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Ureteral Reimplantation

Ureteral reimplantation (ureteroneocystostomy) restores continuity between the ureter and bladder. The reconstructive target is a tension-free, well-vascularized, spatulated, watertight, stented ureterovesical anastomosis; when reflux prevention matters, the operation also needs an adequate detrusor/submucosal tunnel to create a flap-valve mechanism.[1][2][3]

The operation serves two overlapping worlds:

  • Pediatric antireflux / megaureter surgery — vesicoureteral reflux (VUR), primary obstructive megaureter (POM), duplex systems, ureterocele-associated reflux or obstruction, and failed endoscopic injection.[1][3][4]
  • Adult distal ureteral reconstruction — iatrogenic injury, distal ureteral stricture, endometriosis, radiation injury, retroperitoneal fibrosis, distal ureterectomy for urothelial carcinoma, and congenital distal anomalies presenting in adulthood.[2][5][6]

For cross-cutting upper-tract reconstruction principles, see Upper Tract Reconstruction Principles. For adult stricture workup and the reconstruction ladder, see Ureteral Stricture. For longer defects, see Boari Flap & Psoas Hitch.

Indications​

Pediatric​

Common pediatric indications include:

  • VUR with breakthrough febrile UTI on prophylaxis, high-grade reflux, progressive renal scarring, declining function, persistent reflux after observation/endoscopic therapy, or family preference for definitive correction.[1][3][4]
  • Primary obstructive megaureter when surveillance fails because of recurrent UTI, worsening hydronephrosis, declining split function, pain, stones, or progressive ureteral dilation.[7][8]
  • Duplex systems, ectopic ureters, ureteroceles, and refluxing or obstructing ureteral limbs when reconstruction preserves the renal unit.
  • Failed endoscopic injection therapy, especially with persistent high-grade reflux or recurrent febrile UTI.[3][9]

Adult​

Adult reimplantation is usually reconstructive rather than antireflux-driven. Indications include:

  • Iatrogenic distal ureteral injury during gynecologic, colorectal, urologic, vascular, or pelvic oncologic surgery.[5][10]
  • Distal ureteral stricture from prior surgery, stones, radiation, endometriosis, retroperitoneal fibrosis, ischemia, or chronic inflammation.[2][6]
  • Distal ureterectomy for selected distal ureteral urothelial carcinoma when oncologic margins and bladder preservation are appropriate.
  • Transplant ureteral complications and selected congenital distal ureteral anomalies persisting into adulthood.[2]

Core Principles​

Every durable reimplantation follows the same rules:[2][5][10]

  1. Reach without tension. If the ureter cannot reach the bladder comfortably, mobilize the bladder, add a psoas hitch, or escalate to a Boari flap.
  2. Preserve ureteral blood supply. Keep periureteral adventitia and longitudinal vessels intact; avoid skeletonizing the distal ureter.
  3. Debride to healthy ureter. Ischemic, radiated, scarred, or devitalized distal ureter should not be sewn into the bladder.
  4. Spatulate the ureter. A wide mucosa-to-mucosa anastomosis reduces the risk of secondary ureterovesical junction obstruction.
  5. Stent the repair. Most adult reconstructions and many pediatric reimplants are supported with a double-J or externalized stent during early healing.
  6. Use absorbable suture. Fine 4-0 to 6-0 absorbable suture is typical, scaled to patient size and tissue quality.
  7. Create a tunnel when reflux matters. A tunnel-to-ureter diameter ratio of roughly 4-5:1 is the classic antireflux target.
  8. Drain and protect the field. Leave a catheter and, for adult/open/robotic injury reconstructions, a closed suction drain near the repair.

The pediatric operation is usually judged by reflux resolution and preservation of bladder function. The adult operation is judged by ureteral patency, renal preservation, leak avoidance, and durability in hostile tissue.

Technique Selection​

SituationPreferred TechniqueKey Trade-off
Pediatric unilateral VURLich-Gregoir, Cohen, or Politano-LeadbetterExtravesical is less painful; intravesical is familiar and versatile
Pediatric bilateral VURCohen or selected bilateral Lich-GregoirCohen avoids urinary retention concern; Lich-Gregoir reduces cystotomy morbidity in selected hands
Primary obstructive megaureterReimplantation with or without taperingTailoring adds ischemic risk but may be needed for very dilated ureters
Adult short distal ureteral lossDirect ureteroneocystostomyRefluxing adult reimplant is often acceptable if bladder is low pressure
Adult distal/mid defect under tensionPsoas hitch +/- reimplantMobilizes bladder to ureter; avoid genitofemoral nerve injury
Longer mid/proximal defectBoari flap +/- psoas hitchUses bladder flap length; requires adequate capacity and tissue quality
Marginal ischemic distal ureterNon-transecting or adventitia-preserving reimplantPreserves vascular reserve when complete transection is risky
Bladder unavailable or frozen pelvisTransureteroureterostomy, ileal ureter, autotransplantationSalvage options with higher complexity

Intravesical Reimplantation​

Intravesical operations open the bladder, mobilize the ureteral orifice from within, and create a submucosal tunnel. They are especially familiar in pediatric VUR and duplex-system surgery.[1][11]

Cohen cross-trigonal​

The Cohen technique creates a cross-trigonal submucosal tunnel from the native ureteral orifice toward the contralateral bladder wall. The ureter is advanced through the tunnel and matured at the new hiatus.[11][12]

Strengths

  • high reflux-resolution rate,
  • well-established worldwide,
  • works well for bilateral VUR,
  • avoids creating a new extravesical hiatus.

Limitations

  • future retrograde ureteral access can be difficult because the ureteral orifice is relocated across the trigone,
  • cystotomy increases bladder spasm, hematuria, catheter time, and postoperative discomfort compared with extravesical approaches,
  • not ideal when preserving orthotopic ureteral access is important.[12][13][14]

Politano-Leadbetter​

Politano-Leadbetter reimplantation creates a new superolateral bladder hiatus and tunnels the ureter submucosally toward a trigonal orifice position. It preserves a more natural ureteral trajectory and facilitates future retrograde access compared with Cohen.[11][15]

Its main penalty is obstruction risk at the new hiatus or tunnel, particularly if the ureter kinks, the tunnel is tight, or the ureter is over-mobilized.[11][15]

Glenn-Anderson​

Glenn-Anderson advances the ureter distally along the trigone, maintaining a more orthotopic ureteral course. It is less common than Cohen or Politano-Leadbetter but remains relevant in POM and pneumovesicoscopic variants, where preserving a natural course and limiting kinking are valuable.[16]

Extravesical Reimplantation​

Lich-Gregoir​

The Lich-Gregoir technique is the workhorse extravesical reimplant. The detrusor is opened longitudinally down to intact bladder mucosa, the ureter is anastomosed to a small mucosal opening, and the detrusor is closed over the ureter to create an antireflux tunnel.[13][17]

Step sequence

  1. Mobilize the distal ureter with periureteral adventitia intact.
  2. Spatulate the ureter.
  3. Mobilize the bladder enough to eliminate tension; add psoas hitch if needed.
  4. Incise detrusor for a 4-5:1 tunnel length while preserving mucosa.
  5. Open bladder mucosa at the distal end of the trough.
  6. Perform mucosa-to-mucosa ureterovesical anastomosis.
  7. Place a stent.
  8. Close the detrusor over the ureter without compression.

Advantages

  • avoids cystotomy,
  • shorter operative time and catheterization in many series,
  • less hematuria, bladder spasm, and postoperative pain than intravesical repair,
  • well-suited to robotic adult distal reconstruction and pediatric unilateral VUR.[12][13][14]

Limitations

  • bilateral extravesical dissection can transiently impair bladder emptying through disruption of periureteral pelvic plexus fibers,
  • tunnel length may be limited in small bladders,
  • care is needed to avoid closing the detrusor too tightly over a large or tapered ureter.[12][18]

A 2026 meta-analysis comparing Cohen and Lich-Gregoir in pediatric VUR found shorter operative time, shorter hospitalization, and lower bladder-spasm and hematuria signals with Lich-Gregoir, with no clear difference in persistent VUR or UTI.[12] A randomized pediatric comparison of Lich-Gregoir versus Politano-Leadbetter similarly found excellent reflux resolution with less postoperative discomfort after Lich-Gregoir.[13]

Adult Distal Reconstruction​

Adult reimplantation is often performed for injury or stricture rather than reflux, so the most important technical question is whether the ureter reaches the bladder without tension.[2][5][10]

Direct ureteroneocystostomy​

Direct reimplant is appropriate when the distal ureteral defect is short and the bladder dome can reach the ureter after mobilization. In low-pressure adult bladders, a refluxing reimplant can be acceptable; nonrefluxing Lich-Gregoir is preferred when feasible, especially in children, high-risk renal units, or higher-pressure bladders.[2][10]

Psoas hitch​

When direct reimplant is under tension, the bladder is mobilized and fixed to the ipsilateral psoas tendon, bringing the bladder to the ureter rather than pulling the ureter to the bladder.[2][19]

Key points:

  • place fixation sutures caudal/medial enough to avoid the genitofemoral nerve on the psoas,
  • confirm bladder capacity is adequate,
  • reimplant into the mobilized bladder dome without tension,
  • avoid in severely contracted bladder, hostile frozen pelvis, or neurogenic high-pressure bladder unless the bladder problem is addressed.[2][19]

Boari flap​

If psoas hitch is insufficient, a wide-based full-thickness bladder flap is raised, rotated cranially, and tubularized to bridge a longer ureteral gap. It is often combined with a psoas hitch and can reach the mid or even upper ureter in selected patients with adequate bladder capacity.[20][21][22]

Radiation injury, prior pelvic surgery, and reduced bladder capacity are the key constraints. Postoperative lower urinary tract symptoms can occur, particularly in women after large flap reconstruction, but are often medically manageable.[21]

Transureteroureterostomy​

Transureteroureterostomy is a second-line option when the ipsilateral bladder cannot be used and the contralateral ureter is healthy. It should be used selectively because it places the contralateral renal unit at risk.[10]

Minimally Invasive and Robotic Reimplantation​

Robot-assisted ureteral reimplantation (RALUR) most commonly uses an extravesical Lich-Gregoir-style repair in children and adults. Its value is suturing precision, shorter recovery, and easier bladder mobilization for psoas hitch or Boari flap compared with conventional laparoscopy.[6][18][23]

Pediatric RALUR​

A 2026 pediatric systematic review and meta-analysis found similar success and complication rates for robotic and open ureteral reimplantation, with shorter hospital stay and lower analgesic use after RALUR but longer operative time.[23] Earlier multi-institutional pediatric data also show high overall success for minimally invasive reimplantation, with robotic approaches comparing favorably to pure laparoscopy for operative time and complications.[24]

Learning curve remains real. Contemporary pediatric series using CUSUM methods suggest competence and efficiency improve after early case accumulation, with operative times falling as teams standardize port placement, detrusorotomy length, top-down closure, and stent strategy.[25]

Adult robotic reimplantation​

Adult robotic reimplantation has become a major option for benign distal strictures and iatrogenic injuries. Multicenter and comparative series show shorter length of stay, lower blood loss, shorter catheterization, and comparable complications versus open repair.[6][26] Robotic psoas hitch and Boari flap extend the same benefits to longer defects when bladder capacity and tissue quality permit.[20]

Pneumovesicoscopic reimplantation​

Pneumovesicoscopic reimplantation places ports directly into the bladder and performs a Cohen, Politano-Leadbetter, or modified Glenn-Anderson repair under CO2 cystoscopy. It reduces incision morbidity but is technically demanding, takes longer early in experience, and is limited by small bladder working space.[16][27]

Endoscopic Injection for VUR​

Endoscopic injection is not ureteral reimplantation, but it is part of the same VUR treatment ladder. Dextranomer/hyaluronic acid copolymer (Deflux) is injected beneath or within the ureteral tunnel to coapt the ureteral orifice.[28][29]

TechniqueConceptBest Use
STINGSubureteric injection below the orificeLower-grade reflux, straightforward anatomy
HITIntraureteral injection under hydrodistentionHigher-grade reflux, coaptation of the distal tunnel

AUA guideline summaries report lower single-procedure success than open reimplantation, but injection avoids hospitalization and can be repeated.[3] Success is grade-dependent and reduced by bladder-bowel dysfunction, while open reimplantation remains highly successful even in the presence of bladder-bowel dysfunction.[3][28][29]

Cochrane review data do not show endoscopic injection to be clearly superior to antibiotic prophylaxis for preventing febrile UTI or renal scarring, so it should be framed as a minimally invasive reflux-correction option rather than a proven renal-scar-prevention strategy.[30]

Primary Obstructive Megaureter​

Primary obstructive megaureter is often observed, but surgery is indicated when obstruction declares itself clinically or functionally.[7][8]

Operative choices:

  • Reimplant without tapering when the ureteral diameter is modest and a nonobstructing tunnel can be created.
  • Excisional tapering when the ureter is too large to tunnel safely without obstruction.
  • Plication tapering when preserving blood supply is prioritized.
  • Temporary refluxing ureterovesicostomy in selected infants or small bladders where definitive reimplantation would be disproportionate.[31][32][33]

Tailoring is not benign: it adds dissection, ischemic risk, and obstruction risk. In a pediatric complication analysis, ureteral tapering, obstructing megaureter, duplex anatomy, and refractory voiding dysfunction were associated with higher complication rates.[34]

Complications​

Most complications are minor, but the operation has a few predictable failure modes.[15][34][35][36]

ComplicationPattern
Postoperative hydronephrosisCommon early; usually transient, especially after high-grade reflux or megaureter repair
Febrile UTIMost common in the first postoperative year; risk increases with bladder-bowel dysfunction and residual obstruction
Secondary ureterovesical junction obstructionMore concerning after tight tunnels, Politano-Leadbetter hiatus, tapering, ischemic ureter, or robotic learning-curve cases
Persistent or recurrent VURUsually low-frequency after open repair; higher in early robotic or endoscopic series
Urinary retentionClassic concern after bilateral extravesical dissection
Bladder spasms and hematuriaMore common after intravesical/cystotomy approaches
Contralateral de novo VURUsually low-grade and often transient
Leak or urinomaSuggests anastomotic tension, devascularization, distal obstruction, or stent malfunction

Early ultrasound is often abnormal. Postoperative hydronephrosis should be interpreted with symptoms, febrile UTI, renal function, and interval trend rather than treated as automatic failure.[35]

Follow-up​

Routine follow-up usually includes renal/bladder ultrasound after catheter or stent removal, with VCUG or nuclear imaging reserved for recurrent febrile UTI, worsening hydronephrosis, concerning renal function, or institutional pediatric protocols.[3][15]

Long-term pediatric data suggest that children with an uncomplicated first year and no obstruction have very low late technical-failure risk. Extended surveillance is more important after Politano-Leadbetter repair, POM, reflux nephropathy, recurrent UTI, voiding dysfunction, solitary kidney, or complex adult reconstruction.[15][37]

Operative Pearls​

  • Reach beats force. If the ureter barely reaches, add a psoas hitch or Boari flap.
  • Do not skeletonize the ureter. Adventitial blood supply is the repair's margin of safety.
  • Tunnel size matters. Too short refluxes; too tight obstructs.
  • Bilateral extravesical repair needs bladder-emptying respect. Preserve periureteral nerves and counsel about transient retention.
  • Adult refluxing reimplant is sometimes acceptable. Patency and tension-free healing may matter more than a perfect tunnel in a low-pressure adult bladder.
  • Megaureter tapering should be deliberate. Tailor only when the ureter is too large for a safe nonobstructing tunnel.
  • A hostile bladder changes the ladder. Radiation, small capacity, neurogenic high pressure, or frozen pelvis may push the surgeon toward augmentation, bowel substitution, TUU, or autotransplantation.

References​

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2. White C, Stifelman M. Ureteral reimplantation, psoas hitch, and Boari flap. J Endourol. 2020;34(S1):S25-S30. doi:10.1089/end.2018.0750

3. Peters CA, Skoog SJ, Arant BS Jr, et al. Summary of the AUA guideline on management of primary vesicoureteral reflux in children. J Urol. 2010;184(3):1134-1144. doi:10.1016/j.juro.2010.05.065

4. Montini G, Tullus K, Hewitt I. Febrile urinary tract infections in children. N Engl J Med. 2011;365(3):239-250. doi:10.1056/NEJMra1007755

5. de'Angelis N, Schena CA, Marchegiani F, et al. 2023 WSES guidelines for the prevention, detection, and management of iatrogenic urinary tract injuries during emergency digestive surgery. World J Emerg Surg. 2023;18(1):45. doi:10.1186/s13017-023-00513-8

6. Ziewers S, Dotzauer R, Thomas A, et al. Robotic-assisted vs. open ureteral reimplantation: a multicentre comparison. World J Urol. 2024;42(1):194. doi:10.1007/s00345-024-04875-9

7. Lopez M, Perez-Etchepare E, Bustangi N, et al. Laparoscopic extravesical reimplantation in children with primary obstructive megaureter. J Laparoendosc Adv Surg Tech A. 2023;33(7):713-718. doi:10.1089/lap.2019.0396

8. Rivetti G, Marzuillo P, Guarino S, et al. Primary non-refluxing megaureter: natural history, follow-up and treatment. Eur J Pediatr. 2024;183(5):2029-2036. doi:10.1007/s00431-024-05494-7

9. Kirsch AJ, Cooper CS, Lackgren G. Non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx, Deflux) for endoscopic treatment of vesicoureteral reflux: what have we learned over the last 20 years? Urology. 2021;157:15-28. doi:10.1016/j.urology.2021.07.032

10. Drain A, Jun MS, Zhao LC. Robotic ureteral reconstruction. Urol Clin North Am. 2021;48(1):91-101. doi:10.1016/j.ucl.2020.09.001

11. Burbige KA. Ureteral reimplantation: a comparison of results with the cross-trigonal and Politano-Leadbetter techniques in 120 patients. J Urol. 1991;146(5):1352-1353. doi:10.1016/S0022-5347(17)38090-4

12. Wang M, Xi Y, Huang N, Zhang L, Liu J. Comparative efficacy and safety of Cohen versus Lich-Gregoir ureteral reimplantation in pediatric vesicoureteral reflux: a systematic review and meta-analysis. PeerJ. 2026;14:e20636. doi:10.7717/peerj.20636

13. Schwentner C, Oswald J, Lunacek A, et al. Lich-Gregoir reimplantation causes less discomfort than Politano-Leadbetter technique: results of a prospective, randomized, pain scale-oriented study in a pediatric population. Eur Urol. 2006;49(2):388-395. doi:10.1016/j.eururo.2005.11.015

14. Fujii T, Satoh H, Sato A, et al. Lich-Gregoir vs. Cohen ureteral re-implantation surgery for bilateral vesicoureteral reflux: a propensity score analysis. Pediatr Int. 2025;67(1):e70010. doi:10.1111/ped.70010

15. Gerwinn T, Zellner M, Prouza A, et al. Long-term follow-up after ureteral reimplantation in children: a 12-year analysis. Pediatr Surg Int. 2025;41(1):95. doi:10.1007/s00383-025-05992-1

16. Pan H, Wang R, Jiang M, et al. Long-term efficacy and learning curves of Cohen and modified Glenn-Anderson pneumovesicoscopic ureteral reimplantation for primary obstructive megaureter: a retrospective cohort study with meta-analysis. Pediatr Surg Int. 2026;42(1):164. doi:10.1007/s00383-026-06404-8

17. Hudry D, El Hajj H, Narducci F, Leblanc E. Laparoscopic ureteral reimplantation applying the modified psoas hitch and Lich-Gregoir onlay technique: a 10-step surgical video. Int Urogynecol J. 2022;33(9):2577-2579. doi:10.1007/s00192-021-04990-w

18. Boysen WR, Ellison JS, Kim C, et al. Multi-institutional review of outcomes and complications of robot-assisted laparoscopic extravesical ureteral reimplantation for treatment of primary vesicoureteral reflux in children. J Urol. 2017;197(6):1555-1561. doi:10.1016/j.juro.2017.01.062

19. Riedmiller H, Becht E, Hertle L, Jacobi G, Hohenfellner R. Psoas-hitch ureteroneocystostomy: experience with 181 cases. Eur Urol. 1984;10(3):145-150. doi:10.1159/000463777

20. Dell'Oglio P, Palagonia E, Wisz P, et al. Robot-assisted Boari flap and psoas hitch ureteric reimplantation: technique insight and outcomes of a case series with at least 1 year of follow-up. BJU Int. 2021;128(5):625-633. doi:10.1111/bju.15421

21. Hardesty JK, Burns RT, Soyster ME, Jansen NE, Mellon M. Female bladder dysfunction following Boari bladder flap ureteral reconstruction. Urology. 2024;186:31-35. doi:10.1016/j.urology.2024.01.020

22. Andrade C, Narducci F, Bresson L, Leblanc E. Boari flap ureteroneocystostomy in an oncological patient. Gynecol Oncol. 2016;143(1):193. doi:10.1016/j.ygyno.2016.07.115

23. Gazzaneo M, Bosisio M, Mandarano G, Boroni G, Alberti D. Comparative outcomes of open and robotic ureteral reimplantation in children with vesicoureteral reflux: a systematic review and meta-analysis. J Pediatr Surg. 2026;61(3):162883. doi:10.1016/j.jpedsurg.2025.162883

24. Chertin L, Kocherov S, Bakaleyshchik P, et al. Laparoscopic and robot-assisted laparoscopic reimplantation for lower ureter pathology: a multi-institutional comparative study in 1343 patients. Urology. 2024;186:166-171. doi:10.1016/j.urology.2024.02.021

25. Shengkun S, Xin L, Xiaoming Y, et al. Mastering the learning curve with quality assurance: outcomes of robot-assisted ureteral reimplantation in a pediatric cohort. J Pediatr Surg. 2026;61(5):162941. doi:10.1016/j.jpedsurg.2026.162941

26. Carbonara U, Branche B, Cisu T, et al. Robot-assisted ureteral reimplantation: a single-center comparative study. J Endourol. 2021;35(10):1504-1511. doi:10.1089/end.2021.0083

27. Canon SJ, Jayanthi VR, Patel AS. Vesicoscopic cross-trigonal ureteral reimplantation: a minimally invasive option for repair of vesicoureteral reflux. J Urol. 2007;178(1):269-273. doi:10.1016/j.juro.2007.03.059

28. Escolino M, Kalfa N, Castagnetti M, et al. Endoscopic injection of bulking agents in pediatric vesicoureteral reflux: a narrative review of the literature. Pediatr Surg Int. 2023;39(1):133. doi:10.1007/s00383-023-05426-w

29. Puri P, Kutasy B, Colhoun E, Hunziker M. Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux. J Urol. 2012;188(4 Suppl):1485-1489. doi:10.1016/j.juro.2012.02.023

30. Williams G, Hodson EM, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev. 2019;2:CD001532. doi:10.1002/14651858.CD001532.pub5

31. DeFoor W, Minevich E, Reddy P, et al. Results of tapered ureteral reimplantation for primary megaureter: extravesical versus intravesical approach. J Urol. 2004;172(4 Pt 2):1640-1643. doi:10.1097/01.ju.0000138529.43179.dd

32. Khondker A, Rickard M, Kim JK, et al. Should a refluxing internal diversion be considered a temporizing procedure? Extended follow-up and outcomes after side-to-side ureterovesicostomy for primary obstructive megaureter in young children. J Urol. 2024;212(1):196-204. doi:10.1097/JU.0000000000003966

33. Mittal S, Srinivasan A, Bowen D, et al. Utilization of robot-assisted surgery for the treatment of primary obstructed megaureters in children. Urology. 2021;149:216-221. doi:10.1016/j.urology.2020.10.015

34. Suer E, Ozcan C, Mermerkaya M, et al. Can factors affecting complication rates for ureteric re-implantation be predicted? Use of the modified Clavien classification system in a paediatric population. BJU Int. 2014;114(4):595-600. doi:10.1111/bju.12746

35. Babajide R, Andolfi C, Kanabolo D, Wackerbarth J, Gundeti MS. Postoperative hydronephrosis following ureteral reimplantation: clinical significance and importance of surgical technique and experience. J Pediatr Surg. 2023;58(3):574-579. doi:10.1016/j.jpedsurg.2022.07.002

36. Neeman BB, Kocherov S, Jaber J, et al. Long term results of non-refluxing ureteral reimplantation in the pediatric population. Pediatr Surg Int. 2023;39(1):173. doi:10.1007/s00383-023-05466-2

37. Diamond DA, Chan IHY, Holland AJA, et al. Advances in paediatric urology. Lancet. 2017;390(10099):1061-1071. doi:10.1016/S0140-6736(17)32282-1