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Surgery Versus Epilation for the Treatment of Minor Trichiasis in Ethiopia: A Randomised Controlled Noninferiority Trial

Surgery Versus Epilation for the Treatment of Minor Trichiasis in Ethiopia: A Randomised Controlled Noninferiority Trial
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  Surgery Versus Epilation for the Treatment of MinorTrichiasis in Ethiopia: A Randomised ControlledNoninferiority Trial Saul N. Rajak  1 , Esmael Habtamu 2 , Helen A. Weiss 1 , Amir Bedri Kello 3 , Teshome Gebre 2 , Asrat Genet 4 ,Robin L. Bailey 1 , David C. W. Mabey 1 , Peng T. Khaw 5 , Clare E. Gilbert 1 , Paul M. Emerson 6 , Matthew J.Burton 1,5 * 1 The London School of Hygiene and Tropical Medicine, London, United Kingdom,  2 The Carter Center, Addis Ababa, Ethiopia,  3 Light For The World, Addis Ababa,Ethiopia,  4 The Amhara Regional Health Bureau, Bahir Dar, Ethiopia,  5 NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and UCL Institute of Ophthalmology and UCL Partners AHSC, London, United Kingdom,  6 The Carter Center, Atlanta, United States of America Abstract Background:   Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for allcases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is commonand was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis ( , six lashestouching eye). This trial investigated whether epilation is noninferior to surgery for managing minor trichiasis. Methods and Findings:   1,300 individuals with minor trichiasis from Amhara Regional State, Ethiopia were recruited andrandomly assigned (1:1) to receive trichiasis surgery or epilation. The epilation group were given new forceps and epilationtraining. The surgical group received trichiasis surgery. Participants were examined every 6 months for 2 years by cliniciansmasked to allocation, with 93.5% follow-up at 24 months. The primary outcome measure (‘‘failure’’) was  $ five lashestouching the eye or receiving trichiasis surgery during 24 months of follow-up, and was assessed for noninferiority with a10% prespecified noninferiority margin. Secondary outcomes included number of lashes touching, time to failure, andchanges in visual acuity and corneal opacity. Cumulative risk of failure over 24 months was 13.2% in the epilation groupand 2.2% in the surgical group (risk difference=11%). The 95% confidence interval (8.1%–13.9%) includes the 10%noninferiority margin. Mean number of lashes touching the eye was greater in the epilation group than the surgery group(at 24 months 0.95 versus 0.09, respectively;  p , 0.001); there was no difference in change in visual acuity or corneal opacitybetween the two groups. Conclusions:   This trial was inconclusive regarding inferiority of epilation to surgery for the treatment of minor trichiasis,relative to the prespecified margin. Epilation had a comparable effect to surgery on visual acuity and corneal outcomes. Wesuggest that surgery be performed whenever possible but epilation be used for treatment of minor trichiasis patientswithout access to or declining surgery. Trial registration:   http://ClinicalTrials.gov NCT00522912 Please see later in the article for the Editors’ Summary  . Citation:  Rajak SN, Habtamu E, Weiss HA, Kello AB, Gebre T, et al. (2011) Surgery Versus Epilation for the Treatment of Minor Trichiasis in Ethiopia: A RandomisedControlled Noninferiority Trial. PLoS Med 8(12): e1001136. doi:10.1371/journal.pmed.1001136 Academic Editor:  Susan Lewallen, Kilimanjaro Centre for Community Ophthalmology, Tanzania Received  April 5, 2011;  Accepted  October 18, 2011;  Published  December 13, 2011 Copyright:    2011 Rajak et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the srcinal author and source are credited. Funding:  This study was funded by grants from the Band Aid Foundation (via Fight For Sight) and The Wellcome Trust (080741/Z/06/Z). Johnson & Johnsondonated all sutures. Tweezerman donated all forceps. Tweezerman made a donation towards the production costs of a trichiasis surgery training DVD. No fundingbodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests:  PTK is a member of the Scientific Advisory Boards for Alcon and Bausch & Lomb. All other authors have declared that no competinginterests exist. Abbreviations:  CC, central corneal scarring; CO, corneal opacification; OR, odds ratio; TT, trachomatous trichiasis; WHO, World Health Organization* E-mail: matthew.burton@lshtm.ac.uk  PLoS Medicine | www.plosmedicine.org 1 December 2011 | Volume 8 | Issue 12 | e1001136  Introduction Trachoma is the leading infectious cause of blindness worldwide[1]. Recurrent episodes of ocular  Chlamydia trachomatis   infection inearly childhood provoke chronic conjunctival inflammation (activetrachoma). This inflammation can lead to conjunctival scarring,which may cause the eyelids to roll in (entropion) and the lashes totouch the surface of the eye (trachomatous trichiasis [TT]).Trichiasis is probably the main risk factor for the development of corneal opacification (CO) and visual impairment in trachoma.However, TT encompasses a very wide spectrum of disease. Atone extreme there may be only a few metaplastic eyelashes withoutentropion. At the other extreme the whole eyelid can be entropicwith all eyelashes and even the skin of the upper eyelid in contactwith the ocular surface. The risk of developing CO is related to theseverity of the trichiasis, and a distinction has been made betweenminor TT (one to five lashes touching the eye) and major TT(  . five lashes touching the eye) [2– 5].Trachoma is endemic in around 50 countries, which are striving to control the disease through the implementation of the SAFEstrategy: surgery for trichiasis, antibiotics for infection, and facialcleanliness and environmental improvements to reduce transmis-sion [1,6]. Currently, the World Health Organization (WHO)recommends that all individuals with one or more trichiaticeyelashes should be offered surgery, irrespective of lash location(central or peripheral) or the degree of entropion. The rationale forthis recommendation is a practical one: patients with only a minordegree of trichiasis may not be seen again for a long time and thereis a risk that the trichiasis will progress and cause visualimpairment [6]. There is broad consensus that major TT shouldbe treated surgically. However, for the management of minor TTthe reality is often different, with many patients and clinicianspreferring to defer surgery until the TT becomes moreproblematic. In some countries, such as The Gambia, there hasbeen a policy of epilation (repeated removal of lashes with forceps)for minor trichiasis and surgery for major trichiasis, whichpredated the WHO guidelines [7].In recent years the number of individuals (mainly children) withactive trachoma has declined significantly from 146 million in1996 to 40 million in 2007, indicating that the A, F, and Ecomponents are effective [1,8]. In contrast, the estimates of thenumber of people (mainly adults) living with untreated TT havenot shown such encouraging declines: 10.6 million in 1996, 7.6million in 2003, and 8.2 million in 2007 [1,8]. Available datasuggest that current surgical activity is probably keeping up withincident TT but may not be clearing the backlog. For example, inEthiopia (the country with the most cases of TT) 1.3 million peoplewere estimated to have TT in 2006, but only around 300,000operations were performed in the last 5 y [1,9].The reasons for this treatment gap are complex and multiple.Firstly, there may be insufficient services to address the backlog inmany regions. Many of the health workers trained in TT surgeryhave been lost from programmes, may have conflicting clinicalpriorities,ordonothavethe instrumentsorconsumables toperformsurgery[10,11].Secondly,servicesmaynotbe accessibletopatients. Several studies have shown financial constraints, transport difficul-ties, and lack of time to be barriers to attending for surgery [7,12– 14]. Thirdly, in many regions many patients (often the majority)refuse the offer of surgery, even when major barriers are addressedby the provision of free surgery at community level [7,13 – 15]. It is likely that in the next 5 y at least, the overwhelming majority of people with TT will not receive surgical treatment, irrespective of whether the TT is minor or major.In trachoma endemic regions, TT surgery is usually provided bynonophthalmologists who receive about 2-wk training in one of the WHO recommended procedures: bilamellar tarsal rotation(BLTR) or posterior lamellar tarsal rotation (PLTR) [16,17]. Well-conducted surgery can be a permanent solution. However,trichiasis frequently recurs after surgery, particularly underoperational conditions (as compared to clinical trials) where ratesas high as 60% recurrence have been reported [3,18 – 20]. Currently limited longitudinal data are available on which tobase recommendations for individuals with minor TT. One cohortstudy of individuals with TT who refused surgery found that over a4-y period, 37% progressed from minor to major TT and 5.1%developed new corneal opacity [4]. In a parallel cohort of patientsfrom the same area who had accepted TT surgery, thecomparable risks were 41% and 5.2%, respectively [18]. A secondlongitudinal study also found no difference in risk of developing new corneal opacity between people receiving TT surgery andthose declining it, over a 1-y period [21]. Studies from severaltrachoma endemic regions suggest that the majority of people withTT epilate [7,22]. Two cross-sectional studies have found that epilation is associated with a reduced risk of corneal opacity [2,23].In high-income settings patients with a minor degree of trichiasis,such as metaplastic or misdirected lashes caused by lid margindisease, are often managed by repeated epilation. Epilation issimple for a trained helper to perform. However, it is an ongoing treatment that needs to be repeated when eyelashes regrow andshould be conducted using good quality forceps.In view of the prevalence of unoperated TT, the limitedcapacity of current surgical services, concerns over programmaticsurgical outcomes, and the high rates of refusal, epilation might bean acceptable alternative to surgery for the management of minorTT. In this randomised trial we tested the hypothesis that epilationis noninferior to surgery for the treatment of minor TT. Methods Ethics Statement The National Health Research Ethics Review Committee of theEthiopian Ministry of Science and Technology, the LondonSchool of Hygiene and Tropical Medicine Ethics Committee, andEmory University Institutional Review Board approved the trial.Potential participants were provided with both written and oralinformation in Amharic about the trial. For those agreeing toparticipate, written informed consent in Amharic was requiredprior to enrolment. If the participant was unable to read and write,the information sheet and consent form were read to them andtheir consent recoded by witnessed thumbprint. An independentData Safety Monitoring Committee reviewed the trial for patientsafety and there were no deviations from the srcinal protocol. Nointerim analyses for efficacy or futility were planned or conducted.The trial protocol is described in Text S1 and the CONSORTstatement in Text S2. Participants Eligible participants were individuals aged 18 y or over withpreviously unoperated minor trichiasis (  , six trichiatic eyelashes,some of which may have been epilated and were regrowing) whopresented during a TT treatment campaign in rural villages in WestGojjam, Amhara Region, Ethiopia from March to June 2008.Exclusion criteria were previous eyelid surgery, medically unfit, orpregnancy (self-reported or clearly evident). The campaigns wereadvertised in local markets, churches, and schools. Additionally,health extension workers from the subdistricts (  kebele   ) in the study Trial of Epilation for Trachomatous TrichiasisPLoS Medicine | www.plosmedicine.org 2 December 2011 | Volume 8 | Issue 12 | e1001136  area were trained to recognize trichiasis and visited each village intheir  kebele   to identify patients. In individuals with bilateral TT, onlyone eye was randomly designated as the study eye and included inthe analysis, although both eyes were treated. Baseline Clinical Assessment The clinical assessments and surgery were performed ingovernment health centres. A field worker administered aquestionnaire in Amharic. Height and weight were measured.Unaided and pinhole LogMAR visual acuities were measured at4 m, using an ETDRS equivalent Tumbling-E LogMAR chart(Hong Kong Low Vision Centre). The testing distance wasreduced to 2 or 1 m if necessary. For those unable to read theLogMAR chart at 1 m their visual acuity was tested by counting fingers at 1 m or hand movements at 0.5 m. For visual acuities of counting fingers or less, LogMAR values were attributed: counting fingers, 2.0; hand movements, 2.5; perception of light, 3.0; noperception of light, 3.5. No patients had spectacles for distancecorrection. In this report we present only unaided visual acuities.Ophthalmic examinations were conducted in a darkened roomusing 2.5 6 magnification loupes and a bright torch. A singleophthalmologist (SNR) performed all baseline examinations. Thenumber of lashes touching the eye was counted (‘‘lash burden’’)and also subdivided by the part of the eye contacted when looking straight ahead: cornea, lateral conjunctiva, or medial conjunctiva.Clinical evidence of epilation was identified by the presence of broken or newly growing lashes, or areas of absent lashes. Upperlid entropion was graded by assessing the degree of inwardrotation of the eyelid margin (Table S1). The degree of conjunctivilisation of the lid margin (anteroplacement of themuco-cutaneous junction) was assessed (Table S1). The degree of corneal scarring was classified using a modified WHO detailedtrachoma grading system (FPC) in which the degree of centralcorneal scarring (CC2) was subdivided into four, to provide moredefinition (Table S1) [24]. The Simplified WHO TrachomaGrading System corneal opacity measure (CO) is equivalent toCC2 and CC3 [25]. Tarsal conjunctival papillary inflammation,follicles, and scarring were classified using the WHO FPC grading system [24]. Standardised high-resolution digital photographswere taken of each of these features. Interventions Following the baseline clinical assessment, participants wererandomised to one of two intervention groups: surgery orepilation. The posterior lamella tarsal rotation procedure wasused in all surgery cases [17]. Surgery was performed under localanaesthesia administered by subcutaneous infiltration of the uppereyelid: 2–3 ml of lidocaine 1%, with adrenaline. The lid was theneverted and the posterior lamella (tarsal conjunctiva and tarsalplate) incised parallel to and 3 to 4 mm above the lid margin. Theposterior and anterior (obicularis oculi and skin) lamellae wereseparated by blunt dissection. Three sets of 4/0 silk everting sutures (three-eighth circle, 16-mm cutting needles, Mersilk,Ethicon) were placed to externally rotate the lower border of theeyelid. Postoperatively, the operated eye was padded until the nextmorning and tetracycline eye ointment was self-administered twicea day for 2 wk. Five nurses, who had previously been trained inand were regularly performing TT surgery, performed the surgeryin this trial. They were identified as the best surgeons from a largergroup of nine during a 2-d standardisation workshop. Thistraining was conducted by an experienced Ethiopian ophthalmol-ogist (ABK), who had contributed to the development of theWHO TT surgeon certification manual [17]. The posteriorlamellar tarsal rotation techniques of the five nurses were carefullyobserved and standardised to ensure that all performed theoperation in the same way. The intraoperative quality of surgerywas periodically reviewed during the course of the trial.Individuals randomised to the epilation group were each giventwo pairs of high quality, machine-manufactured epilation forcepswith round edged tips (for corneal safety) and flat, opposing platesto improve grip and reduce the likelihood of breaking lashes(Tweezerman). The patient and an accompanying adult (‘‘epila-tor’’) with good near vision were trained to perform epilation.They observed the trainer epilate one or two lashes, withparticular attention paid to removing the lash at its base tominimise broken stubs. The epilator was then observed epilating lashes and given advice on technique. Follow-up Clinical Assessments  All participants in the surgery arm were seen 7–10 dpostoperatively, at which point the sutures were removed andany complications noted and treated as needed. Several differentophthalmic nurses who did not take part in subsequent follow-upsconducted the 7–10-d suture removal follow-up. Follow-upassessments were conducted for both groups at 6, 12, 18, and24 mo. On each occasion an ophthalmic examination wasperformed and digital photographs taken. Visual acuity wasmeasured at 12 and 24 mo. The preoperative, 12-mo, and 24-moexaminations were conducted by a single ophthalmologist (SNR)and the 6- and 18-mo were conducted by a single ophthalmicnurse (EH). Neither of these examiners was involved in performing treatments in this trial. The examiners were standardised to eachother and showed strong agreement between these two observersfor the presence of trichiasis in a preliminary assessment of 200eyes (kappa=0.86). The presence/absence of notching (overcor-rection of the central portion of the lid) and conjunctivalgranuloma were noted. Any individual who showed evidence of disease progression,defined as five or more trichiatic lashes or corneal changes relatedto observed lashes at any follow-up examination, was immediatelyoffered surgery (epilation arm) or repeat surgery (surgery arm) tobe performed by a senior surgeon. These individuals continued tobe followed up according to the trial protocol. Individuals inwhom other ophthalmic pathology (e.g., cataract) was detectedwere referred to the regional ophthalmic services. New epilating forceps were provided as required. At the final follow-up (24 mo),all participants in the epilation arm were offered TT surgery. Outcome Measures The primary outcome measure was the proportion of individuals at any follow-up who had ‘‘failed,’’ defined as either(1) five or more eyelashes touching the globe or (2) a history of surgery performed in the trial eye at any point during the follow-up period (in the case of the surgical arm this would be repeatsurgery). The five or more lash threshold for failure was chosen tomake it slightly more stringent than the inclusion criteria. A prioridefined secondary outcome measures at 12- and 24-mo were: CO, visual acuity, entropion, conjunctival inflammation and symptomsof pain, subjective visual acuity, epiphora, and dryness.Change in CO was assessed both by direct comparison of the 1-and 2-y photographs with the baseline photograph, and bycomparison of the field grading scores. Photographs for each timepoint were viewed on a computer screen at about 10 6 magnification by a single masked observer (MJB). They were firstgraded using the trial grading system (Table S1). Then the 1- and2-y images were compared side by side with the baseline image,allowing the direct comparison of opacities to assess whether theyhad changed; these were graded as improved, no change, or Trial of Epilation for Trachomatous TrichiasisPLoS Medicine | www.plosmedicine.org 3 December 2011 | Volume 8 | Issue 12 | e1001136  worse. The baseline photographic and field CO scores showedgood correlation (linear weighted kappa score 0.74; quadraticweighted kappa score 0.87). Randomisation, Allocation Concealment, and Masking Participants were randomly allocated to the epilation or surgerygroups using a 1:1 allocation ratio for each surgeon, using acomputer-generated randomisation sequence with random block sizes. Randomisation was stratified by surgeon because of possibleintersurgeon variability (each surgeon had a separate sequence).The London-based statistician held the master randomisation lists.The random allocation sequences for each surgeon wereconcealed in sequentially numbered, sealed, opaque envelopes,which were colour coded for surgeon and placed in separatecontainers for each surgeon. The person who prepared theseenvelopes was independent of all other aspects of the trial.Following the baseline examination, participants were allocated tothe next available surgeon. A field worker was responsible forimplementing the intervention assignment in a dedicated area,separated from those performing the preoperative examinations.The two individuals (SNR, EH) responsible for all the clinicaloutcome measurements were masked to the allocation. At follow-up, the trichiasis and corneal examination was performed andrecorded before the eyelid was everted, so that the examiner wasmasked to whether surgery had been performed on the tarsalconjunctiva. The posterior lamella tarsal rotation technique usedin this study does not involve a skin incision, so there were noexternal marks of previous surgery that could unmark theobserver. Statistical Methods  A noninferiority trial design was chosen to investigate epilationin the management of minor trichiasis because of the potentialsecondary benefits of this intervention (greater acceptability andavailability). Epilation is an ongoing treatment, which is performedwhen a trichiatic lash regrows. As such it is intrinsically less likelyto be effective than surgery at always preventing lashes fromtouching the eye. In a noninferiority trial a slightly reduced clinicalefficacy might be accepted if this is balanced by other secondarybenefits; in the case of epilation these include greater acceptabilityand availability in an endemic population compared to surgery.We chose a noninferiority margin (  D  ) of 10% at the outset of thistrial as we considered this level to balance the considerations of clinical efficacy and secondary benefits.The sample of 1,300 trial participants provided 90% power todetect noninferiority based on a two-sided 95% CI approach,assuming a 10% loss to follow-up over 2 y, a 5% failure rate in thesurgery group, and a  D  of 10% between the epilation and surgerygroups respectively [3,26].Data were double-entered into an Access (Microsoft) databaseand transferred to Stata 11 (StataCorp). Data were analysed byintention to treat. For participants who had bilateral treatmentonly the randomly designated ‘‘study eye’’ was included in theanalysis. Patients were excluded from a specific analysis if they hadmissing data relevant to that analysis, as indicated in the results.Missing data were not imputed.The 95% CI for the difference in the proportion of ‘‘failures’’(proportion having  $ five lashes touching the eye or having surgeryduring follow-up period) between the two groups was estimatedusing exact methods. The primary outcome and binary secondaryoutcomes were compared between the two groups using logisticregression analyses to estimate the odds ratio (OR) and 95% CI.Time to failure was analysed with Kaplan-Meier survival curves,and Cox regression models to estimate hazard ratios (HRs) and95% CI. Individuals who had reached endpoint at a previous timepoint or were permanently lost to follow-up from that timeonwards were censored. The number of lashes touching the eyewas analysed using zero-inflated Poisson regression to allow for thehigh proportion of eyes with no lashes touching  [27]. The signed-rank test was used to analyse the difference in the number of lashestouching the eye between baseline and 24-mo follow-up. Changesin LogMAR visual acuity score were analysed by logisticregression. A multivariable logistic regression model was used toassess associations of failure with potential explanatory factors.Variables that were associated with the outcome on univariableanalyses (   p , 0.2) were retained in the multivariable model. Forparticipants in the surgery arm, the cumulative risk of adversesurgical outcomes was estimated, including recurrence (  $ onelashes touching the eye or clinical evidence of epilation),granuloma, and lid notching. Results Participant Recruitment and Flow Trial participants were recruited between March and June2008. Several thousand people presented with eye complaintsduring the course of the surgical outreach campaign and wereassessed for eligibility for this trial. The majority had otherophthalmic conditions such as cataract. A total of 1,300consecutive eligible individuals were identified, all of whomconsented to participate, were randomised, and received theirallocated treatment (650 participants per group) (Figure 1).Primary outcome data are available for 637/650 (98.0%)participants in the epilation group and 641/650 (98.6%)participants in the surgery group (Figure 1). Overall, 84.1% of participants were seen at all five scheduled visits over 24 mo: 517/650 (79.5%) in the epilation group and 576/650 (88.6%) in thesurgery group. There were slightly fewer follow-up examinationsin the epilation group (2,374/2,600 [91.3%]) compared with thesurgery group (2,467/2,600 [94.9%],  p , 0.001). 22 participantswere not seen after baseline (13 epilation group, nine surgerygroup,  p =0.39). Baseline Demographic and Clinical Characteristics  All participants were Ethiopians of Amharan ethnicity. Theirmean age was 50.3 y and the majority (66.4%) were female.Baseline sociodemographic characteristics were generally balancedby randomisation group, although there were slightly fewer femaleparticipants in the epilation group than the surgery group (63.9% versus 68.9%) (Table 1). Clinical features were also balanced(Table 1) with the exception of central corneal opacity (CC2/CC3or CO), which was more frequent in the epilation group (175;26.9%) than the surgery group (137; 21.1%) at baseline. Primary Outcome Overall, 98 individuals developed the primary outcome: 84(13.2%) in the epilation group and 14 (2.2%) in the surgerygroup. In the epilation arm 74 had $ five lashes and an additionalten participants had received repeat surgery elsewhere; in thesurgery arm four had $ five lashes and a further ten had receivedrepeat surgery elsewhere. The difference in cumulative risk of failure was 11.0% (95% CI 8.1%–13.9%). The 95% CI includesthe prestated margin of inferiority (  D , 10.0%), so the trial isinconclusive and does not show evidence of noninferiority of epilation versus surgery, with respect to this prespecifiednoninferiority margin.The rate of failure was greater in the epilation group (hazardratio [HR]=6.38, 95% CI 3.62–11.23) (Figure 2). The mean Trial of Epilation for Trachomatous TrichiasisPLoS Medicine | www.plosmedicine.org 4 December 2011 | Volume 8 | Issue 12 | e1001136  number of lashes touching the eye at each visit was small (Table 2),but was significantly greater in the epilation group (   p , 0.001). Thenumber of lashes touching the eye reduced significantly betweenbaseline and 24 mo in both groups (   p , 0.001). Among patients inthe epilation group, successful epilation (no lashes touching) atbaseline was associated with reduced risk of failure (adjustedOR=0.33, 95% CI 0.13–0.86) and baseline entropion of greaterthan grade 1 was associated with increased risk (adjustedOR=1.72, 95% CI 0.98–3.02) (Table 3). There were too fewfailures in the surgery group to model. Visual Acuity There was no evidence of a difference in change in visual acuity(Table 2) from baseline to follow-up between the two groups ateither 12 mo (OR=1.17, 95% CI 0.87–1.59) or 24 mo(OR=1.16, 95% CI 0.88–1.53). There was similarly no evidence Figure 1. Trial profile. doi:10.1371/journal.pmed.1001136.g001Trial of Epilation for Trachomatous TrichiasisPLoS Medicine | www.plosmedicine.org 5 December 2011 | Volume 8 | Issue 12 | e1001136
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