Effect of Preoperative Left Ventricular Mass on Outcomes After Aortic Valve Replacement for Aortic Regurgitation.

BACKGROUND: We determined the left ventricular mass index (LVMI) cut-off value for the risk of major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing aortic valve replacement (AVR) for aortic regurgitation (AR) and investigated the effect of preoperative left ventricular remodeling on long-term outcomes postoperatively. METHODS AND RESULTS: Of the 1,580 patients who underwent surgical AVR at Shiga University of Medical Science between January 2002 and December 2022, we retrospectively analyzed data for 263 patients who underwent surgery for AR. The receiver operating characteristic curve showed that the cut-off value of preoperative LVMI for the incidence of MACCE was 200 g/m2(area under the curve=0.692). We compared postoperative outcomes between patients with preoperative LVMI >200 g/m2(n=92) and those with preoperative LVMI ≤200 g/m2(n=171) after adjusting for preoperative characteristics using inverse probability of treatment weighting. The mean (±SD) follow-up period was 6.9±5.1 years. The rate of MACCE at 10 years was significantly higher in patients with preoperative LVMI >200 g/m2than in those with preoperative LVMI ≤200 g/m2(25.6% vs. 13.5%; P=0.020). In multivariable Cox models, preoperative LVMI >200 g/m2was significantly associated with a higher risk of MACCE (hazard ratio 2.356, P=0.006). CONCLUSIONS: Preoperative LVMI >200 g/m2was associated with a higher rate of MACCE in patients undergoing AVR for AR.

Later aorta operation after aortic valve replacement for bicuspid aortic valve.

BACKGROUND: We investigated long-term outcomes, particularly later aorta operations and overall death in patients who underwent aortic valve replacement for bicuspid aortic valve without aortic surgery. METHODS: Between January 2002 and December 2022, 274 patients underwent aortic valve replacement for bicuspid aortic valve at our institution. Of them, 181 patients who did not undergo aortic surgery, in accordance with current guidelines, were analyzed retrospectively. RESULTS: The median follow-up duration was 6.1 (2.0-10.6) years, and follow-up was completed in 97.8% of pateints. There were 3 patients (1.7%) who underwent later aorta operation during follow-up period. The cumulative later aorta operation rate at 10 years adjusting overall death as competing risk was 16.3%, and the estimated rates of freedom from overall death at 10 years was 83.7%. Fine-Gray competing risk regression model showed that aortic valve stenosis was only the predictor of later aorta operation (hazard ratio 8.477; p = 0.012). In multivariable Cox models, predictors of overall death were aortic valve stenosis (hazard ratio: 8.270, 95% confidence interval: 1.082-63.235; p = 0.042) and operation time (hazard ratio: 1.011, 95% confidence interval: 1.004-1.017; p = 0.002). CONCLUSIONS: Patients with bicuspid aortic valve with ascending aortic diameter less than 45 mm are at low risk of later aorta operation after isolated aortic valve replacement.

Off-pump bilateral internal thoracic artery grafting in patients with left main coronary artery disease.

BACKGROUND: To compare postoperative outcomes in patients with left main coronary artery disease who underwent off-pump isolated coronary artery bypass grafting for multivessel disease using either skeletonized bilateral or single internal thoracic artery (ITA). METHODS: Among 1583 patients who underwent isolated coronary artery bypass grafting (CABG) in our hospital between 2002 and 2022, 604 patients with left main coronary artery disease underwent single (n = 169) or bilateral (n = 435) ITA grafting. We compared postoperative outcomes between the two groups after adjusting preoperative characteristics using inverse probability of treatment weighting. RESULTS: After adjustment using inverse probability of treatment weighting method, the sum of weights was 599.74 in BITA group and 621.64 in SITA group. There was no significant difference in postoperative deep sternal wound infection (p = 0.227) and 30-day mortality (p = 0.612). Follow-up was completed in 98.7% (596/604) of the patients, and the mean follow-up duration was 6.7 years. At 10 years, the overall survival following bilateral versus single ITA grafting was 71.2% and 60.6%, respectively (log-rank test, p = 0.040), and freedom from major adverse cardiac and cerebrovascular events (MACCE) was 63.3% and 46.3%, respectively (log-rank test, p = 0.008). In multivariate Cox proportional hazard models, bilateral ITA grafting was significantly associated with a lower risk of all-cause death (hazard ratio [HR]: 0.706, 95% confidence interval [CI]: 0.504-0.987; p = 0.042) and MACCE (HR: 0.671, 95% CI: 0.499-0.902; p = 0.008). CONCLUSIONS: Bilateral skeletonized ITA grafting is associated with lower rates of all-cause death and MACCE than single ITA grafting in patients with left main coronary artery disease undergoing off-pump CABG.

Successful revascularization using a saphenous vein for a ruptured brachial artery aneurysm in a patient with neurofibromatosis type I.

Vasculopathy in patients with type 1 neurofibromatosis is known. Brachial artery aneurysms in patients with type 1 neurofibromatosis are rare, but any rupture can be extremely serious. A 56-year-old woman presented to our hospital with sudden pain in her right upper arm. Computed tomography revealed a ruptured brachial artery aneurysm, and operative reconstruction using a saphenous vein graft was performed. This is one of the few case reports of such successful revascularization using saphenous vein. The pathologic findings suggest neurogenic tumor invasion, and end-to-side anastomosis was effective in avoiding hemorrhagic complications.

[Total Arch Replacement with Open Stent Grafting for Chronic Dissecting Aortic Aneurysm with Aberrant Right Subclavian Artery:Report of a Case].

A 59-year-old man was referred to our hospital for surgery for a dissecting aortic aneurysm with an aberrant right subclavian artery( ARSA). He had a history of surgery for atrial septal defect at the age of 3 and developed Stanford type B aortic dissection at the age of 53. The maximum diameter of the aortic aneurysm was 68 mm, and the entry was located close to the ARSA origin. We established cardiopulmonary bypass using the femoral artery and vein and performed a median re-sternotomy. We performed total arch replacement with the open stent-grafting technique. The ARSA was ligated from the right thoracic cavity. Three arch branches were reconstructed in situ, and the right axillary artery was bypassed with a 9 mm Dacron graft. Six months after that operation, reduction of the false lumen was observed. This strategy is considered to be effective for chronic aortic dissection with ARSA.

Is central repair with coronary artery bypass grafting enough for multi-organ malperfusion in acute type A aortic dissection with coronary malperfusion?

OBJECTIVES: Acute type A aortic dissection with coronary malperfusion syndrome is rare but associated with high mortality. Multi-organ malperfusion is an independent predictor of acute type A aortic dissection. Coronary malperfusion requires treatment, but it is not feasible to treat all malperfusions. The adequacy of "central repair and coronary artery bypass grafting" for patients with coronary and other organ malperfusion is unknown. METHODS: Of the 299 patients who underwent surgery between 2008 and 2018, 21 patients with coronary malperfusion, who received cental repair with coronary artery graft bypass, were analyzed retrospectively. They were divided; into Group M (n = 13, coronary and other organ malperfusion) and Group O (n = 8, coronary malperfusion only). The patient background, surgical content, details of malperfusion, surgical mortality and morbidity, and long-term outcome were compared. RESULTS: There was no difference in operation time (205 ± 30 vs. 266 ± 88, p = 0.49), but the time from arrival to circulatory arrest tended to be shorter in Group M (81 vs. 134, p = 0.05). Among Group M, cerebral malperfusion was the most common at 92%. Two of the three cases with mesenteric malperfusion died. The mortality of Group M and Group O was 13% and 15% (P = 0.85), respectively. There was no difference in long-term mortality (p = 0.62). CONCLUSIONS: Central repair and coronary artery bypass grafting is a sufficiently acceptable treatment for patients with acute type A aortic dissection and multi-organ malperfusion, including coronary malperfusion.

Off-Pump Bilateral Skeletonized Internal Thoracic Artery Grafting in Octogenarians.

BACKGROUND: We compared postoperative outcomes in octogenarians who underwent off-pump isolated coronary artery bypass grafting for multivessel disease using either skeletonized bilateral or single internal thoracic artery (ITA).Methods and Results: Among 1,532 patients who underwent isolated coronary artery bypass grafting between 2002 and 2021, 173 octogenarians were analyzed retrospectively. After inverse probability of treatment weighting, we found no statistically significant difference regarding patients' preoperative characteristics. No patient experienced deep sternal wound infection. More patients in the single than bilateral ITA group died within 30 days after surgery (5.0% vs. 0%, respectively; P=0.003). The mean follow-up duration was 4.2 years. At 5 years, the freedom from overall death following bilateral versus single ITA grafting was 78.2% and 53.7%, respectively (log-rank test, P=0.003), and freedom from major adverse cardiac and cerebrovascular events (MACCE) was 67.9% and 44.8% respectively (log-rank test, P=0.002). In multivariable Cox models, bilateral ITA grafting was significantly associated with a lower risk of overall death (hazard ratio [HR] 0.555; 95% confidence interval [CI] 0.342-0.903; P=0.018) and MACCE (HR 0.586; 95% CI 0.376-0.913; P=0.018). CONCLUSIONS: Compared with single ITA grafting, off-pump skeletonized bilateral ITA grafting is associated with lower rates of overall death and MACCE in octogenarians undergoing CABG and does not increase the risk of deep sternal wound infection.

[A Rapidly Growing Cardiac Calcified Amorphous Tumor in a Peritoneal Dialysis Patient:Report of a Case].

A calcified amorphous tumor( CAT) is a non-neoplastic cardiac tumor, which has been reported to be associated with hemodialysis dependent end-stage renal disease. We report a case of CAT attached to mitral annular calcification (MAC) in the posterior leaflet annulus of the mitral valve in a 56-year-old man who had been receiving peritoneal dialysis for three years. The CAT grew to 10 mm long in a half year. Peritoneal dialysis dependent end-stage renal disease is associated with MAC. Additionally, MAC-related CAT has been reported growing rapidly. We should perform periodic echocardiography not only for hemodialysis patients but also for peritoneal dialysis patients. When CAT is diagnosed, operation should be performed early to prevent embolism such as cerebral infarction.

[Stanford Type A Aortic Dissection with Tricuspid Regurgitation in a Patient with Situs Inversus Totalis].

Situs inversus totalis is a congenital anomaly characterized by a mirror image transposition of the normal visceral organs, which makes it difficult to perform aortic surgery accurately. Stanford type A aortic dissection in patients with this condition is very rare and difficult to assess and manage. We report a case of Stanford type A aortic dissection with situs inversus totalis. The patient presented with severe tricuspid regurgitation with annulus enlargement due to chronic atrial fibrillation, requiring ascending aortic replacement and tricuspid annuloplasty. These procedures were performed after the operator swapped the left and right positions during the operation. Postoperative course was uneventful. By carefully checking the preoperative computed tomography images and changing the operator's position during the operation, it is possible to safely perform Stanford type A aortic dissection surgery in patients with situs inversus totalis.

Extended Sandwich Patch Technique via Right Ventriculotomy for Acute Ventricular Septal Rupture.

BACKGROUND: Surgical repair for postinfarction ventricular septal rupture (VSR) was still a challenging operation, especially when required in the acute phase or posterior VSR. The extended sandwich patch technique is characterized by large double patches fixed by circumferential transmural large mattress sutures via right ventricle incision. In the present study, we report early and midterm clinical and echocardiographic outcomes of this technique. METHODS: Of 33 consecutive patients undergoing VSR repair using the extended sandwich patch technique between 2008 and 2018, 25 received surgery within 1 week from the onset of myocardial infarction (early group) and 8 received surgery after 1 week (late group), including 12 patients with posterior VSR. All patients underwent surgery within 24 hours of VSR diagnosis. RESULTS: Intraoperative transesophageal echocardiography identified no residual shunt, but 2 patients received reoperative VSR repair at 9 days and 2 months after the first VSR repair. The 30-day mortality and 1-year survival in the early and late groups were 20% and 12.5%, and 58% and 88%, respectively. After VSR repair, right and left heart chamber sizes were significantly decreased, and these improvements were stable throughout the subsequent follow-up period (median 4.0 years). Tricuspid annular plane systolic excursion and right ventricular fractional area change remained constant throughout the observation period without changing after VSR repair. CONCLUSIONS: The extended sandwich patch technique through a right ventriculotomy offered safe and simple, leak-free repair even in technically demanding acute phase or posterior VSR. No significant decline was found in the right heart function after surgery.

Total arch replacement in octogenarians.

OBJECTIVES: We investigated the effect of a preoperative age ≥80 years on postoperative outcomes in patients who underwent isolated elective total arch replacement using mild hypothermic lower body circulatory arrest with bilateral antegrade selective cerebral perfusion. METHODS: A total of 140 patients who had undergone isolated elective total arch replacement between January 2007 and December 2020 were enrolled in the present study. We compared postoperative outcomes between 30 octogenarian patients (≥80 years old; Octogenarian group) and 110 non-octogenarian patients (≤79 years old; Non-Octogenarian group). RESULTS: Overall 30-day mortality and hospital mortality were 0% in both groups, and there was no significant difference in overall survival between the 2 groups (log-rank test, P = 0.108). Univariable Cox proportional hazard analysis showed that age as continuous variable was only the predictor of mid-term all-cause death (hazard ratio 1.08, 95% confidence interval 1.01-1.16; P = 0.037), but not in the Octogenarians subgroup (P = 0.119). CONCLUSIONS: Preoperative age ≥80 years is not associated with worse outcomes postoperatively after isolated elective total arch replacement with mild hypothermic lower body circulatory arrest and bilateral antegrade selective cerebral perfusion.

Impact of Aortic Valve Replacement for Aortic Stenosis on Coexisting Mitral Stenosis.

PURPOSE: The course of coexisting mitral valve stenosis is not clear after aortic valve replacement (AVR) for aortic stenosis (AS). We investigated the effect of AVR for AS on coexisting mitral stenosis (MS). METHODS: Between January 2002 and December 2019, 1338 consecutive patients underwent surgical AVR at Shiga University of Medical Science. Of them, 34 patients with moderate MS (mitral valve area [MVA]: 1.5-2.0 cm2) were included in the present study. We evaluated the postoperative clinical outcomes in these patients. RESULTS: Mean MVA in our cohort significantly increased 1 week after operation compared with preoperative values, and the change was maintained for 5 years after surgery. Follow-up was completed in 94.1% (32/34) patients, and mean follow-up duration was 4.0 ± 3.0 years. No patients underwent mitral surgery for remaining MS after AVR during postoperative follow-up. CONCLUSION: AVR for AS resulted in increased MVA in patients with MS, and the change was maintained during follow-up.

Differences Between Patients with and without Atherosclerosis in Expression Levels of Inflammatory Mediators in the Adipose Tissue Around the Coronary Artery.

Perivascular adipose tissue (PVAT) secretes large amounts of inflammatory mediators and plays a certain role in atherosclerosis formation from the exterior of the vessel. In the present study, we examined the expression level of inflammation-related mediators using adipose tissue samples harvested from patients with and without coronary artery disease (CAD). The subjects were 23 patients who underwent elective coronary bypass surgery (CAD group) and 17 patients who underwent elective mitral valve surgery (non-CAD group) between January 2017 and March 2018. The adipose tissue was harvested from three sites: the ascending aorta (AO), subcutaneous fat (SC), and pericoronary artery (CO) for the measurement of the expression levels of interleukin (IL) -1ß, IL-6, IL-10, tumor necrosis factor (TNF) -α, interferon (INF) -γ, and arginase (Arg) -1. In both the non-CAD and CAD groups, the expression levels of all mediators, except Agr-1, which showed a tendency to have higher levels in the SC than in the AO and CO, tended to upregulate in the AO than in the SC and CO. The CAD group had higher values of almost all mediators, except Arg-1. Most importantly, the expression levels of IL-1ß, IL-6, and IL-10 in the coronary artery were significantly higher in the CAD group. The expression levels of inflammatory mediators in the pericoronary adipose tissue were significantly higher in the CAD than in the non-CAD group. The adipose tissue appears to influence atherosclerosis formation from the exterior of the coronary artery.

Internal thoracic artery graft ipsilateral to the arteriovenous fistula in haemodialysis patients.

OBJECTIVES: The aim of this study was to investigate the impact of in situ internal thoracic artery (ITA) grafting ipsilateral to the arteriovenous fistula (AVF) on postoperative outcomes in haemodialysis patients undergoing isolated coronary artery bypass grafting (CABG). METHODS: We reviewed 132 haemodialysis patients who underwent isolated CABG between January 2002 and December 2019. With a difference between the left and right upper arms blood pressure measurement of ≥20 mmHg, we did not use the ITA on the lower value side. We categorized patients into 55 patients (41.7%, ipsilateral group) whose left anterior descending artery was revascularized using the in situ ITA ipsilateral to the AVF, and 77 patients (58.3%, contralateral group) whose left anterior descending artery was revascularized using the ITA opposite the AVF. We compared patients' postoperative outcomes after adjusting for their backgrounds using weighted logistic regression analysis and inverse probability of treatment weighting. RESULTS: No patients developed coronary steal postoperatively, and there was no significant difference in 30-day mortality between the groups (P = 0.353). The adjusted 5-year estimated rates of freedom from all-cause and cardiac death in the ipsilateral vs contralateral groups were 52.3% vs 54.0% and 78.2% vs 88.6%, respectively; survival curves were not statistically significantly different (P = 0.762 and P = 0.229, respectively). CONCLUSIONS: In situ ITA grafting ipsilateral to the AVF was not associated with postoperative early and mid-term worse outcomes in haemodialysis patients undergoing isolated CABG.

Total arch replacement in patients with chronic kidney disease.

BACKGROUND: We investigated the effect of preoperative renal dysfunction on postoperative outcomes in patients undergoing elective isolated total arch replacement (TAR) with mild hypothermic lower body circulatory arrest with antegrade selective cerebral perfusion (SCP). METHODS: One hundred and forty-four patients who had undergone elective isolated TAR between January 2002 and December 2019 were retrospectively analyzed. Patients were divided into two groups according to whether their preoperative estimated glomerular filtration rate (eGFR) was lower than or higher than 60 ml/min/1.73 m2 . We compared perioperative data and mid-term outcomes after adjusting for patients' baseline characteristics using weighted logistic regression analysis and inverse probability of treatment weighting. RESULTS: More patients underwent postoperative stroke in the chronic kidney disease group compared with the normal group (2.8% vs. 0%, respectively; p = .049). Overall 30-day mortality and hospital mortality were 0% in both groups, and there was no significant difference in overall survival between the two groups (log-rank test, p = .129). Multivariate Cox proportional hazard analysis showed that eGFR < 60 ml/min/1.73 m2 was not an independent predictor (hazard ratio: 1.636, 95% confidence interval 0.829-3.231; p = .156). CONCLUSIONS: Preoperative eGFR <60 ml/min/1.73 m2 was not associated with worse outcomes after elective isolated TAR with mild hypothermic lower body circulatory arrest with antegrade SCP.

Bilateral internal thoracic artery grafting in haemodialysis patients with diabetic nephropathy.

OBJECTIVES: To compare postoperative outcomes in patients with diabetic nephropathy receiving haemodialysis and undergoing isolated coronary artery bypass grafting (CABG) using bilateral or single skeletonized internal thoracic artery (ITA). METHODS: Among 1441 consecutive patients undergoing isolated CABG between 2002 and 2019 at our university hospital, we retrospectively analysed data for 107 patients with diabetic nephropathy receiving haemodialysis. After inverse probability of treatment weighting, we found no statistically significant differences regarding patients' preoperative characteristics. RESULTS: All patients underwent myocardial revascularization using the off-pump technique. There was no statistical significance in postoperative deep sternal wound infection (P = 0.902) and 30-day mortality (P = 0.755). However, the bilateral ITA group had a lower rate of postoperative stroke versus the single group (0% vs 5.5%, respectively; P = 0.021). Follow-up was completed in 95.3% (102/107) of the patients, and the mean follow-up duration was 3.3 years. Thirty-eight deaths occurred in the bilateral ITA group and 18 in the single ITA group. There was no significant difference in all-cause death (P = 0.558) and cardiac death rates (P = 0.727). Multivariable Cox regression models showed that the independent predictors of all-cause death were age [hazard ratio (HR) 1.031; P = 0.010], previous percutaneous intervention (HR 1.757; P = 0.009) and gastroepiploic artery grafting (HR 0.582; P = 0.026). CONCLUSIONS: Bilateral ITA grafting in patients with diabetic nephropathy receiving haemodialysis did not improve mid-term outcomes.

In situ skeletonized gastroepiploic artery grafting in hemodialysis patients.

OBJECTIVES: There is no firm treatment strategy of coronary artery bypass grafting in hemodialysis patients. We investigated postoperative outcomes in hemodialysis patients undergoing isolated coronary artery bypass grafting using in situ skeletonized gastroepiploic artery. METHODS: From January 2002 to December 2019, 143 hemodialysis patients underwent isolated coronary artery bypass grafting in our institution. Among them, 49 consecutive patients with gastroepiploic artery grafting were retrospectively analyzed. RESULTS: No patient was converted from off-pump to on-pump surgery. The mean distal anastomoses were 3.6 ± 1.0 per patients. Seven patients (14.3%) required proximal anastomosis to aorta. Thirty-day mortality was 4.1% (2 of 49). The early (3-20 days after surgery) patency rate of the gastroepiploic artery was 96.9% (63 of 65 anastomoses). The adjusted rates of survival free from overall death at 1, 5 and 10 years after surgery were 91.7%, 72.6% and 32.5%, respectively. Multivariate Cox proportional hazard regression analysis showed that age (hazard ratio 1.131, 95% confidence interval 1.055-1.212, p < 0.001) and LVEF < 40% (hazard ratio 9.411, 95% confidence interval 1.963-45.919, p = 0.005) were independent predictors of mid-term death from all causes (Table 6). CONCLUSIONS: Short and mid-term outcomes were acceptable. The use of in situ skeletonized gastroepiploic artery can decrease the time of touching aorta, so gastroepiploic artery grafting may be an important option for coronary artery bypass grafting in hemodialysis patients with limited conduits.

Impact of vital capacity on outcome after total arch replacement.

OBJECTIVES: Although chronic obstructive pulmonary disease has been recognized as a significant risk factor for open-heart surgery, the relationship between vital capacity and postoperative outcomes remains unclear. Our objective was to analyze the effect of vital capacity on outcomes after total arch replacement. METHODS: Between January 2003 and December 2018, 228 patients undergoing total arch replacement who were elective cases with preoperative spirometry records were retrospectively reviewed. Patients were divided into two groups, based on whether their preoperative vital capacity was less than or greater than 2.5 L. We compared perioperative data and long-term outcome after adjusting their backgrounds by propensity score matching analysis. RESULTS: The lower vital capacity group had more tracheostomy patients (5.1% vs 0.0%; p = 0.045). The actuarial survival rate was 58.0% in the lower vital capacity group and 86.3% in the higher vital capacity group at 8 years. Log-rank analysis revealed a significant difference between the two groups (p = 0.011). In the multivariate Cox proportional hazard model, vital capacity < 2.5 L (p = 0.024) and estimated glomerular filtration rate < 30mL/minute/1.73 m2 (p = 0.012) showed a significant association with a higher risk of long-term mortality. CONCLUSIONS: Vital capacity should be considered an important risk factor for postoperative respiratory complications and long-term mortality in patients undergoing total arch replacement.

Spinal cord collateral flow during antegrade cerebral perfusion for aortic arch surgery.

OBJECTIVE: We aimed to monitor regional oxygen saturation levels using near-infrared spectroscopy in patients undergoing total aortic arch replacement and to determine the range of collateral flow via antegrade cerebral perfusion to the spinal cord during lower body circulatory arrest. METHODS: Eighteen consecutive patients undergoing total aortic arch replacement in our hospital were prospectively enrolled. Optodes of near-infrared spectroscopy were attached to the skin at the right and left forehead, and above the paravertebral muscles at the level of the third (T3) and tenth (T10) thoracic vertebra. Within- and between-group differences were compared using mixed-effect model repeated-measures analysis. RESULTS: Regional oxygen saturation levels, which had been rapidly declining immediately after circulatory arrest at a tympanic temperature of <25°C and a core temperature of <30°C, showed a rapid increase at the forehead with the initiation of antegrade cerebral perfusion (total flow rate 0.81 ± 0.08 L/min, perfusion pressure 37 ± 6 mm Hg, temperature 25°C). Saturation levels remained only partially elevated at the upper thoracic level (T3) and continued to decline without showing signs of recovery at the lower thoracic level (T10). CONCLUSIONS: Antegrade cerebral perfusion partially perfused the upper thoracic cord via collateral circulation from vertebral arteries through an anterior spinal artery, but it did not reach the lower thoracic cord sufficiently to change the oxygenation level. Cooling is a more important means of protection for the lower spinal cord during lower body circulatory arrest than is antegrade cerebral perfusion.