relative risk 3.9 [1.8 to 8.5]) were significant risk factors for in-hospital death. Late VF compared to early VF had no prognostic implication (relative risk 1.0 [0.6 to 1.6]). For patients discharged from the hospital, risk factors were heart failure (1.8 [1.1 to 2.8]) and previous AMI (1.6 [1.3 to 2.1]).(ABSTRACT TRUNCATED AT 250 WORDS)

First passage radionuclide cardiography for determination of cardiac output: evaluation of an improved method.

A noninvasive method for determination of cardiac output by aid of first passage radionuclide cardiography is presented. As opposed to most other scintigraphic methods, a forward blood flow is measured, even in patients with valvar incompetence. In addition, the technique allows measurement of cardiac output in the presence of cardiac arrhythmias. No geometrical assumptions, corrections for radiation attenuation, loss of tracer, or empirical correction factors due to extracardiac radioactivity are required. We have evaluated the method in 19 patients with various heart diseases by comparison of the radionuclide cardiac outputs with those derived from the thermodilution technique performed simultaneously. Eight patients had valvar incompetence and 2 had cardiac arrhythmias. The mean radionuclide and thermodilution cardiac output values were 5.03 l/min (SD 1.21) and 5.18 l/min (SD 1.09), respectively. The 95% confidence interval for the bias was -0.40 to 0.10 l/min, and correlation analysis demonstrated an excellent correlation between results obtained with the two methods, r = 0.91 (P less than 0.001). This study shows that the improved gamma camera method represents a valid noninvasive technique for determination of cardiac output.

Hemodynamic effects of alcohol at rest and during upright exercise in coronary artery disease.

The hemodynamic effects of acute alcohol intoxication were studied at rest and during upright exercise in 28 patients with coronary artery disease by right-sided heart catheterization and radionuclide cardiography. The mean arterial blood pressure at rest was reduced by 5% and the left ventricular ejection fraction at rest decreased 2% because of end-systolic dilation during intoxication (serum ethanol 21 mmol/liter). No changes were observed in heart rate, stroke volume, pulmonary artery pressure, pulmonary artery wedge pressure or total peripheral resistance. No significant changes occurred in plasma catecholamines, and no changes occurred in any variable during mild exercise corresponding to a 30 to 40% heart rate increase. Thus, alcohol ingested in moderate doses causes slight impairment of left ventricular emptying and a reduction in the arterial blood pressure at rest in patients with coronary artery disease. A mild exercise load can be tolerated during alcohol intoxication without hemodynamic changes.

Cardiac function after alcohol ingestion in patients with ischemic heart disease and cardiomyopathy: a controlled study.

Thirty male patients with ischemic heart disease and cardiomyopathy entered a controlled study of the acute effects of alcohol on cardiac function evaluated by right heart catheterization. Twenty patients, nine with angina pectoris and 11 with congestive heart failure, were studied during alcohol intoxication, and ten patients, five with angina pectoris and five with heart failure, served as a control group. The mean serum ethanol concentration in the alcohol group was 93 mg/100 ml (S.D. 17). The systemic arterial blood pressure was reduced by 6% in the alcohol group, P less than 0.05 compared with the control group. No significant changes occurred in the central venous pressure, the pulmonary artery pressure, the pulmonary capillary wedge pressure, or in cardiac output, stroke volume and total peripheral resistance. Alcohol intake in moderate doses has no measurable effect on pulmonary blood pressures or cardiac output in patients with ischemic heart disease and cardiomyopathy. Such an effect may, however, be masked by a reduction of afterload.

First-pass radionuclide determination of cardiac output: an improved gamma camera method.

A technique for noninvasive determination of cardiac output by aid of first-pass radionuclide cardiography is described. After intravenous injection of 10-15 mCi technetium-99m-(99mTc) labeled red blood cells the method requires acquisition of a first passage time-activity curve recorded with a gamma camera over the left ventricle, the background corrected left ventricular count rate recorded after complete mixing of the tracer in the circulation, and determination of the distribution volume of the tracer. The method was applied in 14 patients with heart disease of various origins and evaluated against the conventional tracer dilution technique with arterial sampling of blood activity. Cardiac output determinations by external counting ranged from 2.30 to 8.56 l/min, mean +/- s.d. 4.50 +/- 1.66 l/min and by arterial blood sampling from 1.88 to 8.96 l/min, mean +/- s.d. 4.52 +/- 1.71 l/min. An excellent correlation was demonstrated between the two techniques, r = 0.978 (p less than 0.001). When no background subtraction was applied to the left ventricular counts at equilibrium, radionuclide cardiac output values were approximately 40% higher than those obtained by arterial sampling. The new first-pass radionuclide cardiographic technique may prove a useful tool in the noninvasive evaluation of cardiac function, especially in patients with arrhythmias and/or valvular incompetence.