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92 Upper Tract Obstruction
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Figure 7.9 Unpredictable natural history of PUJ obstruction. (a) An ultrasound at 1 month of
age. Appearances suggestive of PUJ obstruction, good renal cortex, AP diameter of renal pelvis (not shown) 18 mm. Conservative management was adopted. (b) Follow-up MAG study at
36 months showing type 3b O’Reilly curve (equivocal). Conservative management was maintained.
(c) Ultrasound at 4 years of age. Complete resolution of dilatation, normal appearances of kidney. The
child was discharged from further follow-up. (d) At 9 years of age he represented acutely with pain
and infection. This ultrasound scan demonstrates severe dilatation due to recurrent PUJ obstruction.
Pyeloplasty was curative.
Urinary tract infection used to be the
commonest mode of presentation in infants
and young children before the advent of prenatal ultrasound. In severe cases, infection
within the obstructed system may progress to
pyonephrosis – a serious condition characterised by high fever, systemic ill health, and ultrasound ndings of debris within the collecting
system.
Pain is typically encountered as a presenting feature of PUJ obstruction due to aberrant
crossing vessels in older children. Although
usually sited in the region of the loin, the pain
may be more generalised within the abdomen,
giving rise to possible diagnostic diculties.
Unlike non-specic abdominal pain, however,
pain arising in the obstructed kidney usually
persists for many hours or several days.
Presentation / Conservative versus Surgical Management 93
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Haematuria may occur spontaneously,
but is more commonly associated with minor
trauma – to which obstructed kidneys are more
susceptible. A grossly dilated kidney can sometimes present as an abdominal mass mimicking
a Wilm’s tumour. e distinction can be readily
made with ultrasound, CT or MR imaging.
Occasionally, a dilated kidney comes to light
as an incidental nding – for example, on an
abdominal ultrasound performed for presumed
non-specic abdominal pain, a CT scan performed for abdominal trauma or MR imaging
for a spinal condition such as scoliosis.
Investigation
e diagnostic pathway has already been considered above. Typically, the sequence comprises
ultrasound followed by
renography. However, MRI is being increasingly
used a the principal imaging modality. Other
imaging modalities are only required in complicated cases: for example, to investigate secondary
PUJ obstruction in the presence of gross reux.
DMSA scintigraphy is used to assess dierential
function in poorly functioning obstructed kidneys to guide the decision on whether to perform
pyeloplasty or nephrectomy.
99m
Tc MAG3 dynamic
Management
Prenatally detected PUJ obstruction
e majority of infants are asymptomatic and
would have remained undiagnosed (at least in
infancy) if it had not been for the information
yielded by the antenatal ultrasound scan.
e indications for pyeloplasty in children with prenatally detected PUJ obstruction
remain controversial, although there is a broad
consensus in favour of conservative management if dierential function in the aected kidney is normal (dened as greater than 40%). e
ndings of early follow up studies reported from
Great Ormond Street Hospital, UK indicated
that when the initial AP diameter of the renal
pelvis was less than 20 mm, 11% of patients eventually required a pyeloplasty for deterioration in
function or symptoms. When the AP diameter
was 20–29 mm the pyeloplasty rate was 40% and
when the AP diameter was 30–39 mm the pyeloplasty rate was 90%. Pyeloplasty (for reduced
function or symptoms) was required in every
child (100%) in those in whom the AP diameter
exceeded 40 mm. Broadly comparable results for
conservative management have been reported
in other studies employing the system devised
by the Society for Fetal Urology for grading the
severity of prenatally detected hydronephrosis.
Fieen to twenty percent of infants have
bilateral dilatation. In these circumstances less
reliance can be attached to the renographic
assessment of dierential function and greater
weight must be attached to the severity of dilatation. In practice it is rare to encounter bilateral
obstruction of equal severity, and if surgery is
indicated it is usually reasonable to operate on
the more severely dilated kidney and monitor the
contralateral kidney. Only rarely is it necessary
to operate on both kidneys simultaneously or in
quick succession.
Conservative versus Surgical
Management
e published outcome data have been derived
almost entirely from observational studies and
there have been very few randomised controlled
trials of operative versus conservative management. e authors of a Cochrane review concluded (from the very limited trial data) that the
majority of newborns and infants under 2-years
of age who are managed conservatively do not
experience signicant deterioration in dierential function, with only 20% coming to early
pyeloplasty.
Incidentally detected PUJ
obstruction
Conservative management can be adopted initially if the PUJ obstruction has been identied as
an asymptomatic incidental nding and dierential function is 40% or higher. Ultrasound follow
up should be maintained until such time as the
dilatation shows signs of resolving. Worsening
hydronephrosis or the onset of symptoms are
indications to proceed to surgery.
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Infection (pyonephrosis)
Patients presenting with acute urosepsis are oen
very unwell with a high fever, tachycardia, a tender loin mass, and possible signs of haemodynamic instability. Initial management comprises
resuscitation, urine culture, and intravenous
antibiotics. Investigation comprises tests of renal
function and septic markers and urgent ultrasound imaging of the urinary tract. e presence
of debris in the collecting system is an indication
to proceed to surgical intervention to decompress
the obstructed kidney and drain the infected
material. Ultrasound guided percutaneous nephrostomy is the preferred way of achieving this in
children because it provides more rapid and eective drainage and is technically more straightforward than cystoscopic JJ stenting.
Once the condition has been stabilised, imaging is performed to conrm the diagnosis of
obstruction (e.g. by antegrade pyelography via the
nephrostomy catheter) and to assess dierential
function (e.g. by
information then permits a decision on whether
to advise pyeloplasty or nephrectomy.
99m
Tc DMSA scintigraphy). is
●
Asymptomatic obstruction and initial AP
diameter of the renal pelvis equal to or greater
than 30 mm
●
Failure of conservative management, i.e. deteriorating function or increasing dilatation
Surgical Procedures
Although, the Anderson-Hynes dismembered
pyeloplasty remains the most widely performed
procedure for the correction of PUJ obstruction
other options have also been described. ese
include balloon dilatation, endopyelotomy, and
the vascular hitch procedure (in cases due to
aberrant lower pole vessels). Primary ureterocalicostomy can yield good results in selected cases.
Anderson-Hynes dismembered
pyeloplasty
Regardless of whether this is performed by an
open or laparoscopic approach, the fundamentals
of the technique are the same (Figure 7.10).
Symptoms (pain)
Children who present with classical episodic
loin pain are almost invariably cured by surgical intervention. In the majority of cases, the
obstruction is due to aberrant crossing vessels
and the standard approach is to perform a pyeloplasty in which these vessels are transposed posteriorly to lie behind the anastomosis. However,
an alternative approach (laparoscopic vascular
hitch procedure) is being increasingly adopted.
e PUJ is preserved intact and aer the obstructing lower pole vessels have been mobilised from
the PUJ they are anchored at a higher position on
the anterior wall of the renal pelvis. e technical
aspects are described in Chapter 23.
In summary, the indications for pyeloplasty are:
●
Symptomatic PUJ obstruction, e.g. pain,
infection, palpable renal mass
●
Asymptomatic obstruction with reduced
function (generally interpreted less than 40%)
at the time of initial evaluation
Figure 7.10 Anderson-Hynes dismembered
pyeloplasty. The procedure of choice in children.
Presentation / Other Surgical Procedures 95
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Gentle tissue handling, minimal mobilisation of the ureter, protection of the ureteric blood
supply and creation of a widely patent, tensionfree, watertight anastomosis all contribute to a
successful outcome. Following excision of the
PUJ, the proximal ureter is incised for a short
length – ‘spatulated’. Depending on surgical preference some of the redundant renal pelvis can be
excised (reduction pyeloplasty) – although there
is little evidence that this promotes more eective
drainage postoperatively. Most paediatric urologists use interrupted sutures to begin the anastomosis between the spatulated ureter and renal
pelvis. To minimise the risk of stenosis it is advisable to perform the anastomosis over a tube even
if it is not intended to drain the kidney with an
indwelling tube postoperatively.
Although many dierent methods of postoperative drainage have been described, published
studies have mostly failed to demonstrate any
statistically signicant advantage of one over
another.
Currently, the most widely used forms of
postoperative drainage are either an indwelling JJ stent (with the drawback that this needs
removing cystoscopically under a further general
anaesthetic some 4–6 weeks postpyeloplasty) or
an externalised pyeloureteral stent (‘nephrostent’). is is, in eect, a JJ stent with an extension which crosses the renal pelvis, exits through
the parenchyma or renal pelvis and emerges from
the skin. Such stents can be easily removed without the need for a second anaesthetic, usually 1–2
weeks post-pyeloplasty. Some paediatric urologists prefer to avoid any form of transanastomotic stent, but rely instead on simple extrarenal
drainage.
Open pyeloplasty
Despite the increasing number of pyeloplasties
being performed by a laparoscopic or roboticassisted laparoscopic technique there is still a
very denite place for open surgery, particularly
in the rst few months of life. Depending on the
age of the child and the surgeon’s preference,
open pyeloplasty can be performed via either an
anterior, subcostal, extraperitoneal muscle splitting incision, or a muscle cutting loin incision.
e posterior lumbotomy approach provides
more direct access to the kidney and is well tolerated postoperatively. However, the more limited
access oered by this incision can create diculties if the surgeon is forced to deal with unexpected anatomical ndings or intraoperative
problems.
e minimally invasive open technique is a
modication of the open approach which utilises
a smaller skin incision. In infants under 1 year
of age an incision of 1–1.5 cm in length may be
adequate. e incision is then deepened through
underlying fascia and by manoeuvring the overlying skin incision the kidney can be exposed.
If necessary, two narrow blade retractors can
be used separate the edges of the skin incision.
Decompression of the renal pelvis by needle aspiration allows the PUJ to be delivered out of the
incision to enable the surgeon to perform the
anastomosis. When used selectively this technique can oer a high success rate with a very
short (<24 hours) hospital stay.
Laparoscopic and robotic-assisted
laparoscopic pyeloplasty
e technical aspects of minimally invasive procedures and their relative advantages and drawbacks are considered in detail in Chapter 23.
In a recent survey, 50% of paediatric urologists
stated their preference for a minimally invasive
approach in children aged 2 years and upwards.
Robotic-assisted laparoscopically pyeloplasty
(RALP) oers a number of advantages over conventional laparoscopic pyeloplasty (LP) and has shorter
learning curve. However, costs are higher for RALP.
Other Surgical Procedures
Laparoscopic transposition of
crossing lower pole vessels
e technical aspects of the vascular hitch procedure are described in Chapter 23.
Endourological interventions
e use of balloon dilatation and endopyelotomy
have both been reported children but the results
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are inferior to pyeloplasty. Nevertheless, there
may be a very occasional role for antegrade or retrograde endopyelotomy in cases of failed pyeloplasty in older children due to a short (<10 mm)
stricture at the PUJ.
Ureterocalicostomy (Figure 7.11)
In this procedure, the ureter is detached from the
renal pelvis and anastomosed directly to the most
dependent lower pole calyx. Ureterocalicostomy is
only appropriate in cases with severe caliceal dilatation and cortical thinning. Although rarely indicated as a primary procedure, ureterocalicostomy
may provide more eective drainage than pyeloplasty in cases of recurrent PUJ obstruction or PUJ
obstruction occurring in a horseshoe kidney.
Pyeloplasty in duplex kidney
PUJ obstruction in a duplex kidney almost invariably aects the lower pole. It is usually caused by
stenosis at the point where the lower pole pelvis
joins the ureter descending from the upper pole.
e anastomosis is performed using a modied ‘sh mouth’ technique to minimise the risk
of obstruction to drainage from the upper pole.
When the obstruction is caused by aberrant crossing vessels the surgical technique is determined
by the individual operative ndings.
Nephrectomy
When deciding whether to advise pyeloplasty or
nephrectomy, most paediatric urologists apply an
arbitrary ‘cut o’ value for dierential function in
the range of 10–15%.
99m
Tc DMSA scintigraphy is
the most reliable method for obtaining an accurate measure of dierential function in these circumstances. To assess the potential for recovery
of function a period of temporary percutaneous
nephrostomy drainage or JJ stent insertion may
be helpful in borderline cases.
Complications of Dismembered
Pyeloplasty
Figure 7.11 Ureterocalicostomy. The ureter
is disconnected from the renal pelvis and the
pelviureteric junction closed. The ureter is then
anastomosed directly to the lower pole calyx.
●
Wound infection
●
Urinary infection
●
Haematoma
●
Stent related problems
●
Urine leak
●
Urinoma formation
●
Recurrent obstruction
e majority of paediatric urologists in the
United Kingdom employ some form of intrarenal postoperative drainage in the belief that it
reduces the risk of complications. Nevertheless,
early postoperative complications of some type
occur in 5%-10% of cases.
Follow-Up and Surgical Outcomes
Postoperative follow up relies mainly on ultrasound. If this clearly demonstrates that the dilatation is resolving (or reduced in severity) it can
be reasonably assumed that the operation has
successfully relieved the PUJ obstruction and
it is not necessary to conrm this with a
MAG3 renogram. However, this investigation is
99m
Tc
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advisable if ultrasound demonstrates persisting
dilatation with no discernable reduction in its
severity. Nevertheless, it may be a considerable
time before renogram drainage curves revert to
normal in kidneys which were grossly dilated
before pyeloplasty. Dismembered pyeloplasty is
a good operation, with a long-term success rate
of >95%. Most failed procedures are diagnosed
within 3 years of surgery and redo pyeloplasty,
open or minimally invasive, has a high success
rate (8 0–10 0%).
VESICOURETERIC JUNCTION
OBSTRUCTION
Ureteric dilatation (megaureter) is classied as
follows:
●
Obstructed megaureter: e obstruction
is usually intrinsic with either stenosis or
an adynamic segment of distal ureter at the
VUJ (Figure 7.12). Secondary causes include:
tumour, scarring and brosis, neuropathic
bladder, or bladder outow obstruction.
Most cases are due to primary obstruction
at the VUJ, and hence the synonym ‘VUJ
obstruction’.
●
Non-reuxing, non-obstructed megaureter:
e aetiology of such cases is oen unclear
but it is thought that many represent the
legacy of ‘burnt-out’ VUJ obstruction, in
which the original obstruction has resolved,
leaving residual dilatation.
●
Reuxing megaureter: Occasionally obstruction and reux co-exist simultaneously
within the same ureter.
Aetiology of Primary VUJ Obstruction
is is characterised by a marked discrepancy
between the diameter of the terminal segment
of the distal ureter and the dilated, oen tortuous, length of ureter above it. Although a
narrowed stenotic segment can be identied in
some cases, in others the distal ureter is relatively normal in calibre and only appears narrow by comparison with the dilated ureter.
In such cases the obstruction is thought to be
functional in aetiology, with failure of normal
coordinated urine transport across the distal
ureter and vesico ureteric junction. Histological
studies have demonstrated a range of abnormalities including a reduction in interstitial cells of
Cajal (thought to be important for normal ureteric peristalsis), smooth muscle hypertrophy,
and collagen deposition.
Clinical Presentation
Figure 7.12 Obstructed megaureter. The ureter
has been mobilised and divided at the level of
the bladder. Dilatation of the ureter proximal to
a short stenotic segment at the vesicoureteric
junction.
Most cases of primary obstructed megaureter
are now detected prenatally. Data derived from
routine prenatal ultrasound screening point
to an incidence of 1:1500–1:2000. Megaureter
occurs more frequently in males, the le side
is more commonly aected than the right and
25% of cases have bilateral involvement. Infants
with prenatally detected primary megaureter are
almost invariably asymptomatic. However, the
condition is not always detected prenatally and
some children still present clinically with symptoms of urinary infection, loin pain, haematuria,
failure to thrive, an abdominal mass, or associated urolithiasis. VUJ obstruction can also present occasionally with intermittent loin pain, in a
manner similar to intermittent PUJ obstruction
(Fi g ure 7.13).
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Investigation
Ultrasound cannot distinguish between dilatation due to obstruction and dilatation associated
with the higher grades of VUR. For this reason
an MCUG is an essential investigation in the
assessment of children with megaureter.
Once reux has been excluded an isotope
renogram is then required to quantify dierential function and to assess drainage. However,
it is important to be aware that drainage curves
Figure 7.13 (a) Intravenous urogram in a
12-year-old girl with a long history of intermittent abdominal pain diagnosed as ‘abdominal
migraine’. Ultrasound (not shown) and IVU
performed between episodes of pain were consistent with non-obstructive dilatation. (b) MAG3
renogram shows good preservation of function.
The ndings were interpreted as non-obstructive
dilatation consistent with ‘burnt out’ obstructed
megaureter. (c) However, an ultrasound scan
performed acutely during an episode of pain
demonstrated a dramatic increase in the severity
of caliceal dilatation. Diagnosis: intermittent VUJ
obstruction. Her symptoms resolved completely
following surgery.
may be dicult to interpret because clearance
of isotope from a capacious, grossly dilated
upper tract is oen delayed even in the absence
of obstruction. Moreover, closer scrutiny of
the ‘hard copy’ images oen demonstrates that
although isotope has drained from the kidney
(interpreted as non-obstruction) it has simply
emptied into the capacious ureter rather than
draining into the bladder. In clinical practice,
the diagnosis of signicant obstruction oen
Vesicoureteric junction obstruction / Surgical Procedures 99
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has to rely on information on dierential function and ultrasound assessment of changes in
the severity of dilatation- in addition to drainage curve data.
Management of Prenatally Detected
Obstructed Megaureter
e majority of infants with prenatally detected
VUJ obstruction are healthy and asymptomatic
at birth. Early surgical intervention (because
of reduced dierential function) is required in
around 10% of cases and a further 10–20% of
children will eventually require surgery for the
indications outlined below. Conservative management has a long-term success rate of 70–80%.
Indications for surgical intervention:
●
Impaired dierential function (<40%) on
initial assessment
●
Increasing dilatation and/or deterioration of
dierential function on follow up
●
Occurrence of symptoms (typically febrile
urinary infection)
e severity of dilatation on initial assessment is
a reasonable predictor of the likely success or failure of conservative management with a ureteric
diameter ≥14 mm indicating an increased risk of
surgery being required during the course of follow up.
Urinary infection of mild to moderate severity is not an automatic indication for surgery if
other parameters (dierential function, ureteric
diameter 1 cm or less) are favourable. A period
of antibiotic prophylaxis and trial of conservative treatment are appropriate in such cases, but
surgery is indicated in the event of recurrent or
severe infection.
Stone formation associated with stasis in
a dilated but non obstructed ureter has been
reported to occur as late complication of otherwise – successful conservative management.
Surgical Procedures
e denitive treatment of VUJ obstruction consists of excising the distal ureteric segment and
reimplanting the ureter into the bladder. JJ stenting and endoscopic balloon dilatation have also
been reported as temporising (or even denitive)
alternatives to reimplantation.
Most paediatric urologists prefer to avoid
reimplantation of megaureters in the rst year of
life because of the disparity in size of the dilated
ureter and the small capacity bladder. Moreover,
there is strong anecdotal evidence that this type
of surgery in small infants carries some risk of
later neurogenic bladder dysfunction due to damage to pelvic innervation sustained during dissection in the vicinity of the bladder. Despite these
reservations, however, some paediatric urologists
have claimed good results and low complication
rates following reimplantation of megaureters in
the rst year of life.
Endourological interventions
e use of a JJ stents was initially described as
a temporising manoeuvre but it has since been
reported that a prolonged period (>6 months)
of indwelling stent drainage may be curative in
its own right. Success rates ranging from 26% to
66% have been reported. However, stent insertion by a purely endoscopic technique may not
be technically possible in a small infant and open
cystotomy may be required. A complication rate
of up to 70% has been reported, including; urinary infection, stent migration, and deterioration
in function – leading in some cases to nephrectomy. Higher success rates of 70–100% have been
claimed when JJ stenting is combined with high
pressure balloon dilatation or use of ureteroscopic endoureterotomy.
Temporary urinary tract diversion
Historically, severe forms of obstructed megaureter in small infants were sometimes managed
by temporary cutaneous ureterostomy pending
denitive surgery at a later age. A novel alternative has recently been described, which consists
of a temporary internal diversion in which the
dilated ureter is divided proximal to the obstructing segment and an end to side anastomosis
is performed with the bladder – thus converting the obstructed megaureter into a reuxing
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megaureter. Denitive reconstruction is then
performed at around 1 year of age.
Excision of obstructing segment
and ureteric reimplantation
e standard open surgical technique consists of
excision of the obstructing ureteric segment and
intravesical reimplantation of the ureter into the
bladder in a way that ensures good upper tract
drainage without introducing VUR. Where the
dilatation is of mild to moderate severity this
may be achievable with a conventional Cohen
cross-trigonal tunnel technique. For more
severely dilated ureters, however, a PolitanoLeadbetter reimplantation is usually indicated.
is can be combined with reducing the diameter of the distal ureter using one of the techniques described below. A psoas hitch procedure
is advisable to prevent kinking and obstruction
at the entry point of the ureter into the bladder
(Fi g u re 7.14). More recently, a combination of
excision of the obstructing segment, remodelling
Figure 7.15 Method of ureteric plication using
the Starr technique.
and an extravesical antireux procedure has been
reported to yield excellent results.
Ureteric tailoring
is may be required to achieve an antireux
reimplantation in grossly dilated ureters. e
available techniques include:
●
Hendren excisional tapering
●
Kalicinski plication and folding
●
Starr ureteral imbrication (Fi g u r e 7.15)
Figure 7.14 The politano-leadbetter reimplanta-
tion procedure combined with psoas hitch, which
is often better suited to megaureters than the
Cohen cross-trigonal reimplantation technique.
Laparoscopic and robotic surgery
A number of dierent approaches are being
developed for the minimally invasive management of obstructed megaureter – including tailoring and dierent reimplantation techniques.
Satisfactory early results have been reported in
small series of patients but medium and longterm results are still awaited. As with other
forms of innovative minimally invasive urological surgery in children, a high level of expertise
is required.
Surgical Complications
ese comprise:
●
Wound infection
●
Urinary infection
●
Haemorrhage
●
Stent related problems
●
Recurrent VUJ obstruction
●
VUR
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Follow-Up and Surgical Outcomes
is typically consists of a postoperative ultrasound scan 4–6 weeks aer surgery (or JJ stent
removal) followed by an ultrasound and isotope
renogram at around 6–12 months. Excision of
the obstructing segment combined with ureteric
reimplantation usually results in reduction in
the severity of dilatation and good preservation
of dierential function. Any postoperative VUR
tends to be low grade and can be managed conservatively. e outcomes of surgical management of obstructed megaureter are generally very
good with reported overall success rates in the
region of 90–95%.
KEY POINTS
●
PUJ obstruction is a heterogeneous
condition with a number of dierent
causes and a variable natural history.
●
Hydronephrosis due to PUJ obstruction accounts for 30–50% of clinically signicant prenatally detected
uropathies. A renal pelvic AP diameter
exceeding 30 mm is associated with
a signicant likelihood of functional
impairment. Conversely, an AP diameter of less than 15 mm is most unlikely
to denote signicant obstruction.
●
Magnetic resonance imaging can
combine anatomical and functional
information in a single investigation
and may in time become the investigation of choice. Drawbacks are the
additional cost and requirement for
anaesthesia in younger children.
●
Laparoscopic and robotic-assisted
pyeloplasty are being increasingly
used for reconstruction particularly
in children who are no longer infants.
Advantages are improved cosmesis,
reduced postoperative pain and a
shorter hospital stay.
●
Primary obstructed megaureter can be
managed conservatively in the majority of cases with surgery being limited
to specic indications. Controversy
continues to surround some aspects of
the surgical management in the rst
year of life.
FURTHER READING
Chacko JK, Koyle MA, Mingin GC, et al. The
minimally invasive open pyeloplasty. J
Pediatr Urol. 2006;2(4):368–372.
Dekirmendjian A, Braga LH. Primary non-
reuxing megaureter: analysis of risk factors
for spontaneous resolution and surgical
intervention. Front Pediatr. 2019;7:126.
Jude E, Deshpande A, Barker A, et al.
Intravesical ureteric reimplantation for
primary obstructed megaureter in infants
under 1 year of age. J Pediatr Urol.
2017;13 (1): 47.e1– 47. e7.
Nguyen HT, Benson CB, Bromley B, et al.
Multidisciplinary consensus on the classication of prenatal and postnatal urinary tract
dilation (UTD classication system). J Pediatr
Urol. 2014;10(6):982–998.
Varda BK, Wang Y, Chung BI, et al. Has the
robot caught up? National trends in utilization, perioperative outcomes, and cost for
open, laparoscopic, and robotic pediatric
pyeloplasty in the United States from 2003
to 2015. J Pediatr Urol. 2018;14(4):336.
e1–336.e8.
Weitz M, Portz S, Laube GF, et al. Surgery
versus non-surgical management for
unilateral ureteric-pelvic junction obstruction in newborns and infants less than two
years of age. Cochrane Database Syst Rev.
2016;7:CD010716.
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