1. health and fitness
2. disease

GENERAL
DISCUSSION
173
174
general discussion
Part 1 Clinical aspects of febrile urinary
tract infection
In part I of this thesis, unresolved issues in the management of febrile urinary tract infection (UTI)
are discussed point-by-point following the clinical questions 1, 2.
When should a patient with febrile UTI be hospitalized?
In the Netherlands, the vast majority of patients with urinary tract infection (UTI) are managed by
general practitioners (GP) according to the guideline of the Dutch College of General Practitioners
on the management of UTIs 3. Being within the top rank on the list of most common reasons for
consulting a GP, UTIs are part of the routine daily practice of primary care 4, 5. As most UTIs are
limited to the bladder, a short course of antibiotic treatment will usually suffice and referral for
specialist care is rarely needed 3, 6. The incidence of resistant causal uropathogens is low but even
than the symptoms of UTI generally relieve with empirical antibiotic or symptomatic treatment 6-8.
Thus, to a considerable extent, UTI at primary care is indeed a self-limiting disease.
However, when fever develops the management of UTI at primary care is not that straightforward.
Fever in UTI is considered to be a sign of more advanced disease reflecting bacterial invasion of
tissues of the urinary tract. Usually, this implies the presence of acute pyelonephritis but in men it
may also represent the presence of bacterial prostatitis (Figure 1) 9-11. Furthermore, fever may be
a first sign of bacterial invasion of the blood stream, that is bacteremia (Figure 1). Accompanied
with the systemic inflammatory response syndrome any UTI, especially those caused by gram-negative microorganisms, may progress to a life-threatening severe urosepsis, multiple organ failure
and ultimately death 12-16. Still, though the overall mortality rate of acute pyelonephritis is around
0.3%, the risk of mortality in bacteremic UTI patients is notably higher ranging from 7% to 50%,
that depends mainly on the severity of underlying coexisting diseases 12, 17-20. Thus, when confronted with a febrile UTI patient, the attending GP first of all needs to evaluate whether the patient
is at risk for such deterioration (Figure 1), in order to judge whether outpatient management with
oral antibiotics is safe or referral to hospital is needed. However, clear guidance from the medical
literature to back up such judgment is limited as the majority of studies on outpatient management
were restricted to non-pregnant otherwise healthy young to middle aged women 21-28. Moreover, the
definition of ‘young to middle aged woman’ differed between studies. Yet, there is general consensus that at least premenopausal previously healthy nonpregnant women with febrile UTI or
acute pyelonephritis are good candidates for outpatient management with oral antibiotic treatment 29-31. Whether patients with coexisting diseases, the elderly and men can also be managed as
outpatients remains unclear and has not been addressed in any prospective study. However, based
on expert opinion, general recommendations might be followed. Ramakrishnan et al proposed to
use the following absolute indications for referral to hospital in patients with acute pyelonephritis:
175
figure 1
Flow of events in extending UTI. After peri-urethral colonization, the uropathogen invades the bladder (cystitis). Then it may
ascend to the kidney (acute pyelonphritis) and/or translocate to the prostate in men (bacterial prostatitis). Via these routes
it can spread to the blood stream (bacteremia or urosepsis syndrome).
Inferior caval vein
Advanced sisease
Kidney
Uropathogen
π Escherichia coli
Ureter
π Proteus spp.
π Klebsiella spp.
π Entercoccus spp.
π Pseudomonas aeroginosa
π Staphylococcus spp.
Bladder
Fever
Prostate
Urethra
general discussion
persistent vomiting, progression of uncomplicated UTI, suspected sepsis, uncertain diagnosis,
urinary tract obstruction and pregnancy, and the following relative indications: age above 60 years,
anatomic abnormality of the urinary tract, immunocompromised state (e.g. diabetes mellitus,
malignancy), inadequate access to follow-up and frailty 32. The National Health Service (NHS) of
the United Kingdom uses similar criteria and specifically emphasizes to use a low threshold for
hospitalization in patients with any of the above listed coexisting conditions 33. Furthermore, the
NHS stresses that if the patient is treated at home, clinical improvement must be evident within 24
hours of antibiotic therapy. If not, subsequent hospitalization is absolutely indicated 33. Somewhat
differently, the American College of Obstetricians and Gynecologists uses less specific criteria for
hospitalization, that is: women who are severely ill, have complications, are unable to tolerate
oral medications, who the clinician suspects to be noncompliant with outpatient therapy or who
does not have a notable clinical response by 48-72 hours 34. In contrast, the guideline of the Dutch
College of General Practitioners is less strict and recommends referral to hospital only, in case of
pregnancy, suspected sepsis or failure of antibiotic therapy 3. Unfortunately, within this guideline
the terms ‘suspected sepsis’ and ‘failure of antibiotic therapy’ are not otherwise specified leaving
its interpretation up to the individual GP. According to the NHS and the Society of Critical Care
Medicine, clinical signs of sepsis include a body temperature greater than 38˚C in combination
with marked signs of illness (altered mental state, perfuse sweating, rigors, pallor) and/or significant tachycardia (pulse rate > 90/min), hypotension or breathlessness (respiratory rate > 20/
min) 15, 33. Following this definition, it is not surprising that the majority of febrile UTI patients, in
particular those with co-morbidity, do indeed have ‘suspected sepsis’. Thus, despite the available
guidelines, dealing with the uncertainty upon need for hospitalization and unpredictability about
the risk for complications, GPs may tend to rely on their gut feeling or general sense of alarm 35, 36.
With the aim to gain more insight into the risk of complications in febrile UTI and thus to generate
tools to help guide physicians in such clinical decision making, we performed a large prospective
observational multicenter study including consecutive adults with febrile UTI, either at primary
care (PC) or emergency departments (ED) of affiliated hospitals.
In Chapter 1 we describe the results of 153 adults with febrile UTI managed at home by their GP
with oral antibiotic therapy (ciprofloxacin) and we compared those to 242 patients who were referred to the hospital 37. We found that the majority of individuals managed at home were patients
with co-morbidity above the age of 50 years while a considerable number were men. Moreover,
10% of the patients treated at home had bacteremia but contrary to previous reports this was not
associated with a complicated outcome. Indeed, despite the fact that during follow-up about 5%
were hospitalized, no one of these treated at home required admission to an intensive care unit
(ICU) nor were there any attributable deaths. In contrast, referred patients had a 7% risk for ICU
admission and a 5% mortality risk within 30 days. These patients were characterized by more signs
of sepsis (higher body temperature and pulse rate, lower blood pressure) and at ED presentation
they more frequently already had antibiotic UTI treatment. We concluded that GPs adhered well
to their guideline 3 and together with their gut feeling on severity of disease they were able to
177
select a broad population of patients with febrile UTI for outpatient management. Thus, this study
provided the first evidence that even among the elderly, men and patients with co-morbidity or
bacteremia, many can safely be treated at home with oral antibiotics.
178
However, this study also confirmed previous findings that around 90% of febrile UTI patients who
present at EDs were subsequently being hospitalized while the majority of those had an uncomplicated course 17, 37-39. Apparently, ED physicians tend to use a low threshold for hospitalization
likely because the referring GP judged the patient not to be manageable at home. This leaves open
the question whether part of the hospitalizations might have been avoidable, an important issue
on the cost aspect. In this respect, a clinical severity assessment tool dividing febrile UTI patients
into low-risk patients being candidates for outpatient management, and high-risk patients being
candidates for hospital admission, would be of particular value. For community-acquired pneumonia there are validated clinical prediction rules guiding need for hospitalization. As there are no
such tools for UTI and the predicting factors are not specific for pneumonia, such as age, co-morbidity and signs of sepsis, we considered these rules might also apply for febrile UTI 40-43. Thus, we
evaluated the predictive value of two bedside-available prediction rules, the modified pneumonia
severity index (PSI) and the CRB-65 (newly confusion, respiratory rate ≥ 30/minute, systolic blood
pressure < 90 mmHg, age ≥ 65 years), in predicting complicated outcome of febrile UTI defined as
death within 30 days or need for ICU admission 40, 42, 43. Using data of the above mentioned study
with 787 evaluable patients, the results of this are described in Chapter 2. We found that for predicting 30-day mortality, a modified PSI score (range 18-180 points) of ≥ 100 points and CRB-65
score ≥ 1 point had 86% and 100% sensitivity and 83% and 42% specificity, respectively. The composite outcome death within 30 days or ICU admission were predicted with a negative predictive
value of 0.98 and 1.00 for modified PSI and CRB-65. Patients with a modified PSI score < 100 points
(n = 636) or CRB-65 score < 1 (n = 320) point had a very low risk (<2%) of adverse outcome making them potential candidates for outpatient management. Using these prediction rules for risk
assessment to determine out- or inpatient management, this may save 74% of hospitalizations for
febrile UTI when using modified PSI, and 31% when using CRB-65. However, though the results
are promising, further validation of these predicting rules among other populations is required
before its widespread use for hospitalization guidance can be recommended 44. Moreover, its actual
implementation into clinical practice warrants further studies in order to evaluate whether indeed
the prediction rule will safely lead to a reduction in hospitalizations. As costs of acute pyelonephritis are predominantly determined by hospitalizations rates, such a study should preferably
include an evaluation of its cost-effectiveness 19, 45, 46. A stepped wedge cluster-randomized noninferiority trial, sequentially rolling out the intervention (introduction of the modified PSI guiding
hospitalization of patients with febrile UTI) at the participating centers (clusters) over a number of
time periods, would probably be an ideal and feasible design for such a study 47, 48. Awaiting such
validation studies, the current practice of using the Dutch guideline should be continued as this is
proofed to be a safe strategy.
general discussion
When should radiologic imaging of the urinary tract be considered in a patient
with febrile UTI?
Routine performance of radiologic imaging in UTI are reported to be of little value as the incidence
of underlying abnormalities of the urinary tract is low 49, 50. Nevertheless, one of the complications
of febrile UTI is the appearance of obstructing renal stones leading to the accumulation of pus in
the pyelum, pyonephrosis (Figure 2). This is associated with a protracted clinical course requiring
additional drainage therapy and possibly it also requires longer antibiotic treatment. Once the attending physicians considers such a complication, radiologic imaging has to be done. Then, ultrasonograpphy of the urinary tract is the radiologic method of choice as it is non-invasive, readily available, radiation free and sensitive in detecting urinary obstruction 51-54. Usually, attending physicians
will only consider radiologic imaging when there is a sufficiently high index of suspicion, as this
is a rare complication. However, the clinical signs of pyonephrosis are not specific all be it that the
persistence of fever despite 3 days of active antibiotic treatment might be indicative 30, 55-57. To date,
this is generally accepted to be an absolute indication for radiologic evaluation. In addition, it has
been advocated to consider radiologic imaging in diabetics, men and patients with recurrent UTI or
symptoms of urolithiasis 54, 58-60. We noticed that a significant number of febrile UTI patients presenting at EDs do indeed have such a risk factor and thus underwent radiologic imaging while the yield
of detecting clinical relevant abnormalities was low. Therefore, we derived and validated a clinical
prediction rule predicting radiologic outcome with the aim to use future radiologic resources more
efficiently. The results of this study are discussed in Chapter 3. We found that approximately 70%
of adults presenting at EDs with febrile UTI did undergo radiologic imaging of the urinary tract. A
simple prediction rule being the presence of a history of urolithiasis and/or urine pH ≥ 7.0 and/or
renal insufficiency (MDRD ≤ 40 ml/min/1.73m3) at presentation accurately predicted clinical relevant
radiologic findings 61. Moreover, the absence of these three risk factors ruled out the occurrence of
pyonephrosis with 94-100% certainty and withholding radiologic imaging in those without a risk
factor would potentially reduce the use of imaging to 40% of the febrile UTI patients (absolute reduction ≈ 30%). However, further confirmation in additional validation and implementation studies is
needed. Preferably, such studies will be performed in different settings and populations and include
a cost-effectiveness evaluation in order to characterize its definite place in the ED management of
febrile UTI patients 44.
In addition, this study evaluated the course of fever. Once on antibiotic treatment, 65%, 82% and 90%
of the patients become afebrile within 1, 2 and 3 days respectively. Such patterns were also noticed
in previous studies 62, 63 but contrary to other studies we could not demonstrate a relation between
fever duration and the risk for developing a complication like pyonephrosis 55-57, 64. Nevertheless,
our data support clinical experience that in febrile UTI patients the fever generally resolves within 72
hours of active antibiotic treatment 34, 56. In this respect, the criterion of the NHS, entailing clinical
improvement within 24 hours of antibiotic treatment, appears to be too strict 33. Yet, the term ‘failure
of antibiotic therapy’ as used in the Dutch UTI guideline might be specified as ‘clinical deterioration
during antibiotic treatment or persistent fever despite 3 days of antibiotic treatment’ 3.
179
figure 2
Complication of acute pyelonephritis: obstructive renal stone in the distal right ureter leading
to accumulation of pus in the obstructed pyelum (=pyonephrosis).
Inferior Caval vein
Kidney
180
Obstructed Pyelum
obstructed Ureter
Obstructive Renal stone
Bladder
Prostate
Urethra
general discussion
Who needs a blood culture when febrile UTI or urosepsis is suspected?
As discussed above, fever in UTI can be a first sign of bacteremia (Figure 1). This is associated with
higher mortality, prolonged hospitalization and higher complication rates 12, 17-20, 65-67. For this reason clinicians are vigilant to identify bacteremia as soon as the patient presents, because a positive
finding may have implications for the therapeutic management. The golden standard for detection
of bacteremia remains the performance of at least two blood cultures to achieve sufficient sensitivity 68. The importance of detecting bacteremia has been highlighted by sepsis guidelines and thus
in clinical practice a low threshold for obtainment of blood cultures is being practiced 69, 70. By
consequence, this approach may not be the most cost-effective one, as the majority of blood cultures do not grow any pathogen while the risk of getting a false-positive result (i.e. contamination)
amounts to 7% 71. In order to use blood culture resources more efficiently, predictive patient characteristics may help to differentiate those with high or low risk for bacteremia. However, clinical
models predicting bacteremia in UTI appeared to have poor predictive values 65-67, 72. In this regard,
the biomarker procalcitonin (PCT) may be of additional value in predicting bacteremia as it is supposed to be a marker of inflammation provoked by bacterial tissue (as opposed to viral) invasion
18, 73
. This was subject of a study of which the results are described in Chapter 4. We found that
bacteremia was associated with older age, diabetes mellitus, shaking chills, altered mental status
and higher temperature and pulse rate but, as previous findings, these predictors could not reliably
predict the presence of bacteremia 65-67, 72. In contrast, a PCT value > 0.25 μg/l was a fairly good
predictor for bacteremia with a negative and positive predictive value of 97% and 36% respectively.
Using PCT > 0.25 μg/l as a single decision tool for doing a blood culture in febrile UTI would have
resulted in 40% (absolute reduction) fewer blood cultures being taken while still identifying 94
to 99% of patients with bacteremia. Such a strategy is likely to be a cost-effective method to avoid
unnecessary blood cultures at EDs but this warrants further confirmative studies before the widespread use of PCT guidance on doing blood cultures can be recommended.
Another issue upon taking blood cultures in UTI patients has been addressed in Chapter 5 74. As
the causal pathogen of UTI can, by definition, be detected in urine, the usefulness of blood cultures in febrile UTI patients has been doubted because of its low additional diagnostic value over
urine cultures 75-78. This is consistent with the current clinical practice. After obtaining blood and
urine specimens for culture, febrile UTI patients will empirically be treated with antibiotics and
once the culture result becomes available the antibiotic therapy will be optimized according to the
susceptibility of the detected causal pathogen. In almost all cases of bacteremic UTI, the isolated
pathogen from the blood is similar to the one isolated from the urine. In other words, the result of
the urine culture is sufficient to guide antibiotic treatment. There may however be some situations
in which the blood culture result is different from the urine culture result; in previous studies this
occurred in about 2% of the cases 75-78. In our study we found the blood and urine cultures to be
discordant in 5% of 583 patients with febrile UTI. Furthermore, we demonstrated that discordant
urine and blood culture results were associated with prior antibiotic UTI treatment, malignancy
and the presence of an indwelling urinary catheter. Taken together with our finding in Chapter 1
181
that bacteremia is of no prognostic value, these findings suggest that in febrile UTI patients blood
cultures are of very little clinical relevance. Thus while Chapter 4 discusses a strategy of limiting
blood cultures to patients with a PCT value > 0.25 μg/l, an even more efficient strategy might be
the avoidance of blood cultures in all febrile UTI patients except those who are severly ill (to help
exclude other possible mimicking infections), those on antibiotic treatment or those with underlying malignancy or an indwelling urinary catheter.
What are risk factors for antibiotic resistance?
182
In patients with UTI, antimicrobial resistance is associated with prolonged and complicated illness 79, 80. Therefore, when the choice of empirical antibiotic therapy has to be made, the attending
physician needs to judge whether there is a considerable risk for a resistant causal uropathogen.
This specifically holds for E. coli, being the most frequent causal pathogen, and its susceptibility
to fluoroquinolones (FQs). FQs are the preferred agents for oral empirical therapy of febrile UTI,
based on the pharmacokinetic profile (e.g. good tissue level) and low rate of resistance in the community compared to other agents 29, 81-84. However, even for FQs the reported rates of resistance
vary over the years and between regions ranging from < 1% to 38% 27, 85, 86. Moreover, there are
signs that the incidence of FQ resistant E. coli is also increasing in the Dutch community, especially among patients at urology services 81, 87. Furthermore, it is of concern that the noted rise in
resistance may come from an animal reservoir and if so, this may be a potential thread for further
spread of resistant E. coli among the community 88-94. Thus, with the data gathered in the previously
discussed observational study, we evaluated risk factors for FQ resistant E. coli among patients with
febrile UTI and the impact on clinical outcomes. The results of this study are described in Chapter 6.
We found the presence of an indwelling urinary catheter, recent hospitalization to be independent
moderate risk factors for FQ resistance, but the foremost risk factor appeared to be individual
use of FQs in the preceding six months. In addition, FQ resistance was associated with crossresistance to other antibiotics (i.e. amoxicillin-clavunalate and trimethoprim-sulfamethoxazole)
whereas FQ susceptibility almost excluded the presence of extended spectrum beta-lactamase. Environmental risk factors such as daily contact with pets or livestock, home care medical support
or a household member with UTI were not associated with FQ resistance. This does not support
the concern for an animal or human reservoir causing FQ resistance it the community. However, it
should be emphasized that the current evidence for animal-human and human-human transmission of FQR E. coli in UTI is limited to specific strains 89, 90, 92, 95. Furthermore, it must be realized
that our study does not exclude a possible 2-hit mechanism for FQ resistance, with an initial input
of FQ resistant strains from food supply of colonized animals into the population followed by selection at the individual level by personal FQ use. Further studies are thus still warranted to explore
this hypothesis, particularly as to date the relation between animal food supply and FQ resistant
E. coli in humans revealed conflicting results but at least indicate this is could be a thread for the
community 88, 93, 96, 97.
With respect to clinical outcomes we found no relation between FQ resistance and the duration of
fever but, though not statistically significant, there was trend towards a two-fold higher mortality
general discussion
risk. Interestingly, the majority of patients with a FQ resistant strain who were empirically treated
with ciprofloxacin, recovered quickly as their fever resolved before the outcome of the urine culture became available and antibiotic treatment was subsequently switched. This may indicate that
febrile UTI is to some extent a self-limiting disease or possibly ciprofloxacin may be still effective
despite the causing E. coli is deemed to be resistant based on in vitro testing (defined as ciproflocacin MICs > 1 mg/L according to EUCAST criteria) 98. Based on the observed absence of a relation
between FQ resistance and clinical outcomes, the clinical relevance of detecting resistance at the
individual patient level is not straightforward. Nevertheless, as individual FQ use seems to be the
driving force for FQ resistance, as has also be demonstrated by many others 85, 99-104, this might be
easily detected by just asking the patient’s recent pharmacological history.
How long should a patient with febrile UTI ideally be treated?
Current strategies on the management of UTIs recommend antibiotic treatment for 14 days in case
of febrile UTI 3, 30, 32, 34, 105, 106. However, studies in previously healthy young non-pregnant women
demonstrated that treatment for 5 to 7 days is sufficient 27, 28. In addition, other studies indicate
that in many other patients, such as men, the elderly and patients with co-morbidity, the duration
of treatment may also safely be shortened to around 7 days 107-111. However, in none of the studies
the duration of treatment was the sole objective. Moreover, studies on patients other than young
healthy non-pregnant women were too small to draw definite conclusions. Thus there remains an
overall lack of evidence of treatment duration shorter than 14 days.
To address this issue we recently started a randomized double-blind placebo-controlled trial, including consecutive adults with febrile UTI. In this study, participating patients are randomised
to either 7 or 14 days of antibiotic treatment with the second week being either ciprofloxacin or
placebo twice daily. The background, rationale and design of this study are discussed in detail in
Chapter 7 112. Awaiting the results of this study, expected to become available in 2011-2012, the
above noted recommendations with respect to treatment duration of febrile UTI will sustain.
Part II Relation between pelvic floor
dysfunction and urinary tract infection
Part II addresses the possible relation between pelvic floor dysfunction (PFD) and UTI. PFD is
a is a general term for functional clinical problems affecting the urinary, rectal and/or sexual
function 113. It is generally believed to be a contributing factor for the development of UTI as
it disturbs normal bladder emptying and thus enhances bacterial bladder invasion and growth
(Figure 3) 114-118.
However, the relation between PFD and UTI has almost exclusively been studied in children and
young female adults 115-117, 119. Recently, it has been shown that around 20-25% of adult women
are affected by symptoms compatible with PFD but in this study a relation with UTI was not
183
figure 3
The possible role of pelvic floor dysfunction in the pathophysiology of urinary tract infection.
Factors enhancing
bacterial growth
and/or affecting
Factors enhancing
Factors enhancing
immune
susceptibility
bladder invasion
response
Pelvic floor
Factors enhancing
Pelvic floor
Pelvic floor
dysfunction?
exposure and
dysfunction?
dysfunction?
transmission
184
Immunity
Periurethral
Susceptible Host
colonization
Asymptomatic
(E. coli)
bacteriuria
Symptomatic UTI
Host response
Bacterial virulence characteristics
evaluated 120. To unravel the role of PFD in UTI, we evaluated the pelvic floor function of adults by a
validated questionnaire obtained 30 days after they presented with febrile UTI 121, 122. The results of
this are described in Chapter 8 and Chapter 9 123. In a case-control study comparing patients with
febrile UTI to healthy individuals without febrile UTI, we found the prevalence of PFD to be 21%
and 23%, respectively. In this study, PFD was not a risk factor for febrile UTI. Furthermore, PFD
was not related with previous UTI or bacteriuria. In another nested case-control study, comparing
febrile UTI patients with PFD to febrile UTI patients without PFD, we found neither relation of
PFD with a history of recurrent UTI nor with the outcome of febrile UTI with respect to presence of
bacteremia, fever duration and presence of bacteriuria during 30-day follow-up.
Based on these studies we conclude that, though PFD is common among adults, a pathophysiologic role of PFD in UTI is questionable. This contradicts the general believe that PFD is a considerable cause of (recurrent) UTI in adults. This may have implications for future research on PFD
and UTIs; in particular with respect to specific PFD treatment, like biofeedback physiotherapy, for
the prevention of UTI as this seems rather controversial 118.
general discussion
Part III Complicated cases of urinary tract
infection
Part III discusses complicated cases of UTI.
In Chapter 10 several patients with complicated UTI related to intermittent bladder catherization
are described. After many antibiotic treatments, these patients with neurogenic bladder developed
recurrent UTIs with a multiresistant E. coli leaving very limited antimicrobial treatment options.
Finally, treatment with intravesical gentamicin was successfully applied. Additionaly, a systematic
review on intravesical treatment with aminoglycosides for UTI was performed. Based on the results, it can be concluded that intravesical gentamicin is a reasonable treatment option in selected
patients practicing intermittent catherization who suffer difficult to treat recurrent UTIs. However,
as studies on this topic are rather limited, further studies are warranted.
Chapter 11 describes a patient who developed a fungus ball with Candida spp. of the bladder after
uterine artery embolization 124. We hypothesize that ischemic necrosis of the bladder wall provided
a niche for Candida outgrowth. Thus this report can be considered a word of warning to gynaecologists that uterine artery bladder embolization might be complicated by complicated fungal UTI.
Finally, Chapter 12, describes a patient with recurrent bacteremic UTI with Enterococcus faecalis based
on underlying chronic bacterial prostatitis 125. As the preferred antibitiotics to treat Enterococcus spp.
poorly penetrate the prostatic gland, treatment options of chronic bacterial prostatitis with Enterococci are very limited 11, 126. This patient was successfully treated with moxifloxacin and thus it might
be a reasonable treatment option for chronic bacterial prostatitis with susceptible Enterococci.
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