CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 REVIEW URRENT C OPINION Herpetic eye disease study: lessons learned Tanja Kalezic a, Mostafa Mazen b, Eric Kuklinski b, and Penny Asbell b Purpose of review Ophthalmic herpes simplex virus (HSV) of the anterior segment is responsible for a range of corneal complications such as scarring, thinning, neovascularization, and severe loss of vision. This review provides current guidelines for treating anterior segment disease related to HSV. Recent findings We first review findings from the Herpetic Eye Disease Study (HEDS) clinical trials, and then review new topical and antiviral therapies developed since the HEDS studies. The development of vaccines to prevent recurrent episodes of herpetic infection is briefly reviewed. New corneal surgical procedures, developed since HEDS, may put patients at risk for ocular HSV disease: cross-linking and excimer refractive surgery. Summary HEDS established the standard of HSV ocular therapy and is still valid today. However, newer antivirals may provide easier compliance with improved bioavailability, efficacy, dosage, and tolerability. Further research is needed to prevent latency of HSV, decrease recurrences, and more effectively treat necrotizing keratitis associated with HSV. Keywords antivirals, herpes simplex virus, HSV, keratitis INTRODUCTION Herpetic eye disease is the most common infectious cause of corneal blindness in the USA [1,2 ]. Herpes infections have been recognized for many centuries: from Hippocrates’ description of skin lesions that ‘creep and crawl,’ to Vidal who noted human-tohuman transmission in 1893 and Lowenstein who found transmission of herpes simplex virus in a laboratory setting in 1919 . Herpes simplex virus (HSV) is a prevalent viral pathogen infecting approximately 90% of the world’s population [4–6]. Whereas oral and genital lesions are the most common manifestations, HSV type 1 (HSV-1) can also cause disease in the lids, conjunctiva, cornea, uveal tract, and retina . Clinical manifestations of primary ocular HSV infections are rare and usually occur early in life [5,6]. Every year in the USA, approximately 500 000 new cases of active ocular herpes simplex infection are reported [7,8]. However, only 20–30% have ocular clinical manifestations . Usually, it occurs as a unilateral case, but 1.3–12% can be bilateral, especially in younger patients . The most recent survey conducted by National Health and Nutrition Evaluation revealed a seroprevalence of HSV-1 in 53.9% of 14–49-year-olds in the United States from 2005 to 2010. It is estimated that 90% of adults 50 years or older are seropositive for the HSV [7,11]. & Herpes simplex virus is responsible for a variety of ocular diseases in the anterior and posterior segment, but most commonly it involves the anterior segment and manifests as an epithelial keratitis, stromal keratitis, endotheliitis, and/or iritis [12,13]. Epithelial disease typically presents as dendritic disease, but can progress to geographic keratitis, which often has elements of a neurotrophic ulcer. There are two manifestations of stromal disease from HSV: necrotizing stromal keratitis which occurs from direct viral invasion, and immune stromal keratitis (interstitial) as a result of immune reaction within the stroma itself [14,15]. Necrotizing stromal keratitis is characterized as an ulceration and necrosis with infiltration of the stroma beneath an overlying epithelial defect [16–18]. On the contrary, immune stromal keratitis is stromal inflammation (focal, multifocal, or diffuse), and the a University of Belgrade, Faculty of Medicine, Clinic for Eye Disease, Clinical Center of Serbia, Belgrade, Serbia and bDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, USA Correspondence to Tanja Kalezic, Clinic for Eye Disease, University of Belgrade, Faculty of Medicine, Belgrade, Serbia. Tel: +381638148843; e-mail: email@example.com Curr Opin Ophthalmol 2018, 29:000–000 DOI:10.1097/ICU.0000000000000482 1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 Corneal and external disorders KEY POINTS The review focuses on treatment of HSV infection of the anterior segment, especially the cornea. New therapeutic options, such as valacyclovir and gancyclovir, which are more efficacious and less toxic than trifluridine, have become available since HEDS. HERPETIC EYE DISEASE STUDY Topical antivirals currently available include acyclovir 3% ointment, gancyclovir 0.15% gel and trifluridine 1% solution. Oral antivirals include acyclovir, valacyclovir and famcyclovir. Prophylaxis with oral antivirals is suggested in patients with a history of HSV keratitis/iritis, especially if excimer laser for LASIK, PRK, or corneal cross-linking being considered. Steroids for HSV stromal herpes keratitis have advantages such as inhibition of cellular response, opacification, scarring and inhibition of neovascularization. However, disadvantages are stimulation of viral replication, exacerbation, corneal thinning and finally steroid induced glaucoma and cataracts. HSV leads to latency and recurrent disease. At present, there is no treatment to eradicate latent virus. Oral antivirals can reduce recurrences, but only when they are in use. Although no vaccine is currently available, research is underway. overlying epithelium is typically intact. Other clinical findings include anterior chamber inflammation, ciliary flush, stromal edema, immune ring, and, most importantly, neovascularization, which may occur at any level of the cornea leading to stromal scarring, thinning, and severe loss of vision [15,18,19]. Herpes simplex virus replication usually leads to host cell death. However, HSV in neural cells can be less destructive, allowing the virus to remain dormant in an infected patient without producing any signs and/or symptoms. This is known as latency. Recent studies explain the role of viral transcripts called latency-associated transcripts (LATs), which are the key in inducing and maintaining viral latency . For recurrent ocular HSV disease, the trigeminal ganglion is the main source of recurrent infection. Many factors have been reported as triggers for recurrent disease, including exposure to ultraviolet light, psychological stress, ocular surgery, trauma, and hormonal fluctuation [5,20,21]. Herpes simplex virus also mimics many other eye diseases, and is often on the differential diagnosis of any kind of inflammatory eye disease of the anterior segment that has an unclear cause. This may include marginal ulcer, pseudodendrites, limbitis, and infectious keratitis, such as acanthamoeba corneal infections. 2 www.co-ophthalmology.com The Herpetic Eye Disease Study (HEDS) was a series of randomized, double-masked, placebo-controlled clinical trials funded by the National Eye Institute (NEI) that studied various approaches to treating ocular HSV, and is still considered the gold standard for clinical care for anterior segment HSV disease . Herpetic Eye Disease Study: topical steroids in stromal keratitis Patients received either topical steroids or placebo starting eight times per day and tapered over the following weeks. All patients also received topical antiviral, trifluridine. Corticosteroid group showed 68% more reduction in progression of stromal keratouveitis. The study also showed that postponing topical steroids for a few weeks led to delayed resolution of stromal keratitis, but had no detrimental effect as assessed by visual outcome at 6 months. This study concluded that steroid use can reduce progression and speed recovery, but with no effect on the visual outcome . At 6 months after randomization, no clinically or statistically significant difference in visual outcome was seen between the placebo and the steroid group. The use of anti-inflammatory therapy for herpes simplex stromal keratitis is still controversial. Corticosteroids suppress inflammation by interfering with normal immunological response. They suppress the local antibody- forming B lymphocytes, but this effect lasts only as long as the treatment . Corticosteroids are contraindicated during herpes simplex viral infection of the ocular surface, but are used to suppress herpes simplex stromal keratitis. Corticosteroid therapy may need to be tapered very slowly for most patients with herpes simplex stromal keratitis because of risk of recurrence or making the present keratitis worse. Herpetic Eye Disease Study: oral acyclovir for herpes simplex virus stromal keratitis Patients received either 400 mg oral acyclovir or placebo 5 times daily for 10 weeks and follow up for 6 months. All patients also received standard regimen of topical corticosteroids, solution prednisolone phosphate 1% eight times daily for 1 week, tapered to six times daily for second week, on third week tapered to four times daily, on fourth week two times daily, and on fifth week once a day. At sixth Volume 29 Number 00 Month 2018 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 Herpetic eye disease Kalezic et al. week, a 0.125% solution of corticosteroids was given four times daily, on seventh week two times daily, and from eighth to tenth week, it was once a day. From week 11 to 26, it was not given to participants. Trifluridine was used four times a day for first 3 weeks, tapered to two times daily until the tenth week and then stopped. Treatment failure was observed later in the acyclovir group (84 days) vs. the placebo group (62 days). The trial, however, concluded that oral acyclovir did not significantly improve the outcome of the stromal keratitis as measured by the time to resolution and visual outcome, respectively . history of active ocular HSV disease within the past year. The recurrence rate of any type of ocular HSV disease during that period of treatment was 19% in the acyclovir group compared with 32% in the placebo group. The magnitude of absolute benefit was greatest among patients with the highest number of prior episodes of ocular HSV disease. The benefit in preventing stromal keratitis was seen solely among patients with a history of stromal keratitis. This HEDS study concluded that the long-term use of oral acyclovir therapy reduces the rate of recurrent HSV epithelial keratitis and stromal keratitis by about 50% . Herpetic Eye Disease Study: oral acyclovir for herpes simplex virus iritis Herpetic Eye Disease Study: predictors of recurrent herpes simplex virus keratitis Patients received either 400 mg oral acyclovir or placebo 5 times daily for 10 weeks. Follow up examinations were performed weekly during the treatment period, every 2 weeks for 6 weeks posttreatment, and then at 26 weeks. All patients also received standard regimen of topical corticosteroids and trifluridine. Treatment failure occurred in 50% of patients in acyclovir group and 68% of patents in the placebo group. Although the number of patients was too small to achieve statistically significant results, the trend in this study of oral acyclovir suggested that it may be beneficial but this trend was noted only after 3 weeks of treatment . The HEDS research group assessed how previous HSV eye disease affects the risk of recurrent HSV, and evaluated if any demographic or other predictors play a role in recurrent HSV disease. During 18 months of follow-up, 18% developed recurrent epithelial keratitis and 18% developed recurrent stromal keratitis. The risk of epithelial keratitis was similar among patients who reported previous epithelial keratitis and among those who did not. In contrast, previous stromal keratitis increased the risk of stromal keratitis 10-fold, and the risk was strongly related to the number of previous episodes. Demographic and other predictors such as age, sex, ethnicity, and nonocular herpes were not significantly associated with recurrences, and no seasonal effects were observed . Herpetic Eye Disease Study: oral acyclovir for prevention of stromal keratitis or iritis in patients with epithelial herpes simplex virus keratitis Patients with HSV epithelial keratitis of 1 week or less duration were treated with topical trifluridine and were randomly assigned to receive 400 mg oral acyclovir five times a day or placebo for 3 weeks and follow up for 12 months. Stromal keratitis or iritis developed in 11% of the acyclovir group and in 10% of the placebo group. The development of stromal keratitis or iritis was more frequent in patients with a history of HSV stromal keratitis or iritis than in those without such a history (23 vs. 9%). No apparent benefit of a 3-week course of oral acyclovir in preventing HSV stromal keratitis or iritis was seen during the 1 year of follow-up . Herpetic Eye Disease Study: oral acyclovir for prevention of recurrent herpes simplex virus and prophylaxis Patients were assigned either 400 mg oral acyclovir twice per day or placebo for 12 months, if they had a Herpetic Eye Disease Study: psychological stress and other potential triggers for recurrences of herpes simplex virus Patients were examined with a history of ocular HSV in the previous year and observed for 15 months. The participants recorded if psychological stress, systemic infection, sunlight exposure, menstrual period, contact lens wear, and/or eye injury occurred in the week prior to the onset of a recurrence. Psychological stress did not appear to be a trigger for recurrences of HSV eye disease . During the study, a systemic infection was reported on 13% of the weekly logs, sun exposure of more than 21 h in a week on 7%, and contact lens wear in 10%. None of these potential triggers were found to be associated with recurrences. Although no association was found between the onset of the menstrual period and a recurrence, the study’s power was too low for any assessment. Similarly, eye injuries were reported too infrequently to have a valid conclusion . 1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 3 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 Corneal and external disorders Table 1. Topical antivirals for ocular herpes simplex virus Drug/concentration Epithelial keratitis Gancyclovir 0.15% gel Five times a day, after healing three times a day for 7 days Acyclovir 3% ointment Five times a day Trifluridine 1% solution Nine times a day, every 2 h Data from . NEW TREATMENTS SINCE HERPETIC EYE DISEASE STUDY Treatment options today for HSV keratitis and/or iritis include topical  and oral antivirals  (Tables 1 and 2). Topical treatments for herpes simplex virus Trifluridine is a synthetic pyrimidine nucleoside that has been US FDA-approved since 1980 (Table 1) . It was originally developed as an anticancer agent and later was noted to be an effective antiviral . At the time of the HEDS studies, it was the most widely prescribed topical antiviral agent for treatment of HSV keratitis in USA. However, side effects such as punctate keratopathy, allergic conjunctivitis, and toxicity to the ocular surface have led to the decline of its use as new topical antivirals have become available . Two new topical antivirals against HSV have become available since the HEDS study: gancyclovir and acyclovir. Acyclovir is a nucleoside analog that is selectively phosphorylated by the thymidine kinase induced by the HSV in infected cells . It is highly specific for herpes infected cells. The DNA polymerase of HSV has 10–30 times greater affinity for acyclovir than that of uninfected cells . Gancyclovir ophthalmic gel 0.15% is a synthetic purine nucleoside and analog of guanosine. It is similar to acyclovir, because it is phosphorylated only in infected cells and inhibits synthesis of viral DNA. It also contributes to less toxicity, so it is well tolerated in contrast to trifluridine, which causes conjunctival and corneal toxicity. Furthermore, gancyclovir gel has similar toxicity to artificial tears, while providing prolonged corneal contact time, and a long and stable shelf life [35–37]. These two agents – acyclovir and gancyclovir – are considered more specific and less toxic for the anterior segment. Both agents are not activated by phosphorylation in host cells, but only in virusinfected cells containing viral thymidine kinase, earning the name ‘selective antiviral agents.’ Acyclovir ointment has been shown to be more efficacious and less toxic in comparative studies to other nonselective antivirals such as vidarabine or idoxuridine [38–40]. Trifluridine and acyclovir appeared more effective than vidarabine. No significant differences were found in comparisons between acyclovir ointment and trifluridine . A comparative study between gancyclovir gel 0.15% and acyclovir ointment 3% showed similar therapeutic efficacy and similar healing rates . Gancyclovir gel 0.15% was significantly better tolerated by patients and has been approved by US FDA in the USA since 2009. Acyclovir ointment for ocular use is not US FDA-approved in the USA, but is available in Europe and other areas of the world. Oral antivirals for herpes simplex virus treatment New oral antivirals, such as valacyclovir and famcyclovir, have easier dosing regimens compared to oral acyclovir (Table 2) . Acyclovir itself is poorly Table 2. Oral antivirals in ocular herpes simplex virus Drug/route Epithelial keratitis Stromal keratitis Prophylaxis Acyclovir Dendritic: 400 mg, 3–5 times/day, 7–10 days Geographic: 800 mg, five times/day, 14–21 days 400 mg b.i.d. 1 year Valacyclovir Dendritic: 500 mg, two times per day, 7–10 days Geographic: 1 g, three times per day, 14–21 days Without ulcer: 400 mg, b.i.d. With ulcer: 800 mg, 3–5 times/day, 7–10 days Endotheliitis: 400 mg, 3–5 times/day Without ulcer: 500 mg, once a day With ulcer: 1 g, three times per day, 7–10 days Endotheliitis: 500 mg, two times/day Famcyclovir Dendritic: 250 mg, two times/day, 7–10 days Geographic: 500 mg, two times/day, 14–21 days Without ulcer: 250 mg, two times/day With ulcer: 500 mg, two times/day, 7–10 days Endotheliitis: 250 mg, two times/day 250 mg 2 times/ day 1 year 500 mg once a day 1 year Data from . HSV, herpes simplex virus. 4 www.co-ophthalmology.com Volume 29 Number 00 Month 2018 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 Herpetic eye disease Kalezic et al. absorbed in the gastrointestinal tract; its oral bioavailability is 10–20%. In contrast, valacyclovir is more than 10 times more permeable than acyclovir. Valacyclovir’s oral bioavailability is more than 55%, which allows comparable blood levels to parenteral acyclovir. The mechanism of both famcyclovir and valacyclovir is inhibition of viral DNA polymerase, similar to acyclovir. Dosage modification is required in patients with renal impairment, because there is a risk of renal toxicity. It is suggested to measure the peak plasma concentration level associated with oral intake of valacyclovir [42 ]. As noted in the Table 1, oral antivirals can be used instead of topical treatment for HSV keratitis and may be preferred if significant ocular surface disease and/or inability to use topical medications. Valacyclovir is a prodrug converted in vivo to acyclovir. It is more bioavailable (50%) than acyclovir, better tolerated, has fewer side effects, and is easier to use because of the lower dose per day and decreased frequency needed. Famcyclovir is another alternative to acyclovir and valacyclovir. It is a guanosine analog antiviral drug used for the treatment of various herpes virus infections, most commonly for herpes zoster. It is a prodrug form of pencyclovir with improved oral bioavailability. Oral acyclovir has been reported to be as effective as topical antivirals for epithelial keratitis (400 mg, five times daily for 10 days); oral acyclovir is the preferred treatment in patients unable to tolerate topical medications and with good renal function. The use of systemic acyclovir is preferred over topical agents in the treatment of HSV keratitis, particularly for patients with pre-existing ocular surface disease who are at high risk for toxicity from topical medications, for patients who are immunocompromised, and for pediatric patients. Some physicians prescribe both oral and topical antiviral agents in conjunction when treating infectious HSV keratitis [43,44]. Newer oral antiviral drugs, such as valacyclovir and famciclovir, further simplify the dosing regimens; however, the optimal dose for ocular disease has not been determined [42 ,45]. & & of 80 genes . It also has an outer lipid bi-layer embedded with glycoproteins (gB, gC, gD, gH) which facilitate virus to host cell attachment, fusion, and permeability . This is an important concept in understanding the therapy for herpetic infection because both topical and oral agents rely on their anti-DNA transcription properties to achieve effectiveness. Therapeutic agents inhibit the viral DNA, stopping protein synthesis and replication. Clinical trials for HSV vaccines have been ongoing for more than three decades, yet none have reported data on the eye. HSV-1 specifies at least 11 glycoproteins that are expressed in infected cells. Most of the research on subunit vaccines have used HSV envelope glycoproteins, specifically glycoprotein gB and/or gD, as immunogens, because these are the dominant targets for neutralizing antibody production in HSV-infected people . Glycoprotein gD received the greatest attention as a subunit vaccine candidate . A major concern associated with the use of live recombinant or attenuated virus vaccines is the possibility that nonvirulent strains of HSV-1 can give rise to a virulent HSV-1 strain in vivo via recombination or mutation. CD8 T cells of the adaptive immune response function to inhibit viral reactivation within the trigeminal ganglion using nonlytic mechanisms. Therefore, a therapeutic vaccine designed to boost the CD8 T-cell response within latently infected ganglia may achieve inhibition of viral reactivation and subsequent corneal inflammation without the need for daily oral medication . Nesburn and Mohamed [47–49] developed a novel approach using several immune white-cell parts from the two most responsive glycoproteins (gB and gD) expressed by the herpes virus, allowing researchers to develop a candidate vaccine to target them [48,49]. Consistent with this hypothesis, a small controlled trial in humans demonstrated a significant reduction in HSV-1 ocular recurrences following subcutaneous administration of heatinactivated HSV-1 [18,47,48]. RISK OF HERPES SIMPLEX VIRUS REACTIVATION WITH NEW CORNEAL PROCEDURES ONGOING RESEARCH Key unsolved issues for herpetic disease are the development of latency and recurrent disease. Current research investigates HSV vaccine strategies with the goal of inhibiting viral reactivation within the trigeminal ganglia and preventing reactivation events. The herpes viruses are classified as DNA viruses . HSV has a linear double stranded DNA composed Refractive surgery with excimer laser (laser-assisted in situ keratomileusis/ photorefractive keratectomy) The safety of laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) is still unknown in patients with HSV-1. Excimer laser PRK is a surgical procedure utilizing a 193 nm ultraviolet light to alter the curvature of the cornea and hence 1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 5 Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. CE: M.S.; ICU/290412; Total nos of Pages: 7; ICU 290412 Corneal and external disorders correct vision. Reactivation of ocular herpes simplex keratitis following such excimer laser PRK has been reported [50,51]. History of ocular HSV is considered a relative contraindication for excimer treatment to the eye. Perioperative and postoperative antiviral therapy should be given to all patients with a history of ocular HSV infection. Patients should be well informed regarding the remote risk of HSV reactivation following LASIK or PRK [20,50]. Cross-linking of the cornea with ultraviolet light Corneal collagen cross-linking (CXL) using UVA and riboflavin has been found to be effective in halting the progression of keratoconus. A UVA surface dose of 5.4 J/cm2 is used for CXL . Corneal collagen CXL arrests further progression of corneal collagen thinning that is otherwise progressive in keratoconus stromal collagen, thereby increasing the biomechanical stability of the cornea. CXL is used off-label for infection of the cornea, and also as pre-excimer laser surgery to possibly reduce the risk of ectasia [52,53]. Several papers have been published that report development of HSV keratitis following CXL [52,53]. It has been shown that exposure to ultraviolet light can reactivate latent HSV infection [53,54]. Moreover, the epithelial debridement, damage to the corneal nerves, and use of topical steroid drops have been proposed as risk factors . It has been suggested that prophylactic antiviral therapy may decrease the possibility of herpetic keratitis after CXL in patients with a history of herpetic disease [55–57]. CONCLUSION Herpetic Eye Disease Study clinical trials have established the gold standard for clinical treatment of ocular HSV for the anterior segment. New therapeutic options have become available since HEDS, such as topical gancyclovir and valacyclovir, which are more efficacious and less toxic than triflurdine [36,40,41,42 ]. Patients with HSV keratitis need to be monitored closely in an outpatient clinic until the disease is inactive. Any suspicious corneal infiltrate in the presence of HSV epithelial keratitis should be cultured for possible secondary microbial infection. Contact lens wear should be used with caution. Inactive keratitis or a history of previous HSV disease is also considered a relative contraindication to LASIK, PRK, or CXL. Although no vaccine is currently available, research is underway. & Acknowledgements None. 6 www.co-ophthalmology.com Financial support and sponsorship The study has no financial interest or funding received. Conflicts of interest Penny A. Asbell: Receives research funding from the National Eye Institute and Office of Dietary Supplements of the National Institutes of Health (U10EY022881), MC2 Therapeutics and Novartis; is a consultant for Novartis, ScientiaCME, Shire, and WebMD; has received travel/financial compensation from Novartis, Santen, ScientiaCME, and Shire. Tanja Kalezic: No financial disclosures. Mostafa Mazen: No financial disclosures. Eric Kuklinski: Receives research funding from the National Eye Institute and Office of Dietary Supplements of the National Institutes of Health (U10EY022881), and MC2 Therapeutics No financial interest or funding received. 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. Sudesh S, Laibson PR. The impact of the herpetic eye disease studies on the management of herpes simplex virus ocular infections. Curr Opin Ophthalmol 1999; 10:230–233. 2. Farooq AV. Herpes simplex virus keratitis and resistance to acyclovir. Cornea & 2017; 36:e4–e5. This is the first study of resistance of acyclovir in herpes simplex keratitis. 3. Whitley RJ, Roizman B. Herpes simplex virus infections. Lancet 2001; 357:1513–1518. 4. Johnston C, Gottlieb SL, Wald A. Status of vaccine research and development of vaccines for herpes simplex virus. Vaccine 2016; 34:2948–2952. 5. 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