Drug-delivering devices in the urinary tract: A systematic review

Figures & data

Table 1. Eligibility criteria of the systematic review

Eligibility criteria
Human (male and female) or animal
Placement of DES or dilatation with DCB for investigating their potential use in the urinary tract for the management of ureteric or urethral pathologies.
Clinical trial or experimental studies
No restriction in date of publication
No language restriction
Articles in peer-reviewed journals and abstracts from major congresses (EAU, WCE, AUA, SIU) – same studies as above

EAU, European Association of Urology; SIU, Société Internationale d’Urologie; WCE, World Congress of Endourology.

Figure 1. PRISMA flow chart of the systematic review

Table 2. Comparison of the experimental (in vitro) trials of DES/DCS

Reference	Aim/primary endpoint	Intervention	Results
Antimisiaris et al., 2000 [9]	In vitro preparation of liposome-covered metal stents and loading of liposomal drug formulations that will slowly release the drug in the vicinity of the stent.	Apply to pieces of stent a large multi-lamellar liposomes empty or entrapping the corticosteroid anti-inflamatory-drug	A mean (SD) 39.11 (6.8)% of the lipid and 50.84 (5.48)% of the drug was released from the stent pieces during 48 h incubation in the presence of artifical urine.
Cadieux et al., 2006 [12]	Test of the effects of triclosan-impregnated stent segments on the growth and survival of Proteus mirabilis	Instillation with 1 × 10^6 P. mirabilis 296 Randomised groups, intravesical stent: -Triclosan -Optima® -Percuflex Plus® Urine culture: days 1, 3 and 7. Day 7: Incrustation and viable organisms in stents.	Urine culture: significantly less P. mirabilis in the triclosan group than in the Percuflex Plus group at all time points and in the Optima group on days 3 and 7
Barros et al., 2015 [10]	The evaluation of the in vitro elution profile of ketoprofen impregnated in the biodegradable ureteric stent during its degradation	To impregnate with ketoprofen the biodegradable ureteric stents with each formulation: alginate-based, gellan gum-based	Ketoprofen-impregnated stents were able to the release ketoprofen in the first 72 h in artificial urine solution.
Barros et al., 2017 [11]	The use of an ex vivo porcine model to assess the permeability of the anti-cancer drugs (PTX, doxorubicin) delivered from a BUS across porcine ureter	The permeability of the anti-cancer drugs (PTX, doxorubicin) alone or released from the developed BUS	PTX and doxorubicin drugs released from the BUS were able to remain in the ex vivo ureter and only a small amount of the drugs can cross the different permeable membranes with a permeability of 3% for PTX and 11% for doxorubicin. The estimated amount of PTX remains in the ex vivo ureter tissue and was shown to be effective against the cancer cells and did not affect the non-cancer cells.
Chew et al., 2006 [13]	The bactericidal and bacteriostatic effect of a triclosan-eluting ureteric stent against common bacterial uropathogens in an in vitro setting	Control stent and eluting stent with triclosan were suspended in artificial urine with bacterial pathogens to assess growth, virulence-promoter activity, and bacterial adherence	Triclosan stents had significantly fewer adherent viable bacteria than control stents. Growth was inhibited in a dose-dependent fashion by triclosan eluate in all strains except P. aeruginosa and Ent. faecalis
Elayarajah et al., 2011 [14]	Evaluation of ureteric stents made of silicone impregnated with one or more antimicrobial agents (ofloxacin and ornidazole) to inhibit the growth of different bacterial pathogens that colonise the device surface	Stent pieces were impregnated in a polymer mixed antibiotic solution (ofloxacin and ornidazole) for uniform surface coating (drug-carrier-coated stents) to inhibit the growth of different bacterial pathogens that colonise the device surface	In qualitative test, the zone of inhibition around the coated stents showed sensitivity against the clinical isolates. In quantitative test, the number of adhered bacteria on the surface of coated stents was reduced to a significant level (P < 0.05).
Johnson et al., 2010 [15]	Comparison of commercially available, antibiotic-coated Foley catheters regarding activity, comparative potency and effect durability	An inhibition zone assay (diffusible inhibition) and an adherence assay was used to assess the inhibitory effect of coated urethral catheters, 2 with silver and 1 with nitrofurazone	The nitrofurazone-coated catheter showed the greatest and most durable (through day 5) inhibitory activity. One of the 2 silver-coated catheters showed sparse but measurable inhibition zone activity on day 1, but not thereafter and no statistically significant activity on adherence assay. The other lacked detectable activity using either test system.
Kotsar et al., 2009 [16]	To assess the degradation process and the biocompatibility of biodegradable urethral DES.	The effect of cytokines and other inflammatory mediators on control stents (bacterial lipopolysaccharide as a positive control) and biodegradable stent material (poly-96 L/4D-lactic acid [PLA]) using the human cytokine antibody array	The increase in the production of inflamatory mediators with the PLA-stent material was smaller than in the cells treated with lipopolysaccharide
Ma et al., 2016 [17]	To assess the degradation process and the biocompatibility of biodegradable ciprofloxacin-eluting ureteric stents.	Poly(L-lactide-co-ε-caprolactone) degradation process and the biocompatibility of biodegradable ciprofloxacin-eluting ureteric stents. Ciprofloxacin-eluting ureteric stents were prepared by the dipping method.	Stage I: mainly controlled by chain scission instead of the weight loss or morphological changes of the coatings. Stage II: the release profile was dominated by erosion resulting from the hydrolysis reaction autocatalysed by acidic degradation residues. Ciprofloxacin-loaded coatings displayed a significant bacterial resistance against E. coli and S. aureus without obvious cytotoxicity to human foreskin fibroblasts.

BUS: biodegradable ureteric stent; PTX: paclitaxel.

Table 3. Comparison of the clinical (in vivo) trials of DES/DCS

Reference	Subjects	Site	Intervention	Method study	Results	Limitations
El-Nahas et al., 2018 [18]	126 patients	Ureter	RCT Postoperative stent placement Control group: 69 patients SSD-coated stent: 68 patients	At placement and at removal of the stent: Urine and stent culture, USSQ	No significant differences between groups in the incidence of bacteriuria and USSQ scores.	Short duration of stenting. Relatively small sample size
Cadieux et al., 2009 [19]	8 patients	Ureter	Each pacient: Control stent 3 months with antibiotics preoperative and postoperative After this: change to triclosan-eluting stent 3 months with no antibiotics	Stent removal and processing: cut into three equal-length sections (bladder, ureteric, and kidney) Encrustation and surface: blinded technician and air dried. stent-adherent organisms: brain heart Infusion agar susceptibility to triclosan was determined via duplicate plating on Mueller Hinton agar	Staphylococcus isolated more in control stents Enterococcus isolated more in triclosan stents. Fewer antibiotics were used during triclosan stenting, coinciding with a slightly higher number of positive urine cultures and significantly fewer symptomatic infections.	Not mentioned
Cauda et.al., 2008 [20]	5 patients with bilateral obstructions	Ureter	For each pacient heparin-coated JJ stent and a traditional polyurethane JJ stent for 1 month.	Before placement and after removal stents were analysed using FESEM, EDS, and Micro-IR. Comparison of thickness, extension, and composition of encrustation. Analysis of two heparin-coated stents at 10 and 12 months.	FESEM: significant differences between groups for encrustation thickness and extension. EDS and Micro-IR: in heparinised stents the encrustations were not as uniform and compact as those in the uncoated stents. 10–12 months: free of encrustations and had no changes in the heparin layer.	Small number of patients. Relatively arbitrary nature of how the encrustations were quantified.
Chew et al., 2010 [21]	92 Yorkshire pigs	Ureter	Randomisation in to 5 groups Control: non-DES + oral KL, n = 12 Autopsy at 2, 5, 15 days Control: non-DES, n = 20 15% KL-loaded stent, n = 20 13% KL-loaded stent, n = 20 7% KL-loaded stent, n = 20 Groups 2,3,4,5: Necropsies at 2, 5, 15, 30, 60 days	Percutaneous aspiration of urine and venipuncture were obtained immediately before the autopsy. KL levels were measured in plasma, urine, and tissue sampled from ureters, bladder, kidneys, and liver using HPLC. Remainder of the genitourinary organs and liver: fixed and processed for histopathological analysis and analysed for any abnormality by a veterinarian pathologist blinded to the treatment group	Majority of KL first 30 days. Highest levels of KL: Group 1. Highest levels of KL in ureter and bladder tissues: KL stent dose-dependent fashion. Gastric ulcerations: Group 1.	Not named
Cirioni et al., 2007 [22]	5 adult female Wistar rats	Ureter	2 × 10^7 CFU/mL S. aureus: inoculated into the bladder Control group C0 without a bacterial challenge Challenged control group (C1) without antibiotic prophylaxis i. 10 mg/kg of body weight teicoplanin intraperitoneally immediately after stent implantation ii. RIP-coated (0.2-cm^2) sterile stents iii. stents coated with intraperitoneal teicoplanin	Culturing serial 10-fold dilutions (0.1 mL) of the bacterial suspension on blood agar plates. 37°C for 48 h. Quantification: number of CFU/plate. Toxicity: presence of any drug-related adverse effects.	C0: None had microbiological evidence of stent infection. C1: all stents presented with infection with a mean (SD) of 6.6 (1.9) × 10^6 CFU/mL. i. 3.8 (0.8) × 10^3 CFU/mL ii. 6.7 (1.4) × 10^4 CFU/mL (P < 0.05) iii. no bacterial counts (P < 0.001). None of the rats included in any group died or had any clinical evidence of drug-related adverse effects.	Not named
Han et al., 2018 [23]	6 dogs	Urethra	12 EW-7197-eluting NFCSs were placed in the proximal and distal urethras in each dog. Control stent (CS) group (n = 3) received NFCSs. Drug-stent (DS) group (n = 3) recived EW-7197 (1000 μg)-eluting NFCSs. All dogs were killed 8 weeks after stent placement	Urethrography: 4–8 weeks after stent’s placement. The histological samples were longitudinally sectioned at the three different portions of the segment with the stent. H&E and MT stains were used to study the samples. The items were submucosal inflammatory cell infiltration, the number of epithelial layers, the thickness of submucosal fibrosis, and the thickness of papillary projection.	Urethrographic analysis: mean luminal DS group > CS group at 4 and 8 weeks after stent placement (all P < 0.001) Histological examination: thicknesses of the papillary projection, thickness of submucosal fibrosis, number of epithelial layers, and degree of collagen DS group < CS group (all P < 0.001). Degree of inflammatory cell infiltration was not significantly different	Small sample size Quantitative analyses for the expression levels of TGF-t and its mediators were not possible. Some of the measurements in this study were obtained subjectively. Long-term effectiveness of the EW-7197-eluting NFCS was not evaluated.
Kallidonis et al., 2011 [24]	10 pigs and 6 rabbits	Ureter	A zotarolimus-eluting stents (ZES) and a bare metal stents (BMS) were inserted in each ureter and in the contralateral ureter as a control.	Evaluation Porcine: CT every week/4 weeks Rabbit: IVU every week/8 weeks. Renal scintigraphies were performed before stent insertion and during the third week in all animals. Optical coherence tomograph (OCT): evaluation of the luminal and intraluminal condition of the ureters with stents. Histological examination: glycol-methacrylate	Hyperplastic reaction in both groups. 7 porcine ureter: BMS completely obstructed. Porcine ureters with ZES stents without obstruction. 2 rabbit ureter: BMS completely obstructed. No rabbit ureter obstruction with ZES stent. OCT: hyperplastic reaction in the ureters with BMS > ureters with ZES.	The evaluation model was based on the comparison of the ZES with control BMS. The effect of these stents in cases of ureteric pathology was not evaluated. Lack of thorough statistical analysis
Kim et al., 2018 [37]	36 male Sprague-Dawley rats	Urethra	Randomisation equally: Group A: control biodegradable stents. Group B: stents coated with 90 μg/cm^2 sirolimus Group C: stents coated with 450 μg/cm^2 sirolimus Each group: 6 rats killed after 4 weeks, the remaining after 12 weeks.	Retrograde urethrography and histological examination (H&E stained slices)	Urethrographic and histological examination: Granulation tissue formation Groups B, C < A (P < 0.05 for all). No significant differences between B and C. Number of epithelial layers B > C at 4 weeks after stent placement (P < 0.001) Apoptosis C > B, A (P < 0.05)	Stents were placed in rats with normal urethras. Follow-up duration of 12 weeks may not have been sufficient to identify rebound effects. Physical stent changes not assessed
Kotsar et al., 2009 [16]	16 male rabbits	Urethra	4 groups: the stents inserted into the prostatic urethra. Drugs: indomethacin, dexamethasone and ciprofloxacine. 80 L/20D-PLGA stents without a drug coating served as controls. 4 rabbits in each group, were killed after 1 month	The urethra surrounding the stent was dissected from the rabbits en bloc. Tissue blocks: H&E following routine techniques Biodegradation process evaluated by optic microscopic analyses. Biological response eosoniphilia, acute inflammatory changes (polymorphonuclear leucocytes), chronic inflammatory changes (lymphocytes, plasma cells) and the amount of fibrosis	Control stents and the dexamethasone-eluting stents degraded totally during the follow-up period. Indomethacin- and ciprofloxacine-eluting stent groups, the degradation process was significantly delayed and they induced an increase in epithelial hyperplasia. All the stents induced eosinophilia. No significant differences in the intensity of acute or chronic inflammatory reactions and fibrosis.	Not named
Kotsar et al., 2012 [26]	24 male New Zealand White rabbits	Urethra	4 groups. Biodegradable braided pattern PLGA urethral stents coated with rasemic 50 L/50D PLA with two different concentrations of indomethacin were inserted into the prostatic urethra Half of the rabbits in each group were killed after 3 weeks and the other half after 3 months.	Histological analyses using H&E staining. Following biological response parameters: Inflammatory changes (neutrophil infiltration), chronic inflammatory changes (lymphocyte and plasma cell infiltration), foreign body reaction, fibrosis, calcification, and eosinophil infiltration The degradation process of the stent and the development of epithelial hyperplasia (polyposis) was evaluated by SEM.	SEM analysis revealed that indomethacin coating had no effect on the degradation process of the stents. Histological analyses at 3 weeks: indomethacin-eluting stents caused more calcification but no significant differences in other tissue reactions At 3 months: the indomethacin-eluting stents caused less inflammatory reaction and calcification compared with the control stents.	Not named
Kram et al., 2020 [28]	48 male 9-week-old Sprague–Dawley rats	Ureter	3 groups, all n = 16: 1. Dissection of the left ureter without uretero-ureteric anastomosis but blunt manipulation of the ureter 2. Transsection of the left ureter and end-to-end anastomosis with insertion of an uncoated ureteric stent 3. Transsection of the left ureter and end-to-end anastomosis with insertion of either a pacitaxel-coated ureteric stent.	Received daily intraperitoneal injections of 5-bromo-2-deoxyuridine the first 8 postoperative days, and were killed on day 28. Healing of the ureteric anastomosis and proliferation of urothelial cells was examined histologically (H&E staining) and immunohistochemically	Both types of stents showed inflammation, fibrosis and urothelial changes. Proliferation of urothelial cells was significantly lower in rats with PTX-coated stents compared to those with uncoated stents (labelling index 41.27 vs 51.58, P < 0.001).	The surgical procedure of end-to-end ureteric anastomosis is demanding. There are differences in morphology and in the degree of stent-induced reactions compared to humans
Krambeck et al., 2010 [29]	276 patients	Ureter	Randomisation was 1:1 to KL or control stent groups. Stents were removed by pull-string or cystoscopically. Patients were followed for 30 days after stent removal. Primary study endpoint was intervention for pain. Secondary endpoints included: intervention due to stent, pain medication use, VAS assessed pain, and patient sat isfaction assessed using a 5-point scale	Blood and urine samples were obtained for routine chemistry studies, serum KL levels and urine analysis on days 0, 1, 2, 4, 7 and 10 after placement, the day of stent removal, and days 2 and 30 after stent removal.	None of the safety cohort had detectable serum KL levels. No difference in primary (9.0% KL loaded vs 7.0% control, P > 0.66) or secondary (22.6% KL loaded vs 25.2% control, P > 0.67) intervention rates. Pain pill count at day 3: KL < Control (P < 0.05). use no or limited pain medications: KL > Control. Male KL > Female KL, Male and Female control (P < 0.05)	Subjective nature of ureteric stent pain and the lack of an adequate assessment tool.
Krane et al., 2011 [30]	12 Sprague-Dawley Rats	Urethra	Formation urethral scars via electrocautery. Groups (n = 6 in each): Group 1, coated with HF Group 2, uncoated First inserting the silicone catheter, then placing a 30-G needle transversely completely through the corpora spongiosum and catheter and applying 10 W of electrocautery to the needle for 3 s. At 2 weeks: killed and excision urethral tissue.	Histopathological analysis: MT stain or anti-alpha-1 collagen and then examined with bright-field microscopy. Drug levels: tissue specimens – >HF concentration analysis via spectrophotometry. Blood: HF concentration via spectrophotometry absorption at 243 nm on a standard curve.	Group 1: Local urethral concentration of HF was 10fold higher than serum concentration. Had no new type I collagen deposition after urethral injury. Gruop 2: had increased periurethral collagen type I deposition, typical of urethral stricture formation.	Small number of rats in each group. Systemic concentration was evaluated with spectroscopy and not HPLC, which may provide more accurate measurements.
Liatsikos et al., 2007 [31]	10 female pigs	Ureter	Randomly placed in either the right or left ureter in each of the 10 pigs 1. R-Stent (n = 10) 2. PTX-eluting coronary stent (n = 10) Percutaneous nephrostomy was performed under ultrasonographic guidance and the collecting system was visualised. Deployment of the stent was finalised: nephrostomy tube was capped.	Patency evaluation of uretericlumen: Radiograph of the nephrostomy tract, IVU, and virtual endoscopy at 24 h and 21 days after the initial procedure, respectively. Conventional ureteroscopy at 21 days. Pathology examination of ureter: same pathologist minimising possible bias.	21 day follow-up: Group 1: 5 completely occluded 2 partially stenosed Group 2: no occluded stent Pathology examination 21 days: Obstructed R-stents generated severe inflammation with metaplasia PTX-eluting MS generated a mild inflammatory response without hindering ureteric patency	The difference in length of the two stent groups
Lin et al., 2018 [32]	5 New Zealand White rabbits	Ureter	5 cm segment of the analgesic (KL and lidocaine)-eluting nanofibre-incorporated ureter stent was inserted. Urine and blood samples were collected 1, 3, 7, 14, 21, and 28 days.	Infrared spectra of the analgesic-loaded nanofibrous matrix were evaluated employing FTIR spectrometry. Elution behaviour characteristics of lidocaine and KL from the analgesic-eluting ureteric stents were evaluated using an in vitro release scheme	Analgesic-eluting ureteric stents could liberate high strengths of analgesics in vitro and in vivo for at least 50 and 30 days, respectively. The blood levels were much lower throughout the study period.	Results show a local and sustainable elution of KL and lidocaine from the nanofibrous matrix-loaded ureteric stents, the efficacy of released anal gesics is yet to be confirmed. The rabbit model is limited in terms of its ability to be reproduced in human studies.
Mendez-Probst et al., 2012 [34]	20 patients requiring short-term stenting (7–15 days)	Ureter	Group 1: n = 10, Percuflex Plus® non-eluting stent (control) Group 2: n = 10, Triumph® triclosan-eluting stent. Group 1: 3 days of levofloxacin prophylaxis (500 mg once daily) Group 2: did not recived antibiotic.	Midstream urine samples were collected from each subject just prior to both stent placement and removal. Urine culture Stents: cut into three equal length sections, brain heart infusion agar supplemented with 0.5% yeast extract. Stent isolates were sent for identification and standard antibiotic susceptibility testing	Stent placement after: Group 1: 9 ureteroscopic and 1extracorporeal shockwave lithotripsy Group 2: 8 ureteroscopic and 2 extracorporeal shockwave lithotrips No significant differences were observed for culture Group 2: reductions in lower flank pain scores during activity (58.1% reduction, P = 0.017) and urination (42.6%, P = 0.041), abdominal pain during activity (42.1%, P = 0.042) and urethral pain during urination (31.7%, P = 0.049).	Lack of an additional patient group containing subjects receiving both the triclosan eluting stent and postoperative antibiotics
Shin et al., 2005 [35]	20 male dogs	Urethra	20 PTX-eluting polyurethane-covered stents (drug stents) and 20 polyurethane-covered stents (control stents) were placed alternately between the proximal and distal urethra. Group 1: n = 10 killed after 4 weeks 1.1.: drug stent in proximal urethra. 1.2.: control stent in distal urethra. Group 2: n = 10 killed after 8 weeks 2.1.: control stent in proximal urethra. 2.2.: drug stent in distal urethra.	Group 1: retrograde urethrography after sacrifice to evaluate percentage diameter of stenosis Group 2: retrograde urethrography at 4 weeks and 8 weeks before sacrifice. The sectioned tissue samples were stained with H&E: number of epithelial layers, thickness of granulation tissue, thickness of the papillary projection, and degree of submucosal inflammatory cell infiltra tion	Strong tendency toward a lower percentage diameter of stenosis and numeric mean values of the four histological findings, which indicates less formation of tissue hyperplasia in the proximal urethra than in the distal urethra. Thickness of the papillary projection was significantly less in drug stents than in control stents in the proximal urethra in the 8-week group (P = 0.016)	The effective dose of PTX was not quantified to suppress the tissue response secondary to inserted stents. Retrograde urethrography results could be intrinsically inaccurate.
Wang et al., 2011 [36]	34 male New Zealand White rabbits with urethral strictures 4 male New Zealand White rabbits, without urethral strictures and stents	Urethra	Group 1: n = 17, control stents and strictures. Group 2: n = 17, drug PTX-stents and strictures Group 3: n = 4, without urethral strictures and stents	Changes in the stent and the urethral stent-area: examined with paediatric urethroscope at 4, 8, and 12 weeks after stent implantation. 12 weeks: Retrograde urethrography to assess the urethral lumen. Urodynamics: bladder capacity and urethral pressure. Histological analysis: H&E. Biological changes were assessed for DES and compared to control stent groups.	Retrograde urethrography and urodynamic results at 12 weeks showed no comparable differences among the three groups Urethroscopic and histological follow-up indicated that the drug stents had minimised the stent-related inflammatory responses, urothelial hyperplasia, and scar formation compared with the drug-free stents	Not named

CFU: colony-forming units; EDS: energy dispersive spectroscopy; FTIR: Fourier transform infrared; H&E: haematoxylin and eosin; HF: halofungione; HPLC: high-performance liquid chromatography; KL: ketorolac; Micro-IR: micro-infrared spectrophotometry; MT: Masson’s trichrome; NFCS: nanofibre-covered stent; PLA: poly-96 L/4D-lactic acid; PLGA: poly(lactic- co-glycolic acid; PTX: paclitaxel; RIP: RNAIII-inhibiting peptide; (FE)SEM: (field-emission) scanning electron microscopy; SSD: silver sulfadiazine; VAS: visual analogue scale.

Table 4. Comparison of the clinical trials (in vivo) of DCBs

Reference	Subjects	Site	Intervention	Method study	Results	Limitations
Barbalias et al., 2017 [3]	11 rabbits	Urethra	A. n = 2, balloon dilatation without PTX B. n = 3, PTX-coated balloon dilatation, urethra removed immediately C.n = 3, PTX-coated balloon dilatation, urethra removed after 24 h D.n = 3, PTX-coated balloon dilatation, urethra removed after 48 h	H&E and immunohistochemistry with polyclonal anti‐PTX antibody in posterior urethra	Existence of ruptures across the urethras of all the rabbits. A. No PTX, no inflammation B. PTX distributing in all layers, no inflammation C. PTX distributing in all layers, mild acute inflammation D. PTX distributing in all lauers, mild acute inflammation	The use of PTX-coated balloons is designed for the treatment of vascular diseases. The distribution of PTX was only evaluated in the posterior urethra, which is different from anterior urethra.
Liourdi et al., 2014 [33]	9 domestic pigs	Ureter	Right ureter of each pig: PTX-eluting balloon dilatation Left ureter of each pig: conventional balloon dilatation Ureter removal: Immediately After 12 h After 24 h	A, B, C: 2 samples from each ureter. 1 sample: investigated by nuclear magnetic resonance spectroscopy. 1 sample: histology and immunohistochemistry using a specific for PTX polyclonal antibody.	Groups B and C: reduced inflammation compared to controls. PTX present in urothelial, submucosal and muscle layer. Concentration of the PTX C < B Group A: PTX present in urothelium and submucosal layer.	Short period of investigation (24 h) Did not evaluate the distribution and effect of PTX in the case of ureteric stricture. The use of DCB is designed for vascular applications.

H&E: haematoxylin and eosin; PTX: paclitaxel.

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