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Intra-abdominal Sepsis After Ileocolic Resection in Crohn’s Disease

The Role of Combination Immunosuppression

McKenna, Nicholas P., M.D.1,2; Habermann, Elizabeth B., Ph.D., M.P.H.1,2; Glasgow, Amy E., M.H.A.2; Dozois, Eric J., M.D.3; Lightner, Amy L., M.D.3

doi: 10.1097/DCR.0000000000001153
Original Contributions: Inflammatory Bowel Disease
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BACKGROUND: Intra-abdominal sepsis complicates <10% of ileocolic resections for Crohn’s disease, but the impact of combination immunosuppression and repeat resection on its development remains unknown.

OBJECTIVE: The purpose of this study was to determine risk factors for intra-abdominal sepsis after ileocolic resection, specifically examining the role of combination immunosuppression and repeat intestinal resection.

DESIGN: This was a retrospective review of patient records from 2007 to 2017.

SETTINGS: The study was conducted at a single-institution IBD tertiary referral center.

PATIENTS: Patients with a diagnosis of Crohn’s disease who were undergoing ileocolic resection with primary anastomosis were included. Diverted patients were excluded.

MAIN OUTCOME MEASURES: Preoperative and intraoperative variables, including preoperative immunosuppressive regimens and previous intestinal resection, were evaluated as potential risk factors for intra-abdominal sepsis.

RESULTS: A total of 621 patients (55% women) underwent ileocolic resection for Crohn’s disease; 393 (63%) were first-time resections. The rate of 30-day intra-abdominal sepsis was 8% (n = 50). On univariate analysis, triple immunosuppression (combination of a corticosteroid, immunomodulator, and biological) and previous intestinal resection were significantly associated with intra-abdominal sepsis. Both risk factors remained significant on multivariable analysis (OR for triple immunosuppression (vs none) = 3.53 (95% CI, 1.27–9.84); previous intestinal resection OR = 2.27 (95% CI, 1.25–4.13)). A significant trend was seen between an increasing number of these risk factors (triple immunosuppression and previous intestinal resection) and rate of intra-abdominal sepsis (5%, 12%, and 22% for 0, 1, and 2 risk factors; p < 0.01). A trend was observed between increasing number of previous intestinal resections and the rate of intra-abdominal sepsis (p < 0.01).

LIMITATIONS: This study is limited by its single-institution tertiary referral center scope.

CONCLUSIONS: Combination immunosuppression and previous intestinal resection were both associated with the development of intra-abdominal sepsis. In light of these results, surgeons should consider the effects of combination immunosuppression and a history of previous intestinal resection, in addition to other risk factors, when deciding which patients warrant temporary intestinal diversion. See Video Abstract at http://links.lww.com/DCR/A664.

1 Department of Surgery, Mayo Clinic, Rochester, Minnesota

2 The Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota

3 Division of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota

Funding/Support: None reported.

Financial Disclosure: None reported.

Podium presentation at the meeting of The American Society of Colon and Rectal Surgeons, Nashville, TN, May 19 to 23, 2018.

Correspondence: Nicholas P. McKenna, M.D., 200 First Street SW, Rochester, MN 55905. E-mail: mckenna.nicholas@mayo.edu. Twitter: @NPMcKenna.

Crohn’s disease is a chronic, debilitating inflammatory disease of the GI tract, and its transmural inflammation results in its inflammatory, stricturing, or penetrating phenotypes. Between 40% and 60% of patients with Crohn’s disease eventually require intestinal resection,1–3 most commonly of the ileocecal region,4 largely because of medically refractory disease. Unfortunately, surgery is not curative, and <50% of these patients require a repeat resection.5 Each ileocolic resection performed has the risk of postoperative intra-abdominal sepsis accompanied by its associated increased length of stay and hospital cost.6

A heterogenous group of risk factors for the development of postoperative intra-abdominal sepsis after intestinal resection in Crohn’s disease have been proposed, including steroids,7 biologicals,8 positive histologic margins,9 and repeat resection.10 Particular attention has been paid to the controversial impact of biological agents8 , 11–13 and repeat intestinal resection.10 , 14 However, previous studies investigating biologicals have largely examined each class of biological agents in isolation and have not accounted for the commonly used multimodal immunosuppressive approach.15 , 16 In addition, studies investigating the impact of previous intestinal resection on postoperative complications have been underpowered to adequately determine whether there is a correlation between an increasing number of previous resections and the rate of intra-abdominal sepsis.14 Strong evidence identifying perioperative risk factors for the development of intra-abdominal sepsis would allow surgeons to optimize their intraoperative decision-making regarding who may benefit from intestinal diversion at the time of primary resection and anastomosis.

Therefore, the aims of this study were to determine independent risk factors for the development of intra-abdominal sepsis after ileocolic resection in Crohn’s disease and the impact of an increasing number of previous intestinal resections on the rate of postoperative intra-abdominal sepsis in a large institutional cohort of ileocolic resections for Crohn’s disease.

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PATIENTS AND METHODS

After institutional review board approval was obtained, all patients aged ≥18 years who were undergoing ileocolic resection for Crohn’s disease at Mayo Clinic Rochester between July 2007 and August 2017 were identified. A retrospective chart review was conducted to collect preoperative, operative, and postoperative data points of interest.

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Definitions

To be consistent with previous work investigating intra-abdominal sepsis after ileocolic resection in Crohn’s disease,7 , 9 , 14 , 17–20 intra-abdominal sepsis was defined as an intraperitoneal abscess or anastomotic leak within 30 days of surgery and was graded using the Clavien–Dindo classification.21 Previous intestinal resection was defined as previous intestinal resection for Crohn’s disease. Corticosteroid use and immunomodulator use were considered positive if the last dose was taken within 4 weeks of surgery. Biological use was considered positive if the last dose was received within 12 weeks of surgery. If a patient was on any 2 classes of medications, it was defined as dual immunosuppression, and if on all 3 classes, it was defined as triple immunosuppression. Serum laboratory values were collected if within 2 weeks of surgery, except for albumin, which was collected within 4 weeks. Elective surgery was defined as admission for a scheduled operation. Urgent surgery was defined as surgery performed during an admission for an acute Crohn’s flare with failure of medical rescue. Emergent surgery was defined as surgery for an acute abdomen.

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Patient Selection

Adult patients with a diagnosis of Crohn’s disease who underwent an ileocolic resection with primary anastomosis by a board-certified colon and rectal surgeon were included. For patients who underwent multiple ileocolic resections during the study period, only the most recent operation was evaluated for intra-abdominal sepsis, but the lifetime number of previous intestinal resections, performed both at our institution or at an outside hospital, served as an exposure variable. Patients who underwent an ileocolic resection with primary anastomosis and a diverting loop ileostomy were excluded, which is consistent with previous work in this area.7 , 9 , 14 , 19 , 22 , 23

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Operative Approach

At our institution, a laparoscopic approach is preferred; however, the operating surgeon made the ultimate decision on whether to proceed in a laparoscopic or open manner. The core tenets of intestinal resection for Crohn’s disease were followed, with removal of all macroscopic disease. The decision to perform additional stricturoplasty, small-bowel resection, or colon resection was at the discretion of the operating surgeon and by the pathology identified preoperatively and intraoperatively. Anastomotic configuration and the use of handsewn versus stapled technique were also at the discretion of the operating surgeon. A surgical drain is not routinely placed at the time of ileocolic resection by the surgeons at our institution. Lastly, the decision to protect the anastomosis with a diverting loop ileostomy belonged to the operating surgeon. Typical reasons cited for diversion in the operative dictations included poor nutrition, penetrating Crohn’s phenotype, and prolonged exposure to preoperative immunosuppression.

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Outcomes

The primary outcome of interest was the diagnosis of intra-abdominal sepsis within 30 days of surgery. Secondary outcomes included the relationship between intra-abdominal sepsis and other complications, the time to presentation of intra-abdominal sepsis, the Clavien–Dindo grade of intra-abdominal sepsis, risk factors for intra-abdominal sepsis, and the correlation of the number of previous intestinal resections with intra-abdominal sepsis.

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Covariates

Patient variables included age, sex, smoking status, and BMI (underweight defined as <18.5 kg/m2 and obese as ≥30 kg/m2). Disease characteristics included duration of Crohn’s disease, previous intestinal resection, phenotype of Crohn’s disease by Montreal classification,24 the presence of perianal disease, and past use of biological medications. Preoperative comorbidities included diabetes mellitus and ASA score. Medication data collected included the use of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, methotrexate, tacrolimus, and mycophenolate), and biological agents (infliximab, adalimumab, certolizumab pegol, vedolizumab, natalizumab, and ustekinumab). Medications were grouped into 1 of 6 categories (none, steroids only, immunomodulator only, biologic only, dual therapy, or triple therapy as defined earlier). For the univariate analysis of risk factors for leak, the biological-alone group was stratified into antitumor necrosis factor (TNF) agents, anti-integrins, and ustekinumab. The multivariable model biological-alone group only included anti-TNF agents because of small sample size in the anti-integrin (n = 7) and ustekinumab (n = 4) groups. Preoperative laboratory tests included hemoglobin, white blood cell count, platelet count, albumin, and C-reactive protein. Perioperative and intraoperative variables included elective, urgent, or emergent case status; surgical approach (open or laparoscopic); handsewn or stapled anastomosis; anastomotic configuration (side-to-side, end-to-end, end-to-side, or side-to-end); additional surgical procedures at time of ileocolic resection (additional small-bowel resection, stricturoplasty, or sigmoid resection); the identification of an abscess or fistula at surgery; estimated blood loss; and operative time.

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Statistical Analysis

Data were expressed as number (percentage) for categorical variables and as median (interquartile range) for continuous variables. Missing data were excluded from univariate comparisons. Postoperative complications were compared between those experiencing intra-abdominal sepsis and those without using χ2 or Fisher exact test, as appropriate. The occurrence of intra-abdominal sepsis was analyzed as a binary outcome on univariate analysis using χ2 or Fisher exact test for categorical variables and by the Student t test or Wilcoxon rank-sum test for continuous variables on the previously mentioned covariates. A multivariable logistic regression model was then built to determine independent risk factors for the development of intra-abdominal sepsis. Covariates with a p value of <0.10 or deemed clinically relevant (smoking) were included in the multivariable model. A risk estimate for intra-abdominal sepsis based on the number of risk factors was calculated using variables significant on multivariable analysis. Cochran–Armitage trend test was used to assess the relationship between the number of risk factors and intra-abdominal sepsis and between the number of previous ileocolic resections and intra-abdominal sepsis. Significance was set at p < 0.05 and, where appropriate, a Bonferroni correction was applied for multiple comparisons, with significance set as <0.05 divided by the number of comparisons. All of the analyses were performed using SAS 9.4 and JMP version 13.0.0 (SAS Institute Inc, Cary, NC).

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RESULTS

Patient Demographics

During the study period, 679 consecutive ileocolic resections with primary anastomosis for Crohn’s disease were performed. A total of 621 patients (91%) were not diverted at the time of surgery, and they make up the study population presented here, whereas 58 patients (9%) had a protective diverting loop ileostomy performed. A comparison between patients who had a diverting loop ileostomy performed and those who did not revealed that the diversion group more often underwent urgent or emergent operations and more often had an intraoperative abscess identified (Table 1). These patients were excluded from additional analysis, and all of the subsequent data reflect the 621 patients who were not diverted.

TABLE 1

TABLE 1

More than half (n = 340 (55%)) of the patients were women, and the median age was 37 years (range, 18–86 y). Median BMI was 23.4 (range, 15.0–48.0), with 68 patients (11%) underweight (BMI <18.5 kg/m2) and 105 patients (17%) obese (BMI ≥30 kg/m2). The majority of patients did not use tobacco (n = 497 (80%)). A small number were diabetic (n = 18 (3%)) or had an ASA class III or IV (n = 69 (11%); Table 2).

TABLE 2

TABLE 2

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Crohn’s Disease Characteristics and Preoperative Medications

Median disease duration before ileocolic resection was 9 years (range, 0–75 y), and disease phenotype was predominantly Montreal class B2 stricturing (n = 355 (57%)), followed by B3 penetrating (n = 203 (33%)) and B1 nonstricturing, nonpenetrating (n = 63 (10%)) at the time of surgery. More than one third (n = 228 (37%)) of the patients had a previous intestinal resection (137 had 1 previous resection; 91 had ≥2 previous resections), and more than one fourth (n = 199 (32%)) had been treated with ≥2 biologicals in the past.

The majority (n = 480 (77%)) of patients presented for surgery on a corticosteroid, immunomodulator, biological, or combination of these medications. Specific medication regimens included dual immunosuppression (n = 184 (30%)), biological only (n = 151 (24%)), immunomodulator only (n = 57 (9%)), triple immunosuppression (n = 51 (8%)), and corticosteroids only (n = 37 (6%); Table 3).

TABLE 3

TABLE 3

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Operative Characteristics

Twelve surgeons performed the 621 operations, with half of the cases completed laparoscopically (n = 314 (51%)). An enteric fistula was identified in 151 cases (24%) and an intraperitoneal abscess in 61 cases (10%). A stapled anastomosis was performed in more than half of the cases (n = 378 (61%)), and the most common anastomotic configuration was an antiperistaltic side to side (n = 427 (70%)). Additional procedures performed at the time of ileocolic resection included additional small-bowel resection (n = 48 (8%)), stricturoplasty (n = 37 (6%)), and colon resection (n = 27 (4%); Table 4).

TABLE 4

TABLE 4

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Intra-abdominal Sepsis and Associated Complications

The overall incidence of intra-abdominal sepsis was 8% (n = 50; 14% grade 2, 40% grade 3a, 26% grade 3b, and 20% grade 4), and diagnosis was made at a median of 9 days postoperation (range, 2–28 d). Almost two thirds (n = 31; 62%) of patients were diagnosed in the outpatient setting. Other complications, including superficial surgical site infection, urinary tract infection, pneumonia, partial small-bowel obstruction or ileus, readmission, and total length of hospital stay were increased in the intra-abdominal sepsis group.

On univariate analysis, triple immunosuppression (versus none) and previous intestinal resection were the only 2 factors significantly associated with intra-abdominal sepsis (both p < 0.01). On multivariable logistic regression, both triple immunosuppression (versus no therapy; OR = 3.53 (95% CI, 1.27–9.84)) and previous intestinal resection (OR = 2.27 (95% CI, 1.25–4.13)) remained the only 2 independent risk factors for intra-abdominal sepsis (Table 5).

TABLE 5

TABLE 5

To further investigate the impact of medications on intra-abdominal sepsis, a second multivariable logistic model was built with triple immunosuppression as the medication reference instead of no medication. This revealed a significant decrease in the odds of intra-abdominal sepsis in patients on no therapy (versus triple immunosuppression; OR = 0.28 (95% CI, 0.10–0.79)), on an anti-TNF only (versus triple immunosuppression; OR = 0.38 (95% CI, 0.15–0.99)), or on dual immunosuppression (versus triple immunosuppression; OR = 0.36 (95% CI, 0.14–0.90)).

Lastly, to evaluate the impact of the overall number of previous intestinal resections, a Cochran–Armitage test was conducted and showed a significant overall trend with increasing number of resections (1-sided p < 0.01; Fig. 1). In addition, the preoperative medication profile demonstrated a positive trend from no medications to triple immunosuppression (Fig. 2). Lastly, the rate of intra-abdominal sepsis increased as the number of risk factors increased, with a rate of 5% for neither triple immunosuppression nor previous intestinal resection, 11% for previous intestinal resection only, 15% for triple immunosuppression alone, and 22% for both triple immunosuppression and previous intestinal resection (Cochrane–Armitage trend test overall p = 0.03; p < 0.01 for both risk factors vs no risk factors and for previous intestinal resection versus no risk factor; and p = 0.02 for triple immunosuppression only versus no risk factors; Fig. 3).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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DISCUSSION

In the largest institutional series of ileocolic resections for Crohn’s disease to date, we found multimodal immunosuppression and previous intestinal resection to be independent risk factors for the development of intra-abdominal sepsis. This finding underscores the need for preoperative consideration of the effects of combination immunosuppression in the biological era, a time where escalation of medical management is often pursued before operative intervention. Given that the risk of intra-abdominal sepsis exceeds 20% in patients who are both on preoperative triple immunosuppression and undergoing a repeat intestinal resection, surgeons should strongly consider temporary intestinal diversion for these patients.

Our overall rate of 8% for intra-abdominal sepsis is in concordance with previous reports that used the same definition.7 , 8 , 22 Although this figure represents the minority of surgical patients, its impact is significant and warrants special attention. Intra-abdominal sepsis is associated with increased rates of concomitant nonsurgical infectious complications and unplanned 30-day returns to the operating room. In addition, almost two thirds of the cases of intra-abdominal sepsis presented in the outpatient setting, necessitating unplanned hospital visits and readmissions, which are known to increase cost25 and patient dissatisfaction.26 Therefore, much can be gained by identifying high-risk patients and diverting them temporarily while modifiable risk factors, such as malnutrition and anemia, are corrected.

This is the first study to identify triple immunosuppression as a risk factor for intra-abdominal sepsis after ileocolic resection in Crohn’s disease. The majority of previous studies investigating the effect of preoperative medications on intra-abdominal sepsis have predominantly looked at steroids, immunomodulators, and biologicals in isolation. Although steroids are consistently associated with an increased risk of postoperative complications,7 , 17 , 18 immunomodulators9 , 19 , 20 and biological therapy remain controversial.8 , 11–13 , 27 , 28 Because an increasing number of patients are on combination immunomodulator and biological therapy for improved steroid-free remission16 or corticosteroids because of loss of response to a biological,29 it is logical to study these classes of medications in concert, rather than individually. To date, only 1 other group has investigated the combination of anti-TNF agents and steroids and found an increased risk of intra-abdominal sepsis in patients on dual immunosuppression. However, only 16 of 217 patients were on dual immunosuppression, and triple immunosuppression was not evaluated.23 The authors concluded that additional study on the effects of combined immunosuppression was needed. Thus, our study adds evidence to the theory that combined immunosuppression may be driving the increased risk of intra-abdominal sepsis after ileocolic resection in Crohn’s disease rather than any solo agent alone. Additional analysis of the various combinations of dual immunosuppression revealed that the rates of intra-abdominal sepsis among the 3 possible groupings were similar, and none were significantly higher than the no-preoperative-medication group. Therefore, in the absence of other risk factors, it appears safe to perform a primary anastomosis without diversion in patients on any combination of dual immunosuppression and that the risk is in patients on triple immunosuppression.

In addition to combination immunosuppression, we identified previous intestinal resection as an independent risk factor for intra-abdominal sepsis. Repeat resection has been suggested recently to increase the anastomotic leak rate after ileocolic resection for Crohn’s disease,10 , 14 but this is the first study to show an association between intra-abdominal sepsis and repeat resection on both univariate and multivariable analyses. It is possible that the need for repeat resection is a reflection of a more aggressive form of Crohn’s disease that could impair anastomotic healing, although a penetrating phenotype, typically considered the more aggressive phenotype, was not predictive of intra-abdominal sepsis. More likely, because there was a parallel increase in intra-abdominal sepsis with an increasing number of intestinal resections, the increased rate of intra-abdominal sepsis reflects the more difficult adhesiolysis or the potential for compromised blood supply at the anastomosis. Our findings support the recently published data from Lahey Hospital and Medical Center that suggested an increased risk of intra-abdominal sepsis with previous intestinal resection on univariate analysis,14 but we were able to confirm this finding on multivariable analysis. In addition, we had a larger sample (228 versus 83 patients with ≥1 previous resection) and extended the number of previous resections to ≥5. Because a previous intestinal resection is not a modifiable risk factor, in patients with additional previously identified risk factors, such as anemia,8 malnutrition,17 or combination immunosuppression, surgeons should consider temporary intestinal diversion to allow for optimization of nutrition and possible weaning of immunosuppressive medications.

Interestingly, previously identified risk factors for morbidity after ileocolic resection including steroids,7 , 17 , 18 biologicals,8 , 22 , 30 the presence of an abscess at surgery,7 , 18 , 31 increased operative duration,20 a handsewn anastomosis,20 , 32 and increased intraoperative blood loss33 were not associated with the development of intra-abdominal sepsis in this study. This may be because of our exclusion of all diverted patients, unlike previous studies.8 , 17 , 30 Exclusion of diverted patients would remove patients considered to be high risk by the operating surgeon, as demonstrated by the increased rate of diversion in nonelective cases. These findings may also reflect varying measures of postoperative morbidity, because some studies include intra-abdominal sepsis alone7 , 17 , 18 , 30 , 32 and others include all of the postoperative complications grouped together.8 , 10

Because intra-abdominal sepsis is the most feared, and potentially preventable, complication after ileocolic resection, it is of critical importance to identify associated risk factors to enable better decision-making regarding the use of diversion in the operating room. The inclusion by other studies of patients with diverting ostomies, known to reduce anastomotic leak,34 and the analysis of all postoperative morbidity, instead of focusing on intra-abdominal sepsis, limits their ability to direct the appropriate use of diversion. In contrast, 2 key strengths of our analysis were the focus on intra-abdominal sepsis alone and the exclusion of patients who were not diverted at the time of resection.

Although this is the largest institutional study to date on the development of intra-abdominal sepsis after ileocolic resection for Crohn’s disease, it is limited by being a retrospective study at a single tertiary referral center for IBD. As such, we cannot fully characterize how ill a patient is before surgery with respect to recent weight loss, for example. Thus, triple immunosuppression likely reflects a combination of the deleterious effects of these medications in addition to a patient sect with more severe disease. Second, some data were unavailable, including the histologic margin status of all specimens, which has been recently reported to be associated with an increased risk of anastomotic leak,9 the precise timing of the last infusion of biological therapy, and the preoperative serum level of biological medications, which have been suggested previously to be associated with postoperative complications.12 Third, laboratory values were often missing, because we do not routinely check laboratory values on all of the patients undergoing surgery; therefore, we could not fully assess the impact of preoperative anemia and malnutrition. Similarly, because of a low prevalence of tobacco use among our patients with Crohn’s disease, we were underpowered to fully assess the impact of preoperative tobacco use on intra-abdominal sepsis. Regardless, because of its association with intra-abdominal sepsis35 and Crohn’s disease recurrence,31 smoking cessation in patients with Crohn’s disease should continue to be advised.

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CONCLUSION

In the largest institutional series to date of >600 patients undergoing ileocolic resection for Crohn’s disease, triple immunosuppression was found to be a novel risk factor for the development of intra-abdominal sepsis, which likely reflects the deleterious effects of the medications and a more severe presentation of Crohn’s disease. This study also confirms the risk of repeat intestinal resection in the development of intra-abdominal sepsis. Patients with both risk factors have a >20% chance of developing intra-abdominal sepsis, whereas patients undergoing their fourth or more resection also have a risk of ≈20%. Patients on combination immunosuppression who are undergoing repeat resection warrant strong consideration of temporary diversion at the time of ileocolic resection.

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Keywords:

Crohn’s disease; Immunosuppression; Intra-abdominal sepsis

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