Long-term Outcomes After Pulmonary Endarterectomy in 499 Patients Over a 20-Year Period.

BACKGROUND: Pulmonary endarterectomy (PEA) is a curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension (PH) after PEA is not uncommon, and its impact on long-term outcomes is poorly understood. We investigated the effects of residual PH on current long-term survival and on postoperative status. METHODS: Data of 499 consecutive patients who underwent PEA between December 1995 and December 2014 were analyzed retrospectively. Kaplan-Meier survival analysis was used to estimate the survival rates with the 95% confidence interval. RESULTS: Overall survival at 5, 10, and 15 years postoperatively was 84.8% ± 1.9%, 77.1% ± 2.7%, and 59.2% ± 5.3%, respectively. Survival after discharge at 5, 10, and 15 years was 93.9% ± 1.5%, 85.4% ± 2.6%, and 65.6% ± 5.8%, respectively. Of all, 166 patients had residual PH immediately after PEA and a poorer prognosis regarding freedom from CTEPH-related death. CTEPH-related survival at 10 years in patients with normal pulmonary artery pressure vs residual PH was 89.0% ± 2.7% vs 67.9% ± 4.7%, respectively (P < .001). There was a trend to CTEPH-related survival after discharge being affected by residual PH (P = .092). At follow-up, patients with residual PH had worse exercise tolerance (P < .001) and symptoms (P < .001) compared with those with normal pulmonary artery pressure. The probability of developing PH over time was 41.9% at 15 years. CONCLUSIONS: Survival after hospital discharge is excellent for patients undergoing PEA. Postoperative PH is associated with more symptoms and poorer functional capacity. Patients who have clinically relevant postoperative PH should be monitored closely and may be candidates for additional medical therapy.

Graft Dilatation May Cause Secondary Regurgitation in Aortic Valve-Sparing Operations.

Aortic valve-sparing operations are meant to stabilize the root in order to provide stable aortic valve function. The possibility of graft dilatation has been known in other forms of aortic replacement but is largely ignored in valve-preserving surgery. We describe graft dilatation as a cause of failure late after aortic valve reimplantation. It was corrected by applying the concepts of aortic valve repair.

An Evaluation of the Learning Curve in Pulmonary Endarterectomy Using Propensity Score Matching.

OBJECTIVE: Pulmonary endarterectomy (PEA) is the only causative, but demanding treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). We analyzed our results with PEA to evaluate the learning curve. METHODS: Consecutive 499 patients who underwent PEA between 1995 and 2014 were divided into two groups according to the temporal order: early cohort (n = 200, December 1995-March 2006), and late cohort (n = 299, March 2006-December 2014). We assessed perioperative outcomes after PEA as compared between the early and the late cohort also in propensity-score-matched cohorts. RESULTS: Age at the surgery was older in the late cohort (p = 0.042). Preoperative mean pulmonary artery pressure (mPAP) was 46.8 ± 11.0 mm Hg in the early cohort and 43.5 ± 112.7 mm Hg in the late cohort (p = 0.0035). The in-hospital mortality in the early and late cohorts was 14.0% (28/200) and 4.7% (14/299), respectively (p = 0.00030). The duration of circulatory arrest (CA) became much shorter in the late cohort (42.0 ± 20.5 min in the early and 24.2 ± 11.6 min in the late cohort, respectively, p < .0001). In matched cohorts, the in-hospital mortality showed no significant difference (8.7% in the early cohort and 5.2% in the late cohort, < 0.0001). The CA duration, however, was still shorter in the late cohort (p <0.0001). CONCLUSIONS: Over time, older patients have been accepted for surgery, more patients were operated for lesser severity of CTEPH. Duration of CA and mortality decreased even beyond the first 200 patients, indicating a long learning curve.

Unicuspid aortic valve repair with bicuspidization in the paediatric population.

OBJECTIVES: Aortic stenosis or regurgitation that requires operations in children often results from unicuspid valve morphology. In all paediatric patients with this anomaly, we have performed unicuspid valve repair by bicuspidization, creating a new commissure via adding patch material. This study reviewed our experience with this procedure. METHODS: All patients with a unicuspid aortic valve who underwent bicuspidization at ≤18 years of age between 2003 and 2018 were evaluated. Autologous pericardium had initially been used for cusp augmentation. Since 2014, decellularized xenogeneic tissue or expanded polytetrafluoroethylene membrane has been applied. RESULTS: There were 60 consecutive patients. The median operative age was 13 (1-18) years. Thirty patients had prior surgical or catheter valvuloplasties. Aortic regurgitation, aortic stenosis and their combination were present in 22, 11 and 27 patients, respectively. Autologous pericardium decellularized tissue and expanded polytetrafluoroethylene were used in 45, 11 and 4 patients, respectively, without intraoperative conversion to valve replacement. The overall survival was 96% at 10 years with 2 late deaths. Twenty patients underwent aortic valve reoperation due to patch degeneration (n = 11), suture dehiscence of the patch (n = 3), subaortic stenosis (n = 3) or other reasons (n = 3). Freedom from aortic valve reoperation was 73% and 50% at 5 and 10 years, respectively. Fifteen patients (25%) required valve replacement with pulmonary autograft (n = 14) or prosthesis (n = 1) 5.2 (0.2-13) years after bicuspidization at the age of 19 (10-32) years. CONCLUSIONS: Bicuspidization is a safe and reproducible alternative to valve replacement with acceptable freedom from reoperation. It can serve as a bridge to valve replacement providing superior outcomes in adults.

Aortic Root Remodeling in Acute Aortic Dissection.

OBJECTIVES: To evaluate the long-term results of remodeling in acute aortic dissection type A (AADA) to define operative risk and root and valve stability. METHODS: Between October 1995 and December 2018, a total of 352 patients were treated surgically for AADA. Of these, 90 patients with AADA (<2 weeks from onset; age: 57 ± 15 years; 70 males) with a root diameter of >43 to 45 mm (depending on patient size) (48 ± 4.1 mm) underwent aortic root remodeling and were analyzed further. As the control group, we chose the patients with normally sized aortic roots who had been treated by tubular replacement only (n = 227). Other procedures were performed in 35 cases. RESULTS: Early mortality was 9% in the remodeling group versus 15% in the tubular ascending aortic replacement (TAR). Actuarial survival at 10 and 15 years was 68 ± 5% and 58.3 ± 6.4%, respectively, in the root remodeling group versus 68 ± 4% and 66 ± 4% in the TAR group (p = 0.99). Freedom from reoperation on the aortic valve or root was 95 ± 3% at 10 years and at 89 ± 6% at 15 years. Freedom from proximal reoperation after TAR at 10 and 15 years was 93 ± 3% and 91 ± 3% (n = 31 patients at risk), respectively, not statistically different from that after remodeling (p = 0.75). CONCLUSIONS: The long-term stability of aortic root remodeling for enlarged roots with AADA was comparable to TAR preserving a normal aortic root.

Geometry of cusp and root determines aortic valve function.

The aortic valve is the functional unit of cusp and root. Various geometrical and functional analyses for the aortic valve unit have been executed to understand normal valve configuration and improve aortic valve repair. Different concepts and procedures have then been proposed for reparative approach, and aortic valve repair is still not standardized like mitral valve repair. It has become apparent, however, that interpretation of the geometry of the aortic cusp and root and its appropriate application to operative strategy lead to creating a functioning aortic valve. Herein, the aortic valve geometry and its clinical implications are reviewed to provide information for the selection of appropriate operative strategies.

Aortic root remodeling in bicuspid and tricuspid aortic valves-long-term results.

BACKGROUND: Root remodeling is one form of valve-preserving root replacement to treat patients with aortic regurgitation (AR) and root aneurysm. We have consistently used it for patients with and without connective tissue disease and different aortic valve morphologies. The objective of this retrospective study was to review 23 years of experience with root remodeling. METHODS AND PATIENTS: Between 10/95 and 9/2018, 1004 of 1038 root remodeling procedures were performed in patients with tricuspid (n = 589) or bicuspid (n = 414) anatomy of the aortic valve in our institution. Aortic aneurysm was present in 932 cases, 73 procedures were performed for acute aortic dissection type A. The severity of aortic regurgitation ranged from grade I to grade IV (mean 2.5 ± 0.8). RESULTS: All patients underwent root remodeling, concomitant operations were performed in 433, and cusp repair in 883 instances. Hospital mortality was 2%. Overall freedom from reoperation was 92% at 10 years and 89% at 15 years. It was 94% for tricuspid valves at 10 and 15 years, and 88% for bicuspid aortic valves at 10 years and 80% at 15 years (p = 0.003). CONCLUSION: In conclusion, root remodeling is a viable option in valve-preserving root replacement. If combined with careful assessment and, if necessary, correction of aortic valve form reproducible restoration of aortic valve function can be achieved.

Long-term Results of Differentiated Anatomic Reconstruction of Bicuspid Aortic Valves.

Importance: Bicuspid aortic valve (BAV) repair has been used in limited cohorts, but its long-term results in a large population are unknown. Objectives: To analyze the long-term stability of BAV repair for survival and the factors associated with repair failure and to evaluate whether a differentiated anatomic repair approach may improve repair stability. Design, Setting, and Participants: In this case series, 1024 patients underwent BAV repair for aortic regurgitation or aneurysm between October 1995 and June 2018, with a mean (SD) follow-up time of 56 (49) months and maximum follow-up of 271 months. Systematic modifications in technique based on anatomic principles were introduced in 2009 and applied for the last 727 patients. Data were acquired prospectively and analyzed retrospectively. Exposures: Repair of BAV with or without concomitant aortic replacement, as well as postoperative clinical and echocardiographic follow-up. Main Outcomes and Measures: Survival and incidence of reoperation or recurrent aortic regurgitation, as well as factors associated with valve repair failure. Results: Among the 1024 patients in the study (920 male [89.8%]; mean [SD] age, 47 [13] years [range, 15-86 years]), the survival rate at 15 years was 82.1%. The cumulative incidence of reoperation was 30.7% (95% CI, 22.7%-38.7%) at 15 years. Cusp calcification (subdistribution hazard ratio, 1.78; 95% CI, 1.14-2.77; P = .01), asymmetric commissural orientation (subdistribution hazard ratio, 1.95; 95% CI, 1.02-3.72; P = .04), and use of a pericardial patch for cusp repair (subdistribution hazard ratio, 5.25; 95% CI, 3.52-7.82; P < .001) were associated with time to reoperation. At 10 years, the incidence of reoperation was significantly reduced among patients who received the anatomic repair concept compared with those who had undergone surgery in the earlier period (8.8% vs 24.6%; P < .001). Conclusions and Relevance: This study suggests that survival after BAV repair is excellent and that a large proportion of BAV repairs will remain stable. Repair stability can be markedly improved by an anatomic repair concept. Cusp calcification and the need for cusp repair using a patch remain the factors most strongly associated with valve failure. In those instances, valve replacement should be preferred.

Mid-term durability of polytetrafluoroethylene patches in unicuspid aortic valve repair.

OBJECTIVES: Unicuspid aortic valve (UAV) morphology is a cause for aortic valve dysfunction in childhood or adolescence. Repair requires the use of patch material, and polytetrafluoroethylene (PTFE) has been proposed for this purpose because of lack of calcification. We reviewed our mid-term experience with PTFE for the repair of UAV to analyse the durability of this technique. METHODS: Out of 21 patients with an UAV undergoing aortic valve repair for severe aortic regurgitation between 2014 and 2016, 11 patients (52%) were treated using PTFE patch material. Aortic regurgitation was present in all patients, the primary indication for surgery was regurgitation in 8, stenosis in 2 and aneurysm in 1. Symmetric bicuspidization of the UAV was performed in all. One patient required additional root remodelling for root dilatation, and another 3 tubular ascending aortic replacement. RESULTS: No patient died in hospital or during follow-up. Seven patients (63.6%) required reoperation for progressive AR. Freedom from reoperation was 58% at 1 and 35% at 5 years postoperatively. At reoperation the PTFE patches were found dehisced from aortic wall and/or native cusp tissue. In 3 patients re-repair was performed; a stable result was achieved in 1. Two patients underwent valve replacement 3 months and 1 year postoperatively. The other 4 patients underwent valve replacement. CONCLUSIONS: The repair of UAVs using PTFE patch is associated with poor durability, a more durable patch with better healing characteristics material is needed.

Reexamining remodelling in children.

OBJECTIVES: Some studies have suggested that root remodelling is unsuitable as valve-sparing aortic root replacement in children because of the increased risk of valve failure. This study reviewed our experience with root remodelling in children. METHODS: All patients who underwent root remodelling at the age of ≤18 years between 1999 and 2016 were evaluated. In 2004, cusp effective height was measured intraoperatively and prolapse was corrected with central plication on the cusp. Suture annuloplasty was introduced after 2009 for annular dilatation. RESULTS: There were 17 consecutive patients. The median age at operation was 14 (2.8-18) years. Aortic valve morphology was tricuspid in 10 patients, bicuspid in 5 patients, unicuspid in 1 patient and a pulmonary autograft in 1 patient. Marfan syndrome, Loeys-Dietz syndrome and other connective tissue diseases were present in 11, 1 and 2 patients, respectively. Five patients had more than moderate aortic regurgitation. The median graft size used for root remodelling was 24 (18-26) mm. Cusp repair and annuloplasty were performed in 15 and 14 patients, respectively. The mean follow-up time was 6.5 ± 4.3 years. One patient with preoperatively severely depressed ventricular function died in the hospital from persistent heart failure. One patient (operated on before 2004) required aortic valve reoperation due to cusp prolapse. One patient with a unicuspid valve had developed moderate aortic regurgitation, and the other 14 patients had mild or less regurgitation. The median diameter of the sinus of Valsalva at the last follow-up was 36 (30-43) mm, Z-score of 1.5 (-3.5 to 3.9). CONCLUSIONS: Root remodelling can be performed in children with favourable results by appropriate cusp repair and annuloplasty.

In Vivo Biocompatibility of a Novel Expanded Polytetrafluoroethylene Suture for Annuloplasty.

BACKGROUND: Expanded polytetrafluoroethylene (ePTFE) is a suture material for annuloplasty in aortic valve repair. For this particular application, it should induce minimal local stress and promote rapid tissue incorporation. To achieve this, a novel ePTFE suture with a larger diameter and high porosity in its midsection has been developed. Herein, we analyzed the acute and chronic tissue reaction to this suture material compared with a commercially available control ePTFE suture. METHODS: Novel and control suture samples were implanted into dorsal skinfold chambers of BALB/c mice to analyze the early inflammatory response using intravital fluorescence microscopy over 14 days. Additional suture samples were implanted for 4 and 12 weeks in the flank musculature of mice and analyzed by histology and immunohistochemistry. RESULTS: The implantation of novel and control ePTFE suture into the dorsal skinfold chamber did not induce an acute inflammation, as indicated by physiological numbers of rolling and adherent leukocytes in all analyzed venules. Chronic implantation into the flank musculature showed a better tissue incorporation of the novel ePTFE suture with more infiltrating cells and a higher content of Sirius red+ collagen fibers when compared with controls. Cell proliferation and viability as well as numbers of recruited CD68+ macrophages, myeloperoxidase+ neutrophilic granulocytes and CD3+ lymphocytes did not significantly differ between the groups. CONCLUSION: The novel ePTFE suture exhibits a good in vivo biocompatibility which is comparable to that of the control suture. Due to its improved tissue incorporation, it may provide a better long-term stability during annuloplasty.

Concepts of Bicuspid Aortic Valve Repair: A Review.

BACKGROUND: The bicuspid aortic valve (BAV) frequently requires surgical intervention for aortic regurgitation (AR) and aneurysm. Valve-preserving surgery for BAV has evolved over the last 25 years. METHODS: This review summarized experience in BAV repair with a special focus on predictors of failure and specific surgical techniques addressing them. RESULTS: Excellent repair stability can be achieved if a standardized approach addressing all pathologic components of aortic valve and root is used. Anatomic variations must be addressed with special approaches. CONCLUSIONS: Today, BAV repair leads to excellent stability if an anatomy-oriented concept is used. Further improvements of cinical results and reproducibility can be anticipated.

Bilateral papillary muscle repositioning: successful repair of functional mitral regurgitation in dilative cardiomyopathy.

OBJECTIVES: Functional mitral regurgitation (FMR) in patients with non-ischaemic dilative cardiomyopathy (DCM) is associated with heart failure and poor outcome. Aggressively undersized annuloplasty as an annular solution for a ventricular problem ameliorates heart failure but may be associated with recurrent FMR and does not improve survival. We sought to analyse if moderately undersized annuloplasty with repositioning of both papillary muscles can lead to improved valve stability and outcome in patients with DCM and FMR. METHODS: In 66 patients with DCM-associated FMR (age 66 ± 12 years, ejection fraction 29 ± 6% and mean pulmonary artery pressure 35 ± 11 mmHg) and severe leaflet tethering (tenting height ≥10 mm) bilateral papillary muscle repositioning was added to moderately undersized ring annuloplasty (median size 30 mm). Concomitant surgery included tricuspid valve repair in 86% of patients and atrial ablation in 44%. RESULTS: The early mortality rate was 9%. Overall 5-year freedom from all-cause death, left ventricular assist device implantation or heart transplant was 58% (95% confidence interval 45-71%). Six patients underwent reoperation (redo repair n = 4). Reverse remodelling was observed during follow-up in 66% of patients with decreasing left ventricular end-diastolic diameters (66 ± 5 to 61 ± 12 mm; P < 0.001) and left ventricular end-systolic diameters (56 ± 9 to 51 ± 14 mm; P = 0.001). Subgroup analyses (partial versus complete ring, preoperative left ventricular end-diastolic diameters <65 mm vs left ventricular end-diastolic diameter ≥65 mm) documented similar survival rates. A competing risks regression analysis identified cerebral vascular disease (P = 0.01), use of a partial ring (P = 0.03) and absence of tricuspid valve repair (P = 0.03) as independent predictors of death. CONCLUSIONS: The combination of bilateral papillary muscle repositioning and moderately undersized ring annuloplasty leads to stable mid-term repair results and reverse remodelling in patients with DCM and FMR and severe leaflet tethering.

Results of Pericardial Patches in Tricuspid and Bicuspid Aortic Cusp Repair.

BACKGROUND: Aortic valve repair for aortic regurgitation has become an increasingly accepted alternative to replacement. Some cusp pathologies require partial cusp replacement or augmentation using pericardium. There are limited data on pericardial patch durability. We analyzed our long-term results with pericardial patches in aortic cusp repair to clarify whether durability is influenced by aortic valve morphology or underlying cusp pathology. METHODS: From 2000 to 2017, 275 patients (mean age, 53 ± 14 years) underwent aortic valve repair involving pericardial patches with tricuspid aortic valve (n = 139, 50.5%) or bicuspid aortic valve (n = 136, 49.5%) morphology. Pericardial patches were used for either central cusp replacement (n = 64, 23%), closure of defects (n = 55, 20%), fenestrations (n = 104, 38%), cusp augmentation (n = 27, 10%), or commissural reconstruction (n = 25, 9%). Follow-up was complete in 96%. RESULTS: Ten-year survival was 85%, and 10-year freedom from reoperation was 53%. Durability was inferior after bicuspid aortic valve repair (37%) compared with tricuspid aortic valve repair (69%; P < .0001). Best 10-year freedom from reoperation was found after closure of fenestrations (73%) and defects (67%). Suboptimal durability was observed after cusp augmentation (44%), central cusp replacement (39%), and commissural reconstruction (16%, P < .001). CONCLUSIONS: The results of aortic cusp repair using pericardium depend on valve morphology and cusp pathology. Mid- and long-term durability is reasonable in tricuspid aortic valve repair. In bicuspid aortic valve repair valve stability is poor regardless of cusp pathology and repair technique. For any analysis of patch durability, details of pathology and technique have to be considered.

Bicuspidization and Annuloplasty Provide a Functioning Configuration to the Unicuspid Aortic Valve.

BACKGROUND: This study reviewed a 12-year experience with a bicuspidization procedure that created a new commissure and added a patch for unicuspid aortic valve repair. METHODS: All patients with a unicuspid aortic valve who underwent bicuspidization with autologous pericardium between 2003 and 2014 were evaluated. The new commissure had initially been created on the rudimentary anterior commissure, and since 2007, symmetric orientation was designed. Suture external annuloplasty was introduced after 2009 for basal ring dilatation. RESULTS: There were 137 consecutive patients. The median age at operation was 26 years (range, 3 to 64 years). Aortic regurgitation, aortic stenosis, and combined aortic regurgitation and stenosis were present in 68 (50%), 15 (11%), and 54 (39%) patients, respectively. A total of 71 patients were operated on after 2009. Annuloplasty was added in 47 patients. There were 2 early and 3 late deaths. Overall survival was 96% at 10 years. A total of 47 patients required aortic valve reoperation because of patch degeneration (n = 20), suture dehiscence of patch (n = 17), and other causes (n = 10). Freedom from aortic valve reoperation was 77% and 59% at 5 and 10 years, respectively, and 82% and 75% at 5 and 8 years in patients operated on after 2009, respectively. Suture dehiscence of the patch occurred significantly more often in patients with a basal ring diameter of 28 mm or larger before 2009 (38% in 5 years), and it decreased significantly with annuloplasty (9% in 5 years). CONCLUSIONS: Bicuspidization and annuloplasty create a functioning valve configuration in unicuspid aortic valve repair. Patch degeneration remains the main cause of reintervention and is the limiting factor for durability.

Echocardiographic criteria to detect unicuspid aortic valve morphology.

Aims: Unicuspid aortic valve (UAV) is a rare congenital malformation associated with severe aortic stenosis or regurgitation. This study aimed to systematically determine echocardiographic criteria to identify UAV. Methods and results: All patients underwent a preoperative baseline examination, including echocardiography. A total of 69 patients with intraoperatively confirmed UAV underwent an aortic valve repair procedure between August 2001 and May 2011. To compare the findings of UAV cases with those of other valve morphologies, we examined 99 consecutive patients with a bicuspid aortic valve (BAV) and 103 consecutive patients with a tricuspid aortic valve (TAV) undergoing isolated aortic valve surgery before May 2016. The mean age of the 271 patients was 44.2 ± 12.8 years; 85% were male, with a mean body mass index of 26.2 ± 4.0 kg/m2. Patients with UAV were younger and had fewer co-morbidities than patients with BAV or TAV, respectively. The major criteria for the echocardiographic diagnosis of UAV were defined based on our preoperative examination as follows: (i) single commissural attachment zone, (ii) rounded, leaflet-free edge on the opposite side of the commissural attachment zone, (iii) eccentric valvular orifice during systole, and (iv) patient age <20 years and mean transvalvular gradient >15 mmHg. The minor criteria were defined as an associated thoracic aortopathy and age <40 years. Three out of the four major criteria or two out of the four major criteria and one minor criterion were met in all patients with UAV and in none of the patients with BAV or TAV. Associated 95% confidence intervals were calculated for each estimate of sensitivity (94.7-100%) and specificity (98.1-100%), indicating that an adequate number of patients were included in each of the three groups. Conclusion: The proposed echocardiographic score appears to be a specific and sensitive method to distinguish UAV from BAV and TAV.

Early and long-term outcomes for patients undergoing reoperative aortic root replacement.

OBJECTIVES: There are limited data on aortic root replacement (ARR) in patients with previous cardiac surgery. We analysed short-term and long-term results for patients with ARR after previous cardiac surgery. METHODS: From September 1995 to April 2015, 130 patients underwent reoperative ARR. Fifty patients had undergone ARR previously (Group I), and 80 had been treated by isolated aortic valve repair or replacement (Group II). The primary indications for surgery were active endocarditis in 65 patients (50%), aneurysmatic root dilatation in another 37 (28.5%) and valve failure in 27 (20.8%). RESULTS: Overall hospital mortality was 10% (n = 13). Survival at 10 and 15 years was 59.4% and 40.6%, respectively. Survival at 10 and 15 years was 71.5% and 62.5% in Group I and 56.2% and 35.4% in Group II, respectively (P = 0.14). Survival was significantly worse in patients operated for active endocarditis (23.7% vs 56.4% at 15 years; P < 0.001). Inferior 15-year survival was also observed for patients requiring concomitant surgery for cardiac comorbidities (10.5% vs 48.7%; P = 0.003) and in the elderly (≥60 years; 26.8% vs 59.5%; P < 0.001). Ten-year survival was best in patients after valve-preserving root replacement (100%). Multivariable analysis revealed age, active endocarditis and concomitant surgery for cardiac comorbidities as risk factors for death. CONCLUSIONS: ARR after previous cardiac surgery can be performed with reasonable short-term and long-term survival. It is inferior in patients with active endocarditis or cardiac comorbidities and in the elderly. In these scenarios, less invasive procedures may be considered where applicable.