REVIEW URRENT C OPINION

Distinct management issues with Crohn’s disease of the small intestine Steven C.M. Fong a and Peter M. Irving a,b

Purpose of review Small bowel Crohn’s disease can present with clinical challenges that are specific to its location. In this review, we address some of the areas that present particular problems in small bowel Crohn’s disease. Recent findings A key issue specific to small bowel Crohn’s disease relates to its diagnosis given that access to the small bowel is limited. Radiological advances, particularly in small bowel ultrasonography and MRI, as well as the introduction of capsule endoscopy and balloon enteroscopy are helping to address this. In addition, our ability to differentiate small bowel Crohn’s disease from other causes of inflammation, such as tuberculosis, is improving on the basis of better understanding of the features that differentiate these conditions. It is also becoming apparent that jejunal Crohn’s disease represents a distinct disease phenotype with potentially worse clinical outcomes. Finally, because it is a rare complication, our understanding of small bowel cancer associated with Crohn’s disease remains limited. Recent publications are, however, starting to improve our knowledge of this condition. Summary Although small bowel Crohn’s disease presents specific management issues not seen in patients with Crohn’s disease elsewhere in the gastrointestinal tract, our knowledge of how to manage these is improving. Keywords cancer, Crohn’s disease, jejunal, small intestine, tuberculosis

INTRODUCTION About one-third of patients with Crohn’s disease have purely small bowel inflammation at the time of diagnosis [1], with another one-third having ileocolonic disease. Crohn’s disease affecting the small bowel is associated with distinct issues that do not occur in patients with colonic disease. This is related in part to the fact that the small bowel is anatomically and physiologically distinct from the large bowel but is also due to the fact that the disease behaves differently in different areas of the gastrointestinal tract. This is perhaps unsurprising given that there are genetic differences between small and large bowel disease [2 ]. In this review, we shall address several problems peculiar to small bowel Crohn’s disease. Crohn’s disease affecting the small bowel is less easily accessible endoscopically than when the colon is affected. Indeed, by virtue of its discontinuous nature, Crohn’s disease of the small intestine can evade diagnosis by ileo-colonoscopy unless the terminal ileum is affected [3]. This fact contributes to

the delay in diagnosis seen in many patients with Crohn’s disease [3]. As disease paradigms move towards earlier treatment in patients with a poor prognosis to prevent irreversible damage to the bowel, the failure to diagnose disease in a timely fashion represents a significant problem. A second diagnostic challenge comes in the differentiation of small bowel Crohn’s disease from other forms of terminal ileitis. Infections, such as tuberculosis (TB), can sometimes be difficult to differentiate from Crohn’s disease as can druginduced ileal ulceration.

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a

IBD Centre, Guy’s and St Thomas’ Hospital NHS Foundation Trust and Diabetes and Nutritional Sciences Division, King’s College London, London, UK b

Correspondence to Dr Peter M. Irving, Department of Gastroenterology, College House, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. Tel: +44 207 188 2499; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:92–97 DOI:10.1097/MOG.0000000000000149 Volume 31  Number 2  March 2015

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Inflammatory bowel disease Fong and Irving

KEY POINTS  Integrate different modalities (capsule endoscopy, MR/ CT enterography) to diagnose small bowel Crohn’s disease.  Intestinal tuberculosis and Crohn’s disease can be difficult to distinguish. Diagnosis requires a high index of suspicion in appropriate cases combined with clinical, radiologic and pathologic features, as well as diagnostic tests such as IGRAs.  Crohn’s disease of the jejunum is associated with worse clinical outcomes and may be prevalent in some populations.  The management of stricturing small bowel Crohn’s disease is hampered by a lack of useful biomarkers of its development as well as an effective antifibrotic therapy.  Small bowel adenocarcinoma in Crohn’s is a rare but serious complication with no specific diagnostic markers. Attention to particular clinical features and appropriate use of imaging modalities may enable earlier detection.

Once the diagnosis has been made, specific challenges related to ongoing management of Crohn’s disease arise. There is growing recognition that Crohn’s disease affecting the jejunum is associated with an increased risk of relapse compared with ileal Crohn’s disease. In addition, the development of strictures is far more common in small than large bowel disease. Furthermore, although it is possible completely to resect the colon without major longstanding morbidity, there is a limit to the amount of small bowel that can be safely resected before intestinal failure occurs. Finally, small bowel cancer associated with Crohn’s disease is a rare but difficult problem. Only a minority of patients with this condition are diagnosed preoperatively and there is a need for better diagnostic markers. In this overview, recent developments in these areas will be reviewed.

Diagnostic difficulties In contrast to the colon that is easily assessed colonoscopically, the small bowel is relatively inaccessible. Although the last few centimetres of the terminal ileum are normally, if not always, assessed at colonoscopy, the vast majority of the small bowel lies outside the reach of a colonoscope. Accordingly, on the diagnosis of small bowel, Crohn’s disease often requires alternative modalities of assessment. This not only creates challenges in diagnosing

patients with small bowel Crohn’s disease but also makes disease reassessment less easy. Advances in imaging techniques have been hugely helpful in this regard as has the development of faecal biomarkers of inflammation, and endoscopic techniques that allow better access to the small bowel. It is important to note that imaging techniques such as small bowel ultrasound, computed tomography (CT) and magnetic resonance (MR) enterography, along with capsule endoscopy and balloon enteroscopy, should be recognized as complementary investigations for the diagnosis and management of small bowel Crohn’s disease. An integrated approach involving the timely application of different investigations is most likely to result in appropriate and cost-effective assessment of the small bowel. Small bowel ultrasound Ultrasonographic assessment of the bowel in inflammatory bowel disease (IBD) is most common in countries in which gastroenterologists are trained in its use thereby allowing immediate radiological assessment of the small bowel in the outpatient setting [4]. Advances over the past 20 years have increased the diagnostic yield of ultrasonography, and modern technology has improved image quality resulting in better diagnostic yield [5 ]. Colour flow Doppler and contrast-enhanced ultrasound are particularly useful in the evaluation of inflammatory activity. Contrast-enhanced ultrasound involves intravenous administration of microbubble contrast agents that provide real-time depiction of the small bowel microvasculature and its perfusion [6 ]. Accordingly, the use of Doppler and contrast media allows detection and quantification of intramural vascularization in thickened bowel wall. Although a recent systematic review showed that ultrasonography was a useful technique for the diagnosis of small bowel Crohn’s disease, it was less sensitive for diagnosis of disease proximal to the terminal ileum [7]. In a meta-analysis of prospective studies comparing the accuracy of ultrasonography, CT, MRI, scintigraphy and PET in IBD, no significant differences in sensitivity and specificity were observed among these techniques [8]. However, in a recent comparative study, MR was superior to noncontrast ultrasound in defining disease extent [9 ]. Ultrasound is, however, highly operatordependent and correct interpretation of findings requires experience in abdominal and bowel sonography. Ultrasonography also has significant limitations in deep pelvic disease and obese patients.

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Computed tomography and magnetic resonance enterography Both CT and MRI provide clear images of the entire length of the small intestine [10 ]. The diagnostic accuracy of these techniques is comparable [7,11 ]. However, as with ultrasound, MR enterography avoids exposure to ionizing radiation, a significant disadvantage with CT enterography. One advantage of cross-sectional imaging is in the diagnosis of extra-luminal complications of Crohn’s disease, although contrast ultrasound has also been shown to be effective in this regard [12 ]. However, where MR and CT enterography are particularly useful is in providing a ‘roadmap’ prior to surgical intervention given their ability to provide accurate information about the length of the small bowel and, in particular, an idea of the amount of unaffected small bowel [13 ]. Another benefit of MR and CT is that they have high interobserver agreement [14]. Technological advancements in CT and MR imaging continue to evolve. The advent of low-dose CT decreases the radiation exposure associated with its use, and experimental techniques in MRI, which have exciting but unknown potential, include diffusion weighted imaging, spectroscopy and perfusion imaging [15]. &&

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Capsule endoscopy The first prospective study to use wireless capsule endoscopy for diagnosing Crohn’s disease of the small bowel was conducted in 2000 [16]. It now has an established role as a diagnostic tool in patients with suspected Crohn’s disease. For suspected Crohn’s disease, capsule endoscopy was superior to CT enterography (yield of 68 vs. 21%, respectively), small bowel radiography (52 vs. 16%) and ileocolonoscopy (47 vs. 25%) [17]. In addition, a recent prospective study [18] reinforced the conclusion that capsule endoscopy has a higher diagnostic yield than small bowel barium follow through and ileo-colonoscopy. A further benefit of capsule endoscopy is in the assessment of known Crohn’s disease. In a recent study, capsule endoscopy was used to assess mucosal healing and ‘deep remission’ in a cohort of symptomatic patients with small bowel Crohn’s disease treated with an immunomodulator or a biologic [19 ]. About 42% of the cases showed complete mucosal healing, similar to results seen in colonic studies. Although the number of patients enrolled in the study was small (43 participants), the data suggest that capsule endoscopy may have a role in monitoring treatment response. However, diagnosing Crohn’s disease solely on the basis of capsule endoscopy is probably unwise; &&

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confirmation of the diagnosis with endoscopy and biopsy (where possible) is generally advocated [20]. An algorithm incorporating the use of capsule endoscopy has been proposed [21]. Advances in technology continue to push the boundaries of capsule endoscopy. Lateral panoramic 3608 capsule endoscopes containing four high-definition cameras with high frame per second rates and long-lasting battery life have been developed [22 ]. A recent case study showed their capability in detecting extensive small bowel Crohn’s disease [23], although whether this will enhance detection rates of Crohn’s disease remains to be seen. Despite the advent of noninvasive modalities for diagnosing Crohn’s disease, balloon enteroscopy has a useful role in diagnosing small bowel Crohn’s disease. For example, in a prospective study comparing MR enterography and enteroscopy, enteroscopy was more sensitive in the detection of stenoses [24]. &

DIFFERENTIATION OF CROHN’S DISEASE FROM INTESTINAL TUBERCULOSIS Differentiating between Crohn’s disease and other causes of small bowel inflammation can be challenging. Furthermore, misdiagnosis can lead to unnecessary morbidity and cost. Identification of acid fast bacilli on histology has low sensitivity and specificity, and in countries with a high prevalence of TB, a therapeutic trial of antituberculous agents is often used. However, in countries with a low prevalence of TB where Crohn’s disease is the more likely diagnosis but when exclusion of TB has important therapeutic implications, there is a clear need for improved diagnostic techniques. A number of features help to distinguish small bowel Crohn’s disease from TB, including clinical, endoscopic, histologic and radiologic parameters, although having a high index of clinical suspicion in patients at a particular risk is of paramount importance (Table 1) [25]. A recent retrospective study [26] of 141 patients with Crohn’s disease and 47 patients with intestinal TB analysed CT enterography in combination with clinical features to identify diagnostic markers of TB. Clinical features favouring Crohn’s disease included a longer symptom duration, appendectomy history, diarrhoea, haematochezia, weight loss, perianal disease and extra-intestinal symptoms. Fever, night sweats and intercurrent pulmonary TB were more indicative of intestinal TB. On CT, there was more involvement of the ileocaecal valve, the adjacent ileum and right hemicolon in intestinal TB than in Crohn’s disease. Lesions in the ileum, left colon, rectum, perianal region and appendix suggested a more likely diagnosis of Crohn’s disease [26]. Volume 31  Number 2  March 2015

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Inflammatory bowel disease Fong and Irving Table 1. Clinical, radiological, endoscopic and histological features that aid in differentiation of Crohn’s disease and intestinal tuberculosis [25]

Clinical presentation

Favouring intestinal tuberculosis

Favouring Crohn’s disease

Fever

Longer symptom duration

Night sweats

Appendectomy history

Intercurrent pulmonary TB

Diarrhoea Haematochezia Weight loss Perianal disease Extra-intestinal symptoms

CT findings

Increased involvement of ileocaecal valve, adjacent ileum and right hemicolon

Endoscopic findings

Lesions in ileum, left colon, rectum, perianal region and appendix

Asymmetric thickening of colon wall

Symmetric wall thickening

Enlarged necrotic lymph nodes

Mural stratification

Patulous ileocaecal valve

Anorectal involvement

Transverse ulcers

Longitudinal ulcers Aphthous ulcers Cobblestone appearance

Histological

Confluent granulomata with caseating necrosis

Less frequent and smaller granulomata

CT, computed tomography; TB, tuberculosis.

Another retrospective study analysed the clinical, radiological, endoscopic and histological features of 213 patients with intestinal TB, Crohn’s disease or primary intestinal lymphoma [27]. Patients with abdominal pain as the first symptom and with transverse ulcers and caseating granulomas were more likely to have intestinal TB than Crohn’s disease. Stool change as the first symptom, moderate or severe anaemia, thickening of intestinal wall, rectal involvement, skip lesions, prominent lymphoid aggregates and irregular glands were more common in Crohn’s disease. Interferon gamma release assays (IGRAs) are a relatively new development that can be used as a diagnostic aid for latent and active TB. A recent systematic review assessed the accuracy of IGRAs in differentiating intestinal TB from Crohn’s disease in Asians [28 ]. IGRAs were found to have a high specificity for intestinal TB. It was proposed that IGRAs could be used as a supplementary diagnostic tool, especially in the initial workup. Further prospective studies should be carried out before deciding whether this is applicable to different demographic groups. The utility of IGRA in detecting latent TB is particularly important prior to starting antitumour necrosis factor therapy. A recent study [29] showed a detection rate of 21.9% in a cohort of patients with IBD, although concurrent immunosuppressive therapy seems to negatively impact the sensitivity of the test. &

JEJUNAL CROHN’S DISEASE The clinical significance of Crohn’s disease involving the proximal small intestine is beginning to attract interest. In a retrospective study from France, 108 patients with Crohn’s disease underwent small bowel capsule endoscopy to assess for jejunal lesions [30], which were found in more than half of the patients. Their prevalence was higher when the terminal ileum was involved and, interestingly, was associated with an increased risk of further clinical relapse. These findings are in agreement with another study that showed that jejunal disease was a significant risk factor for stricturing disease and multiple abdominal surgeries [31 ]. There is also some evidence that jejunal disease may be more prevalent in certain populations. For example, a study [32] of 1403 Korean patients showed higher rates of jejunal involvement in comparison to Western populations. Jejunal disease was associated with increased rates of stricturoplasties and hospitalizations. Whether this relates to differences in genotype, environment or perhaps a combination of the two is unclear. These data suggest that jejunal disease may predict worse outcome. It has been previously proposed that the current Montreal classification should be revised to include separate designation for jejunal disease [31 ]. Further studies into jejunal Crohn’s disease may help confirm its prognostic value and establish its significance.

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STRICTURING CROHN’S DISEASE The most commonly encountered problem in small bowel Crohn’s disease is the development of strictures. The underlying mechanisms causing intestinal fibrosis remain incompletely understood, but significant progress is being made in identifying key mediators through the use of novel animal models. New concepts involving interleukin (IL)17, Th17 immune responses, the renin-angiotensin system and the relevance of the gut microbiota are currently being explored [33]. Unfortunately, it is difficult to determine which patients will develop strictures and, in addition, there remains a lack of effective antifibrotic therapy [34 ]. Initial management involves the use of imaging to detect strictures in patients with suggestive symptoms. Once found, the balance of active inflammation and fibrosis will help determine whether the disease is likely to respond to medical therapy, although this can be difficult to determine radiologically. The location, length and number of strictures will influence the choice between surgical resection, stricturoplasty or endoscopic dilatation, which with the advent of balloon enteroscopy is now possible throughout the small bowel. Bowel length preservation remains an important principle in Crohn’s disease and, despite the advent of newer therapies, loss of functional bowel is almost inevitable once stricturing has occurred. Accordingly, strategies to avoid resection remain important; a recent uncontrolled study of endoscopic dilatation combined with serial injections of infliximab into strictures showed some potential [35]. &

CROHN’S DISEASE AND SMALL INTESTINE ADENOCARCINOMA Small bowel adenocarcinoma is a rare but recognized complication of Crohn’s disease. It carries a poor prognosis [36] and only a minority of cases are diagnosed preoperatively [37]. Diagnostic delay is compounded by the difficulties of screening for small bowel cancer, difficulties in differentiating the symptoms from those of stricturing small bowel disease and by its low prevalence. Indeed, because it is rare, accurately measuring its incidence is difficult. Standard incidence ratios from three metaanalyses ranged from 27.1 to 33.2 [38–40]. In a recent French prospective, observational study, five new cases of small bowel adenocarcinoma were diagnosed from the 8222 patients with small bowel Crohn’s disease [41 ]. This yielded an incidence rate of 0.235 per 1000 patient-years among those with small bowel involvement. Compared with sporadic small bowel adenocarcinoma, Crohn’s-related small bowel cancer appears in younger patients (fourth decade of life) and

mainly in the ileum [42]. The pathogenesis is poorly defined [36], though there is evidence to suggest that, just like in colonic cancers driven by IBD, an inflammation-dysplasia-adenocarcinoma sequence is involved [30]. Two important clinical indicators (which are by no means exclusive to this condition) are recrudescent symptoms after long periods of relative quiescence and small bowel obstruction that is refractory to medical therapy [43]. With the lack of specific symptoms to define small bowel adenocarcinoma, radiological features are probably the most useful marker that a stricture is malignant rather than benign. Weber et al. [44] conducted a retrospective review to further characterize CT enterography imaging features of small bowel adenocarcinoma. Features concerning malignancy included an annular mass, nodularity at the extraluminal margins of the mass and perforation. Nearly all tumours arose in regions of chronic inflammation and caused luminal narrowing with prestenotic dilatation [44]. In two cases in which MR enterography detected the cancer prior to surgery, radiological characteristics included a long, circumferential, asymmetric and heterogeneous thickening of the ileum with a visible nodule in one case and in the other, a mass of the terminal ileum showing restricted diffusion on diffusion-weighted imaging [45].

CONCLUSION Crohn’s disease of the small intestine continues to challenge physicians and patients alike with a diverse set of clinical quandaries. Improved knowledge and understanding of the nature of these problems, bolstered by advances in imaging and endoscopic technology, will help to address these issues. Some of the clinical dilemmas highlighted here are in need of a more definitive management strategy with better diagnostic markers, and this underscores the importance of further research in these areas. Acknowledgements None. Financial support and sponsorship None.

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Conflicts of interest P.M.I. has received honoraria for acting in an advisory capacity or speaking on behalf of Abbvie, MSD, Takeda, Genentech, Warner Chilcott, Falk, Ferring, Tillotts Pharma. For the remaining author, none were declared. Volume 31  Number 2  March 2015

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn’s disease in population-based cohorts. Am J Gastroenterol 2010; 105:289–297. 2. Cleynen I, Gonzalez JR, Figueroa C, et al. Genetic factors conferring an incre& ased susceptibility to develop Crohn’s disease also influence disease phenotype: results from the IBDchip European Project. Gut 2013; 62:1556–1565. This retrospective study highlights how the NOD2 gene is an independent predictive factor for Crohn’s disease affecting the ileum. 3. Pimentel M, Chang M, Chow EJ, et al. Identification of a prodromal period in Crohn’s disease but not ulcerative colitis. Am J Gastroenterol 2000; 95:3458–3462. 4. Calabrese E. Bowel ultrasound for the assessment of Crohn’s disease. Gastroenterol Hepatol (N Y) 2011; 7:107–109. 5. Kralik R, Trnovsky P, Kopacova M. Transabdominal ultrasonography of the & small bowel. Gastroenterol Res Pract 2013; 2013:896704. This review highlights the various ultrasound modalities that can be used in visualizing the small bowel. 6. Quaia E. Contrast-enhanced ultrasound of the small bowel in Crohn’s dis& ease. Abdom Imaging 2013; 38:1005–1013. Contrast-enhanced ultrasound is an important tool in the detection of small bowel Crohn’s disease. 7. Panes J, Bouzas R, Chaparro M, et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease. Aliment Pharmacol Ther 2011; 34:125–145. 8. Horsthuis K, Bipat S, Bennink RJ, Stoker J. Inflammatory bowel disease diagnosed with US, MR, scintigraphy, and CT: meta-analysis of prospective studies. Radiology 2008; 247:64–79. 9. Castiglione F, Mainenti PP, De Palma GD, et al. Noninvasive diagnosis of && small bowel Crohn’s disease: direct comparison of bowel sonography and magnetic resonance enterography. Inflamm Bowel Dis 2013; 19:991–998. MR enterography is superior to noncontrast ultrasound in detecting small bowel Crohn’s disease. 10. Amitai MM, Ben-Horin S, Eliakim R, Kopylov U. Magnetic resonance enter&& ography in Crohn’s disease: a guide to common imaging manifestations for the IBD physician. J Crohns Colitis 2013; 7:603–615. This review provides useful insights regarding indications for MR enterography, techniques and radiological findings in Crohn’s disease to aid the IBD doctor in daily practice. 11. Patel NS, Pola S, Muralimohan R, et al. Outcomes of computed tomography & and magnetic resonance enterography in clinical practice of inflammatory bowel disease. Dig Dis Sci 2014; 59:838–849. CT and MR enterography have comparable accuracy in diagnosis of small bowel Crohn’s disease. 12. Kumar S, Hakim A, Alexakis C, et al. Small intestinal contrast ultrasonography & for the detection of small bowel complications in Crohn’s disease: correlation with intra-operative findings and MR enterography. J Gastroenterol Hepatol 2015; 30:86–91. Ultrasound can detect extra-luminal complications of Crohn’s disease with a similar accuracy to MR enterography. 13. Sinha R, Trivedi D, Murphy PD, Fallis S. Small-intestinal length measurement & on MR enterography: comparison with in vivo surgical measurement. AJR Am J Roentgenol 2014; 203:W274–W279. By measuring small bowel length, MR enterography can provide a ’roadmap’ to surgeons regarding optimal surgical plan 14. Schleder S, Pawlik M, Wiggermann P, et al. Interobserver agreement in MR enterography for diagnostic assessment in patients with Crohn’s disease. Rofo 2013; 185:992–997. 15. Maccioni F, Patak MA, Signore A, Laghi A. New frontiers of MRI in Crohn’s disease: motility imaging, diffusion-weighted imaging, perfusion MRI, MR spectroscopy, molecular imaging, and hybrid imaging (PET/MRI). Abdom Imaging 2012; 37:974–982. 16. Fireman Z, Mahajna E, Broide E, et al. Diagnosing small bowel Crohn’s disease with wireless capsule endoscopy. Gut 2003; 52:390–392. 17. Dionisio PM, Gurudu SR, Leighton JA, et al. Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn’s disease: a meta-analysis. Am J Gastroenterol 2010; 105:1240–1248. 18. Leighton JA, Gralnek IM, Cohen SA, et al. Capsule endoscopy is superior to small-bowel follow-through and equivalent to ileocolonoscopy in suspected Crohn’s disease. Clin Gastroenterol Hepatol 2014; 12:609–615. 19. Hall B, Holleran G, Chin JL, et al. A prospective 52week mucosal healing && assessment of small bowel Crohn’s disease as detected by capsule endoscopy. J Crohns Colitis 2014; 8:1601–1609. This study highlights the potential of capsule endoscopy to monitor treatment response.

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Distinct management issues with Crohn's disease of the small intestine.

Small bowel Crohn's disease can present with clinical challenges that are specific to its location. In this review, we address some of the areas that ...
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