Induced Moderate Hypothermia in Aortic Rupture With Retroperitoneal Bleeding: A Randomized Porcine Study.

OBJECTIVE: Induced hypothermia improves outcome in aortic arch surgery, neonatal neurointensive care, and transplant surgery for example. In contrast, spontaneous hypothermia has been associated with worse outcomes in patients suffering from hemorrhagic shock, mostly explained by its adverse effects on the coagulation system. We investigated if induced hypothermia would impair short-term survival in experimental aortic rupture with retroperitoneal bleeding. METHODS: Anesthetized pigs were randomized into 2 groups: hypothermia by peritoneal lavage of ice-cold Ringer's acetate and external cooling (n = 10) and normothermia (n = 10). Aortic rupture with retroperitoneal bleeding was induced by endovascular means creating a 6 mm hole in the retroperitoneal portion of abdominal aorta. Survival (primary outcome), hemodynamics, and arterial blood gases including lactate were collected and analyzed up to 180 min after aortic rupture. RESULTS: The body temperature (mean ± standard deviation) in the hypothermic group was 31.5 ± 1.0 °C and 38.7 ± 0.4 °C in the normothermic group at the time for aortic rupture. Survival up to 180 min after the retroperitoneal bleeding was significantly higher in the hypothermic compared with the normothermic group (P = 0.023). CONCLUSIONS: Induced hypothermia did not impair survival in this experimental retroperitoneal aortic bleeding model in anesthetized pigs. This finding may indicate a minor role for the coagulation system in this type of bleeding.

Evaluation of left ventricular diastolic function in patients operated for aortic stenosis.

BACKGROUND: Left ventricular diastolic dysfunction is common in patients with aortic valve stenosis (AS) and reportedly affects prognosis after surgical aortic valve replacement (SAVR). Here we investigated whether and how diastolic function (assessed following the most recent guidelines) was affected by SAVR, and whether preoperative diastolic function affected postoperative outcome. We also examined whether long-term mortality was associated with preoperative NT-proBNP and postoperative heart failure (PHF). METHODS: We performed a prospective observational study of 273 patients with AS who underwent AVR with or without concomitant coronary artery bypass surgery. Of these patients, 247 were eligible for assessment of left ventricular (LV) filling pressure. Preoperatively and at the 6-month postoperative follow-up, we measured N-terminal pro-B type natriuretic peptide (NT-proBNP) in serum and assessed diastolic function with Doppler echocardiography. PHF was diagnosed using prespecified criteria. Multivariable logistic regression was performed to explore variables associated with high LV filling pressure. Cox regression was performed to explore variables associated with mortality, accounting for timeto-event. RESULTS: At the time of surgery, 22% (n = 54) of patients had diastolic dysfunction expressed as high LV filling pressure. Of these 54 patients, 27 (50%) showed postoperative diastolic function improvement. Among the 193 patients with preoperative low LV filling pressure, 24 (12%) showed postoperative diastolic function deterioration. Increased long-term mortality was associated with PHF and high preoperative NT-proBNP, but not with preoperative or postoperative diastolic dysfunction. Cox regression revealed the following independent risk factors for long-term mortality: diabetes, renal dysfunction, preoperative NT-proBNP>960 ng/L, age, and male gender. CONCLUSIONS: Surgery for aortic stenosis improved diastolic function in patients with high LV filling pressure in 50% of the patients. Our results could not confirm the previously suggested role of diastolic dysfunction as a marker for poor long-term survival after SAVR. Our findings showed that both PHF and high preoperative NT-proBNP were associated with long-term mortality.

Cardiopulmonary exercise testing for evaluation of a randomized exercise training intervention following aortic valve replacement.

Aortic valve surgery is the definitive treatment for aortic stenosis (AS). No specific recommendation is available on how exercise training should be conducted and evaluated after aortic valve replacement (AVR). This study aimed to examine the effect of aerobic exercise training on exercise capacity following AVR. In addition to our primary outcome variable, peak oxygen uptake (peakVO2 ), the effect on submaximal cardiopulmonary variables including oxygen uptake kinetics (tau), oxygen uptake efficiency slope (OUES) and ventilatory efficiency (VE/VCO2 slope) was evaluated. Following AVR due to AS, 12 patients were randomized to either a group receiving 12 weeks of supervised aerobic exercise training (EX) or a control group (CON). Exercise capacity was assessed by a maximal cardiopulmonary exercise test (CPET). There was a significant increase in peak load (+28%, P = 0·031) and in peakVO2 (+23%, P = 0·031) in EX, corresponding to an increase in achieved percentage of predicted peakVO2 from 88 to 104% (P = 0·031). For submaximal variables, there were only non-statistically significant trends in improvement between CPETs in EX. In CON, there were no significant differences in any maximal or submaximal variable between CPETs. We conclude that 12 weeks of supervised aerobic exercise training induces significant adaptations in cardiopulmonary function following AVR, especially in regard to maximal variables including peakVO2 . In addition, we provide novel data on the effect on several submaximal variables following exercise training in this group of patients.

Longitudinal changes in myocardial T1 and T2 relaxation times related to diffuse myocardial fibrosis in aortic stenosis; before and after aortic valve replacement.

BACKGROUND: Diffuse myocardial fibrosis is associated with adverse outcomes, although detection and quantification is challenging. Cardiac MR relaxation times mapping represents a promising imaging biomarker for diffuse myocardial fibrosis. PURPOSE: To investigate whether relaxation times can detect longitudinal changes in myocardial tissue composition associated with diffuse fibrosis in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR). STUDY TYPE: Prospective longitudinal study. POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Fifteen patients with severe AS. FIELD STRENGTH/SEQUENCE: 3T / 3(3)3(3)5-MOLLI, T2 -GraSE, and 3D-QALAS. ASSESSMENT: Patients underwent MR examinations at three timepoints: before AVR, as well as 3 and 12 months after AVR. Data from each patient was analyzed in 16 myocardial segments. STATISTICAL TESTS: The segment-wise T1 and T2 data were analyzed over time after surgery using linear mixed models for repeated measures analysis. RESULTS: The results showed that T1 relaxation times were significantly (P < 0.05) shorter 3 and 12 months postoperative than preoperative and that the T2 relaxation times were significantly (P < 0.05) longer 3 and 12 months postoperative than preoperative for both 3D and 2D mapping methods. No significant changes were seen between 3 and 12 months postoperative for any of the methods (P = 0.06/0.19 for T1 with 3D-QALAS/MOLLI and P = 0.09/0.25 for T2 with 3D-QALAS/GraSE). DATA CONCLUSION: We demonstrated that changes in myocardial relaxation times and thus tissue characteristics can be observed within 3 months after AVR surgery. The significant changes in relaxation times from preoperative examinations to the follow-up may be interpreted as a reduction of interstitial fibrosis in the left ventricular wall. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

Structure and function of the tricuspid and bicuspid regurgitant aortic valve: an echocardiographic study.

OBJECTIVES: The emerging new treatment options for aortic valve disease call for more sophisticated diagnostics. We aimed to describe the echocardiographic pathophysiology and characteristics of the purely regurgitant aortic valve in detail. METHODS: Twenty-nine men, with chronic aortic regurgitation without concomitant heart disease referred for aortic valve intervention, underwent 2D transoesophageal echocardiographic (TEE) examination prior to surgery according to a previously published matrix. Measurements of the aortic valve apparatus in long and short axis view were made in systole and diastole and analysed off-line. The aortic valves were grouped as tricuspid (TAV) or bicuspid (BAV), and classified by regurgitation mechanism. RESULTS: Twenty-four examinations were eligible for analysis of which 13 presented TAV and 11 BAV. The regurgitation mechanism was classified as dilatation of the aorta in 6 cases, as prolapse in 11 cases and as poor cusp tissue quality or quantity in 7 cases. The ventriculo-aortic junction (VAJ) and valve opening were closely related (TAV r = 0.5, BAV r = 0.73) but no correlation was found between the VAJ and the maximal sinus diameter (maxSiD) or the sinotubular junction (STJ). However, the STJ and maxSiD were significantly related (TAV vs BAV: systole r = 0.9, r = 0.8; diastole r = 0.9, r = 0.7), forming an entity. The conjoined BAV cusps were shorter than the anterior cusps when closed (P = 0.002); the inter-commissural distances of the cusps in the BAV group were significantly different (P = 0.001 resp. 0.03) in both systole and diastole. CONCLUSIONS: The VAJ was independent of other aortic dimensions and should thereby be considered as a separate entity with influence on valve opening. The detailed 2D TEE measurements of this study add further important information to our knowledge about the function and echocardiographic anatomy of the pathological aortic valve and root either as a stand-alone examination or as a benchmark and complement to 3D echocardiography. This may have an impact on decisions regarding repairability of the native aortic valve.

Exercise echocardiography predicts postoperative left ventricular remodeling in aortic regurgitation.

OBJECTIVE: We aimed to investigate if preoperative left ventricular (LV) function assessed by exercise echocardiography could predict late postoperative LV function in aortic regurgitation (AR) patients and to evaluate how LV long-axis function is affected late after aortic valve surgery. DESIGN: A total of 21 male chronic AR patients, aged 49 ( 12 ) years, accepted for surgery were examined preoperatively, 6 months-, and 4 years postoperatively, at rest and during exercise. Besides conventional echocardiographic parameters, the atrioventricular plane displacement (AVPD) by M-mode and peak systolic velocity (s') in the basal LV by color tissue Doppler were measured. RESULTS: Preoperatively EF rest and EF exercise, were 55( 7 )% and 54( 9 )%, respectively, and ∆EF 0( 8 )%. LV dimensions and volumes indexed to BSA had decreased at the 6-month follow-up and were stable at late follow-up. s'rest, s'exercise, AVPD rest, and AVPD exercise were unchanged at both the postoperative examinations (all P ≥ 0.05). Preoperative EF exercise and AVPD exercise showed inverse correlation to late postoperative indexed LV enddiastolic volume (r = -0.68, p < 0.004 and r = -0.86, P < 0.001) and indexed LV endsystolic volume (r = -0.68, P = 0.004 and r = -0.81, P < 0.001), while there was no correlation to preoperative EF rest and AVPD rest (all r < 0.2). CONCLUSIONS: Preoperative exercise echocardiography can detect AR patients with suboptimal LV remodeling late postoperatively.

Differences in recovery of left and right ventricular function following aortic valve interventions: a longitudinal echocardiographic study in patients undergoing surgical, transapical or transfemoral aortic valve implantation.

OBJECTIVES: To evaluate longitudinal left and right ventricular function (LVF and RVF) after transcatheter aortic valve implantation (TAVI) as compared to surgical aortic valve replacement (SAVR) and LVF and RVF after TAVI by the transfemoral (TF) or transapical (TA) approach. BACKGROUND: Knowledge about differences in recovery of LVF and RVF after TAVI and SAVR is scarce. METHODS: Sixty patients (age 81 ± 7 years, logistic EuroSCORE 16 ± 10%), undergoing TAVI (TF: n = 35 and TA: n = 25), were examined by echocardiography including atrioventricular plane displacement (AVPD) and peak systolic velocities (PSV) by tissue Doppler at basal RV free wall, LV lateral wall and septum preprocedurally, 7 weeks and 6 months postprocedurally. Twenty-seven SAVR patients were matched to 27 TAVI patients by age, gender and LVF. RESULTS: Early postintervention, TAVI patients had improved longitudinal LVF. However, when analyzed separately, only TF, but not TA patients, had improved LV lateral and septal AVPD and PSV (all P ≤ 0.01). All TAVI patients, as well as the TF and TA group had unchanged longitudinal LVF between the early and late follow-ups (all P > 0.05). The SAVR group had higher septal LVF than the matched TAVI group preprocedurally, while postoperatively this difference was diminished. Longitudinal RVF was better in the TF group than in the TA group pre- and postprocedurally. Although the SAVR group had superior longitudinal RVF preoperatively, this was inferior to TAVI postoperatively. CONCLUSIONS: Postprocedural longitudinal LVF and RVF in patients undergoing TF-TAVI, TA-TAVI, or SAVR differ considerably. Preservation of longitudinal RVF after TAVI might influence the selection of aortic valve intervention in the future.

Decreased aerobic capacity 4 years after aortic valve replacement in male patients operated upon for chronic aortic regurgitation.

Exercise testing is underutilized in patients with valve disease. We have previously found a low physical work capacity in patients with aortic regurgitation 6 months after aortic valve replacement (AVR). The aim of this study was to evaluate aerobic capacity in patients 4 years after AVR, to study how their peak oxygen uptake (peakVO(2)) had changed postoperatively over a longer period of time. Twenty-one patients (all men, 52±13 years) who had previously undergone cardiopulmonary exercise testing (CPET) pre- and 6 months postoperatively underwent maximal exercise testing 49 ± 15 months postoperatively using an electrically braked bicycle ergometer. Breathing gases were analysed and the patients' physical fitness levels categorized according to Åstrand's and Wasserman's classifications. Mean peakVO(2) was 22·8 ± 5·1 ml × kg(-1) × min(-1) at the 49-month follow-up, which was lower than at the 6-month follow-up (25·6 ± 5·8 ml × kg(-1) × min(-1), P = 0·001). All but one patient presented with a physical fitness level below average using Åstrand's classification, while 13 patients had a low physical capacity according to Wasserman's classification. A significant decrease in peakVO(2) was observed from six to 49 months postoperatively, and the decrease was larger than expected from the increased age of the patients. CPET could be helpful in timing aortic valve surgery and for the evaluation of need of physical activity as part of a rehabilitation programme.

Preoperative longitudinal left ventricular function by tissue Doppler echocardiography at rest and during exercise is valuable in timing of aortic valve surgery in male aortic regurgitation patients.

BACKGROUND: The aim of this study was to evaluate if left ventricular (LV) systolic function by tissue Doppler echocardiography at rest and during exercise preoperatively could predict postoperative LV function and thereby be useful in the timing of aortic valve surgery in patients with severe aortic regurgitation. METHODS: In 29 patients (median age, 59 years; interquartile range, 39-64 years), echocardiography, tissue Doppler echocardiography, and radionuclide ventriculography were performed preoperatively and postoperatively at rest and during supine bicycle exercise. RESULTS: Preoperative ejection fraction (EF) was 62%. Patients formed two groups, with basal LV peak systolic velocity (PSV) 5.9 cm/s preoperatively as the cutoff value between low and high PSV. Preoperatively, patients with low PSV had lower PSV during exercise (P < .005), EF during exercise (P < .05), and atrioventricular plane displacement (AVPD) at rest (P < .005) and during exercise (P < .05) than those with high PSV. Postoperatively, patients with low PSV had smaller AVPD at rest (P < .05), AVPD during exercise (P < .01), and PSV during exercise (P < .01). CONCLUSION: In patients with chronic aortic regurgitation with EFs and LV dimensions not fulfilling criteria for surgery according to guidelines, preoperative PSV and AVPD at rest and during exercise detected postoperative LV dysfunction.

Measurement of physical work capacity in patients with chronic aortic regurgitation: a potential improvement in patient management.

BACKGROUND: Timing of surgery in aortic regurgitation (AR) is important. Exercise testing is recommended upon uncertainty about functional limitations but reports on cardiopulmonary exercise testing (CPET) in populations with pure chronic AR are scarce. METHOD: Twenty-eight patients referred for surgery because of chronic AR (13 in NYHA I, 10 in NYHA II and five in NYHA III) were tested by CPET pre- and 6 months postoperatively. Echocardiography, with measurement of left ventricular ejection fraction (LVEF), diameters (LVED, LVES) and volumes (LVEDV, LVESV) was also performed. RESULTS: The patients had normal LVEF pre- and postoperatively. LV diameters and volumes diminished significantly postoperatively (LVED from 67 to 57, LVES from 49 to 41 mm; P < 0.001). The majority of the patients had a 'low' physical work capacity, none of them performed better than 'average' according to Astrand's classification preoperatively and there was no significant postoperative improvement. The mean peak oxygen uptake (VO(2peak)) was 25 ml kg(-1) min(-1) both pre- and postoperatively, and six of the 28 patients had a VO(2peak) of less than 20 ml kg(-1) min(-1). VO(2peak) was not significantly related to NYHA class. CONCLUSION: LVEF, diameters and volumes at rest did not fulfil the criteria for surgery in most of our AR patients, of whom 46% were asymptomatic. However, many had a remarkably low work capacity, which was neither improved 6 months postoperatively nor correlated to echocardiographic LV dimensions. CPET predicted the postoperative work capacity and may, therefore, be a useful complement for timing of surgery in patients with chronic AR.

Exercise radionuclide ventriculography for predicting post-operative left ventricular function in chronic aortic regurgitation.

OBJECTIVES: Ejection fraction (EF) reaction upon exercise by radionuclide ventriculography and standard echocardiographic parameters was evaluated as predictors for post-operative left ventricular (LV) function in chronic aortic regurgitation (AR). BACKGROUND: The optimal timing of surgery for chronic AR is when the left ventricle is still compensating for the volume and pressure overload without irreversible dysfunction. For asymptomatic patients when EF is normal and LV diameters are borderline, exercise testing is recommended by present guidelines. However, only a limited number of studies have been performed, and data are scarce on this subject. METHODS: Radionuclide ventriculography with multiple gated acquisition at rest and during exercise was performed in 29 consecutive patients with severe chronic aortic regurgitation pre-operatively and 6 months post-operatively. Patient subgroups were formed based on pre-operative EF exercise response (DeltaEF) and were categorized as decreasing (DeltaEF <-5%), unaltered (-5% 5%). A 5% or higher increase was considered normal. The LV diameters and mass were measured by echocardiography. RESULTS: Pre-operative LV diameters were markedly elevated before surgery and diminished significantly after surgery. Left ventricular diameters, LV mass, EF at rest (EF(rest)), and EF change from rest to exercise (DeltaEF) were independent of New York Heart Association functional class. Pre-operative end-diastolic diameter proved to be a predictor for pre- and post-operative DeltaEF (p = 0.003; p = 0.04) but not for the nature of the exercise response post-operatively. Patients with decreasing and unaltered EF pre-operatively presented a significantly higher but still abnormal DeltaEF post-operatively. Those with increasing EF pre-operatively had a similar response and a normal DeltaEF post-operatively. Pre-operative DeltaEF was not only a predictor for post-operative DeltaEF (p = 0.02) but also classified patients into post-operative subgroups (EF decreasing, p = 0.03; unaltered, p = 0.02; increasing, p = 0.0008). CONCLUSIONS: An abnormal EF response to exercise may also occur in patients who do not fulfill criteria for surgery based on LV dimensions or EF. A follow-up of exercise LV function and adjusting the timing of surgery according to the nature of exercise response could, therefore, be beneficial.

[Simple surgical method for intraoperative evaluation of adequacy of tricuspid annuloplasty]. / Egyszeru sebészi módszer a tricuspidalis annuloplasztika eredményének mutét alatti értékelésére.

In tricuspid annuloplasty intraoperative "real time" evaluation using transoesophageal echocardiography requires normal flow to get reliable result. It means that the patient has to be already weaned from the cardiopulmonary bypass by the time of evaluation. In the authors' experience a well functioning tricuspid annuloplasty prevents back-flow through the valve. It can be observed on on-pump beating heart. If the tricuspid valve is competent, it is unnecessary to suck the blood flowing back through the coronary sinus while closing the right atrium. This observation seems to correlate well with post cardiopulmonary bypass transoesophageal echocardiography measurements and the control transthoracic echocardiography right before discharging the patients. These statements are based on a group of 72 patients. Sixty-nine patients (95.8%) were discharged (early mortality 4.2%). Only in one case we could observe a discrepancy between the intraoperative surgical observation and the postoperative echocardiographic finding. Development of functional tricuspid regurgitation in left-sided heart disease is a warning sign for myocardial impairment, which is an indication for surgery. Tricuspid annuloplasty can be performed even with moderate to medium grade regurgitation because it improves the early and late outcome. The described method is an adequate method for intraoperative evaluation of the repaired tricuspid valve competency.

[A complementary clinical method to minimize air embolism during open-heart surgery]. / Kiegészíto klinikai módszer a nyitott szívmutéteknél fellépo légembolisatio csökkentésére.

Air from the left heart is ejected even up to several hours after cardiopulmonary bypass (CPB) despite the use of CO2. The following method is complementary in addition to surgical de-airing in order to further reduce the chance of air embolism, especially from the pulmonary veins. After re-expanding the lungs with standard bag inflation, the ventilation is restarted in consultation with the surgeon. The ventilator is set to the respiratory minute volume used before the CPB but at a respiratory frequency of 10/minutes whereas the regularly beating heart is filled from the heart lung machine. Transoesophageal echocardiography (TEE) reliably controls the effect.

[Intraoperative fires caused by alcoholic skin antiseptic and diathermy]. / Alkoholtartalmú borfertotlenítok és diathermia okozta égések sebészi beavatkozások során.

UNLABELLED: The authors describe two intraoperative fires during cardiac surgery. In both cases, in addition to the usual disinfection and isolation of the operating field, they wanted to reduce the infection hazard and to restore the partly ruined isolation by 70% alcoholic skin antiseptic solution. Soon after the disinfection, but before the evaporation of alcohol, diathermy was used and caused fire. In case of the first patient the fire spread over the isolation film and resulted second grade (5%) and third-grade (1%) burn injury which required plastic surgery. In the second case the patient's beard caught fire causing second-grade (1%) burn that was treated locally. Despite these burn injuries both patients recovered after the heart surgery. These two intraoperative fires are 0.003-0.004% of all surgical procedures. CONCLUSION: Fires during surgery are rare and might have serious consequences. They can be prevented by keeping the discipline of work and instructions of fire protection. The best way of prevention is regular education of all the staff (doctors, nurses, etc.) working in the operating theatre.

Risk factors for postoperative heart failure in patients operated on for aortic stenosis.

BACKGROUND: Risk factors for postoperative heart failure (PHF) have not been specifically studied in valve surgery although it has been acknowledged that patient variables may have a more profound influence on postoperative outcome than valve-related factors. METHODS: All patients undergoing isolated aortic valve replacement for aortic stenosis from January 1995 to December 2000 in the southeast region of Sweden were studied (n = 398). Forty-five patients with aortic valve replacement required treatment for PHF. Univariate and multivariate logistic regression analysis was carried out to identify risk factors for PHF. RESULTS: Thirty-day mortality was 6.7% versus 1.4% for patients with and without PHF, respectively (p = 0.05). With regard to clinical presentation of aortic stenosis, angina was associated with reduced risk, whereas history of congestive heart failure increased the risk for PHF. Five preoperative (hypertension, history of congestive heart failure, severe systolic left ventricular dysfunction, pulmonary hypertension, preoperative hemodynamic instability) and two intraoperative (aortic cross-clamp time, intraoperative myocardial infarction) variables were identified as independent risk factors for PHF. Patient-prosthesis mismatch did not influence the risk of PHF significantly. CONCLUSIONS: Postoperative heart failure was associated with a marked increase in postoperative mortality and morbidity. Risk factors for PHF were variables indicating preexisting myocardial dysfunction, increased right or left ventricular afterload, and intraoperative myocardial injury. Our results highlight issues concerning cross-clamp time and myocardial protection, particularly for patients with preoperatively compromised myocardial function. Asymptomatic patients with significant aortic stenosis should be considered for surgery before substantial echocardiographic evidence of left ventricular dysfunction or increased pulmonary artery pressure develops.

Are patients with isolated chronic aortic regurgitation operated in time? Analysis of survival data over a decade.

BACKGROUND: Patients suffering from chronic isolated aortic regurgitation have a less favorable outcome than patients with aortic stenosis. According to international recommendations, these patients should undergo surgery as soon as left ventricular function begins to deteriorate, that is, surgery is not to be postponed until clinical symptoms become relevant. HYPOTHESIS: The study was undertaken to evaluate how satisfactory our timing of surgery was, as reflected by survival data. METHODS: Survival was studied retrospectively in a consecutive series of patients undergoing surgery for chronic isolated aortic regurgitation during a 10-year period in our institution. Results were compared with data from the literature. By excluding patients with aortic aneurysms and acute endocarditis, we formed a homogeneous patient group of 88 subjects. RESULTS: Thirty-day mortality was 1% and late mortality after a mean follow-up period of 6 years was 11%. Compared with survival data from an earlier study in which the patient population was similar and resided in the same geographic area, the results in our patient group seem to be better. It is noteworthy that despite a strong effort to recommend surgery at an earlier stage of the disease than previously, 35% of the patients had moderate or severe left ventricular dysfunction preoperatively because of late referrals. CONCLUSION: This stresses the importance of early detection and careful preoperative follow-up with noninvasive methods in patients with aortic regurgitation.