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Corresponding authors: Hiroki Yagi, MD., PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, TEL: +81-03-3815-5411 FAX: +81-3-5800-9182, , Eisuke Amiya, MD., PhD. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, TEL: +81-03-3815-5411 FAX: +81-3-5800-9182,
Affiliations
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo; Bunkyo-ku, Tokyo 113-8655, Japan
Corresponding authors: Hiroki Yagi, MD., PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, TEL: +81-03-3815-5411 FAX: +81-3-5800-9182, , Eisuke Amiya, MD., PhD. Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, TEL: +81-03-3815-5411 FAX: +81-3-5800-9182,
Affiliations
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo; Bunkyo-ku, Tokyo 113-8655, JapanDepartment of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo; Bunkyo-ku, Tokyo 113-8655, Japan
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo; Bunkyo-ku, Tokyo 113-8655, JapanAdvanced Medical Center for Heart Failure, Graduate School of Medicine, The University of Tokyo; Bunkyo-ku, Tokyo 113-8655, Japan
Immunoglobulin G4 (IgG4)-related disease (RD) is a systemic disease characterized by serum IgG4 upregulation, massive infiltration of IgG4-positive plasma cells, and storiform fibrosis, which results in nodules or thickening of the involved organs. Cardiologists have recently recognized that IgG4-RD can be complicated by coronary artery events (CAEs); however, the mechanisms and clinical characteristics of this phenomenon are unknown. We evaluated the clinical signs of patients with coronary periarteritis (CP), aortic periarteritis (AP), and pericardial thickening, which are complications of IgG4-RD, to determine the contributing factors.
Methods
We retrospectively examined 19 patients with IgG4-RD who attended or consulted a cardiologist at our department in the University of Tokyo Hospital between January 1, 2004, and December 31, 2021.
Results
The frequency of CAEs was significantly higher in the CP group than that in the non-CP group. Furthermore, the CP group had significantly lower event-free survival than the non-CP group (log-rank test, P = 0.008). However, the frequency of incidents and event-free survival for CAEs after IgG4-RD diagnosis did not differ significantly between the AP and non-AP groups. Although there was no statistically significant difference between the frequency of CAEs between those with and without pericardial thickening, the pericardial thickening group had significantly worse event-free survival than the non-pericardial thickening group (log-rank test, P = 0.017).
Conclusions
The incidence and clinical course of CAEs complicated by IgG4-RD could be predicted by identifying CP and pericardial thickening in IgG4-RD but not AP.
Immunoglobulin G4 (IgG4)-related disease (RD) is characterized by elevated serum IgG4 levels, mass formation, diffuse thickening, swelling, and fibrotic lesions due to the infiltration of IgG4-positive plasma cells. In 2001, Hamano et al. reported the first case of autoimmune pancreatitis with IgG4 infiltration [
]. Subsequently, it became clear that there were pathological conditions with similar serological and histological features in various tissues, including endocrine and exocrine organs, lungs, skin, and kidneys, known as IgG4-RD [[
]]. IgG4-RD is generally responsive to steroid therapy; however, some patients are refractory to glucocorticoids and other immunosuppressive treatments or relapse repeatedly after temporary improvement, and the progression of fibrosis in affected organs can lead to severe functional disability.
The recent development of multidetector-row computed tomography (CT) and other imaging techniques has revealed that IgG4-RD legions extend to cardiovascular organs, causing coronary periarteritis (CP), aortic periarteritis (AP), and pericardial thickening [[[[[[
]]]]]]. However, the factors that determine the affected sites are unknown. AP can lead to aortic aneurysm formation, which requires surgical or endovascular intervention. However, the main symptoms of IgG4-related CP include massive aneurysms or multiple ectasias and stenoses in the coronary arteries, for which there is currently no established treatment. Therefore, predicting coronary artery events (CAEs) in patients with IgG-RD and providing appropriate early treatment is essential.
Therefore, this study aimed to evaluate the clinical signs of patients with IgG4-RD with CP, AP, and pericardial thickening, and investigate their associations with CAEs, and identify the major contributing factors for the occurrence of CAEs in patients with IgG4-RD.
PATIENTS AND METHODS
Patients
We retrospectively investigated 20 consecutive patients with suspected IgG4-RD who visited our department for cardiovascular disease-related signs and symptoms (e.g., chest symptoms and abnormal CT findings, electrocardiogram, and echocardiography) between January 1, 2004, and December 31, 2021. We excluded one case with an incomplete examination, and finally, we analyzed 19 patients diagnosed with IgG4-RD. All patients had been diagnosed with IgG4-RD based on the comprehensive diagnostic criteria for IgG4-RD [
]. Patients with a “possible” diagnosis of IgG4-RD without pathological diagnosis were confirmed to have IgG4-RD using the classification criteria developed by the American College of Rheumatology [
Members of the ACR/EULAR IgG4-RD Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease.
]. IgG4-RD was diagnosed after the following diseases were ruled out: lymphoma, Castleman’s disease, Rosai–Dorfman disease, Erdheim–Chester disease, and anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) [[[[
We analyzed the clinical characteristics of the patients, including their laboratory data, at the time of diagnosis. The patients were divided into two groups according to the presence or absence of CP, AP, and pericardial thickening, and their clinical characteristics and outcomes were CAEs. CAEs are composite of ischemic heart disease (IHD) that require invasive therapy, such as percutaneous coronary intervention (PCI), coronary artery bypass surgery (CABG), and coronary aneurysms that require treatment with aneurysmectomy after or immediately after the diagnosis of IgG4-RD. IHD is characterized by a history of acute coronary syndrome, coronary revascularization >3 months ago, or angiographically documented coronary artery stenosis with at least 75% narrowing of the diameter according to the American Heart Association classification.
Image evaluation
All 19 patients underwent whole-body contrast-enhanced CT during diagnosis and at the discretion of the attending physician during the follow-up period. Experienced radiologists and cardiologists analyzed all imaging data. We performed positron emission tomography-CT on 14 (73.7%) patients. AP and CP were characterized by diffuse circumferential thickening of the arterial wall (adventitia) or a soft tissue mass around the artery with higher CT values than the surrounding normal peri-artery area with lesion sites having a larger diameter than the diameter of adjacent non-lesion sites on contrast-enhanced CT [[
Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts' diagnosis.
]]. Retroperitoneal fibrosis was diagnosed when a soft tissue shadow was observed on the renal pelvis and ureter, or when placoid tumorous lesions were observed in the retroperitoneal region. Pericardial thickening is characterized by discontinuous pericardial thickening on contrast-enhanced CT. An echocardiogram simultaneously confirmed the absence of pericardial effusion to differentiate it from pericardial effusion.
Statistical analysis
All data were expressed as mean ± standard deviation or medians/interquartile ranges. Two-tailed Student’s t-test or Mann–Whitney U-test was used for two-group comparisons, and Fisher’s exact test was used to determine significant differences in frequency. The Kaplan–Meier method was used to construct event-free survival curve for CAEs and compared using the log-rank test. The endpoint of the event-free survival curve was defined as the time of revascularization or CAE-related death, and time zero was defined as the time of IgG4-RD diagnosis. The significance level was set at P < 0.05. Prism 8.0 (GraphPad, La Jolla, CA, USA) was used to statistically analyze all data.
RESULTS
Patient characteristics in this study
Table 1 shows the characteristics of the patients included in this study at the time of diagnosis. Of the 19 patients, 15 (78.9%) were men, and the mean age of the patients was 68.1 ± 7.7 years. Tissue sampling was performed in nine (47.4%) patients, including the submandibular gland, salivary gland, skin, extrapleural soft tissue, retroperitoneum, right infraorbital mass, and left inguinal lymph node. A total of 17 (89.5%) patients had elevated serum IgG4 levels >135 mg/dL, and the median IgG4 level was 661.0 mg/dL (235.0–1290 mg/dL). The mean CRP and the median eosinophil level, which are potential biomarkers of disease activity, were 0.59 ± 0.81 mg/dL and 200.0/μL (150.0–800.0 /μL). Patients with IgG4-RD were diagnosed as definite in seven (36.8%), probable in two (10.5%), and possible in 10 (52.6%) patients based on comprehensive diagnostic criteria for IgG4-RD [
]. The duration of the disease was 8.2 ± 5.4 years. We treated 14 patients (78.9%) with steroids, four (21.1%) with azathioprine, and one (5.3%) with methotrexate.
Table 1Patient characteristics at the time of diagnosis
We investigated the distribution of organ involvement to understand this cohort better. Table 1 shows that 17 (89.5%) patients had multi-organ involvement. Regarding non-cardiovascular involvement, seven (36.8%) patients had eye involvement, such as the lacrimal gland. A total of five (26.3%) patients had autoimmune pancreatitis, five (26.3%) patients had involvement of the salivary, parotid, and submandibular glands; four (21.1%) patients had involvement of the bone, lung, and lymph nodes; and two (10.5%) patients had involvement of the liver, biliary, and kidney. Regarding cardiovascular involvements, nine (47.4%) patients were complicated by CP, and the affected vessel was the left anterior descending (LAD) artery in seven patients, the left circumflex artery in four patients, and the right coronary artery (RCA) in seven patients (Fig. 1). Twelve (63.2%) patients had complicated AP, and the affected vessels were the ascending aorta in six patients, the aortic arch in one patient, the descending thoracic aorta in four patients, the abdominal aorta in seven patients, and the iliac artery in six patients (Fig. 2). Seven (36.8%) patients had retroperitoneal fibrosis, six of whom also had AP. A total of five (26.3%) patients had pericardial thickening (Fig. 3). Venn diagram (Fig.4) shows that four (21.1%) patients with IgG4-RD in this study shared all three cardiovascular involvements, including CP, AP, and pericardial thickening.
Figure 1Contrast-enhanced computed tomography findings of IgG4-related coronary periarteritis. Thickened coronary periarterial lesions of the left anterior descending artery (A–D), left circumflex artery (E), and right coronary artery (F–I) are observed (arrowheads, yellow).
All patients had at least one risk factor for IHD, and eight (42.1%) patients had chronic kidney disease (CKD) with a glomerular filtration rate <60 mL/min/1.73 m2. A total of nine (47.3%) patients had complicated CAEs after or immediately after diagnosis of IgG4-RD, seven patients were treated with PCI or CABG for IHD, and two patients underwent aneurysmectomy for coronary aneurysms. Herein, two patients were diagnosed with IHD before they were diagnosed with IgG4-RD.
Differences in clinical features and the frequency of CAEs between patients with and without CP
Table 2 shows we evaluated the differences in clinical characteristics between the patients with and without CP. No differences in the mean age, serum IgG4 levels, frequency of hypertension, dyslipidemia, diabetes, CKD, and smoking history were observed between the CP and non-CP groups. However, the frequency of incident CAEs was substantially higher in the CP group than in the non-CP group (P = 0.023) (Fig. 5A). We further examined the differences in the Kaplan–Meier event-free survival curves for CAEs after diagnosing IgG4-RD between the CP and non-CP groups. The CP group had significantly lower event-free survival than the non-CP group (log-rank test, P = 0.008) (Fig. 5B).
Table 2Clinical features of patients with and without coronary periarteritis in IgG4- related disease
Figure 5Correlation between coronary periarteritis and coronary artery events complicated by IgG4-related disease. (A) The frequency CAEs in patients with and without CP was presented as numbers and compared using Fisher’s exact test. (B) The Kaplan–Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with and without CP, and the log-rank test was used to compare the distribution of the event-free survival for CAEs. *P < 0.05. CP, coronary periarteritis; CAEs, coronary artery events.
Differences in clinical features and the frequency of CAEs between patients with and without AP
Table 3 shows we investigated the differences in clinical characteristics between patients with and without AP among patients with IgG4-RD. We did not find significant differences in the mean age, serum IgG4 levels, frequency of hypertension, dyslipidemia, diabetes mellitus, CKD, and smoking history between the AP and non-AP groups. Furthermore, no significant differences in the concomitant frequency of CP or the frequency of CAEs were observed between the AP and non-AP groups (Fig. 6A, B). We examined the differences in Kaplan–Meier event-free survival curves for CAEs after diagnosing IgG4-RD between the AP and non-AP groups. We found no significant difference in event-free survival for CAEs between the AP and non-AP groups (log-rank test, P = 0.156) (Fig. 6C).
Table 3Clinical features of patients with and without aortic periarteritis in IgG4- related disease
Figure 6Correlation between aortic periarteritis and coronary artery events complicated by IgG4-related disease. (A) The concomitant frequency of CP in patients with and without AP was presented as numbers and compared using Fisher’s exact test. (B) The frequency of incident CAEs in patients with and without AP was presented as numbers and compared using Fisher’s exact test. (C) The Kaplan–Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with and without AP, and the log-rank test was used to compare the distribution of the event-free survival for CAEs. P < 0.05. AP, aortic periarteritis; CP, coronary periarteritis; CAEs, coronary artery events.
Differences in clinical features and the frequency of CAEs between patients with and without pericardial thickening
Table 4 shows the differences in clinical characteristics between patients with and without pericardial thickening were examined. No significant differences in the mean age, serum IgG4 levels, frequency of hypertension, dyslipidemia, diabetes, CKD, and smoking history were observed between the pericardial thickening and non-pericardial thickening groups. However, the concomitant frequency of CP was significantly higher in the pericardial thickening group than in the non-pericardial thickening group (P = 0.011) (Fig. 7A). We further investigated the differences in the Kaplan–Meier event-free survival curve for CAEs after the diagnosis of IgG4-RD between the pericardial thickening and non-pericardial thickening groups. However, the frequency of CAEs was not significantly different between the pericardial thickening and non-pericardial thickening groups (P = 0.141), the pericardial thickening group had significantly worse event-free survival than the non-pericardial thickening group (log-rank test, P = 0.017) (Fig. 7B, C).
Table 4Clinical features of patients with and without pericardial thickening in IgG4- related disease
Figure 7Correlation between pericardial thickening and coronary artery events complicated by IgG4-related disease. (A) The concomitant frequency of CP in patients with and without pericardial thickening was presented as numbers and compared using Fisher’s exact test. (B) The frequency of incident CAEs in patients with and without pericardial thickening was presented as numbers and compared using Fisher’s exact test. (C) The Kaplan–Meier analysis was performed to assess the differences in the event-free survival for CAEs after the diagnosis of IgG4-RD with and without pericardial thickening, and the log-rank test was used to compare the distribution of the event-free survival for CAEs. P < 0.05. CP, coronary periarteritis; CAEs, coronary artery events. We examined the differences in the Kaplan–Meier event-free survival curves of CAEs after the diagnosis of IgG4-RD between the AP and non-AP groups.
] was complicated by severe IHD, causing tumor-forming CP and multiple systemic aneurysms. Corticosteroid therapy was initiated, following which the inflammatory lesions shrank. However, the large, well-developed, common hepatic, and splenic aneurysms did not change. The patient died of splenic aneurysm rupture in the sixth month of treatment, with a worsening clinical course. An autopsy revealed infiltration of IgG4-positive plasmacytes into the coronary wall and a thinned splenic aneurysm wall.
] showed concomitant coronary artery dilation, pericardial inflammatory nodules, and a coronary–pulmonary fistula aneurysm in addition to several IgG4-RD lesions. Each feature was located close to the thickened pericardium. These lesions might have resulted from inflammation of the pericardial space, which extended to the coronary–pulmonary artery vessels, leading to the formation of aneurysms. The patient underwent surgical intervention to treat coronary–pulmonary fistula aneurysm.
] had a history of autoimmune pancreatitis. Moreover, prominent luminal enlargement (aneurysm) and diffuse periarterial inflammatory thickening of the coronary artery were observed. This patient underwent PCI of the LAD and was treated with prednisolone; however, aneurysmal formation in the peripheral RCA was exacerbated, and the patient eventually underwent aneurysmectomy and CABG.
Case 4 (Figs. 1C and 3D) had a history of autoimmune pancreatitis and IHD in the LAD and proximal RCA without massive aneurysms or multiple ectasias and stenoses. The patient underwent PCI for the LAD and was treated with prednisolone after revascularization. Prednisolone was administered in the other case with pericardial thickening (Figs. 1H and 3E), and the pericardial thickening and CP improved, At this point, the patient had no CAEs.
DISCUSSION
In this study, we demonstrated that the clinical course of CAEs worsens in patients with IgG4-RD complicated by CP and pericardial thickening. In particular, the relationship between pericardial thickening and CAEs seems to have high clinical significance. Therefore, the aggressive prediction of CAEs in patients with IgG4-RD is important when pericardial thickening is detected during image evaluation. Based on our findings, we propose that patients with IgG4-RD complicated by CP or pericardial thickening should have a more extensive cardiac workup, including stress scintigraphy, cardiac contrast-enhanced CT, and coronary angiography.
IgG4-RD is a disease in which IgG4-positive plasma cells infiltrate several organs and form masses, diffuse thickening, swelling, and fibrotic lesions; however, pericardial thickening is not a common complication. Sugimoto et al. and Ibe et al. reported cases of constrictive pericarditis with the upregulation of serum IgG4 levels [[
]]. Furthermore, Kabara et al. reported a case of a patient who had elevated serum IgG4 levels and presented with massive pericardial effusion with infiltration of IgG4-positive plasma cells, which was confirmed by fine-needle aspiration cytology [
]. Other cases have shown fluorodeoxyglucose accumulation in the pericardium on positron emission tomography, suggesting that the pericardium is a site where IgG4-related inflammation is likely to occur [
]. However, the significance and clinical presentation of pericardial thickening associated with IgG4-RD are unknown.
Herein, all five patients complicated by pericardial thickening had concomitant CP, 4 (80 %) of whom had CAEs, and one (20%) had no CAEs (Fig. 7A, B). The frequency of incident CAEs was not significantly different between the pericardial thickening and non-pericardial thickening groups; however, the pericardial thickening group had a significantly worse clinical course of CAEs than the non-pericardial thickening group (Fig. 7B, C). Case reports have shown that IgG4-RD with pericardial involvement had a fatal outcome with a rush clinical course [[
]]. Thus, in cases of IgG4-RD with pericardial thickening, the treatment strategy is often decided with caution, and the clinical course is likely to worsen.
Furthermore, we found that the frequency of incident CAEs was significantly higher in the CP group than that in the non-CP group (Fig. 5A). Angiographically distinguishing the etiology of IHD (atherosclerosis or IgG4-induced inflammation) may be difficult. studies have reported that there is a diffuse wall thickening type and a stenotic type, including occlusive thrombi, in CP [[
]]. Sakamoto et al. reported that serum IgG4 concentrations were higher in patients with angiographically proven IHD than in those without IHD. This finding suggests that IgG4-related immune-inflammation also contributes to the development and progression of coronary artery atherosclerosis [
]. Indeed, the patients in this study were more likely to be older men with multiple coronary risk factors (Table 1). Several patients were at a high risk of atherosclerotic IHD, and 2 (20.0%) patients in the non-CP group were complicated by CAEs after the diagnosis of IgG4-RD (Fig. 5A). However, the two aforementioned patients in the non-CP group were not complicated by pericardial thickening and had lesions that could be treated with conventional PCI without the confusion regarding the treatment strategy. The clinical course remained favorable without worsening, and no deaths related to CAEs were observed in the non-CP group (Fig. 5B). Hence, the presence or absence of CP and pericardial thickening may help predict the clinical course of CAEs in patients with IgG4-RD.
Furthermore, we found that the concomitant frequency of IgG4-related CP was substantially higher in the pericardial thickening group than that in the non-pericardial thickening group (Fig. 7A). However, this phenomenon was not observed in patients with IgG4-RD regardless of the presence of AP (Fig. 6A). This trend suggests that pericardial thickening reflects the intense inflammation of the coronary artery. Although we could not find any difference in the frequency of incident retroperitoneal fibrosis between the AP and non-AP groups (Table 3), studies reported that the close location of the aorta and retroperitoneum in a close space corresponds to the coincidence of AP and retroperitoneal fibrosis [[
] and our findings suggest that the strong inflammation of CP propagates from the adventitia to the intima, media, and pericardium. Based on these findings, diffuse pericardial thickening can be considered a subset of CP. However, the data from this study remain inadequate to explain the causality between CP and pericardial thickening. Further studies are required to better understand the unique manifestations of IgG4-RD.
This study had several limitations. First, it was a single-center retrospective study with a small sample size in Japan. Therefore, we could not investigate the causality of CAEs between CP and pericardial thickening. Second, we could not include all patients who visited our hospital; therefore, we limited our analysis to those patients that visited the cardiology department. Indeed, the clinical phenotype of the patient population in this study did not belong to groups 1-4 as described by Wallace et al. [
ACR/EULAR IgG4-RD Classification Criteria Committee. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.
]. The reason why the results of the group distribution was inconsistent with previous reports is due to the restriction of cases involving cardiologist in this study. Third, cardiac contrast-enhanced CT scans were performed in cases of chest pain and electrocardiographic and echocardiographic abnormalities, and/or when deemed necessary by the attending physician. Therefore, cardiac contrast-enhanced CT scans were not performed for all 19 patients included in this study, and it is possible that mild CP was not fully evaluated. However, we believe that further clarification of the clinical signs of IgG4-RD, is required for a more accurate diagnosis of IgG4-RD.
CONCLUSION
Identification of CP and pericardial thickening, but not AP, in IgG4-RD could predict the occurrence and clinical course of CAEs complicated by IgG4-RD. To the best of our knowledge, this is the first study to focus on the characteristics of CAEs in patients with IgG4-RD, based on their association with the surrounding pericardium. For patients diagnosed with IgG4-RD, proactive evaluation of CP and pericardial thickening and early prediction of CAEs may help clarify the treatment strategies.
Acknowledgments
None
REFERENCES
Hamano H
Kawa S
Horiuchi A
Unno H
Furuya N
Akamatsu T
Fukushima M
Nikaido T
Nakayama K
Usuda N
Kiyosawa K
High serum IgG4 concentrations in patients with sclerosing pancreatitis.
Members of the ACR/EULAR IgG4-RD Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease.
Clinical and pathological characteristics of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis diagnosed based on experts' diagnosis.
ACR/EULAR IgG4-RD Classification Criteria Committee. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.
EA belongs to the Department, endowed by NIPRO-Corp., Terumo-Corp., Senko Medical-Instrument-Mfg., Century-Medical, Inc., ONO-pharmaceutical-Co., Ltd. Medtronic-JAPAN Co., Ltd, Nippon-Shinyaku Co., Ltd, Mochida Pharmaceutical Co., Boehringer Ingelheim Pharmaceuticals Inc., Abiomed-Inc, AQuA-Inc, Fukuda-Denshi Co., Ltd, and Sun-Medical-Technology-Research Corp.. EA received research fund from Bristol-Myers Squibb Co..
Data availability
The data that support the findings of this study are available from the corresponding author on reasonable request.
Authors’ contributions
HY, EA, and MU were directly involved in managing the cases. SM, MH, NT, HA, and IK critically revised the manuscript for important intellectual content. All authors approved the content of the manuscript and confirmed the accuracy and integrity of any part of the work.
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