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ABSTRACT |
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Increased levels of the neutrophil chemokine interleukin (IL)-8 in the lungs of severe trauma patients can predict subsequent development of acute respiratory distress syndrome. Because the lungs of brain-dead organ donors can contain high levels of IL-8, we hypothesized that this may predispose to early graft failure in the recipient after lung transplantation. Twenty-six organ donors prospectively satisfying clinical criteria for lung donation underwent bronchoalveolar lavage and lung biopsy to determine the effect of neutrophil infiltration and IL-8 expression in the donor lung on graft function and survival in 26 respective recipients after lung transplantation. Nine recipients developed severe graft dysfunction, of whom six subsequently died (median survival: 24 d [range: 5 to 39 d]); all others survived beyond 6 mo. The IL-8 signal in the donor lung correlated with the percent neutrophils in bronchoalveolar lavage fluid (BALF) before implantation (42.4 ± 7.24 [mean ± SE]%, p = 0.03) and with the degree of impairment in graft oxygenation after implantation (p = 0.01). An increased level of IL-8 in the donor BALF was associated with the development of severe early graft dysfunction (p = 0.027) and with early recipient mortality (p = 0.0034). Use of donor lungs with high IL-8 levels is associated with a poor prognosis after lung transplantation. Attenuating the donor's inflammatory response before organ retrieval may improve early outcome after lung transplantation, and help maximize lung use from the existing donor pool.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patients with end-stage lung disease undergo lung transplantation in the hope of long-term survival and an improved quality of life. However, many recipients will experience severe early allograft dysfunction, which accounts for the death of 20% of recipients in the first few weeks after transplantation (1).
Early allograft dysfunction results from the development of acute lung injury (ALI) in the transplanted organ. Clinically, this is manifested as impaired gas exchange, diffuse radiologic shadowing, and pulmonary edema (2). The histologic appearance of the injury is characterized by significant lung neutrophilia, a proteinacious intraalveolar exudate, and alveolar-capillary disruption similar to that seen in patients without transplants who have acute respiratory distress syndrome (ARDS) (3).
The mechanism by which early graft injury occurs is believed to be multifactorial, yet experimental work in animal models has concentrated on ischemia-reperfusion injury (4) and on the effectiveness of lung preservation (5) as fundamental mechanisms of graft injury. Observations in clinical lung transplantation suggest that additional factors may be important in the etiology of graft injury (6).
Brain-dead organ donors are at high risk of developing ALI. Many have severe multiple trauma, are ventilated for a prolonged period, and have increased susceptibility to systemic or intrapulmonary infections (7). Furthermore, severe brain injury and brain-stem death have themselves been associated with increased systemic inflammation (8) and with cytokine activation in peripheral organs (9).
In our previous studies of severely traumatized patients at risk for ARDS, we have shown that bronchoalveolar lavage fluid (BALF) levels of the neutrophil chemoattractant and activator interleukin (IL)-8, but not of other chemokines or proinflammatory cytokines, predict subsequent development of ARDS (10). More recently, we have shown that patients brain dead as a result of massive spontaneous intracranial hemorrhage, who represent the major source of human organ donors, also have increased IL-8 levels in their BALF (11).
These observations led to our novel hypothesis, tested in the present study, that early graft dysfunction may be largely an ARDS-like condition. Preexisting subclinical inflammation in donor lungs, specifically with high IL-8 levels, could be transplanted to the recipient and predispose to the development of early graft dysfunction and to an adverse clinical prognosis after lung transplantation.
The significance to recipient outcome of specific factors such
as donor cause of death has only been investigated retrospectively, through epidemiologic techniques (12). In the present
study we prospectively investigated potential lung donors for
evidence of enhanced intrapulmonary inflammation by measuring the degree of neutrophil infiltration, concentrations of
the neutrophil chemokines IL-8, epithelial-derived neutrophil
activator (ENA)-78, and growth-related genes-
(GRO-) in
BALF. We then determined the effect of any enhanced inflammation in the donor lung before implantation on subsequent graft function and survival in the respective recipients after lung transplantation.
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INTRODUCTION
METHODS
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Donor and Recipient Recruitment
Lung donors were recruited from ventilated, brain-stem-dead patients whose relatives gave consent for organ donation. Donors were managed in accordance with standard protocols (13). Recipients received transplants according to clinical priorities and independently of the study results. The study had the approval of the local ethics committee.
Assessing Graft Dysfunction in Recipients
The clinical definition of acute graft injury after lung transplantation is not standardized; therefore, in this study we used the American- European consensus definition of ARDS (14). In the postoperative period, recipients whose ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FIO2) fell below 200 (mm Hg) or 27 (kPa), in association with diffuse radiologic infiltrates in the transplanted lung(s), and who had no evidence of left ventricular impairment, were identified as having significant acute graft injury.
Donor Lavage and Lung Biopsy
Donors were investigated either at the donor hospital (n = 12) before
lung retrieval, through the use of standard bronchoalveolar lavage
(BAL) techniques, or at the transplant unit for lungs imported from
distant centers (n = 14), through the use of minilavage before implantation (15). All procedures were performed by the same investigator.
The two investigative methods were highly comparable. Total and differential counts of recovered cells were performed with a hemocytometer and by cytospin treatment of BALF specimens to determine neutrophil concentrations. Further cytospin preparations were frozen for
subsequent immunolocalization studies. A small donor-lung biopsy
specimen was obtained before organ implantation. Lung biopsy specimens were formalin fixed and sections were stained for histologic examination. When geographic limitations allowed, donor-lung specimens were divided and half of each specimen was snap-frozen in an
isopentane slurry at 
120° C and stored at 70° C for subsequent
RNA extraction and immunolocalization studies.
Enzyme-Linked Immunosorbent Assay Estimation
of IL-8, GRO-, and ENA-78
The concentration of IL-8 in lavage fluid was determined with a previously established technique (16). Lavage fluid samples were investigated without treatment and in triplicate. The quantities of GRO-
and ENA-78 in the fluid were determined through similar methodologies, which have been previously described in detail (17, 18).
IL-8 Immunolocalization Studies
Lung tissue and BALF cytospin preparations were stained for IL-8 according to standard indirect immunohistochemical techniques. Localized antibodies were visualised with the Vector red substrate for lung tissue and with an immunoperoxidase technique for BALF cytospin preparpations. Control tissue was obtained from macroscopically normal lung in patients undergoing lung resection.
IL-8 Messsenger RNA Expression for IL-8 in Donor Lung Tissue
Total RNA was extracted from homogenized frozen lung tissue according to a previously described technique (19). The expression of
IL-8 messenger RNA (mRNA) in the donor lung tissue was estimated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). PCR amplification was done with specific primers designed from the published IL-8 gene sequence (20). The expression of human 
-actin in each RNA sample was determined under identical amplification conditions, using appropriate primers designed from a
published sequence (21). PCR products were resolved on a gel and
visualized before IL-8 mRNA was quantified by densitometry and
corrected for -actin gene expression.
Statistical Methods
Comparisons between recipient groups and between graft function and lavage indices were made nonparametrically with the Mann- Whitney U test and Spearman's rank correlations where appropriate. Confounding factors such as infection or smoking were investigated with Fisher's exact test. A significance level of p < 0.05 was used in all analyses done with statistical software.
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Donor Group
More than 50 potential lung donors were investigated, yielding 26 who satisfied clinical selection criteria for lung donation. These 26 formed the study group. Of the 26 subjects, 12 originated from our own donor zone and 14 from other zones within the United Kingdom.
Eleven of the donors (42%) had suffered brain death of traumatic origin, consisting either of a road traffic accident or isolated head injury. The remaining 15 subjects had suffered fatal nontraumatic intracranial events, consisting either of subarachnoid haemorrhage or stroke. The duration of donor ventilation before organ retrieval was 52 ± 25.6 h (mean ± SD) and the donors' oxygenation (PaO2/FIO2) at the time of organ retrieval was 64.3 ± 10.4 kPa (480 ± 78 mm Hg). Lavage fluid from 16 donors (61%) was culture positive; the organisms isolated comprised Staphylococcus aureus (n = 5); Candida species (n = 5); Haemophilus species (n = 3) and Others (n = 3). Seven (27%) of the accepted donors were current smokers, yet none smoked > 10 cigarettes/d according to the donors' next of kin. The other 19 accepted donors were nonsmokers or ex-smokers. Six of the accepted donors were receiving inotropic support to maintain hemodynamic stability. The remaining 20 were hemodynamically stable, of whom 12 were receiving no pharmacologic support and eight were receiving only renal dose dopamine.
The median percent of neutrophils in donor lavage fluid was 35.6 (range: 0 to 97.3%); this was significantly higher than previously reported in the lungs of normal, healthy nonsmokers (22). There was a significant association between the percent neutrophils and IL-8 concentrations in the donor lavage fluid (Spearman's r = 0.42, p = 0.033). The effects of the various donor characteristics described earlier on the extent of intrapulmonary inflammation as reflected in the donor lung BALF are listed in Table 1; the major findings are described in detail in the following discussion.
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The BALF IL-8 concentrations were not significantly higher in those donors who had suffered a traumatic cause of brain death (Mann-Whitney U test, p = 0.22). There was no correlation between the duration of donor ventilation before lung retrieval and the BALF IL-8 concentration in our donor group (Spearman's r = 0.16, p = 0.42). The neutrophil concentration in BALF (thousands/ml) was significantly higher in culture-positive donors (Mann-Whitney U test, p = 0.009), yet there was no significantly greater IL-8 concentration in culture-positive donors (Mann-Whitney U test, p = 0.36). The current smokers had neither a higher number of neutrophils nor an increased IL-8 concentration than did the nonsmokers or ex-smokers (Mann-Whitney U test, p = 0.39 and p = 0.86, respectively). Those donors requiring inotropic support to achieve hemodynamic stability showed no difference in their degree of pulmonary neutrophilia or BALF IL-8 concentration from donors not requiring such support (Mann-Whitney U test, p = 0.97 and p = 0.35, respectively).
The concentration and percentage of neutrophils recovered from donor lungs by formal BAL and minilavage were highly comparable, at p = 0.78 and p = 0.93, respectively (Mann-Whitney U test). The median IL-8 levels with the two methods were 1.15 ng/ml (range: 0 to 19.7 ng/ml) with formal BAL and 0.81 ng/ml (range: 0.05 to 17.6 ng/ml) with minilavage (Mann-Whitney U test, p = 0.94), suggesting that the use of the two lavage techniques did not produce any bias in the results obtained.
Recipient Group
All 26 donor lungs were used at Freeman Hospital for 14 female and 12 male recipients, who underwent 14 single, nine bilateral sequential, and three heart-lung transplantations between December 1996 and May 1998. The indications for transplantation were obstructive lung disease (n = 8), cystic fibrosis (n = 6), interstitial lung disease (n = 5), pulmonary vascular disease (n = 3), bronchiectasis (n = 3) and retransplantation for chronic lung rejection (n = 1).
The recipients' postoperative course was followed for 6 mo from the time of transplantation, or until death. One recipient died immediately after transplantation from venous thrombosis at the pulmonary vascular anastomosis. Because this was a primary surgical complication, this recipient was excluded from the outcome analysis. Using the consensus definition, nine of the 25 transplant recipients in the analysis developed severe early graft dysfunction. Six of these nine (two single-lung and four bilateral-lung recipients) subsequently died of graft failure and associated multiple organ failure, with a median survival of 24 d (range: 5 to 39 d). All 19 other recipients survived well beyond 6 mo.
Graft Dysfunction and Recipient Mortality
The concentration of IL-8 in donor BALF correlated inversely with the oxygenation capacity of the graft (lowest
PaO2/FIO2 ratio during stay in the intensive care unit after implantation) (Spearman's, r = 0.51, p = 0.01) (Figure 1). Although the median concentration and percent of neutrophils
in donor-lung lavage fluid tended to be higher, no statistically
significant increase in either measure was found for recipients
with severe early graft dysfunction (Mann-Whitney U test,
p = 0.28) or for those who died early in the postoperative period (Mann-Whitney U test, p = 0.87) (Table 2).
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The recipients who developed severe graft dysfunction (n = 9) had significantly higher concentrations of IL-8 in their donor lung than did the recipients whose grafts functioned well (n = 16) (median difference: 1.78 ng/ml; 95% confidence interval [CI]: 0.2 to 3.2 ng/ml; Mann-Whitney U test, p = 0.027) (Table 2, Figure 2). Those recipients (n = 3) who developed severe graft dysfunction and then recovered to survive > 6 mo had the lowest BALF IL-8 concentrations of the nine subjects with severe graft dysfunction. The recipients who died early in the postoperative period (n = 6) received donor lungs with significantly higher levels of IL-8 in lavage fluid than did recipients who survived beyond 6 mo (n = 19) (median difference: 2.13 ng/ml; 95% CI: 1.8 to 16.8 ng/ml; Mann-Whitney U test, p = 0.0034) (Table 2, Figure 3).
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The incidence of severe graft dysfunction could not be explained by an increased incidence of positive cultures in BALF or by donors' current smoking (Fisher's exact test, p = 0.4 and p = 0.63, respectively).
Frozen donor-lung tissue for RNA extraction was obtained
from 10 of the donors investigated. To further elucidate the
role of donor-lung IL-8 in subsequent graft function, we investigated possible sources of increased IL-8 levels in donor lavage fluid by measuring IL-8 mRNA expression in donor lung
tissue. When corrected for human -actin expression, IL-8
mRNA expression was substantially higher in the donor lungs
of recipients who subsequently developed severe graft dysfunction (n = 4) (median = 0.72) than in lungs that functioned
well after transplantation (n = 6) (median = 0.19) (Mann-
Whitney U test, p = 0.06).
Although the median concentrations of ENA-78 or GRO- in donor lavage fluid, tended to be higher in recipients with
severe early graft dysfunction than in those with good early
function, no statistically significant difference between the two
groups was demonstrated (Table 2). There was also no significant difference in levels of these chemokines in recipients
who died early after transplantation and longer-term survivors
(Table 2).
Immunolocalization of IL-8 in Donor Lung
Examination under light microscopy of donor-lung sections stained with hematoxylin and eosin (H&E) revealed a predominantly normal histologic appearance, with intact alveolar-capillary architecture. Higher-power examination showed neutrophil margination in the pulmonary vasculature and increased numbers of alveolar macrophages (AM) and neutrophils in the lung interstitium in a significant number of donor lungs. These changes fell well short of the characteristic changes of ARDS, which were not seen in any donor-lung biopsy specimens.
In cytospin preparations of lavage fluid from donor lungs that subsequently functioned poorly and whose recipients died early after transplantation, specific staining for IL-8 was intense and was distributed throughout the cytoplasm of AM, whereas the staining in cytospin preparations from donor lungs with good subsequent graft function was significantly weaker and limited to the perinuclear region (Figures 3A and 3B). Lavage fluid specimens containing a high proportion of neutrophils had positive surface staining for IL-8 on these cells. The distribution of IL-8 in donor-lung tissue was widespread as compared with that in control tissue (Figures 4A and 4B). High-power examination of donor-lung tissue suggested that AM and epithelial cells were major sources of the increased IL-8 in donor lungs that later functioned poorly (Figures 5A and 5B).
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Donor-organ shortage severely limits lung transplant activity worldwide (23), resulting in the death of approximately 30% of potential recipients while they are on the waiting list for transplantation (24). However, only 20% of potential donor lungs are currently deemed suitable for transplantation (24, 25) according to accepted clinical selection criteria (26). Although there is evidence that use of nonideal or "marginal" donor lungs is associated with effective early graft function (27, 28), fear remains that their use will increase early mortality in the recipients. Despite the use of donor-lung selection criteria, severe graft dysfunction remains a major cause of early morbidity and mortality.
IL-8 is a member of the CXC chemokine subfamily; it has
potent neutrophil chemotactic activity and plays a fundamental role in the recruitment and activation of neutrophils to
sites of acute inflammation (29). Many cell types are capable
of producing IL-8 when stimulated by proinflammatory cytokines such as tumor necrosis factor- and IL-1 (30). Lung conditions characterized by neutrophil infiltration are marked by
higher levels of pulmonary IL-8 (31, 32). Because potential organ donors are at risk of ALI (7), and because early graft injury after lung transplantation is characterized by neutrophil
infiltration, a role for IL-8 in the pathogenesis of this injury
would seem biologically plausible.
In this study we clearly demonstrated that increased levels
of IL-8 in the airspaces of a donor lung are associated with
poor initial graft function and an increase in early mortality in
the recipient. This supports the previous observation in the
nontransplant population that an early increase in intraalveolar IL-8 predicts subsequent development of ARDS in patients at risk (10). Furthermore, the BALF IL-8 differences
detected in our endpoint groups (median differences: 1.73 ng/ml
and 2.13 ng/ml), respectively, for recipients whose grafts functioned well and those who died in the early postoperative period) were significantly greater than that seen in the population at risk for ARDS (median difference: 0.52 ng/ml) (10),
confirming the clinical significance of the IL-8 differences we
observed. In addition, we demonstrated increased expression
of IL-8 mRNA in the tissue of donor lungs that developed severe graft dysfunction as compared with those that functioned
well. This suggests that the increased IL-8 signal was at least
partly due to increased production of IL-8 within the donor
lung. In support of our lavage and tissue data, our immunolocalization studies showed that IL-8 expression was widespread
within donor lung tissue, and in particular that AM and epithelial cells were important sources of the IL-8. Although the
levels in donor-lung lavage fluid of the two other powerful
neutrophil chemokines GRO- and ENA-78 showed no significant prognostic influence, there was a trend toward their
presence at increased levels in donor lungs that subsequently
developed graft dysfunction.
Surprisingly, there was no significant association between the concentration of neutrophils in donor lungs and early graft dysfunction or recipient mortality after transplantation. Again, these data suggest a trend toward an effect of increased donor neutrophils. The lack of a statistically significiant association may have been the result of the study size, and although our data suggest a degree of specificity for increased donor IL-8 expression and early graft dysfunction or recipient mortality, a possible contribution from a more global enhanced inflammation in the donor lung cannot be excluded. Our observations may, however, be explained in several biologically plausible ways. First, many of the neutrophils in the donor lung could have undergone apoptosis and have been cleared by the major phagocytes without a release of injurious mediators (33). Second and potentially more importantly, recruitment of the recipient's own circulating neutrophils into the graft, in response to a preexisting chemotactic gradient in the donor lung, may be responsible for potentiating early graft injury. Additionally, IL-8 in the donor lung may have an etiologic role in graft dysfunction independently of its neutrophil chemotactic activity. Increased IL-8 activity could, by promoting neovascularization, cause excessive extracellular matrix deposition, resulting in alveolar-capillary disruption and impaired graft function in the recipient. Such a fibroproliferative response can be detected within 24 h of ALI (34), and in ARDS patients, in whom the association of ARDS with increased IL-8 levels is well established (35), the extent of the early fibroproliferative response can predict subsequent mortality (36). The importance of IL-8 in the control of angiogenesis has been clearly demonstrated in other lung conditions characterized by neutrophil infiltration (37). In bleomycin-induced lung injury, blocking of the angiogenic activity of the murine IL-8 equivalent (macrophage inflammatory protein-2) dramatically reduced the fibroproliferative response and thus the degree of lung injury without affecting neutrophil infiltration (38).
To determine whether any specific aspects of the donor contributed to increased IL-8 concentrations in BALF, we identified probably risk factors in the donor for the development of subclinical lung injury. In our study population, not the duration of donor ventilation, nor a traumatic cause of death, nor the use of inotropic support in the donor was associated with a significant increase in BALF IL-8. This suggests that no single donor characteristic is the major contributor to increased IL-8 levels in the lung, and suggests that a combination of factors both measurable and immeasurable, such as the individual response to brain death, may be important.
We also considered the possibility that increased IL-8 levels in donor lungs simply reflected donor smoking or infection (39). However, IL-8 levels were no different in current smokers than in nonsmokers, and the incidence of donor smoking was unrelated to graft function or early mortality in recipients. A high incidence of positive cultures from BALF was found in our donor population, the pathologic significance of which is uncertain. Donors with positive cultures had higher concentrations of neutrophils in their BALF, yet their IL-8 levels were not significantly different than those of donors with negative cultures, (p = 0.36), suggesting that in infection, other neutrophil chemoattractants, such as complement (C5a), leukotriene B4, or bacterial peptides may be more important. The incidence of positive cultures was not statistically significantly greater for recipients with severe graft dysfunction or in those who died early; suggesting that although donor infection may contribute to these outcomes, it was not the sole explanation for them in our cohort.
Our findings suggest that reducing preexisting inflammation in the donor lung may offer a therapeutic approach to improving early graft function and survival after lung transplantation. A recent retrospective study showed increased acceptance of potential donor lungs with the use of high-dose steroids (40). However, although it is not universal practice in all centers, the donors in our study received high-dose methylprednisolone immediately before lung procurement, suggesting that either a more specific anti-IL-8 strategy or a prolonged antiinflammatory approach may be necessary for graft survival. The prevention of early graft injury is important, since its implications may extend well beyond the postoperative period to affect long-term graft function and survival (41). In renal transplantation, early graft dysfunction is associated with an increased incidence of chronic graft failure due to chronic rejection (42). The mechanism proposed for this involves enhancement of the organ's immunogenicity, with an increased risk of acute and chronic rejection, a phenomenon known to occur in the lung (43). Furthermore, the importance of IL-8 in longer-term graft survival has been shown in recipients at more than 6 mo after lung transplantation, in whom levels of IL-8 were higher in recipients who subsequently developed chronic allograft rejection (44).
The concept that subclinical lung inflammation and thus the potential for subsequent lung injury can be transplanted from donor to recipient has not previously been demonstrated in clinical transplantation. Our observations may not be unique to the lung, and could be relevant to the early function of other solid-organ transplants. To determine whether measurement of IL-8 in BALF could be used in clinical practice as an objective indicator of donor-lung suitability, further investigation would be required in the form of a large scale, multicenter study sufficiently powerful to identify an appropriate IL-8 cutoff concentration.
Furthermore, the opportunity now exists to investigate whether commencement of specific antiinflammatory or powerful immunosuppressive therapies in the donor before organ retrieval can improve subsequent graft function in the recipient. Such an approach could offer a means of maximizing the use of lungs from the existing donor pool, and could help satisfy the increasing demand on lung transplantation as a therapeutic option.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. Paul Corris, Professor of Thoracic Medicine, University of Newcastle upon Tyne, Freeman Hospital, High Heaton, Newcastle upon Tyne, NE7 7DN, UK. E-mail: paul.corris{at}ncl.ac.uk
(Received in original form May 22, 2000 and in revised form July 26, 2000).
Acknowledgments:
The authors thank Ms. Marie Burdick of the University of
Michigan for technical expertise in the measurement of GRO- and ENA-78;
Dr. David Walshall of the University of Newcastle-upon-Tyne for statistical
advice; and all members of the donor and cardiopulmonary transplant
teams at Freeman Hospital. They also pay tribute to the courageous families
who donated the organs of their loved ones to give others the chance of life.
Supported by the Newcastle Hospitals Special Trustees and Medical Research Council of the United Kingdom, The Wellcome Trust, and Grants P50HL60289 and P50HL56402 from the National Institutes of Health.
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References |
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