Author + information
- Received September 7, 2011
- Revision received November 3, 2011
- Accepted November 24, 2011
- Published online May 1, 2012.
- Ulrich Schäfer, MD⁎,⁎ (, )
- Yen Ho, MD†,
- Christian Frerker, MD⁎,
- Dimitry Schewel, MD⁎,
- Damian Sanchez-Quintana, MD‡,
- Joachim Schofer, MD§,
- Klaudija Bijuklic, MD§,
- Felix Meincke, MD⁎,
- Thomas Thielsen, MD⁎,
- Felix Kreidel, MD⁎ and
- Karl-Heinz Kuck, MD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Ulrich Schäfer, Department of Cardiology, Asklepios Clinics Sankt Georg, Lohmuehlenstrasse 5, 20099 Hamburg, Germany
Objectives This study questioned whether transaxillary transcatheter aortic valve implantation (TAVI) is feasible as a true percutaneous approach using percutaneous closure devices.
Background Transaxillary TAVI is gaining increasing acceptance as an alternative to the transfemoral route; however, the access has always been done via surgical cutdown so far.
Methods Between August 2010 and September 2011, a total of 24 high-risk patients with severe aortic valvular stenosis underwent a percutaneous TAVI procedure by direct puncture of the axillary artery without surgical cutdown. For safety reasons and as a target for the puncture, a wire was advanced via the ipsilateral brachial artery. Moreover, a balloon was placed into the subclavian artery via the femoral artery for temporary vessel blockade before percutaneous vessel closure. Vascular closure was performed using either the ProStar XL system (Abbott VascularDevices, Redwood City, California) or 2 ProGlide systems (Abbott VascularDevices).
Results The true percutaneous approach was successfully completed in all patients (14 left and 8 right axillary artery cases). Overall mortality at 30 days was 8.3%. Acute vascular closure device success was achieved in 17 patients (71%). Vascular closure device success rate was 100% for the ProGlide device and 37% for the ProStar device, respectively. Seven patients (29%) with failing closure devices were treated by endovascular stent graft implantation without the need for surgical repair. For the last 12 treated patients, direct closure was achieved in 11 patients.
Conclusions Direct puncture of the axillary artery for TAVI is feasible and safe if a wire is placed into the subclavian artery via the ipsilateral brachial artery.
In 2002, transcatheter aortic valve implantation (TAVI) was successfully introduced as a new treatment option for aortic valvular stenosis (1). Since then, rapidly rising implantation numbers (>25,000) have proven the feasibility and safety of this technology. Nowadays, TAVI may be considered as a better alternative to surgical aortic valve replacement in high-risk patients. When TAVI was in its infancy, it was still necessary to surgically expose the arterial access vessels under general anesthesia to accommodate the large introducers of the first-generation devices (1–4). Currently, 2 Conformité Européenne (CE)-marked devices for transfemoral TAVI—Sapien XT bioprosthesis (Edwards Lifesciences, Irvine, California) and Medtronic CoreValve System (Medtronic, Minneapolis, Minnesota)—are approved for TAVI via sheathes with an 18- or 19-F diameter. The Sapien prosthesis can also be implanted via a transapical approach (5). The major goal of creating lower-profile devices was to obtain a true percutaneous access in conjunction with local anesthesia (an advantage over the transapical access with its need for general anesthesia) and the use of vascular closure devices, thereby reducing the high vascular complication rates and improving patient outcomes (6,7). In this regard, the recently published PARTNER (Placement of Aortic Transcatheter Valve) A and B studies demonstrated major vascular complications in 11% and 16.2%, respectively. The total number of in-hospital deaths in both randomized treatment arms was increased 3-fold (36% vs. 10.3%) in patients with vascular complications compared with those without vascular complications (8,9). Over the last 3 years, alternative access sites, such as the transaxillary (10,11) or the transaortic (12) approach, have been introduced. For the transaxillary approach, mainly the Medtronic CoreValve and only a few Sapien XT valves have been used in the past (10,11,13,14). All these alternative access sites have surgical exposure of the arterial vessels under general anesthesia in common. Safety and feasibility of the transaxillary approach using a surgical cutdown has been repeatedly demonstrated (10,11).
The present paper describes for the first time, to our knowledge, a new access site technique for direct percutaneous puncture of the axillary artery in a series of 24 consecutive patients for TAVI, not suitable for the transfemoral approach. Puncture technique, site visualization, and closure technique in addition to several treatment options for the management of vascular complications are outlined in the following text.
Between August 2010 and September 2011, a total of 24 patients with severe aortic stenosis underwent percutaneous transaxillary TAVI (self-expandable devices) at our institution (12.1% of 385 TAVI procedures). All patients had symptomatic severe aortic valvular stenosis with an increased operative risk (logistic EuroSCORE >20% or a Society of Thoracic Surgeons [STS] score >10%—or other risk factors for surgical aortic valve replacement, such as porcelain aorta, cirrhosis of the liver, previous radiation treatment of the chest), and all patients were identified as not suitable for the transfemoral approach because of severe peripheral artery disease (severe calcification, significant stenosis/occlusions, or severe vessel tortuosity) as assessed by angiography or multislice computed tomography. Angiography of the subclavian arteries with a graduated pigtail catheter was performed to confirm a sufficient access path for percutaneous transaxillary TAVI. Moreover, a precise evaluation of the aortic annulus (size, morphology, amount of calcification) was carried out via transesophageal echocardiography and angiography using a graduated pigtail catheter. An annulus size between 19 and 27 mm was accepted for implantation of a CoreValve prosthesis (26 or 29 mm, Edwards Lifesciences). Transaxillary TAVI was performed using vascular closure devices with the intention to start and finish TAVI solely by a percutaneous technique without surgical exposure of the access vessel.
Before the procedure, all patients received a clopidogrel loading dose of 300 mg and aspirin 100 mg that was followed by 75 mg of clopidogrel for 3 months and 100 mg of aspirin indefinitely. Intravenous cefazolin was used as antibiotic prophylaxis. In 15 of 24 patients, percutaneous transaxillary TAVI was performed under general anesthesia (62.5%). The decision regarding which side was used (right or left axillary artery) was made with preference to the artery with the least degree of calcification and kinking. Moreover, patent left internal mammary artery grafts were considered as a relative contraindication for TAVI from the left axillary artery. Thus, 7 of 8 patients with left internal mammary artery grafts were treated via the right axillary artery.
For safety reasons, a 6-F sheath (23 cm, Easy Glide, Smiths Medical, Grasbrunn, Germany) was placed into the ipsilateral brachial artery. Retrograde dye injection (5 to 10 ml) through the sheath was used to visualize the axillary artery (Fig. 1A). Using fluoroscopy and a regular J-wire as a landmark, the axillary artery was punctured below the clavicula at a spot significantly lateral to the rib cage to avoid a pneumothorax and to have the possibility for manual compression of the artery (feasible in most cases) (Fig. 1B). In addition, a second long (260 cm) regular J-wire was advanced over the femoral artery in an antegrade manner into the subclavian artery. For safety reasons, an appropriate balloon (regular percutaneous transluminal angioplasty [PTA] balloons 6 to 9 mm, 40-mm length) was inserted over the femoral J-wire into the descending aorta and left in place for immediate vessel blockade if needed. With increasing experience (after Patient #14), a smaller wire (0.018-inch Plywire 400 cm, OptiMed Global Care, Ettlingen Germany) was advanced over a regular diagnostic JR4 catheter via the brachial artery and snared down into the femoral artery, thereby establishing an arterio-arterial monorail access loop for endovascular stent graft implantation if needed. The length of 400 cm was chosen to have a sufficient proportion of wire at both arterial sides (brachial and femoral). Heparin was administered intravenously during the procedure to achieve an activated clotting time >250 ms. After puncture of the axillary artery, a 6-F sheath followed by a 10-F sheath was gradually introduced. Subsequently, a ProStar XL 10-F device (Abbott Vascular Devices, Redwood City, California) was used. Care was taken to place the ProStar into the descending aorta since the ProStar device is generally too long for placement into the ascending aorta. With increasing experience, we mainly used 2 ProGlide 6-F devices (Abbott Vascular Devices) as a closure device. The ProGlide was inserted immediately after introduction of the 6-F sheath into the axillary artery (Figs. 2A and 2B) followed by a 10-F sheath. A stiff guidewire (Amplatz Super Stiff ST-1, AGA Medical Corporation, Plymouth, Minnesota) was then positioned into the left ventricle followed by insertion of the 18-F sheath (COOK Medical, Limerick, Ireland) (Fig. 3A). After standard valvuloplasty (under rapid right ventricular pacing at 180 to 200 beats/min) (Fig. 3B), TAVI was performed (Fig. 4A). After successful valve implantation (Fig. 4B), the sheath was carefully pulled back, and the balloon (regular PTA balloons 6 to 9 mm, 20- to 40-mm length) that was placed at the beginning of the procedure in the descending aorta was advanced to block the subclavian artery (Fig. 5A). After removal of the device sheath, the sutures provided by the ProStar XL or the 2 ProGlide systems were tied down. The Plywire remained in situ as a safety guard to secure access into the vessel at all times. Finally, control angiography of the axillary artery was performed over the long sheath previously placed in the brachial artery (Fig. 5B).
Minor vessel complications that did not affect blood flow and blood supply were treated conservatively, that is, by manual compression or protamine infusion, and carefully examined 10 to 15 min later. In case of either a flow-limiting dissection or persistent bleeding, retrograde or antegrade treatment of the injured vessel segment was performed using balloon dilation and/or stent implantation (stent graft for significant bleeding/perforation, fenestrated stent for dissection).
After discharge from hospital, a regular follow-up was carried out after 6 to 8 weeks. This follow-up included a physical examination, electrocardiography, echocardiography, and laboratory tests.
Patient population and anatomic data
The mean age of the 24 patients was 80.8 ± 7.3 years. Patient characteristics are summarized in Table 1. Mean transvalvular aortic pressure gradient was 39 ± 7.4 mm Hg, and the pre-procedural mean calculated aortic valve area was 0.7 ± 0.2 cm2. The mean left ventricular ejection fraction was 42 ± 13% (range: 15% to 70%), the mean logistic EuroSCORE was 35.3 ± 22.8%, and 96% of the patients were in New York Heart Association functional class III or IV.
TAVI was performed using either the left (n = 16) or the right (n = 8) axillary artery. The mean diameters of the arteries were 7.4 ± 1.7 mm for the axillary artery, 7.3 ± 0.9 mm for the distal subclavian artery, 7.7 ± 1.5 mm for the medial subclavian artery, and 8.6 ± 1.1 mm for the proximal subclavian artery. Most of the patients had a rather straight vessel, and 4 patients had some kinking without significant calcification. Calcification was absent in 12 patients, mild in 11 patients, and severe in 1 patient, respectively. A single patient had to be treated by PTA (7 × 40 mm Admiral, Invatec, Roncadelle, Italy) in the proximal subclavian artery for a focal stenosis, before insertion of an 18-F sheath. Puncture was performed into a proximal location of Segment 1 of the axillary artery at a distance of 1.2 ± 0.9 cm to the lateral border of the rib cage. Care was taken to avoid puncture into side branches of the axillary artery. In 2 patients, an expandable sheath was used (SoloPath, Onset Medical Corporation, Irvine, California).
Procedural success and 30-day major adverse cardiac and cerebrovascular events
Procedural device success according to the Valve Academic Research Consortium (VARC) criteria (15) was achieved in all but 1 patient. In this patient, a second CoreValve prosthesis had to be implanted due to dislocation of the first CoreValve (snare pullback due to deep implantation) into the ascending aorta. In a second patient, implantation success was achieved during a second implantation attempt after complete removal and reloading of the device was performed. Conversion to open-heart surgery was not necessary in any patient, and no patient was lost during TAVI. Invasive mean post-procedural aortic transvalvular gradient was 9.4 ± 2.4 mm Hg, and moderate post-procedural aortic regurgitation was present in 2 (8.3%) patients, mild in 8 (33.3%) patients, and trivial or no aortic regurgitation was seen in 14 patients (58.3%). Thirty-day survival rate was 91.6%. One female patient in a rehabilitation center died suddenly at day 28 due to pneumonia. A second female patient with decompensated aortic valvular stenosis could not get weaned from the respirator despite successful TAVI and died subsequently at day 17.
Thirty-day major adverse cardiac and cerebrovascular events (sudden cardiac death, pericardial tamponade, fatal major bleeding, major disabling stroke) was 0%. The incidence of new-onset complete or high-grade atrioventricular block requiring permanent pacemaker implantation was 25%. No neurological complication or other damage to the brachial plexus was found at the site of puncture. Major vascular complications (VARC criteria) resulting in death or use of ≥4 U of blood transfusions, as well as distal embolization with subsequent end-organ damage requiring surgery or amputation, did not occur in any patient. Seven of 24 patients were treated with a stent graft at the puncture site because of persistent bleeding or failure (avulsion of the sutures) of the vascular closure device (Table 2). A total of 3 patients received 2 U of blood transfusions, with 2 of these patients being treated due to pre-existing anemia in conjunction to closure device failure. Minor bleedings were successfully managed with protamine infusion and manual compression. Thus, acute vascular closure device success was achieved in 71%. Two patients (8.3%) had to undergo repeated endovascular stenting due to a flow-compromising dissection or stent graft thrombosis (at days 8 and 35 after TAVI). In addition, 1 of these 2 cases had to undergo surgical revision of a pseudoaneurysm of the brachial artery at day 8 after TAVI. Overall, 6 patients of the first 16 patients were treated by stenting compared with only 1 patient of the second series of 12 patients (50% vs. 8.3%; Table 2). The ProStar system was significantly less effective than 2 ProGlide systems (closure success: 37% vs. 100%, p < 0.01).
Overall mortality at 30 days was 8.4%. At 30 days, the mean New York Heart Association functional class declined from 3.2 ± 0.4 (pre-procedural) to 2.1 ± 0.4 at 6 weeks post-procedural (p < 0.001). Follow-up echocardiographic results demonstrated a sustained reduction in mean pressure gradients (10.2 ± 2.4 mm Hg). The estimated aortic valve area showed a persistent improvement with the self-expandable bioprosthesis (1.9 ± 0.3 cm2; p < 0.001 vs. before TAVI), and paravalvular aortic regurgitation was present as grade <1 in 75%, as grade 1 to <2 in 20%, and as grade 2 in 5% of the patients.
This is the first study, to our knowledge, to demonstrate TAVI via a direct percutaneous transaxillary access.
The major findings of the present study are first, direct puncture of the axillary artery for TAVI is feasible and safe in patients not suitable for the transfemoral approach, with technical success in all patients. Second, the ProGlide system seems to be more effective for closure of the axillary artery puncture site than the ProStar XL system. Third, if failure of vessel closure devices occurs, access to the axillary artery puncture site can be provided over the ipsilateral brachial artery or the femoral artery for balloon occlusion or stent graft implantation.
The biggest concern for direct puncture of the transaxillary artery is the risk of major bleeding and dissection. The direct puncture of the axillary artery was used in the present study to avoid a surgical cutdown. Puncture was facilitated by angiography via the brachial artery to identify the right spot and by placement of a wire into the axillary artery, which served as a landmark. Either ProStar or ProGlide was used as “pre-closure” technique. Both vascular closure devices are the most commonly used suture-based systems to close the arteriotomies at the femoral site after percutaneous TAVI without surgical cutdown. To our knowledge, the use of vascular closure devices at the axillary or subclavian artery has not been described in the literature so far.
Due to the widespread confusion about the correct anatomic terminology, it should be mentioned that even with a surgical cutdown to the artery, the implantation is always done via the axillary artery and not via the subclavian artery. By terminology, the axillary artery begins at the lateral border of the first rib as a continuation of the subclavian artery (Fig. 6). It changes its name to brachial artery at the lower (inferior) border of the teres major muscle. For a more detailed description, the axillary artery is divided into 3 segments in relation to the pectoralis minor muscle. The first segment is between the lateral border of the first rib and the medial border of the pectoralis minor, the second segment is behind the pectoralis minor, and the third segment is between the lateral border of the pectoralis minor and the inferior border of the teres major. As described before, the puncture of the axillary artery was performed in the area of segment 1, at a distance of 1.3 ± 0.7 cm to the lateral border of the rib cage, to prevent artificial puncture into the pleural cavity. No pneumothorax was observed in our study. In addition, care was taken to avoid puncture into side branches (i.e., superior thoracic artery, thoracoacromial artery, lateral thoracic artery) usually arising from segment 2 of the axillary artery. From our experience, artificial puncture into side branches of any vessel is a frequent cause of closure device failure or significant bleeding, especially at the femoral anatomic site during transfemoral TAVI. In the present study, the incidence of major vascular complications according to VARC was 0%. However, minor complications (VARC definition) necessitating stent graft implantation occurred in 29.2%. It is noteworthy to mention that the threshold for stent graft implantation was rather low, because compression treatment may be difficult (especially in obese patients) in this particular anatomic region (as opposed to the common femoral artery).
Using 2 ProGlide systems was significantly more effective compared with the ProStar system (closure success: 100% vs. 37%). Similar differences in the efficacy between both closure devices have not been observed for the femoral approach. A possible explanation might be the different anatomic structure of the vessel wall of the subclavian/axillary artery compared with the femoral artery. As shown in the vessel specimens (Fig. 7), the subclavian/axillary arteries are of the elastic type with multiple layers of elastic fibers in the media. By contrast, the femoral artery is of the muscular type with a thicker media, mainly containing smooth muscle cells (with only a few strands of elastic fibers) between the internal and external elastic laminae (Fig. 7). Furthermore, the adventitia of the femoral artery is more fibrous and thicker than that of the subclavian artery. These differences in the histological structure may have an impact on the efficacy of the 2 vascular closure devices that were used in our study.
In 7 of 24 patients, we were not able to sufficiently close the puncture site with the used pre-closure technique, necessitating implantation of stent grafts. Interestingly, all failures with vascular closure devices were observed with ProStar. There are several possible explanations for this observation. As mentioned earlier, the elasticity of the axillary artery might impinge on the methodological and mechanical work mode of the ProStar device. For comparison, the ProGlide is operated with 2 needles that are deployed within the tissue track and directed toward the feet of the closure device, which are placed at the inner wall of the artery (16). The feet capture the needles, thereby creating a suture loop leaving behind 2 suture tails (closure is usually achieved with 2 ProGlide) (17). By contrast, the ProStar uses 4 needles simultaneously (2 sutures) directed outward from within the arterial lumen. By pulling on the device handle, the needles are pulled through the arterial wall, leaving behind 4 suture ends (2 sutures) (17). Besides these methodological differences, the ProStar is much stiffer compared with the ProGlide, thereby possibly distorting the vessel wall more (a thinner vessel compared with the femoral artery) with a higher likelihood of subsequent trauma. In addition, the working angle was sometimes very steep (deep anatomic location of the axillary artery), again hampering correct needle placement of the ProStar device. Thus, we had 4 complete avulsions of the sutures and 3 persistent bleedings despite successful knot delivery toward the arteriotomy.
The considerable low incidence of severe bleeding (≥4 U of blood; n = 0) in our series is most likely related to a procedural strategy that anticipated vessel injury/closure device failure even before puncture of the axillary artery. With a wire and a blocking balloon in place (either via the distal brachial access point or the femoral artery), temporary vessel occlusion as well as stent graft implantation can be performed whenever necessary. Moreover, with a blocking balloon in place, vessel closure can be performed without haste under dry conditions. None of the patients developed significant hematoma, and the cosmetic result in all patients was excellent (Fig. 8). In addition, we did not observe a single neurological complication, despite the close proximity of the brachial plexus at the area of the puncture site.
The rate of 29.2% minor vascular complication (despite 0% major vascular complication) may be considered unacceptably high, but compared with the transfemoral approach with reported major vascular complications in the range of 7.3% to 22.9% (Edwards Sapien valves) and between 3.9% and 16.9% (Medtronic CoreValve—definition of vascular complication between various publications) (10,18,19), the transcutaneous transaxillary TAVI seems to be a reasonable alternative. With regard to the high incidence of stenting due to vascular closure device failure, endovascular treatment of the subclavian/axillary artery with stents has been proven to be feasible and safe in numerous studies, with an immediate success rate of 93% to 100% (20–23). In addition, due to the high-flow state of the supra-aortic vessels, long-term primary patency has been shown to range between 72% and 93%, with a secondary patency of up to 96% (24). Thus, the risk and benefit of a direct percutaneous puncture of the axillary artery for TAVI seems to be acceptable. Nevertheless, the risk of injury to the internal thoracic artery remains an issue that may even exclude patients from a transaxillary approach (relative contraindication), but due to the very lateral puncture, we did not see any compromise of the internal thoracic artery in 3 of 7 cases where we had to perform endovascular stenting (3 left, 4 right).
Finally, there is usually a certain stepdown by 1 to 2 mm in vessel diameter from the subclavian artery to the axillary artery, making questionable the concept of balloon-expandable stent grafts at that anatomic site. In fact, 2 patients experienced a distal dissection that occurred several days later, most probably due to a laterally oversized stent. Since the subclavian/axillary artery is particularly prone to dissections, a careful matching of the stent to the vessel size is needed. Thus, the use of self-expanding stents seems to be advisable. The major disadvantage of self-expandable stent grafts is the relatively large sheath size that has to be used (usually 8- to 10-F compared with 6- to 7-F for balloon-expandable stent grafts). To overcome this limitation, an antegrade approach, such as the femoral approach, is usually needed since 8- to 10-F should not be introduced into the brachial artery. Due to the availability of 2 access sites over a single arterio-arterial looped long wire, temporary vessel occlusion can be additionally performed via the brachial artery (rendezvous approach) with subsequent antegrade endovascular stenting under nicely controlled conditions. If anything fails, the vascular surgeon can be called to perform surgical repair without significant bleeding, which was never necessary in this study.
Increasing experience with vascular closure devices in addition to practical knowledge for vascular complication management led us as the first group to develop a new and truly percutaneous approach for transaxillary TAVI (“the Hamburg Sankt Georg approach”). As demonstrated in a series of 24 patients, using vascular closure devices, transaxillary TAVI can be carried out in a true percutaneous fashion and with only local anesthesia in a considerable proportion. The key factor to assure access to possible life-threatening vessel injuries is to place a long “safety-net”-wire from a distal access point (i.e., brachial artery) into the subclavian artery before direct puncture, pre-closure, and device sheath insertion. The long wire should be placed in a looped fashion from the brachial artery to the femoral artery (or vice versa) and a noninflated balloon should be inserted into the thoracic aorta and kept in this position right from the beginning of the intervention.
This is a single-center study with only 24 consecutive patients demonstrating multiple different experiences with this approach (learning curve, lower efficacy of ProStar, problematic use of balloon-expandable stents, and so on). Thus, the number is definitely too small to derive clear conclusions for the future. Despite a 100% success rate with ProGlide for vessel closure, the need of more dedicated percutaneous solutions for the management of vascular access site complications and closure device failures is needed.
The present study shows for the first time, to our knowledge, that direct puncture of the axillary artery for TAVI is feasible and relatively safe. Surgical cutdown of the artery can be avoided. We therefore believe that the true percutaneous transaxillary “Hamburg Sankt Georg” approach has the potential to become an alternative to the percutaneous transfemoral approach in the future. A wire inside the subclavian artery via the ipsilateral brachial and femoral artery is an essential safety tool for immediate balloon occlusion or stent graft implantation, in case vessel closure fails.
Dr. Schäfer is a clinical proctor for Edwards Lifesciences and Medtronic, Inc. Prof. Schofer and Prof. Kuck have received honoraria from Edwards Lifesciences and Medtronic, Inc. Prof. Kuck received speaker's fees and is a consultant for St. Jude Medical, Biosense Webster, Stereotaxis, and Medtronic, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- percutaneous transluminal angioplasty
- transcatheter aortic valve implantation
- Valve Academic Research Consortium
- Received September 7, 2011.
- Revision received November 3, 2011.
- Accepted November 24, 2011.
- 2012 American College of Cardiology Foundation
- Cribier A.,
- Eltchaninoff H.,
- Bash A.,
- et al.
- Grube E.,
- Laborde J.C.,
- Gerckens U.,
- et al.
- Cribier A.,
- Eltchaninoff H.,
- Tron C.,
- et al.
- Webb J.G.,
- Pasupati S.,
- Humphries K.,
- et al.
- Grube E.,
- Schuler G.,
- Buellesfeld L.,
- et al.
- Petronio A.S.,
- De Carlo M.,
- Bedogni F.,
- et al.
- Godino C.,
- Maisano F.,
- Montorfano M.,
- et al.
- Leon M.B.,
- Piazza N.,
- Nikolsky E.,
- et al.
- Thomas M.,
- Schymik G.,
- Walther T.,
- et al.