The effect of the systemic immune-inflammatory index on the no-reflow phenomenon in patients undergoing saphenous vein intervention.

Introduction: The systemic immune inflammation index (SII), based on lymphocyte, neutrophil, and platelet counts, has been shown to be an independent indicator of no-reflow phenomenon during percutaneous intervention. However, the relationship between SII and no-reflow phenomenon (NRP) that develops after the procedure of saphenous vein grafts is unknown. Aim: In this study, we aimed to investigate the relationship between no-reflow phenomenon and SII during percutaneous intervention on saphenous vein grafts. Material and methods: A total of 133 patients who underwent percutaneous intervention for saphenous vein grafts due to acute coronary syndrome between 2019 and 2022 were included in this study. The receiver-operating characteristics (ROC) curve was used to determine the cut-off value of SII to predict the no-reflow. The multivariate regression was used to analyse the correlation between no-reflow and SII. Results: The median value of SII was significantly higher in patients with no-reflow in comparison with normal reperfusion (543 (447, 717) vs. 861 (642, 1272), p < 0.001). The optimal threshold for SII in predicting the no-reflow phenomenon was 613, with sensitivity and specificity of 84% and 66%, respectively. The area under the ROC curve (AUC) was 0.80 (95% CI: 0.73-0.89, p < 0.001). In multivariate analysis, SII ≥ 613 showed an independent predictive value for the no-reflow (OR = 4.02, 95% CI: 1.40-11.57, p < 0.001). Conclusions: Our results showed that high SII levels were independently associated with the development of no-reflow phenomenon in patients presenting with acute coronary syndrome and undergoing percutaneous intervention to the SVG.

The sex prevalence of lower limb varicose vein networks.

OBJECTIVE: To determine the sex prevalence of lower limb varicose networks fed by reflux of the great saphenous vein (GSV), anterior accessory saphenous vein (AASV) and small saphenous vein (SSV) singularly or in combinations. METHODS: We scanned by the means of the same Colour Doppler Sonography (CDS) protocol 3000 lower limbs in 1500 consecutive patients, affected by symptomatic chronic venous insufficiency (CVI) during the decade 2013-2023. Limbs with normal venous function, incomplete scans or affected by post thrombotic syndrome, pelvic reflux, venous malformation, phlebolymphedema and CEAP clinical class C5-C6 were excluded from the final analysis. RESULTS: Overall, 1072 patients, 252 (23.5%) males and 820 (76.5%) females (p<0.0001), matched for age (p=0.692), were included into the study for a total of 1956 limbs affected by primary CVI, clinical class C2-C4. The main finding was the significant prevalence of varicose networks fed by reflux of the AASV alone (OR 1.96, CI 1.26-3.06, p=0.001) or combined with GSV (OR 1.84, CI 1.34-2.52, p=0.0002) in females. On the other hand, GSV insufficiency alone was significantly prevalent in males (OR 0.54, CI 0.43-0.68, p<0.0001). Moreover, we considered the presence of competent terminal valve (TV+) at the level of the sapheno-femoral junction, which resulted more significantly present in female (OR 1.57, CI 1.12-2.19, p=0.0083); to the contrary incompetent terminal valve (TV-) was more common in males (OR 0.64, CI 0.46-0.89, p=0.0083). Finally, considering reflux in the AASV territory in presence of a TV+, a strong prevalence in females was detected (OR 2.28, CI 1.48-3.52, p=0.0002), while males developed reflux along the GSV when a concomitant TV- was present (OR 0.62, CI 0.41-0.94, p =0.0244). CONCLUSIONS: The analysis of the lower limb varicose networks highlights that reflux along the AASV alone, in presence of a competent terminal valve at the junction, or coupled with GSV insufficiency, is more prevalent in females. On the other hand, GSV resulted the main trunk feeding varicose veins in males, in particular when an incompetent terminal valve was detected. Our findings suggest that females could be more prone to develop the varicose vein with an ascending mechanism, whereas in males the descending one seems more common.

Perioperative use of immersive head-mounted virtual reality display enhances patient satisfaction in great saphenous vein surgery: a single-center clinical observation study.

OBJECTIVE: To explore the application effect of head-mounted virtual reality display immersive experience in improving the perioperative satisfaction of patients undergoing great saphenous vein surgery. METHODS: A total of 158 patients undergoing saphenous vein surgery at the First Affiliated Hospital, Jiangxi Medical College, Nanchang University from January 2020 to January 2023 were randomly divided into an observation group and a control group in a 1:1 ratio, with 79 cases in each group. The observation group received head-mounted display virtual reality immersive experience, whereas the control group received midazolam. The study compared the perioperative satisfaction, changes in preoperative and postoperative anxiety and depression scores, intraoperative blood pressure and heart rate, postoperative visual analog scale (VAS) score, and the incidence of postoperative nausea and vomiting between the two groups. Additionally, the satisfaction of patients, anesthesiologists, and chief surgeons was compared. RESULTS: All surgeries were completed successfully. Patients in the observation group exhibited higher perioperative satisfaction compared to those in the control group (P<0.001). There were no significant differences in anxiety or depression scores between the two groups before surgery (P>0.05). However, both groups showed a reduction in anxiety and depression scores postoperatively, with the observation group demonstrating lower scores than the control group (both P<0.05). The observation group also had lower intraoperative blood pressure, heart rate, postoperative VAS scores, and incidence of nausea and vomiting compared to the control group (all P<0.05). Furthermore, the satisfaction levels of the anesthesiologists and chief surgeons were higher in the observation group than in the control group (P=0.043, 0.012). CONCLUSION: Head-mounted display virtual reality immersive experience can enhance perioperative satisfaction among patients undergoing great saphenous vein surgery, reduce anxiety and depression scores, and contribute to the stabilization of hemodynamics during surgery, thereby decreasing postoperative nausea and vomiting.

Ultrasound assessment of the risk of venous thromboembolic complications in thrombosis of varicose transformed tributaries of the great saphenous vein.

OBJECTIVE: Aim: To evaluate the ultrasound criteria for venous thromboembolic complications in patients with thrombosis of varicose veins of the tributaries of the great saphenous vein (GSV). PATIENTS AND METHODS: Materials and Methods: The results of ultrasound examination of 52 patients with thrombosis of varicose veins of the tributaries of GSV were analyzed. The indicators of venous hemodynamics were compared with the control group (CG) (n=32). RESULTS: Results: Varicose transformation of GSV and failure of its valvular apparatus were detected in 44 (84.6%) patients, in 8 (15.4%) patients the superficial venous highway was intact. Vertical reflux was diagnosed in varicose ectasia of GSV: local reflux in 14 (31.8%), widespread reflux in 14 (31.8%), and total reflux in 16 (36.4%) patients. The diameter of GSV in tributary varicothrombophlebitis was 8.9±0.27 mm (p<0.05 vs. CG) and 11.2±0.25 mm (p<0.05 vs. CG) in the horizontal and vertical positions, respectively. The proximal and distal borders of thrombosis exceeded the clinical ones by 15.26±1.21 cm (p<0.05) and 7.94±1.32 cm (p<0.05), respectively. The spread of tributary thrombophlebitis to the superficial venous highway was detected in 14 (26.9%) patients, among whom 12 (85.7%) patients had unfixed apices of thrombotic masses. CONCLUSION: Conclusions: The results obtained convincingly demonstrate the need for early ultrasound examination of patients with tributary thrombophlebitis, which allows to identify the real limits of the thrombotic process, timely diagnose the transition of the thrombotic process to superficial and deep venous lines, effectively predict the risk of venous thromboembolic complications and choose the optimal surgical tactics.

Clinical applications and cadaveric study of the free descending genicular artery perforator flap without the saphenous vein.

BACKGROUND: The descending genicular artery (DGA) and medial thigh region have been underused as donor sites for perforator flaps. This study evaluated the anatomical relationship between the perforators of the DGA and the saphenous vein (SV) to review the clinical applications of the free descending genicular artery perforator (DGAP) flap for locoregional reconstruction. METHODS: Fifteen cadavers were arterially perfused with red latex and dissected. Thirty-one patients with extremity tissue defects were treated with a free DGAP flap, including six patients who received a chimeric flap. The minimum distance between the DGAP and the SV was measured during surgery. RESULTS: In all patients, the skin branch of the descending genicular artery was found in the medial femoral condyle plane in front of the SV. The average distance between the descending genicular artery perforator and the SV was 3.71 ± 0.38 cm (range: 2.9-4.3 cm). Thirty flaps survived completely, and one flap developed partial necrosis; however, this flap healed two weeks after skin grafting. The average follow-up time was 11.23 months. CONCLUSIONS: We conclude that the SV can be preserved when harvesting the descending genicular artery perforator flap, causing less damage to the donor site and having no effect on flap survival. The free descending genicular artery perforator flap without the SV is a better therapy for complicated tissue defects.

Treatment of varicose great saphenous vein with endovenous laser alone or combined with eco-guided foam sclerotherapy: A randomized controlled trial.

Objectives: This study compares Endovenous Laser Ablation (EVLA) alone versus combined with ultrasound-guided foam sclerotherapy (UGFS) for Great Saphenous Vein (GSV) insufficiency. Methods: Sixty patients were randomly allocated to EVLA or EVLA-UGFS groups which focused on GSV occlusion rates, complications, additional treatments, and quality of life (QoL) changes. Results: Among 55 participants, the EVLA group had higher 12-month occlusion rates (92.3% vs. 75.8%, p = 0.11). Nervous injury (NI) was rarer in EVLA-UGFS (3.4% vs. 23.1%, p = 0.04). No significant difference in other complication rates (p > 0.05). QoL improved in both groups (p < 0.001). EVLA-UGFS required more subsequent procedures (24.1% vs. 7.7%, p = 0.03). Conclusions: EVLA and EVLA-UGFS effectively treat GSV insufficiency, enhancing QoL. The combined method reduces NI risk but may require more follow-up procedures.

Comparative outcomes of arterial bypass using the human acellular vessel and great saphenous vein in patients with chronic limb ischemia.

OBJECTIVE: The Human Acellular Vessel (HAV) is a novel, off-the-shelf biologic conduit being evaluated for arterial reconstructions. Regulatory studies in peripheral arterial disease (PAD) to date have consisted of single-arm cohorts with no comparator groups to contrast performance against established standards. This study aimed to compare outcomes of the HAV with autologous great saphenous vein (GSV) in patients with advanced PAD undergoing infrageniculate bypass. METHODS: Patients with advanced PAD and no autologous conduit who underwent bypass with the 6-mm diameter HAV (Group 1; n = 34) (March 2021-February 2024) were compared with a multicenter historical cohort who had bypass with single-segment GSV (group 2; n = 88) (January 2017-December 2022). The HAV was used under an Investigational New Drug protocol issued by the Food and Drug Administration (FDA) under the agency's Expanded Access Program. RESULTS: Demographics were comparable between groups (mean age 69 ± 10 years; 71% male). Group 1 had higher rates of tobacco use (37 pack-years vs 28 pack-years; P = .059), coronary artery disease (71% vs 43%; P = .007), and prior coronary artery bypass grafting (38% vs 14%; P = .003). Group 1 had more patients classified as wound, ischemia, and foot infection clinical stage 4 (56% vs 33%; P = .018) and with previous index leg revascularizations (97% vs 53%; P < .001). Both groups had a similar number of patients with chronic limb-threatening ischemia (Rutherford class 4-6) (88% vs 86%; P = .693) and Global Anatomic Staging System stage III (91% vs 96%; P = .346). Group 1 required a composite conduit (two HAV sewn together) in 85% of bypasses. The tibial vessels were the target in 79% of group 1 and 100% of group 2 (P < .001). Group 1 had a lower mean operative time (364 minutes vs 464 minutes; P < .001). At a median of 12 months, major amputation-free survival (73% vs 81%; P = .55) and overall survival (84% vs 88%; P = .20) were comparable. Group 1 had lower rates of primary patency (36% vs 50%; P = .044), primary-assisted patency (45% vs 72%; P = .002), and secondary patency (64% vs 72%; P = .003) compared with group 2. CONCLUSIONS: Implanted under Food and Drug Administration Expanded Access provisions, the HAV was more likely to be used in redo operations and cases with more advanced limb ischemia than GSV. Despite modest primary patency, the HAV demonstrated resilience in a complex cohort with no autologous conduit options, achieving good secondary patency and providing major amputation-free survival comparable with GSV at 12 months.

Impact of distension pressure on saphenous vein endothelial injury in coronary artery bypass grafting.

Introduction: Long saphenous vein grafts (LSVGs) are pivotal conduits in coronary artery bypass grafting (CABG), yet concerns persist regarding early failure and long-term patency. Endothelial damage, a potent initiator of graft failure, necessitates exploration of factors contributing to endothelial injury during LSVG preparation. Methods: A prospective, single-center study was conducted, assessing the impact of unregulated distension pressure on LSVG endothelium during CABG. Histological and CD31 (cluster of differentiation 31) immunohistochemical analyses were performed on 21 paired vein samples, categorized into non-distended (group A) and distended (group B) groups. Pressure recordings were obtained using different syringe sizes during vein distension. Results: Histological examination revealed a significantly higher percentage of endothelial cell loss in distended veins (31.95% ± 31.31) compared to non-distended veins (11.67% ± 28.65) (p = 0.034). CD31 immunohistochemistry corroborated greater endothelial cell loss in distended veins (p = 0.001). The pressure recordings with a 20-cc syringe, as opposed to using a 10-cc syringe, were considerably lower (44.5 mmHg vs. 92.75 mmHg) emphasizing the inverse relationship between syringe size and pressure generated. In our study, pre-existing endothelial injury was observed in one-third of diabetic patients (36%), with all instances of such injury exclusively identified in individuals with diabetes. Conclusion: Unregulated distension pressure during LSVG preparation is associated with greater endothelial damage, as evidenced by histological and immunohistochemical analyses. The inverse relationship between syringe size and pressure underscores the importance of controlled distension.

Association between overweight and obesity with coronary artery bypass graft failure: an individual patient data analysis of clinical trials.

OBJECTIVES: The association between obesity and graft failure after coronary artery bypass grafting has not been previously investigated. METHODS: We pooled individual patient data from randomized clinical trials with systematic postoperative coronary imaging to evaluate the association between obesity and graft failure at the individual graft and patient levels. Penalized cubic regression splines and mixed-effects multivariable logistic regression models were performed. RESULTS: Six trials comprising 3928 patients and 12 048 grafts were included. The median time to imaging was 1.03 (interquartile range 1.00-1.09) years. By body mass index (BMI) category, 800 (20.4%) patients were normal weight (BMI 18.5-24.9), 1668 (42.5%) were overweight (BMI 25-29.9), 983 (25.0%) were obesity class 1 (BMI 30-34.9), 344 (8.8%) were obesity class 2 (BMI 35-39.9) and 116 (2.9%) were obesity class 3 (BMI 40+). As a continuous variable, BMI was associated with reduced graft failure [adjusted odds ratio (aOR) 0.98 (95% confidence interval (CI) 0.97-0.99)] at the individual graft level. Compared to normal weight patients, graft failure at the individual graft level was reduced in overweight [aOR 0.79 (95% CI 0.64-0.96)], obesity class 1 [aOR 0.81 (95% CI 0.64-1.01)] and obesity class 2 [aOR 0.61 (95% CI 0.45-0.83)] patients, but not different compared to obesity class 3 [aOR 0.94 (95% CI 0.62-1.42)] patients. Findings were similar, but did not reach significance, at the patient level. CONCLUSIONS: In a pooled individual patient data analysis of randomized clinical trials, BMI and obesity appear to be associated with reduced graft failure at 1 year after coronary artery bypass grafting.

Rare Presentation of the Vein of Servelle in a Case of Klippel-Trenaunay Syndrome.

Klippel-Trenaunay syndrome (KTS) is a rare congenital vascular syndrome involving bone and soft tissue hypertrophy of the involved limb and vascular malformations of the lymphatic, capillary, and venous systems. It is often confused with Parkes-Weber syndrome (PWS). KTS is characterized by a triad of capillary malformation in the form of port wine stains, bone or limb hypertrophy, and varicose veins. The vein of Servelle, also known as the lateral marginal vein, is one of the two persisting embryonic veins of the leg, the persistent sciatic vein being the other. Truncal vascular malformation can be a complication of failure of obliteration of these veins. We present a case of a 24-year-old male of KTS who had varicose veins in his right lower limbs since five years of age and macrodactyly with a synchronous presentation of the vein of Servelle.

Compression therapy after endovenous laser ablation: Patient compliance and impact on clinical outcome.

OBJECTIVES: This study aimed to investigate the impact of post-interventional compression therapy on clinical outcomes after endovenous laser ablation (EVLA) of incompetent saphenous veins. METHODS: This prospective, controlled, multicenter study in Germany involved 493 varicose vein patients followed-up for 6 months. RESULTS: Compression therapy significantly reduced symptoms compared to no compression (VCSS: 1.4 ± 1.6 vs 2.2 ± 2.2; p = .007). Post-interventional therapy duration of up to 14 days was found to be most effective for improving patient-reported disease severity (p < .001) and higher quality of life (p = .001). Patient compliance was high (82%), and non-compliance was linked to worse disease severity (VCSS 1.4 ± 1.5 vs 2.1 ± 2.3, p = .009). CONCLUSION: In conclusion, post-interventional compression therapy is beneficial by reducing symptoms and improving quality of life. High patient compliance with the therapy is observed, and non-compliance is associated with worse disease severity.

Comparison of storage solutions on saphenous vein endothelial function using immunofluorescence. A pilot study.

BACKGROUND: Our aim was to establish which of the current and novel storage fluids caused the least harm to the endothelium of the saphenous vein. METHODS: Unmanipulated samples of saphenous vein were obtained. This vein was exposed to four fluids, DuraGraft®, Plasma-Lyte, autologous blood and sodium chloride, and a control medium. The expression of endothelial selectin (E-selectin) and endothelial nitric oxide synthase (eNOS) was measured using confocal microscopy. RESULTS: We identified and quantified platelet endothelial cell adhesion molecules, vascular cell adhesion molecules and endothelial nitric oxide synthase 3 on the endothelium. The results were widely variable. The protein expression of endothelial selectin (p = .17) and endothelial nitric oxide synthase 3 (p = .73) showed no statistically significant differences in levels of preservation when the different solutions were compared. CONCLUSIONS: In this study, we could not determine that any of the solutions were superior at preserving saphenous vein endothelium.

Safety of synchronous prophylactic ablation of the anterior saphenous vein in patients undergoing great saphenous vein thermal ablation- 6 months follow-up data of the SYNCHRONOUS study.

BACKGROUND: The SYNCHRONOUS-study investigates simultaneous ASV-ablation with great saphenous vein (GSV) treatment in endovenous laser ablation (EVLA) for preventing varicose vein recurrence. This sub-study examines complication rates associated with prophylactic ASV-ablation. METHODS: Among 1173 patients with refluxing GSV, 604 underwent GSV-ablation only, and 569 received additional ASV-ablation. Complication rates were compared over 6 months. RESULTS: Approximately 80% of patients were complication-free with minor bruising and dysesthesia being most common complications. After 6 months, additional prophylactic ASV-ablation did not increase the rate of complications compared to GSV-only treatment. CONCLUSION: The 6-months follow-up data suggests that prophylactic ASV-closure, alongside GSV-treatment, is safe, with similar complication rates to GSV-only EVLA.

EndoVenous-assisted invaginated stripping of the great saphenous vein: A pilot and feasibility study.

Objective: By incorporating an endovascular component into Great Saphenous Vein stripping, EndoVenous-assisted Invaginated Stripping (EVIS) aims to make the procedure minimally invasive. A study was conducted to investigate the surgical intervention. Methods: Sketches and videos were used to illustrate the technical aspects of EVIS. A prospective cohort study included 20 patients with chronic venous insufficiency (CVI). Results: EVIS is performed as a day-surgery. Technical success was 100%, and no complications were recorded. The mean operative time was 45 minutes, intraoperative pain score was 4.8, post-operative pain was 2.5, 1.8, 1.2, 0.5 at 48 hours, 1, 4, and 12 weeks, respectively. The mean blood loss was 15 mL, and the mean length of the GSV strapped was 19 cm. The follow-up duplex showed a reduction in the diameter of the residual GSV stump. Conclusions: EVIS is a combination of standard techniques that may prove valuable in managing CVI.

Phlegmasia cerulea dolens after endovenous cyanoacrylate closure of incompetent small saphenous vein.

A previously healthy 70-year-old woman underwent cyanoacrylate closure of an incompetent left small saphenous vein. Six days later, grade 2 treatment-induced thrombosis occurred at the sapheno-popliteal junction. Three days later, the patient presented with pale, cold pain in the left lower extremity. Diffuse thrombosis of the left lower extremity involved the small and great saphenous and deep veins. The patient was admitted and immediately administered heparin with anticoagulant factors, with symptoms began resolving 1 d later. The superficial vein thrombi were resolved. Although a deep venous thrombus remained, symptoms disappeared, and the patient was discharged.

Clinical outcomes after treatment of incompetent saphenous vein combined with segmental popliteal vein reflux.

OBJECTIVE: This study aimed to evaluate whether differences exist in the quality of life changes and complication rates after treatment of incompetent saphenous vein (ISV) based on the presence of segmental popliteal vein reflux (SPVR). METHODS: Patients who underwent treatment for ISV from July 2016 to July 2021 were included and divided into two groups: patients without deep venous reflux (DVR) and patients with SPVR. Patients with axial DVR, a history of deep vein thrombosis, a history of orthopedic surgery, previous venous treatment, and no postoperative follow-up were excluded from the study. Duplex ultrasound examination was performed preoperatively and at 6 and 12 months postoperatively. RESULTS: The study included 233 patients (398 limbs), and 50 (64 limbs) had SPVR. Differences were not observed in gender, age, body mass index, distribution of clinical class according to Clinical-Etiology-Anatomy-Physiology classification, laterality, treatment method, and preoperative Venous Clinical Severity Score or Aberdeen Varicose Vein Questionnaire scores between the two groups with SPVR or without DVR. Furthermore, the Venous Clinical Severity Score and Aberdeen Varicose Vein Questionnaire scores at 6 and 12 months postoperatively were improved in both groups, although without significant differences. A significant difference was not observed in the rate of postoperative complications between the groups based on the presence of SPVR (1.8% vs 1.6%: P = .896). The SPVR improvement rate after ISV treatment was 25% (16/64), and patient-reported outcomes in patients combined with SPVR improved independent of treatment modality, saphenous vein treatment section, and postoperative SPVR improvement. CONCLUSIONS: Complication rates and clinical outcomes after ISV treatment did not differ in the presence of SPVR. In patients with SPVR, after ISV treatment, quality of life improved regardless of treatment modality, saphenous vein treatment section, and postoperative SPVR improvement.

Endovascular therapy versus bypass for chronic limb-threatening ischemia in a real-world practice.

OBJECTIVE: The recent Best Endovascular vs Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) study showed that bypass was superior to endovascular therapy (ET) in patients with chronic limb-threatening ischemia (CLTI) deemed suitable for either approach who had an available single-segment great saphenous vein (GSV). However, the superiority of bypass among those lacking GSV was not established. We aimed to examine comparative treatment outcomes from a real-world CLTI population using the Vascular Quality Initiative-Medicare-linked database. METHODS: We queried the Vascular Quality Initiative-Medicare-linked database for patients with CLTI who underwent first-time lower extremity revascularization (2010-2019). We performed two one-to-one propensity score matchings (PSMs): ET vs bypass with GSV (BWGSV) and ET vs bypass with a prosthetic graft (BWPG). The primary outcome was amputation-free survival. Secondary outcomes were freedom from amputation and overall survival (OS). RESULTS: Three cohorts were queried: BWGSV (N = 5279, 14.7%), BWPG (N = 2778, 7.7%), and ET (N = 27,977, 77.6%). PSM produced two sets of well-matched cohorts: 4705 pairs of ET vs BWGSV and 2583 pairs of ET vs BWPG. In the matched cohorts of ET vs BWGSV, ET was associated with greater hazards of death (hazard ratio [HR] = 1.34, 95% confidence interval [CI], 1.25-1.43; P < .001), amputation (HR = 1.30, 95% CI, 1.17-1.44; P < .001), and amputation/death (HR = 1.32, 95% CI, 1.24-1.40; P < .001) up to 4 years. In the matched cohorts of ET vs BWPG, ET was associated with greater hazards of death up to 2 years (HR = 1.11, 95% CI, 1.00-1.22; P = .042) but not amputation or amputation/death. CONCLUSIONS: In this real-world multi-institutional Medicare-linked PSM analysis, we found that BWGSV is superior to ET in terms of OS, freedom from amputation, and amputation-free survival up to 4 years. Moreover, BWPG was superior to ET in terms of OS up to 2 years. Our study confirms the superiority of BWGSV to ET as observed in the BEST-CLI trial.