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Clinical Mooren’s Ulcer Dr. V.Rahul, DNB, Aravind Eye Hospital, Madurai Epidemiology Mooren's ulcer is a rare disorder, typically seen in healthy adult men1 with no evidence of systemic disease. It has been documented in a 3-year old child2. Wood and Kaufman having reported 9 cases concluded that there were two clinical types of Mooren's ulcer3. The first, limited type, is usually unilateral, with mild to moderate symptoms, generally responds well to medical and surgical treatment. This type is believed to occur in older patients and has become known as typical or benign Mooren's ulcer. In contrast, the second type is bilateral, with relatively more pain and generally a poor response to therapy. The bilateral variety, once believed to occur primarily in younger patients, became known as atypical or malignant Mooren's ulcer. The benign type is quarter time bilateral and the malignant type 75% time bilateral. Usually bilateral progressive form of this disease occurs in older individuals. Keitzman4 et al published a series of 37 cases of progressive Mooren's ulcer in Nigeria affecting primarily healthy men between the age of 20 and 30 years and the clinical course was very rapid, with total involvement and destruction of the cornea within 6 weeks. Perforation occurred in 36% of the patients. A later report by Majekodunmi AA et al5 confirmed that the malignant form was the more common form occurring in the young Nigerian men. As a result, the generalized belief has developed that the progressive and relentless atypical form of Mooren's ulcer has a predilection for young, (black) men. Lewallen and Courtright6, in their review of the published series of Mooren's ulcer, suggest that many of our current concepts of epidemiology of Mooren's ulcer are not supported by available data. They found that younger patients had bilateral disease less frequently than older patients (1.5:1) regardless of race and Caucasians were more than twice as likely to have bilateral disease as blacks. Although they found that men were 1.6 times more likely to have Mooren's ulcer than are women, it was pointed out that it could be due to factors such as increased incidence of ocular trauma in men (an association with Mooren's ulcer is reported by some) or cultural patterns that discourage female clinic attendance in certain countries. Clinical Features Patients with Mooren's ulcer usually complain of redness, tearing, and photophobia, but pain is typically the outstanding feature. The pain often is incapacitating and may well be out of proportion to the inflammation. There may also be a complaint of decreased visual acuity, which may be secondary to associated iritis, central corneal involvement, or irregular astigmatism due to peripheral corneal thinning. Mooren’s ulcer typically begins as a gray- white infiltrate in the peripheral cornea. In most patients, this process begins within the interpalpebral fissure. It is followed by epithelial breakdown and stromal melting. Eventually it develops into a chronic, usually painful corneal ulcer. The corneal ulceration spreads slowly involving the anterior one third to one half of the corneal stroma. The leading edge of the ulcer is undermined, infiltrated and de-epithelialized. Because of the tissue swelling, the exact depth of the undermining is difficult to appreciate unless the overhanging edge is removed. The ulcer progresses circumferentially and centrally. As it progresses, it creates an overhanging edge at its central border. Although the ulcer may begin as a shallow furrow in the peripheral cornea, over time it may involve the 2 limbus. The adjacent conjunctiva and sclera are usually inflamed and hyperemic. The presence of a peripheral corneal ulcer beginning at the limbus with a gray, overhanging infiltrated edge at its central border is characteristic of Mooren’s ulcer. As the disease progresses, the ulcer can spread both peripherally and centrally. Behind the advancing edge of the ulcer, healing may take place in the form of corneal reepithelializaton and vascularization. Associated with this is scarring and thinning. The healed areas remain clouded. Sometimes the remaining residual cornea only consists of descemet’s membrane with a small bit of posterior corneal stroma covered by epithelium known as contact lens cornea. Generally, there is involvement of the limbus, in contrast to some other forms of PUK, such as that seen with rheumatoid arthritis or staphylococcal marginal disease4. Vision may be decreased because of irregular astigmatism caused by peripheral corneal scarring. If the central cornea is involved, vision is permanently impaired. Classification of Mooren’s ulcer Watson.P.G7 has classified the disease based on the clinical presentation and the low dose anterior segment fluorescein findings into 1) Unilateral Mooren’s ulcer 2) Bilateral aggressive Mooren’s ulcer 3) Bilateral indolent Mooren’s ulcer Unilateral Mooren’s ulcer It is a rare condition that primarily affects patients aged above 60 years. Patients present with rapid onset of redness and excessive pain in the affected eye. Examination of the cornea will reveal the typical features of Mooren’s ulcer, which may progress slowly or extremely rapidly form a single focal point. Anterior segment angiography at this stage reveals venular occlusion of all the local episcleral and conjunctival vessels with the disruption of limbal arcade and leakage from deep vessels at the limbus and at the base of the ulcer. AECS Illumination If left untreated or sometimes in spite of treatment, the ulcer advances around the globe and towards the centre. The epithelium at the base of the ulcer and the remaining cornea remains intact. Eventually the central corneal stroma is removed entirely and all that remains is a thin layer of scar tissue covering an intact endothelium and covered by epithelium derived from conjunctiva. Bilateral aggressive Mooren’s ulcer Bilateral Mooren’s ulcer is commonly seen in Indian subcontinent and in communities of Indian origin and in parts of West Africa. It usually affects patients between 14 and 40 years. They may present with unilateral typical lesion in one eye but soon may develop lesion in the other eye. Angiography reveals changes in architecture of episcleral vessels with some areas of closure. There are no changes in conjunctiva but the angiogram reveals a breakup of the limbal arcade, extension of the vessels into the bed of the ulcer and leakage from the tips of these vessels. The ulcers may perforate spontaneously and if left untreated, stromal tissue is eventually removed. Bilateral indolent Mooren’s ulcer It usually affects patients in their fifth decade or older. It presents as bilateral indolent ulcers which progress slowly. Some may heal spontaneously. Angiography does not reveal any abnormality in the vasculature of the episcleral or conjunctival circulations. Abnormality of the limbal circulation and changes at the bases of the ulcer are seen. Pathology The histopathology of Mooren's ulcer suggests an immune process. Young and Watson8 studied the corneas of three patients who underwent grafting. They observed that the involved limbal cornea consisted of three zones. The superficial stroma was vascularized and infiltrated with plasma cells and lymphocytes. In this region, there was destruction of the collagen matrix. Epithelium and Bowman's layer were absent. The midstroma showed hyperactivity of Vol. XIV, No.2, April - June 2014 fibroblasts with disorganization of the collagen lamellae. The deep stroma was essentially intact but contained a heavy macrophage infiltrate. Descemet's membrane and the endothelium were spared. Heavy neutrophil infiltration, as well as dissolution of the superficial stroma, was present at the leading edge of the ulcer. These neutrophils showed evidence of degranulation. The adjacent conjunctiva shows epithelial hyperplasia and a subconjunctival lymphocytic and plasma cell infiltration. Frank vasculitis is not present, and numerous eosinophils may present in the nearby involved conjunctiva during the course of healing. Pathogenesis of Mooren's Ulceration Gottsch 9 et al have shown that serum from patients with Mooren’s ulcer contain antibodies to a cornea associated antigen, COAg. This antigen has now been found to be identical to calgranulin C which only occurs in the corneal stroma and in neutrophils. Recent studies have identified calgranulin C as an important factor in the pathogenesis of Mooren’s ulcer. Calgranulin C is a neutrophil protein that binds to paramyosin, a component of the thick filaments of parasite muscle. Receptors for calgranulin C are also known to occur on the surface of certain helminths. Sensitisation to calgranulin C could occur either acutely as a result of corneal infection or trauma, in which corneal tissue breakdown occurs resulting in the expression of normally cryptic tissue specific corneal antigens, or gradually during the normal slow turnover of tissue throughout the years. In addition, sensitisation to calgranulin C may occur subsequent to helminth infestation. Antigen presenting cells (APC) normally present at the limbus would present these “self ” or “cross reactive” antigens in the form of short peptides bound to HLA class II molecules. Sensitisation would only occur in susceptible individuals with the appropriate HLA genotypes as only a limited repertoire of peptides can associate with each HLA 3 molecule. Under these circumstances antigen/ MHC specific T cells will be primed. At a later date if one or both corneas are injured mechanically, surgically, or as a result of infection there would be macrophage infiltration of the cornea, and IFNg induced upregulation of cellular HLA expression. This would be particularly intense if there is a high circulating level of calgranulin C associated with a concomitant helminth infestation and its accompanying neutrophilia. An autoimmune response would then occur as a result of the presentation to and the response from previously primed effector T cells. Such a course of events would explain the worldwide genetic and geographic distribution, the rarity, and the absolute corneal stromal tissue specificity of this autoimmune condition. Diagnosis Mooren's ulcer is idiopathic and occurs in the absence of any systemic process that may cause PUK. It is a diagnosis of exclusion. Infectious etiologies should be excluded by appropriate cultures, because microbial keratitis can rapidly progress and is usually amenable to antibiotic therapy. Mooren's ulcer is easily distinguished from the noninflammatory corneal degenerations, such as Terrien's or Pellucid marginal degeneration, in which the epithelium remains intact and pain is absent. The presence of Mooren's-like ulcer requires an extensive search for occult and potentially lethal systemic diseases. A thorough medical history and examination is mandatory, as is comprehensive laboratory investigation. The investigation may include a complete blood count with evaluation of the differential count, platelet count, erythrocyte sedimentation rate, rheumatoid factor, complement fixation, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibody (ANCA), circulating immune complexes, liver function tests, VDRL and fluorescent treponemal antibody absorption (FTA-ABS) 4 tests, blood urea nitrogen and creatinine, serum protein electrophoresis, urinalysis, and a chest roentgenogram. Additional testing is done as indicated by the review of systems and physical examination. Differential Diagnosis Rheumatoid arthritis It is a frequent cause of peripheral ulcerative keratitis10. The clinical appearance of the peripheral ulceration is not unique in rheumatoid arthritis. Frequently, there may be an associated scleritis, a feature not characteristic of typical Mooren's ulcer. Other associated ophthalmic findings include keratoconjuctivitis sicca (the most common ophthalmic finding), episcleritis, and sclerosing keratitis. Advanced systemic involvement is usually apparent at time of ocular involvement10. The patient's clinical profile and positive serologic studies, in particular rheumatoid factor, will help establish the appropriate diagnosis. Wegener’s Granulomatosis Wegener's granulomatosis is a rare multisystem granulomatous necrotizing vasculitis with upper and lower respiratory tract and renal involvement. Ocular involvement may be seen in upto 58% of patients, including proptosis due to orbital involvement, scleritis with or without PUK, PUK alone, uveitis, and vasculitis11. A careful review of systems may disclose a history of upper or lower respiratory signs or symptoms (epistaxis, sinusitis, rhinorrhea, hoarseness, dysphagia, cough, or pleurisy), a history of microscopic hematuria, arthralagias, or skin lesions as the result of the underlying vasculitis process. Prompt diagnosis is imperative because the initiation of immunosuppressive therapy, such as cyclophasphamide, can be both sight and life saving11. Polyarteritis nodosa Classic polyarteritis nodosa (PAN) is a rare multisystem disease characterized by necrotizing vasculitis of small and medium-sized muscular AECS Illumination arteries. The etiology is unknown, and the diagnosis rests on the histopathologic identification of typical vascular changes. Microaneurysms at the bifurcation of the medium and small arteries are highly characteristic of the disease, especially in the kidney and mesentery. Choroidal vasculitis is the most common ophthalmic manifestation. Other ophthalmic findings include PUK, conjunctival lesions, scleritis, choroiditis, retinal vasculitis, optic atrophy, papilledema, exudative retinal detachment, and central artery occlusion. Serologic tests for hepatitis B surface antigen (HBsAg) should be obtained because approximately 50% of patients with PAN are seropositve. Staphylococcal marginal keratitis Staphylococcal marginal disease can present as a peripheral corneal infiltrate with overlying epithelial breakdown. There is a clear intervening zone between the infiltrate and limbus, and the keratitis is frequently accompanied by blepharitis. Patients complain of photophobia and irritation, but the severe and debilitating pain noted with Mooren's ulcer is not described. Rapid clinical improvement can usually be seen with mild topical steroids. The ulcers are believed to represent immune complex-mediated reactions to microbial antigens12. SLE Relapsing polychondiritis Systemic sclerosis Inflammatory bowel disease Gaint cell arteritis Herpes simplex corneal ulcer Terriens degeneration It differs from Mooren's ulcer in that it is typically painless, does not ulcerate and is usually non inflammatory. It has been reported more frequently in men and may occur at any age. The disease is usually bilateral but may be asymmetrical13. Terrien's degeneration usually begins in the superior cornea, in contrast to Mooren's ulcer, which typically begins in the interpalpebral region Vol. XIV, No.2, April - June 2014 as a fine, punctate, stromal opacity. A clear zone exists between the infiltrate and the limbus, which becomes superficially vascularized. Slowly progressive thinning follows. The thin area has a sloping peripheral border and a sharp central edge that is highlighted by a white lipid line. The epithelium remains intact, although bulging of thin stroma causes significant astigmatism. The thinning slowly progresses circumferentially but rarely centrally. Pellucid degeneration Pellucid degeneration causes bilateral, inferior corneal thinning that leads to marked, irregular, against-the-rule astigmatism. Pain and inflammation are lacking and the epithelium is intact, thus differentiating it from Mooren's ulcer. Senile furrow degeneration Thinning in the lucid interval between an arcus and limbus may occur in the elderly. However, the epithelium is intact and there is no infiltrate or inflammation. The furrow is shallow and not vascularized, with sloping central and peripheral edges. Progression is extremely slow, and has no risk of perforation. - Ocular rosacea - Leukemia Treatment of Mooren's Ulcer The overall goals of therapy are to arrest the destructive process and to promote healing and reepithelialization of the corneal surface. Historically, the therapeutic agents tried for Mooren's ulcer include subconjunctival dichloride of mercury14, carbonic and nitric acid, formalin15 and tincture of iodine16, trichloroacetic acid16, subconjunctival heparin17, and cyanide of mercury18. In addition, a number of procedures, such as irradiation19, galvanocautery20, paracentesis21, vitamin B1 injections, tuberculin injections22, and delimiting keratotomy23, have been attempted with little success. Today, most experts agree on a step-wise approach to the management of 5 Mooren's ulcer, which is outlined as follows: 1. Topical steroids 2. Conjunctival resection 3. Systemic immunosuppressives 4. Additional surgical procedure 5. Rehabilitation Topical steroids Initial therapy includes intensive topical steroids, consisting of prednisolone acetate or prednisolone phosphate 1%, hourly in association with topical cycloplegics and prophylactic antibiotics 24. If epithelial healing does not occur within 2 to 3 days, the frequency of topical steroid application can be increased to every half hour. Once healing occurs, the frequency can be reduced, and tapered slowly over a period of several months. Some authors have advocated oral pulse therapy (60 to 100 mg daily of oral prednisone) when topical therapy is ineffective after 7 to 10 days or in cases where topical steroids may be dangerous because of precariously deep ulcer or infiltrate. Topical tetracycline or medroxyprogesterone may be used for anticollagenolytic properties of each. A therapeutic soft contact lens or patching of the eye may be beneficial at this stage. Any concomitant eye disease, such as acne rosacea, meibomeitis, blepharitis, dry eye, or eyelid abnormalities is addressed24. Conjunctival Resection Due to its luxurious vascular and lymphatic endowment, the conjunctiva adjacent to the peripheral corneal ulcer has been hypothesized to serve as a major reservoir for various inflammatory cells and cytokines, thereby playing a critical role in the immuno-pathogenesis of peripheral ulcerative keratitis. Moreover, the substantia propria of the conjunctiva is filled with plasma cells25 which are likely involved in the local production of immunoglobulins found in the peripheral cornea. Circulating antibodies against cornea, first found in 1969 in patients with Mooren’s ulcer26, have been postulated to be produced from these plasma cells. 6 If the ulcer progresses despite the steroid regimen, conjunctival resection is performed24. It is usually performed under topical or subconjunctival anesthesia. This consists of conjunctival excision to bare sclera extending at least 2 clock hours to either side of the peripheral ulcer, and approximately 4 mm posterior to the corneoscleral limbus and parallel to the ulcer26. The overhanging lip of ulcerating cornea may also be removed. Cryotherapy of limbal conjunctiva has been advocated by some authors and may have a similar effect28. In Mondino's series29, conjunctival resection healed 3 of 4 unilateral ulcers and 3 of 3 bilateral nonsimultaneous ulcers, but only 2 of 15 bilateral simultaneous ulcers. Brown reported that excision of the limbal conjunctiva adjacent to the progressing ulcer resulted in healing of the ulcers in 8 of 10 eyes treated; however, it may be necessary to repeat this procedure three times before a beneficial effect is seen29. Stilma studied 38 Mooren's corneal ulcers and found that conjunctival excision with thermocoagulation gave some relief at the site of the ulcers, but recurrences at other places occurred in at least 52% of cases31. Kinoshita and colleagues32 reported success in their series of 20 Mooren's patients treated with keratoepithelioplasty. In this procedure, donor corneal lenticles are sutured onto the scleral bed after conjunctival excision. It is postulated that the lenticles form a biological barrier between host cornea and the reepithelializing conjunctiva and the immune components it may carry. In his study, 18 of 20 eyes (90%) showed prompt remission after surgery. Application of isobutyl cyanoacrylate, a tissue adhesive, may work in the same way but perhaps more simply and without the risk of epithelial rejection, glaucoma secondary to the chronic steroid use necessitated by keratoepithelioplasty and development of neurotrophic keratitis32. AECS Illumination Systemic immunosuppression Those cases of bilateral or progressive Mooren's ulcer that fail the preceding therapeutic attempts will require systemic cytotoxic chemotherapy to bring a halt to the progressive corneal destruction24. The most commonly used agents are Cyclophosphamide (2 mg/kg/day), Methotrexate (7.5 to 15 mg once weekly) and Azathioprine (2 mg/kg body weight/day). Cyclophosphamide belongs to nitrogen mustard group of alkylating agents. It has a profound effect on lymphoid cells. It is given in a dose of 2mg/kg body weight/day. The degree of fall in white blood cell count is considered as the most reliable indicator of immunosuppression produced by cyclophosphamide. Common dose limiting side effect includes bone marrow depression and sterile hemorrhagic cystitis. Azathioprine is a prodrug. It is metabolized in the body and is converted into its active metabolite, 6-mercaptopurine. It affects DNA and RNA metabolism by being converted into 6–thioinosine-5 phosphate by the enzyme hypoxanthine guanine phosphoribosyl transferase and is incorporated into nucleic acids leading to false codes being generated. It is given at the dose of 1 – 2.5 mg / kg body weight per day in divided doses. Acute adverse effects of Azathioprine therapy include leucopenia, thrombocytopenia and gastrointestinal disturbances. Methotrexate is a folate analogue which affects the enzyme dihydrofolate recuctase. The enzyme is imperative for production of tetrahydrofolate, an important coenzyme in cell metabolism. Methotrexate has antiproliferative effect on endothelial cells, decreases leukotriene synthesis by leukocytes and suppresses cell mediated immunity. It is given in doses of 7.5 to 25 mg weekly. Folic acid supplementation is recommended during therapy with Methotrexate. Patients are advised to abstain from alcohol. Side effects of Methotrexate therapy include severe depression of white blood cell count and thrombocytopenia. Hepatotoxicity Vol. XIV, No.2, April - June 2014 is a common side effect. Liver enzyme levels twice those of normals warrant withholding or stopping of the medication. Other side effects include acute pneumonitis, impairment of renal function, alopecia. Methotrexate is teratogenic and is not used during pregnancy and birth control is advised for sometime after the medication is stopped. Oral Cyclosporin A (5 - 10 mg/kg/day) has been successfully used to treat a case of bilateral Mooren's ulcer unresponsive to local therapy with topical corticosteroids, silver nitrate, and conjunctival resection, as well as systemic immunosuppression with corticosteroids, cyclophosphamide, and azathioprine33. It affects release of interleukin. It works by suppression of the helper T cell population and stimulation of the depressed population of suppressor and cytotoxic T cells present in patients with Mooren's ulcer. Common side effects include hypertension, renal impairment, parasthesias,hyperuricemia, gingivitis, hypertrichorism. Systemic immunosuppressive therapy is best handled by close collaboration between an ophthalmologist and oncologist. The potentially serious side effects of systemic immunosuppressive agents have led several groups to investigate the efficacy of topical applied cyclosporin A in the treatment of Mooren's ulcer34. In Holland's35 series of a variety of anterior segment inflammatory diseases; two patients had Mooren's ulcer. The first, with bilateral disease, showed reduced inflammation with minimal progression over 3 years, whereas the second, with unilateral disease, showed resolution of the ulcer on this medication. In Zhao and Jin's series, 15 of 18 eyes with Mooren's ulcer improved, and 11 of these were cured with topical cyclosporine A therapy (0.5% solution). In both studies, local or systemic side effects attributable to topical cyclosporine A were not observed. Foster reported arrest of the inflammatory process and preservation of ocular anatomy and function in 8 of 9 patients with bilateral involvement treated with immunosuppressives for 6 to 24 months36. Mondino has reported that 7 immunosuppressive drugs halted progression in 4 of 13 patients with Mooren's ulcer who did not respond to topical corticosteroids or conjunctival resection. In this series immunosuppressive drugs were reserved for only the most severe, resistant cases37. Surgical Procedure Superficial lamellar keratectomy involves resection of overhanging lip of the ulcerating cornea and application of tissue adhesive with bandage soft contact lens application or amniotic membrane. It has been shown to arrest the inflammatory process and allow healing38. Superficial lamellar keratectomy may aid the removal of corneal antigenic stimulus of the autoimmune process that causes stromal melting39. It may also act by reducing activated keratocytes which may be a source of collagenase40 and polymorphonuclear neutrophils which have already invaded the corneal stroma as part of the pathological process. After refining the technique in previous series, Nian and colleagues41 found 34 of 40 eyes to be successfully healed after lamellar keratectomy. Four of 6 eyes with recurrent ulcer healed with retransplantation while the other patients refused further intervention. Some cases may progress to perforation despite management. Small perforations may be treated with application of tissue adhesive and placement of a soft contact lens to provide comfort and to prevent dislodging of the glue24. When a perforation is too large for tissue adhesive to seal the leak, some type of patch graft will be necessary. This may range from a small tapered plug of corneal tissue to a penetrating keratoplasty. In case of larger peripheral perforations, a partial penetrating keratoplasty can be performed. Rarely conjunctival flaps or even penetrating keratoplasty may be necessary. The prognosis of corneal graft in the setting of acute inflammation in patients in setting of Mooren’s ulcer is very poor. Rehabilitation Once the active ulceration has ceased and the remaining cornea has been completely opacified, 8 it is possible to perform penetrating keratoplasty on these patients, even in the face of a thinned and vascularized cornea42. In these instances, a 13 mm tectonic corneal graft is first sutured in place with interrupted 10-0 nylon or prolene sutures with the recipient bite extending into the sclera so that the suture will not pull through the thin host cornea and then a 7.5 or 8.0 mm therapeutic graft is placed. Surgical attempts at rehabilitation in Mooren's ulceration is done only with concurrent immunosuppression, even when the active disease has been arrested, or is 'burned out,' because AECS Illumination attempts at penetrating keratoplasty often are associated with recurrence and graft failure. It is believed that patients with treated Mooren's ulcer should be immunosuppressed prior to cataract surgery or corneal grafting procedure. In absence of donor corneas Stilma31 et al have suggested the usage of a free lamellar scleral auto graft to restore the corneal defect, followed by penetrating keratoplasty later. In his series of 38 eyes with corneal ulcer, six eyes with a progressive iris prolapse and a flat anterior chamber were reconstructed with the above technique. References 1. Tabbara KF. Mooren’s Ulcer. Int Ophthalmol Clin 26 : 91;1986 2. Taylor SJ. Notes of a case of rodent ulcer of the cornea in a child. Trans Ophthalmol Soc UK. 22 : 98, 1902 3. Wood T, Kaufman H: Mooren’s ulcer. AM J Ophthalmol 71:417 – 422, 1971. 4. Keitzman B. Mooren’s ulcer in Nigeria. AM J Ophthalmol 65 : 679 – 685, 1968. 5. Majekodunmi AA. Ecology of Mooren’s ulcer in Nigeria. Doc Ophthalmol 49 : 211 – 219, 1980. 6. Lewallen S. Courtright P: Problems with current concepts of the epidemiology of Mooren’s corneal ulcer. Ann Ophthalmol 22:52-55, 1990 7. P.G. Watson : Management of Mooren’s ulcer. Eye 11, 349 – 356, 1997. 8. Young R. Watson P : Light and electron microscopy of corneal melting syndrome Mooren’s Ulcer. Br. J. Ophthalmol 79:563-567, 1968. 9. Gottsch JD. Liu SH, Minkovitz JB, et al. 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