Comparison of carbon-impregnated and standard ePTFE prostheses in extra-anatomical anterior tibial artery bypass: a prospective randomized multicenter study.

OBJECTIVES: The aim of this study was to find out whether carbon impregnated ePTFE vascular grafts have better long-term patency or limb salvage rates than Standard ePTFE vascular grafts in crural revascularization in patients with chronic critical ischemia. DESIGN: Prospective randomized multicenter trial. Study endpoints were 36 months follow-up, major amputation or death. MATERIALS: We used 6mm carbon ePTFE (Carboflo) and 6mm standard ePTFE vascular grafts (both C.R. BARD Inc./IMPRA). METHODS: From June 1995 to November 1998, 283 patients were randomly assigned either to carbon (C) (n=140) or to standard (St) ePTFE (n=143) vascular grafts at 19 centres. A standard protocol was used with lateral extra-anatomic course of the graft to the anterior tibial artery and of a distal vein patch or cuff. More than 90% of the patients had rest pain or gangrene. RESULTS: Two hundred and sixty-five (C=130; St=135) patients could be analysed in the intention-to-treat (ITT) group. Primary patency, secondary patency and limb salvage rates after 36 months were 33, 43 and 67% in the carbon- and 30, 38 and 58% in the standard PTFE group, respectively, (log-rank test: p=0.20, 0.12 and 0.16). Additional analyses were made per protocol (PP) and as-treated (AT). The retrospective power of the study was calculated as 79 and 83%. CONCLUSION: The ITT, PP and AT analysis, showed no statistically significant advantage of the carbon ePTFE vascular graft in terms of patency or limb salvage over the standard ePTFE vascular graft at 36 months.

Vacuum-sealed mesh graft transplantation in chronic cutaneous ulcers of the lower leg.

BACKGROUND: The covering of defects caused by chronic ulcers on limbs affected by peripheral arterial disease or chronic venous insufficiency is often difficult due to extensive secretion and edema, while chronic bacterial contamination of the wound bed further compromises the conditions for successful healing. PATIENTS AND METHODS: Vacuum-sealed dressing (VSD) offers the option of a closed dressing system for moist wound care that assures firm contact with the wound surface and protection against contamination with nosocomial microbes and decontamination of existing bacteria by means of constant drainage of secretion independent of gravity. VSD is particularly useful in difficult wounds featuring extensive secretion and unfavorable localization and offers many advantages over conventional dressing techniques in terms of improved healing of skin transplants. A total of 35 patients with chronic leg ulcers were treated with vacuum-sealed mesh graft transplantation. RESULTS: Complete healing of the mesh graft transplant was observed in 20 patients (57%). Twelve patients (34%) experienced partial healing (75-90%) of the transplant, while three patients exhibited less than 75% healing of the graft and therefore required a second mesh graft transplantation. CONCLUSIONS: VSD is a simple, quick and inexpensive technique that promotes excellent healing of skin transplants. It is particularly useful in difficult wounds with extensive secretion and/or contamination or infection.

Endovascular exclusion of thoracic aortic aneurysms: mid-term results of elective treatment and in contained rupture.

PURPOSE: The purpose is to present results of endovascular exclusion (stent-graft treatment) of aneurysms of the descending thoracic aorta both in elective cases and in emergencies. METHODS: Indications for stent-graft treatment were dependent on multislice angio-CT evaluation revealing a proximal neck of at least 10 mm between the left common carotid artery and the onset of aneurysm. All stent grafts were inserted in the operating room; 43 transfemoral, 2 transiliac. The stent grafts used were Corvita, Stenford, Vanguard, AneuRx, Talent, and Excluder. Deployment was achieved under fluoroscopic control, endoleaks were checked for with D S A on the operating table and postoperatively by angio-CT. Long-term follow-up consisted of evaluation with angio-CT after 6 and 12 months, and from there on once a year and with plain chest X-rays. Follow-up was achieved in all patients. RESULTS: Mean follow-up is 21 months (1-66); 30-day mortality is 3/45, no permanent neurologic deficit. Thirty patients were treated electively, 15 with contained rupture. Left subclavian artery overstenting proved to be necessary in 12 patients for proper proximal sealing of the aneurysm, type I endoleaks were observed in 10 patients, one early conversion, 7 proximal extension cuffs, one sealed spontaneously, one still at risk. Among patients where LSA had been overstented only one wanted a transposition, all others did well without left-hand ischemia or subclavian steal syndrome. CONCLUSION: Endovascular treatment is less invasive and has reasonable mortality and morbidity but is limited to well-defined morphologies. Mid-term results are promising but it has to be observed whether these will translate into long-term durability.

Treatment of thoracoabdominal aortic aneurysms with a combined endovascular and surgical approach.

AIM: The conventional approach for the repair of thoracoabdominal aneurysms remains complex and demanding and is associated with substantial morbidity and mortality. Moreover, in cases of reoperation the impact can be dramatic either in survival or in quality of life of the patients, albeit the use of adjuncts. A combined endovascular and surgical approach with retrograde perfusion of visceral and renal vessels has been realized in order to minimize intraoperative and postoperative complications. METHODS: Within an experience of 231 aortic stent-grafts between 1995-2000, 4 of the patients with thoracoabdominal aneurysms were treated with a combined endovascular and surgical approach. Three procedures were electively conducted and 1 on emergency basis. Two women, 59 and 68 years old, and 2 men, 68 and 73 years old (maximum aneurysm's diameter was 10, 6, 8 and 9 cm, respectively) were operated with the combined method (the first 2 patients had a previous open repair of a thoracoabdominal aneurysm). The surgical approach was executed in all patients without thoracotomy or re-do retroperitoneal exposure. Revascularization of renal, superior mesenteric (and celiac in 2 cases) arteries was accomplished via transperitoneal bypass grafting. Aneurysmal exclusion was performed by stent-graft deployment. RESULTS: The entire procedure was technically successful in all patients. The 1(st) patient was discharged 6 weeks after the operation, while the postoperative studies revealed the patency of the vessels and no evidence of leak or secondary rupture of the aneurysm; the patient died 3 months after the repair, due to rupture of an aneurysm of the ascending aorta. In the 2(nd) patient, 30 months after the operation, spiral-CT scanning revealed distinct shrinkage of the aneurysm, no graft migration or endoleak and patency of all revascularized vessels. The 3(rd) patient died on the 6th postoperative day due to multiorgan failure after having developed ischemic-related pancreatitis, albeit the successful combined repair. The 4(th) patient followed an uneventful course. No patient experienced any temporary or permanent neurological deficit. CONCLUSION: The combined endovascular and surgical approach is feasible, without cross-clamping of the aorta and with minimized ischemia time for renal and visceral arteries, and seems the appropriate strategy for high risk and previously operated, with a thoracoabdominal trans-diaphragmatic approach, patients.

Endovascular treatment in diseases of the descending thoracic aorta: 6-year results of a single center.

OBJECTIVE: The purpose of this study was to evaluate endovascular treatment in diseases of the descending thoracic aorta. MATERIAL AND METHODS: This study was designed as a single center's (university hospital) experience. Over a 6-year period (1995 to 2001), thoracic endografts were placed in 74 patients with a diseased descending thoracic aorta who were at high risk for conventional open surgical repair: 34 had atherosclerotic aneurysms, six had posttraumatic aneurysms, 14 had type B dissection with aneurysmal dilatation of the false lumen, 12 had isthmic transections from blunt trauma, five had thoracoabdominal aneurysms (treated with a combined procedure), two had aortic coarctation, and one had an aortobronchial fistula. Twenty-six procedures (35.1%) were conducted as emergencies, and 48 (64.9%) were elective. The feasibility of endovascular treatment and sizing of stent grafts were determined with preoperative spiral computed tomography and intraoperative angiography. RESULTS: Endovascular operations were completed successfully in all 74 patients; postprocedural conversion to open repair was necessary in three cases. The overall 30-day mortality rate was 9.5% (seven deaths). Temporary neurologic deficits developed in two patients; not one patient had permanent paraplegia. The primary endoleak rate was 20.3% (15 patients). The mean follow-up period was 22 months (range, 3 to 72 months). Five deaths occurred in the follow-up period, and three patients needed secondary conversion to open repair 2, 3, and 14 months after initial endografting. CONCLUSION: Endoluminal treatment in diseases of the thoracic descending aorta is feasible and may offer results as good as the open method.

[Endoluminal stent-assisted management of acute traumatic aortic rupture]. / Endoluminale stentgestützte Versorgung der akuten traumatischen Aortenruptur.

INTRODUCTION: Open repair of traumatic descending aortic rupture in trauma patients is associated with a mortality rate of 15-20% and a risk of paraplegia of 5-10%. Stent grafts may decrease the morbidity and mortality of these procedures by reducing blood loss and aortic occlusion time. MATERIAL AND METHODS: Within an experience of 52 thoracic stent grafts between 1995 and 2000, eight men with acute traumatic descending aortic rupture were conducted as emergencies without delay. All patients had severe coinjuries and presented with acute onset of mediastinal hematoma due to periaortic bleeding. Successful stent deployment was performed in all eight patients, seven of them required one single stent and one required two stents; within the aortic arch all stents covered the origin of the left subclavian artery. RESULTS: All acute aortic ruptures were sealed successfully. One death occurred in hospital from multiorgan failure. There was no conversion to open repair. Not one patient's condition resulted in temporary or permanent paraplegia. One endoleak required treatment by overstenting. Two patients required secondary surgical procedures (iliac access complication and revascularisation of left subclavian artery). Mean follow-up was 11 months (1-21 months). Mid-term freedom from endoleak was monitored in all patients. CONCLUSION: The treatment of acute traumatic descending aortic rupture with an endovascular approach is feasible and safe and may offer the best means of therapy. The mortality rate and risk of paraplegia are low compared with the risks associated with open operations. Continued surveillance is essential.

Endovascular repair of aortic rupture due to trauma and aneurysm.

OBJECTIVES: to report a single centre experience with endovascular repair of the ruptured descending thoracic and abdominal aorta. DESIGN: prospective non-randomised study in a university hospital. MATERIAL AND METHODS: between 1995 and 2000, endovascular treatment was utilised for 231 aortic repairs; in 37 cases (16%) endografting was conducted on an emergency basis for 21 ruptured infrarenal aortic aneurysms, 15 ruptured descending thoracic aortic lesions, and 1 ruptured thoracoabdominal aortic aneurysm. The feasibility of endovascular treatment and the prostheses' size were determined, based on preoperative spiral CT and intraoperative angiography, both obtained in each patient. RESULTS: endografting was successfully completed in 35 patients (95%). Primary conversion to open repair was necessary in 2 patients (5%). Postoperative 30-day mortality rate was 11% (4 deaths). No patient developed postoperative temporary or permanent paraplegia. In 2 patients (5%) primary endoleaks required overstenting and in 6 patients (16%) secondary surgical interventions were required. Mean follow-up was 19 months (1-70 months); three deaths occurred within three months postoperatively (1-year survival rate 81+/-6%). In one case, secondary conversion to open repair was necessary 14 months postoperatively. CONCLUSION: the feasibility of endoluminal repair of the ruptured aorta has been demonstrated. Endoluminal treatment may reduce morbidity and mortality, and may in time become the procedure of choice in certain centres. However, further follow-up is required to determine the long-term efficacy.

Does a postimplantation syndrome following endovascular treatment of aortic aneurysms exist?

The postimplantation syndrome (PIS) is a weakly defined condition that has been observed following endovascular treatment of aortic aneurysms; the postulated criteria include significant leukocytosis, fever, and/or coagulation disturbances. Among the factors that are supposed to contribute to this syndrome are contact activation by the stent covering with consecutive endothelial activation. Associated clinical parameters of a PIS were perioperatively monitored in the postoperative phase in a total of 69 patients with infrarenal aortic aneurysms treated with Y-stent grafts. C-reactive protein (CRP)-levels, leukocyte concentrations, and body temperature curves were directly compared to those of 50 patients undergoing conventional transperitoneal aneurysm resection. A subgroup of 10 patients of the endovascular group was compared with 13 operated-on patients with regard to an ischemia-reperfusion syndrome of the lower extremities. The mediator determinations were performed on venous (femoral vein) as well as in systemic (arterial) blood samples. The incidence of temperature values above 38 degrees C was higher in patients following endovascular treatment (72%) compared to conventionally operated-on patients (28%). CRP levels were not significantly different within the first 8 post-operative days. During open surgery, significantly higher values for lactate and lower pH levels were observed (p<0.01), as well as higher 6 keto prostaglandin F1alpha (PGF1alpha) levels. There was a short peak of PGF1alpha during eventeration of the intestine during the operative procedure that could not be detected during endovascular manipulations. The clinical and biochemical parameters do not prove the presence of a PIS following endovascular treatment of aortic aneurysms. In contrast, during open surgery the unspecific inflammatory reaction is higher, but not long-lasting. In the future, the suggested phenomenon of a decreased antiinflammatory cytokine response during endovascular surgery needs to be further examined.

Thrombus formation in aortic endografts.

PURPOSE: To examine the incidence of intraprosthetic thrombotic deposits in aortic endografts. METHODS: Transfemoral implantation of tube or bifurcated stent-grafts was performed in 82 patients (75 men; average age 67.7 years, range 25-88) for treatment of aneurysms of the abdominal (n = 73) or thoracic (n = 9) aorta in a 3.5-year period. Patients underwent 3-phase helical computed tomographic (CT) examinations at 3-month intervals. The length and cross-sectional area of any thrombotic deposits were measured from axial and 3-dimensional CT images. RESULTS: Over a 12.1-month mean follow-up, intraluminal deposits of thrombotic material were observed in 19 (23.2%) patients, all with infrarenal endografts that were predominately of a bifurcated design. The first signs of thrombus formation occurred on average 7 months postoperatively (range 1 week to 20 months). In 16 patients, nonocclusive deposits of thrombotic material were seen in the aortic segment of the endograft; a graft limb was involved in 5 patients. Three graft limbs occluded owing to kinking; no thrombus was seen on CT scans taken prior to occlusion. In 3 cases the thrombotic deposits disappeared completely from the prosthesis lumen during follow-up. CONCLUSIONS: Based on this small experience, nearly 1 in 5 patients may experience some degree of intraluminal thrombus following endovascular treatment of aortic aneurysms. Whether the deposition of thrombus is influenced by the geometry of the aortic stent-graft or by flow conditions within the prosthetic lumen must be determined in future studies.

Intraoperative, perioperative and late complications with endovascular therapy of aortic aneurysm.

PURPOSE: To describe the incidence and management of the intraoperative, perioperative and late complications of endovascular aortic aneurysm repair. METHODS: Endovascular aneurysm repair was attempted in 130 patients between October, 1995 and January, 2000. Follow-up including computed tomography (CT) was performed in the immediate postoperative period and then at 3, 6, 9 and 12 months and biannually thereafter. The median follow-up period was 20 months. RESULTS: Intra- and perioperative problems occurred in 26 patients (20%). Conversion to open surgery was required in five cases (4%). The primary technical success rate was 86%. Three patients (2%) died within the first 30 postoperative days. Late problems occurred in 28 patients (26%). These included: endoleaks (type I: 5%; type II: 10%; type III: 1%) and limb occlusion (3%). The cumulative rate of freedom from secondary intervention was in the first 65 patients treated: 86% and 65% after 1 and 3 years, respectively, and in the last 65 patients: 90% at 1 year. CONCLUSIONS: Endovascular aneurysm repair is associated with a higher complication rate than open surgery.

Endograft treatment of anastomotic aneurysms following conventional open surgery for infrarenal aortic aneurysms.

OBJECTIVE: to evaluate the use of endograft therapy for treating anastomotic aneurysm following open surgical repair of infrarenal aneurysms of the abdominal aorta. METHODS: four male patients (age 47-75 years) at high surgical risk (ASA IV n=3, ASA III n=1) developed secondary aneurysms at the site of the central (four aneurysms) and additional peripheral (two aneurysms) anastomosis of their tube or bifurcation prosthesis an average of 13 years (range 1-23 years) after conventional open surgical correction of infrarenal aneurysm of the abdominal aorta. In two patients, there was covered rupture of the aneurysm sac. The aneurysm diameter was 4.8 cm, 8.0 cm, 7.4 cm, 7.0 cm, respectively (mean 6.8 cm). Follow-up included helical CT imaging at 1 week, 3 months and 6 months postoperatively. RESULTS: anastomotic aneurysm was successfully treated in all four cases. No evidence of endoleak was observed during the follow-up period. Two patients died 14 and 18 days after surgery due to myocardial infarction and cerebrovascular accident. The endovascular repair of the two patients who died was intact. CONCLUSION: although no long-term results are available, the use of a graft-in-graft method to repair anastomotic aneurysms following conventional implantation of tube or bifurcation prostheses appears to be effective, particularly in patients at high surgical risk.

Malpositioned or dislocated aortic endoprostheses: repositioning using percutaneous pull-down maneuvers.

PURPOSE: To present the capabilities and potential complications of 2 percutaneous techniques for repositioning malpositioned or dislodged aortic endografts. METHODS: Seven male patients (median age 67.9 years, range 59 to 78) required correction of misplaced or dislocated endografts in the thoracic (n = 1) or infrarenal abdominal aorta (n = 6). In 1 patient, an infrarenal bifurcated stent-graft was mistakenly deployed across a renal artery; repositioning was accomplished by tugging caudally on a guidewire placed across the endograft bifurcation and exteriorized from both femoral arteries. An inflated balloon catheter was used to reposition 3 dislocated aortic devices (1 thoracic, 2 infrarenal) and 3 iliac graft limbs that had disconnected from the main graft body 6 to 12 months after implantation. RESULTS: Repositioning maneuvers were successful in all cases, with the devices being moved from 5 to 27 mm (median 7.8 mm). There were no procedure-related complications. CONCLUSIONS: Nonsurgical repositioning of misplaced aortic prostheses is technically feasible in individual cases. The risk associated with the procedure, however, cannot yet be evaluated.

Leaflet escape in a TEKNA and an original duromedics bileaflet valve.

We report a case of leaflet escape in an Edwards-TEKNA bileaflet valve, in the mitral position. The examination findings of the explanted valve are compared with a similar case of leaflet escape in an original Edward-Duromedics prosthesis. Based on our findings alone, it is not certain whether the TEKNA valve continues to have a higher risk for fracture.

Angiography of leaks after endovascular repair of infrarenal aortic aneurysms.

OBJECTIVE: We examined whether leaks that persist after stent grafting are associated with outflow arteries. SUBJECTS AND METHODS: Selective angiography was performed in 21 patients with persistent leaks after undergoing endovascular repair of infrarenal aneurysms of the abdominal aorta. Late leaks occurred in five patients whose prostheses were originally sealed. Before angiography, the size and position of leaks were determined with CT and color Doppler sonography. RESULTS: Superselective angiography was successful in 19 of 21 patients. In two patients, angiography was performed over the afferent artery supplying the leak. We found one outflow artery at the site of the leak in 10 patients (47%); two outflow arteries in five (23.8%); and as many as five outflow arteries in three (14%). Angiography overlooked outflow arteries in three patients (14%). The lumbar and inferior mesenteric, urethral, and testicular arteries were identified as outflow arteries. CONCLUSION: Other than feeder arteries, persistent leaks are associated with outflow vessels that contribute to the patency of leaks.

Does successful embolization of endoleaks lead to aneurysm sac shrinkage?

PURPOSE: To determine whether embolization of endoleaks after endovascular repair of aortic aneurysms is associated with a decrease in the diameter of the aneurysm. METHODS: Fifteen patients (13 men; median age 76 years) demonstrated primary endoleaks persisting > or =3 months after endovascular abdominal aortic aneurysm repair with a variety of commercial endografts. In 8 patients, coil embolization failed to completely obliterate the leak, whereas embolotherapy proved successful in the remaining 7 patients. Surveillance of endoleaks and the effect of their embolization on aneurysm size were followed with serial computed tomographic (CT) scans. Follow-up after embolization extended for at least 12 months. RESULTS: Patients with persistent leak exhibited a slight increase in mean aneurysm area from 21.41+/-4.25 to 22.47+/-6.70 cm2. Medians differed from 20.03 (range 16.59-28.73) to 23.03 (range 14.14-33.69) cm2 (p = 0.0078, 95% confidence interval [CI] = 0.0075 to 0.0081). Successfully treated patients, however, showed a mean decrease from 20.58+/-3.63 (median 19.87) to 16.36+/-6.46 cm2 (median 18.10) at 1 year (p = 0.0156, 95% CI = 0.0151 to 0.0160). The medians differed significantly between groups (p < 0.05). CONCLUSIONS: Persistent endoleaks after endovascular aortic aneurysm treatment led to an increase in the diameter of the aneurysm, whereas complete occlusion was associated with a significant decrease in aneurysm diameter.

Endoluminal grafting of infrarenal aortic aneurysms.

BACKGROUND: The department policy regarding therapy fo infrarenal aortic aneurysms is reviewed, based on the treatment results of a 12-months period. METHODS: From October 1996 to August 1997, 60 patients with infrarenal aortic aneurysms were admitted to our department. Of these 31 (52%) were found to be anatomically or pathomorphologically suitable for endovascular treatment, based on the premises that: 1. Whenever the anatomy is suitable and confirmed with CT or angiography, repair is by means of stent placement. 2. In emergencies and in cases where the anatomical relationships are unfavourable, patients undergo conventional open surgery. RESULTS: In all 31 patients treated endovascularly, stent placement was technically successful. Procedure-associated mortality was zero. The following stenting complications occurred: seven endoleaks, one thrombotic iliac occlusion, one femoral arterial dissection, two puncture-related inguinal hematomas. Elective open surgery was performed in the other 29 patients. One of these died from the effects of renal failure. CONCLUSIONS: This comparison shows that endovascular treatment of infrarenal aortic aneuryms is possible in a large proportion of patients and is not associated with an unfavourable rate of complications. Endovascular treatment can significantly reduce patients' postoperative hospitalization (three days) and time spent in intensive care.

[Value of stent-assisted aneurysm treatment]. / Der Stellenwert der stentgestützten Aneurysmabehandlung.

The aim of this study was to compare the outcome of consecutive patients with abdominal aortic aneurysms treated by open operation and endoluminal procedure. Between October 1996 and April 1998 consecutive patients with abdominal aortic aneurysms underwent surgical repair. Of these, 50 patients had conventional open repair, and 48 patients were treated endoluminally. Follow-up was made by clinical examination in the operation group; the stent group was controlled by spiral CT and angiography 1, 3, 6, and 12 months after operation. No significant difference was found in the perioperative mortality rate between the open repair group and the stent group. This study suggests that the endovascular procedure is safe and results in a shorter length of hospital stay and a shorter length of intensive care unit stay. As there are no long-term results, the endoluminal method requires a careful follow-up.

[Paraganglioma of the carotid bifurcation. Diagnostic and therapeutic strategy]. / Das Paragangliom der Carotisgabel. Diagnostische und therapeutische Strategie.

The carotid body tumors are semimalignant tumors. According to our results, the best diagnostic procedure is a combination of Doppler color flow imaging ultrasound, computed tomography and selective angiography. In our opinion, the treatment of choice is radical resection of the tumor with the carotid bifurcation, especially to reduce recurrence of the tumor. Considering the problems in recurrent tumors, consequent monitoring of the patients is necessary.

[Duration of the preventive use of antibiotics in colorectal surgery--single administration versus short-term prevention]. / Dauer der Antibioticaprophylaxe in der colorectalen Chirurgie--Einmalgabe versus Kurzzeitprophylaxe.

The effect of a combination of 4 g mezlocillin and 0.5 g metronidazole for the prophylaxis against infections in a one-shot dose immediately preoperatively compared to a short-time dose of 2 days given to 90 patients with resection of colorectal carcinoma was investigated in a prospective and randomized study. 6 patients developed a wound infection in the early postoperative phase; 4 of these infections (3 were severe, 1 was mild) occurred in the one-shot group and 2 in the short-time prophylaxis group. After more than 20 days postoperatively 3 late infections were observed which had a mild course (2 cases in the one-shot group, 1 case in the short-time prophylaxis group). All infections were localized in the sacral wound region in patients with abdominoperineal resection. The abdominal wounds healed per primam in each case. Besides those, 26 infections of the urinary tract were observed, which occurred significantly more often after the one-shot dose (40.9%) than with the short-time prophylaxis (18.6%). Intraoperative smears of the lumen of the bowels showed a remaining bacterial settlement. Besides Bacteroides species, especially Escherichia coli were found among the isolates. Moreover in some cases Clostridium, Klebsiella, Proteus and Pseudomonas could be identified. Smears of the site of operation (sacral/peritoneal cavity) were contaminated in over 50%, above all by Bacteroides species; besides those, E. coli were found most often. The subcutaneous smears showed a growth of the germs only in a few cases. Aerobic bacteria in 93.8%, anaerobic bacteria except for thetaiotaomicron and B. asaccharolyticus in 85.1%.(ABSTRACT TRUNCATED AT 250 WORDS)