Pulmonary artery coarctation repair in univentricular heart: indications and optimal timing.

BACKGROUND: To analyse surgical outcomes of pulmonary artery coarctation in univentricular hearts, focusing on surgical indications and optimal timing. METHODS: We retrospectively reviewed 49 patients with pulmonary artery coarctation in univentricular hearts treated at our institution between 1993 and 2022. Twenty-eight patients were diagnosed before first-stage palliation. Of these, 14 underwent systemic-pulmonary shunt only as first-stage palliation (Group 1), and 14 underwent systemic-pulmonary shunt plus surgical pulmonary artery plasty as first-stage palliation (Group 2). Twenty-one patients diagnosed after first-stage palliation underwent surgical pulmonary artery plasty at the time of bidirectional Glenn procedure (Group 3). RESULTS: Follow-up period after initial palliation was 6±8 years. The Fontan procedure was successful in 35 patients (71%) aged 28±26 months (range 18-139). Freedom from interstage death (Group 1, 53%; Group 2, 85%; Group 3, 93%) and interstage reintervention (Group 1, 50%; Group 2, 75%; Group 3, 73%) rates were significantly lower in Group 1 (p = 0.01). Five and four patients in Group 1 and Group 3, respectively, needed additional shunts before the bidirectional Glenn procedure. In Group 1, one patient with a non-confluent pulmonary artery achieved hemi-lung Fontan circulation. In Group 2, one patient suffering with a non-confluent pulmonary artery could not achieve Fontan circulation, whereas another patient with pulmonary venous obstruction achieved hemi-lung Fontan circulation. CONCLUSIONS: Surgical pulmonary artery plasty performed at first-stage palliation improved outcomes of pulmonary artery coarctation in univentricular hearts, particularly when pulmonary artery coarctation had already progressed during the neonatal period or early infancy.

Norwood Operation with Right Ventricular-Pulmonary Artery Shunt Versus Comprehensive Stage II After Bilateral Pulmonary Artery Banding Palliation.

As a strategy for the primary Norwood operation, the right ventricular-pulmonary artery shunt is associated with satisfactory early outcome. However, use of this shunt after bilateral pulmonary artery banding remains controversial. This study compared the operative outcomes and late hemodynamics in patients who underwent the Norwood operation, preceded by bilateral pulmonary artery banding, with a right ventricular-pulmonary artery shunt or with bidirectional Glenn anastomosis (comprehensive stage II strategy). We retrospectively reviewed 38 patients who underwent the Norwood operation preceded by bilateral pulmonary artery banding between 2004 and 2017. Of these, 17 underwent the Norwood operation with a right ventricular-pulmonary artery shunt (Group S), whereas 21 underwent the comprehensive stage II strategy (Group G). 5 years after the Norwood operation, 10 (60%) and 17 (81%) patients in Group S and Group G, respectively, underwent the Fontan procedure. Group S showed significantly lower pressure in the superior vena cava after bidirectional Glenn anastomosis than Group G (13 ± 2 mmHg vs. 18 ± 3 mmHg; p < 0.01), but pressures were similar after the Fontan procedure. The right ventricular end-diastolic volume at 1 year post-Fontan procedure was significantly higher in Group S than in Group G (142 ± 41% vs. 91 ± 28%; p < 0.01). In terms of early outcomes, the Norwood operation with a right ventricular-pulmonary artery shunt enabled low pressure in the superior vena cava, but in the long term, this shunt adversely influenced the right ventricular volume.

Congenital Non-Confluent Pulmonary Artery Sourced from Bilateral Arterial Ducts: A Rare Anomaly.

This study aimed to identify the influence of the non-confluent pulmonary artery originating from the bilateral arterial ducts (AD) on the outcomes of the Fontan circulation. We retrospectively reviewed the records of nine patients with bilateral AD and a non-confluent pulmonary artery in a single ventricle at our institution between 1993 and 2023. Three patients showed maintained AD or underwent a systemic-pulmonary shunt for stenotic AD, followed by the Glenn procedure. Four patients underwent systemic-pulmonary shunt with angioplasty as the first palliation, followed by the Glenn procedure. Two patients underwent systemic-pulmonary shunt or AD stenting as the first palliation and systemic-pulmonary shunt with angioplasty as the second palliation. There were no cases of interstage mortality. Pulmonary arteries grew and achieved a good balance (pre-Fontan pulmonary artery index [PAI], 164 ± 27 mm2/m2; right/left PAI ratio, 1.06 ± 0.23). All patients underwent the Fontan procedure (median, 3.5 years; range, 2.3-6.4 years) and were followed up for 7.8 years (range, 0.1-16.4 years) after the procedure. One patient required hospitalization for heart failure at 1.8 years, and three patients required catheter intervention for pulmonary stenosis within 2 months after the Fontan procedure. Non-confluent pulmonary arteries originating from the bilateral AD do not preclude Fontan completion and good Fontan outcomes by restoring balance to pulmonary blood flow. Due to the limited sample size in this study, additional research is imperative to delve deeper into our findings and enhance understanding of the most effective surgical approach for this disease.

Outlet Ventricular Septal Defect: Impact of Surgery on the Late Aortic and Pulmonary Valve Functions.

This study retrospectively evaluated long-term post-operative aortic and pulmonary valve functions in outlet ventricular septal defects. We evaluated aortic regurgitation and pulmonary regurgitation using pre- and post-operative echocardiograms. Overall, 158 patients who underwent intracardiac repair due to outlet ventricular septal defects with aortic valve deformity or congestive heart failure were included. The median follow-up period was 7 years (interquartile range: 0-17 years), without deaths or pacemaker implantations. The age, weight, ventricular septal defect size, and mild aortic regurgitation at surgery were factors associated with post-operative residual aortic regurgitation. Mild pulmonary regurgitation was observed in 12%, 30%, and 40% of patients 5, 10, and 15 years after surgery, respectively. There were no significant differences in age and weight at which surgery was performed between patients with mild pulmonary regurgitation and those with less than mild pulmonary regurgitation. However, the number of sutures across the pulmonary valve was associated with post-operative pulmonary regurgitation (P < 0.01). As some patients with mild pre-operative aortic regurgitation may not improve even after surgery, early surgical intervention is necessary when aortic regurgitation appears. Some patients may develop post-operative pulmonary regurgitation in the long term, suggesting the need for careful follow-up.

Influence of Bovine Arch Anatomy on Surgical Outcomes of Coarctation of the Aorta.

This study aimed to evaluate the outcome of coarctation of the aorta (CoA) repair with a special interest in bovine arch anatomy. Fifty-six patients who underwent CoA repair between 2010 and 2021 were included in this retrospective study. Of these, 11 patients had bovine arch anatomy. Surgical outcomes were reviewed. Computed tomography was used to analyze aortic arch geometry for all cases preoperatively. The gap between anastomotic sites was calculated at the linear region of the lesser curvature of the aortic arch between the distal ascending aorta and the proximal descending aorta. CoA repair was performed at a median age of 39 days (median body weight 3.3 kg). Thirty-two patients underwent extended direct anastomosis, 22 patients underwent direct anastomosis, and two patients underwent lesser curvature patch augmentation. The median follow-up period was 47 months. There were no early deaths. In patients who underwent direct and extended direct anastomosis, nine recoarctation and one left pulmonary venous obstruction events occurred. Moreover, freedom from these adverse events was 81% in normal arch and 50% in bovine arch patients at 10 years (P = 0.04). Two patients with a bovine arch anatomy who underwent lesser curvature patch augmentation had good outcomes. The distal arch was narrower and longer, and the gap between anastomotic sites was longer in patients with a bovine arch anatomy than with a normal arch (P < 0.01). In CoA with a bovine arch anatomy, the gap between anastomotic sites was long. This adversely influenced the outcomes of the CoA repairs.

Management of neonatal cardiac rhabdomyoma obstructing the aortic valve.

Rhabdomyomas associated with tuberous sclerosis are common cardiac tumors in children, and no surgical intervention is needed in most cases. However, when the tumor causes left ventricular outlet tract obstruction (LVOTO), immediate surgical intervention is indicated. Here, we report a newborn who was diagnosed antenatally with multiple cardiac rhabdomyomas, one of which blocked the aortic valve during systole. The tumor was resected early in the postnatal period with excellent outcomes. Until surgery, we maintained ductus arteriosus patency and systemic circulation using prostaglandin E1, which helped to reduce the risk of sudden death due to LVOTO. Postoperative two-dimensional echocardiography at discharge showed that surgery was effective in resolving LVOTO.

Anticoagulation Therapy After the Fontan Procedure.

The optimum postoperative anticoagulation therapy type and duration after the Fontan procedure remains unclear. This study aimed to evaluate whether our approach of administering only oral antiplatelets without warfarin due to serious bleeding complication risks in children is reasonable. We retrospectively reviewed the data of 249 patients who underwent the Fontan procedure. Total cavopulmonary connection with extracardiac conduit was performed in 230 patients (92%), the lateral tunnel Fontan procedure was performed in 18 patients (8%), and intraatrial conduit Fontan procedure was performed in one patient. Aspirin administration (initial dose: 5 mg/kg/day) was continued in all patients. Only 29 patients (11%) received combined administration of aspirin and warfarin for various reasons, and warfarin was discontinued in 20 (71%) of these within a median of 16 months postoperatively. Sixteen patients at high risk of thromboembolism were started on warfarin. Hospital mortality was 0%, with no thromboembolic or bleeding event-related early death. Nine late deaths, not associated with bleeding nor thromboembolism, occurred except one resulting from cardiac infarction 1.9 years after the procedure. During hospitalization, five patients experienced graft thromboembolism, two of which underwent graft exchange, and the others were started on warfarin. In the late phase (3.1 ± 6.6 years), cerebral infarction (n = 3), peripheral pulmonary artery occlusion (n = 2), gastrointestinal bleeding (n = 5), and respiratory hemorrhage (n = 4) occurred. Eight of nine patients with bleeding events received only aspirin. Thromboembolic events occurred in six patients within the first year after the procedure. Bleeding events occurred at 8 ± 5.5 years after the procedure. Expected freedom from a thromboembolic event was 99.8% at 1 year and 93.4% at 20 years. Expected freedom from a bleeding event was 100% at 1 year and 88.4% at 20 years. In children at low risk of thromboembolism after the Fontan procedure, continuous administration of an oral antiplatelet agent alone without warfarin seems to represent a reasonable prophylactic approach.

Reconstruction in left main coronary artery atresia with bypass graft obstruction.

Paediatric coronary artery bypass surgery with internal thoracic artery grafting is the optimal choice for left main coronary artery atresia; we report successful reconstruction in a patient with bypass graft obstruction. The pulmonary trunk was transected to expose the left main coronary stem, which was opened beyond the obstruction and the incision extended through the left main coronary artery to the circumflex bifurcation and left anterior descending artery. A funnel-shaped coronary ostium was created with a glutaraldehyde-treated autologous pericardium onlay patch. Surgical reconstruction is a good alternative for left main coronary artery atresia with graft obstruction and preserves the remaining internal thoracic artery for future use.

Randomized phase II trial comparing carboplatin plus weekly paclitaxel and docetaxel alone in elderly patients with advanced non-small cell lung cancer: north japan lung cancer group trial 0801.

BACKGROUND: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. METHODS: Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. RESULTS: Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. CONCLUSION: The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.

Impact of Optimal Fenestration Size on Outcomes of High-Risk Fontan Patients.

BACKGROUND: We aimed to analyze mid-term outcomes of the fenestrated Fontan procedure, focusing on the fenestration size. METHODS: We retrospectively reviewed the outcomes of the fenestrated Fontan procedure. Among 165 patients who underwent the Fontan procedure from 2011 to 2021, fenestration was created in 27 patients with the highest risks, including those with hypoplastic left heart syndrome, hypoplastic pulmonary arteries, heterotaxy syndrome with high pulmonary vascular resistance, and pulmonary arterial pressure >15 mm Hg. The patients underwent the procedure at a median age of three years (body weight, 11.4 kg; body surface area, 0.54 m2). Fenestration sizes were 3.5 to 5 mm. RESULTS: Spontaneous fenestration closure occurred within one year postoperatively in nine patients. Among them, three experienced Fontan failure, necessitating refenestration. Although fenestration size did not differ, the size corrected by body surface area at the time of surgery was smaller in patients with fenestration closure (6.4 mm/m2 vs 8.3 mm/m2, P < .05). Patients with a fenestration <7 mm/m2 were more likely to have fenestration closure within one year postoperatively, and those with a fenestration >9 mm/m2 were more likely to have severe desaturation and require home oxygen therapy following discharge. CONCLUSIONS: Spontaneous fenestration closure affected the frequency of Fontan complications. A very small fenestration size corrected by body surface area was a significant risk factor for spontaneous closure. Conversely, a very large fenestration size corrected by body surface area resulted in severe desaturation. The optimal fenestration size to prevent early spontaneous closure and severe desaturation is approximately 8 mm/m2.

Impact of the Rudimentary Chamber on Outcomes in Fontan Patients.

Background: We sought to evaluate the influence of the rudimentary ventricle on long-term outcomes after the Fontan operation, focusing on exercise capacity and cardiac performance. Methods: Between 1995 and 2021, 290 patients underwent a total cavopulmonary connection. "Two-ventricle" Fontan circulation was defined as a rudimentary ventricle >30% of the dominant ventricle or >50% of its predicted normal value. This cohort was compared with patients with single-ventricle Fontan circulation. The primary endpoint was Fontan failure, and the secondary endpoints were VO2 and cardiac catheterization data at ten years postoperatively. Results: The median follow-up after the Fontan operation was 7.9 years (interquartile range: 1.9-13.9). No significant difference was found in Fontan failure-free survival between the "two-ventricle" Fontan circulation group and the single-ventricle Fontan circulation group (83/91, 93% vs 156/199, 78%), respectively at 20 years; P = .11). No significant difference was found in VO2 or cardiac performance except cardiac index, with 2.9 (2.3-4.8) versus 2.5 (2.3-4.3) L/min/m2 (P = .047). Fifty-one patients in the "two-ventricle" Fontan circulation group were followed up for over ten years after the Fontan operation. In the subgroup analysis of this cohort, the rudimentary ventricular end-diastolic volume/dominant ventricular end-diastolic volume ratio showed a significant positive correlation with dominant ventricular end-diastolic pressure (r = 0.58 [95% CI 0.35-0.74], P = .002) and a significant negative correlation with VO2 (r = -0.61 [95% CI -0.80 to -0.28], P = .001). Conclusions: The rudimentary ventricle was not significantly associated with any clinical disadvantages regarding Fontan failure. However, a large rudimentary ventricle was significantly associated with higher end-diastolic pressure and lower exercise capacity.

Congenital Mitral Regurgitation Repair Based on Carpentier's Classification: Long-Term Outcomes.

BACKGROUND: There are few reports of the outcomes of standardized surgical management addressing the etiologic and morphologic aspects of mitral valve malformation according to Carpentier's classification. This study aimed to evaluate the long-term outcomes of mitral valve repair in children according to Carpentier's classification. METHODS: Patients who underwent mitral valve repair at our institution between 2000 and 2021 were retrospectively reviewed. Preoperative data, surgical techniques, and outcomes were analyzed according to Carpentier's classification. The proportion of patients free of mitral valve replacement and reoperation was estimated using Kaplan-Meier analysis. RESULTS: Twenty-three patients (median operative age, four months) were followed up for 10 (range, 2-21) years. Preoperative mitral regurgitation was severe in 12 patients and moderate in 11 patients. Eight, five, seven, and three patients had Carpentier's type 1, 2, 3, and 4 lesions, respectively. Ventricular septal defect (N = 9) and double outlet of the great arteries from the right ventricle (N = 3) were the most commonly associated cardiac malformations. There were no cases of operative mortality or deaths during the follow-up. The overall five-year rate of freedom from mitral valve replacement was 91%, whereas the five-year rates of freedom from reoperation were 74%, 80%, 71%, and 67% in type 1, 2, 3, and 4 lesions, respectively. Postoperative mitral regurgitation at the last follow-up was moderate in three patients and less than mild in 20 patients. CONCLUSIONS: Current surgical management of congenital mitral regurgitation is generally considered adequate; however, more complicated cases required a combination of various surgical techniques.

Bilateral pulmonary artery banding for transposition of the great arteries complex with coarctation.

Surgical approaches for transposition of the great arteries with aortic arch obstruction include primary repair and two-stage repair. However, neither approach provides a satisfactory outcome. We report a case of patient who underwent two-stage repair, wherein arterial switch operation combined with aortic arch reconstruction was preceded by bilateral pulmonary artery banding; this yielded good outcomes. This approach safely avoids primary repair in the neonatal period and allows for the opportunity to evaluate right ventricle outlet tract stenosis before the definitive repair.

Norwood procedure for hypoplastic left heart syndrome associated with valvular pulmonary stenosis.

Association between hypoplastic left heart syndrome and valvular pulmonary stenosis is very rare. Severity of valvular pulmonary stenosis in this setting limits management options. Consequently, patients with this condition are considered poor candidates for Norwood stage one reconstruction. Herein, we describe a newborn with hypoplastic left heart syndrome and significantly dysplastic pulmonary valve who successfully underwent the Norwood procedure with neoaortic valve reconstruction. Therefore, the Norwood procedure with neoaortic valve reconstruction might be an option for this difficult condition.

Coarctation of Aorta With Circumflex Aorta: Risk of Bronchial Compression and Recoarctation.

Coarctation of the aorta with a circumflex aorta is a very rare congenital heart anomaly. This report describes the treatment of 3 patients with this condition. All patients underwent direct anastomosis for aortic arch repair. However, postoperatively, in 2 patients, left main bronchial compression with gradual traction of the descending aorta toward the left side developed. The third patient experienced recoarctation of the aorta resulting from excessive tension. Surgical strategies for coarctation of the aorta should consider the positional relationship of the descending aorta and aortic arch, such as cases of a circumflex aorta.

Aortic-to-Right Ventricle Shunting for Rare Cardiovascular Conditions.

Pulmonary atresia with hypoplastic right ventricle and ventricular septal defect with right ventricle-dependent coronary circulation are very rare congenital heart anomalies. This report describes the case of a patient in whom aortic-right ventricle shunting was surgically established with a satisfactory postoperative course. Aortic-right ventricle shunting can enhance oxygenation of the sinusoidal communication and reduce the incidence of myocardial ischemia without influencing the left ventricular volume load through the ventricular septal defect despite preservation of the septal defect.

Effects of docosahexaenoic acid on in vitro amyloid beta peptide 25-35 fibrillation.

Amyloid beta peptide(25-35) (Abeta(25-35)) encompasses one of the neurotoxic domains of full length Abeta(1-40/42), the major proteinaceous component of amyloid deposits in Alzheimer's disease (AD). We investigated the effect of docosahexaenoic acid (DHA, 22:6, n-3), an essential brain polyunsaturated fatty acid, on the in vitro fibrillation of Abeta(25-35) and found that it significantly reduced the degree of fibrillation, as shown by a decrease in the intensity of both the thioflavin T and green fluorescence in confocal microscopy. Transmission electron microscopy revealed that DHA-incubated samples were virtually devoid of structured fibrils but had an amorphous-like consistency, whereas the controls contained structured fibers of various widths and lengths. The in vitro fibrillation of Abeta(25-35) appeared to be pH-dependent, with the strongest effect seen at pH 5.0. DHA inhibited fibrillation at all pHs, with the strongest effect at pH 7.4. It also significantly decreased the levels of Abeta(25-35) oligomers. Nonreductive gradient gel electrophoresis revealed that the molecular size of the oligomers of Abeta(25-35) was 10 kDa (equivalent to decamers of Abeta(25-35)) and that DHA dose-dependently reduced these decamers. These results suggest that DHA decreases the in vitro fibrillation of Abeta(25-35) by inhibiting the oligomeric amyloid species and, therefore, Abeta(25-35)-related neurotoxicity or behavioral impairment could be restrained by DHA.

Pulmonary venous obstruction after extracardiac total cavopulmonary connection in right atrial isomerism.

BACKGROUND: Patients with functional single ventricle and right atrial isomerism (RAI) often have multiform cardiac pulmonary venous (PV) connection, which could be a risk factor for pulmonary venous obstruction (PVO) after extracardiac total cavopulmonary connection (EC-TCPC) owing to compression of the conduit. OBJECTIVE: To investigate the anatomical risk factors for PVO after EC-TCPC in RAI. METHODS: Twenty-nine patients with RAI without extracardiac total anomalous pulmonary venous connection were enrolled. No patients had PVO before EC-TCPC. A total of 14 and 15 patients had PV orifices ipsilateral and contralateral to the extracardiac conduit, respectively. The former 14 patients were assigned to two groups based on development of PVO after EC-TCPC (groups O and N). The pre- and post-operative cardiac morphologies and their relationship with the conduit were compared. RESULTS: After the EC-TCPC, the pressure gradients between the atrium and the PV were 5.0 ± 2.5 and 0.44 ± 0.2 mmHg in groups O and N, respectively (p < 0.01); however, the pressure gradients in the left and right PVs were not significantly different, suggesting stenosis of the common PV orifice. The ratio of the horizontal distance from the vertebrae to the PV orifice and to the lateral edge of the atrium was significantly higher (0.38 ± 0.2 vs. 0.17 ± 0.1; p = 0.04) and the orifice was smaller (8.9 ± 2.0 vs. 15 ± 4.7 mm; p < 0.01) in group O than in group N. CONCLUSION: In cases with ipsilateral locations of the conduit and PV orifice, small size and more lateral location of the PV orifice may be preoperative risk factors for development of PVO.

Mechanism of docosahexaenoic acid-induced inhibition of in vitro Abeta1-42 fibrillation and Abeta1-42-induced toxicity in SH-S5Y5 cells.

The mechanism of the effect of docosahexaenoic acid (DHA; C22:6, n-3), one of the essential brain nutrients, on in vitro fibrillation of amyloid beta (Abeta(1-42)), Abeta(1-42)-oligomers and its toxicity imparted to SH-S5Y5 cells was studied with the use of thioflavin T fluorospectroscopy, laser confocal microfluorescence, and transmission electron microscopy. The results clearly indicated that DHA inhibited Abeta(1-42)-fibrill formation with a concomitant reduction in the levels of soluble Abeta(1-42) oligomers. The polymerization (into fibrils) of preformed oligomers treated with DHA was inhibited, indicating that DHA not only obstructs their formation but also inhibits their transformation into fibrils. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (12.5%), Tris-Tricine gradient(4-20%) gel electrophoresis and western blot analyses revealed that DHA inhibited at least 2 species of Abeta(1-42) oligomers of 15-20 kDa, indicating that it hinders these on-pathway tri/tetrameric intermediates during fibrillation. DHA also reduced the levels of dityrosine and tyrosine intrinsic fluorescence intensity, indicating DHA interrupts the microenvironment of tyrosine in the Abeta(1-42) backbone. Furthermore, DHA protected the tyrosine from acrylamide collisional quenching, as indicated by decreases in Stern-Volmer constants. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide-reduction efficiency and immunohistochemical examination suggested that DHA inhibits Abeta(1-42)-induced toxicity in SH-S5Y5 cells. Taken together, these data suggest that by restraining Abeta(1-42) toxic tri/tetrameric oligomers, DHA may limit amyloidogenic neurodegenerative diseases, Alzheimer's disease.