Mycotic Antimicrobial Localized Injection: A Randomized Clinical Trial Evaluating Intrastromal Injection of Voriconazole.

PURPOSE: To determine if there is a benefit to adjuvant intrastromal voriconazole (ISV) injections for primary treatment of filamentous fungal keratitis. DESIGN: Outcome-masked, randomized controlled clinical trial. PARTICIPANTS: Patients with moderate vision loss resulting from a smear-positive fungal ulcer. METHODS: Study eyes were randomized to topical natamycin plus ISV injection versus topical natamycin alone. MAIN OUTCOME MEASURES: The primary outcome of the trial was microbiological cure on 3-day repeat culture analysis. Secondary outcomes included microbiological cure on 7-day repeat culture analysis; 3-week and 3-month best spectacle-corrected visual acuity; infiltrate or scar size or both; rate of perforation; therapeutic penetrating keratoplasty (TPK); and other adverse events. RESULTS: A total of 151 patients with smear-positive ulcers were screened and 70 were enrolled at Aravind Eye Hospital, Pondicherry, India. Baseline cultures grew Fusarium in 19 samples (27%), Aspergillus in 17 samples (24%), and other filamentous fungi in 19 samples (27%) and showed negative results in 13 samples (19%). Those randomized to ISV injection had 1.82 times the odds of 3-day culture positivity after controlling for baseline culture status (95% confidence interval [CI], 0.65-5.23; P = 0.26, bias-corrected logistic regression) and 1.98 times the odds of positive 7-day culture results, after controlling for baseline culture status (95% CI, 0.69-5.91; P = 0.20, bias-corrected logistic regression). Those randomized to ISV injection showed 0.5 logMAR lines (approximately 0.5 Snellen lines) of decreased visual acuity (95% CI, -2.6 to 3.6 lines; P = 0.75) and 0.55 mm worse infiltrate or scar size or both at 3 months after controlling for baseline values (95% CI, -0.13 to 1.25; P = 0.11). Intrastromal voriconazole injections showed a 2.85-fold increased hazard of perforation after controlling for baseline infiltrate depth (95% CI, 0.76-10.75; P = 0.12) but no difference in the rate of TPK (hazard ratio, 0.95; 95% CI, 0.44-2.04; P = 0.90). CONCLUSIONS: There seems to be no benefit to adding ISV injections to topical natamycin in the primary treatment of moderate to severe filamentous fungal ulcers. Studies consistently suggest that voriconazole has a limited role in the treatment of filamentous fungal ulcers.

Prevalence and risk factors for myopia and other refractive errors in an adult population in southern India.

PURPOSE: To investigate prevalence and risk factors for myopia, hyperopia and astigmatism in southern India. METHODS: Randomly sampled villages were enumerated to identify people aged ≥40 years. Participants were interviewed for socioeconomic and lifestyle factors and attended a hospital-based ophthalmic examination including visual acuity measurement and objective and subjective measurement of refractive status. Myopia was defined as spherical equivalent (SE) worse than -0.75 dioptres (D), hyperopia as SE ≥+1D and astigmatism as cylinder <-0.5. RESULTS: The age-standardised prevalences of myopia, hyperopia and astigmatism were 35.6% (95% CI: 34.7-36.6), 17.0% (95% CI: 16.3-17.8) and 32.6 (29.3-36.1), respectively. Of those with myopia (n = 1490), 70% had advanced cataract. Of these, 79% had presenting visual acuity (VA) less than 6/18 and after best correction, 44% of these improved to 6/12 or better and 27% remained with VA less than 6/18. In multivariable analyses (excluding patients with advanced cataract), increasing nuclear opacity score, current tobacco use, and increasing height were associated with higher odds of myopia. Higher levels of education were associated with increased odds of myopia in younger people and decreased odds in older people. Increasing time outdoors was associated with myopia only in older people. Increasing age and female gender were associated with hyperopia, and nuclear opacity score, increasing time outdoors, rural residence and current tobacco use with lower odds of hyperopia. After controlling for myopia, factors associated with higher odds of astigmatism were age, rural residence, and increasing nuclear opacity score and increasing education with lower odds. CONCLUSIONS: In contrast to high-income settings and in agreement with studies from low-income settings, we found a rise in myopia with increasing age reflecting the high prevalence of advanced cataract.

Effect of pretreatment with antifungal agents on clinical outcomes in fungal keratitis.

BACKGROUND: To determine if pretreatment with antifungal agents is predictive of worse clinical outcome in a fungal keratitis clinical trial. DESIGN: Non-pre-specified subgroup analysis of a randomized controlled trial in a tertiary hospital. PARTICIPANTS: Three hundred twenty-three fungal ulcer cases with an enrolment visual acuity of 20/40 to 20/400. METHODS: The Mycotic Ulcer Treatment Trial I was a randomized, double-masked trial to determine the optimal treatment for filamentous fungal keratitis at the Aravind Eye Care System, India. Enrolled cases were randomized to receive topical natamycin or voriconazole. Prior antifungal medication use, dose and duration were collected at enrolment. A subgroup analysis was performed to determine if patients using natamycin or azoles at presentation have worse clinical outcomes compared with those who were not pretreated. MAIN OUTCOME MEASURES: Three-month visual acuity (primary), 3-month infiltrate or scar size, corneal perforation and/or transplant and re-epithelialization time. RESULTS: Of the 323 patients enrolled, 44% presented on an antifungal agent. Pretreated patients had larger mean baseline infiltrate size (P < 0.001) and epithelial defect size (P = 0.02). Multivariate regression analysis demonstrated that pretreatment was associated with significantly worse 3-month visual acuity (P = 0.006), larger 3-month scar size (P < 0.001) and increased odds of corneal perforation and/or transplant (P = 0.001). CONCLUSIONS: Fungal keratitis that is smear-positive despite being pretreated with appropriate antifungal agents appears to be a risk factor for worse outcomes, likely a result of initial ulcer severity and treatment failure. These patients may benefit from more aggressive multimodal therapy at a tertiary centre.

Validation of the C-DU(KE) Calculator as a Predictor of Outcomes in Patients Enrolled in Steroids for Corneal Ulcer and Mycotic Ulcer Treatment Trials.

PURPOSE: The aim of this study was to validate the C-DU(KE) calculator as a predictor of treatment outcomes on a data set derived from patients with culture-positive ulcers. METHODS: C-DU(KE) criteria were compiled from a data set consisting of 1063 cases of infectious keratitis from the Steroids for Corneal Ulcer Trial (SCUT) and Mycotic Ulcer Treatment Trial (MUTT) studies. These criteria include corticosteroid use after symptoms, visual acuity, ulcer area, fungal etiology, and elapsed time to organism-sensitive therapy. Univariate analysis was performed followed by multivariable logistic regressions on culture-exclusive and culture-inclusive models to assess for associations between the variables and outcome. The predictive probability of treatment failure, defined as the need for surgical intervention, was calculated for each study participant. Discrimination was assessed using the area under the curve for each model. RESULTS: Overall, 17.9% of SCUT/MUTT participants required surgical intervention. Univariate analysis showed that decreased visual acuity, larger ulcer area, and fungal etiology had a significant association with failed medical management. The other 2 criteria did not. In the culture-exclusive model, 2 of 3 criteria, decreased vision [odds ratio (OR) = 3.13, P < 0.001] and increased ulcer area (OR = 1.03, P < 0.001), affected outcomes. In the culture-inclusive model, 3 of 5 criteria, decreased vision (OR = 4.9, P < 0.001), ulcer area (OR = 1.02, P < 0.001), and fungal etiology (OR = 9.8, P < 0.001), affected results. The area under the curves were 0.784 for the culture-exclusive model and 0.846 for the culture-inclusive model which were comparable to the original study. CONCLUSIONS: The C-DU(KE) calculator is generalizable to a study population from large international studies primarily taking place in India. These results support its use as a risk stratification tool assisting ophthalmologists in patient management.

Patterns of Antifungal Resistance in Adult Patients With Fungal Keratitis in South India: A Post Hoc Analysis of 3 Randomized Clinical Trials.

IMPORTANCE: Antifungal resistance has been shown to impact treatment success, but research analyzing antifungal resistance is scarce. OBJECTIVE: To evaluate changes in antifungal resistance over time. DESIGN, SETTING, AND PARTICIPANTS: Ad hoc analysis of 3 randomized clinical trials including consecutive patients 18 years and older presenting with smear-positive fungal ulcers to Aravind Eye Hospitals in Madurai, Coimbatore, Pondicherry, and Tirunelveli in South India who participated in 1 of 3 clinical trials: the Mycotic Ulcer Treatment Trials (MUTT) I (2010 to 2011) or II (2010 to 2015) or the Cross-Linking Assisted Infection Reduction (CLAIR) trial (2016 to 2018). This post hoc analysis was designed in March 2021 and data were analyzed in May and November 2021. INTERVENTIONS: Minimum inhibitory concentration (MIC) of natamycin and voriconazole was determined from corneal cultures obtained using standardized methods outlined in the Clinical and Laboratory Standards Institute. MAIN OUTCOMES AND MEASURES: The primary outcome of this post hoc analysis was MIC of natamycin and voriconazole. RESULTS: A total of 890 fungal isolates were obtained from 651 patients (mean [SD] age, 49.6 [13.0]; 191 [43.3%] female) from 2010 to 2018. MICs were available for 522 samples in 446 patients. Fungal isolates overall demonstrated a 1.02-fold increase per year in voriconazole resistance as measured by MICs (95% CI, 1.00-1.04; P = .06). In subgroup analyses, Fusarium species demonstrated a 1.04-fold increase in voriconazole resistance per year (95% CI, 1.00-1.06; P = .01). Fungal isolates showed a 1.06-fold increase in natamycin resistance per year overall (95% CI, 1.03-1.09; P < .001). Fusarium species had a 1.06-fold increase in natamycin resistance (95% CI, 1.05-1.08; P < .001), Aspergillus had a 1.09-fold increase in resistance (95% CI, 1.05-1.15; P < .001), and other filamentous fungi had a 1.07-fold increase in resistance to natamycin per year (95% CI, 1.04-1.10; P < .001). CONCLUSIONS AND RELEVANCE: This post hoc analysis suggests that susceptibility to both natamycin and voriconazole may be decreasing over the last decade in South India. While a trend of increasing resistance could impact treatment of mycoses in general and infectious fungal keratitis in particular, further study is needed to confirm these findings and determine their generalizability to other regions of the world. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00996736 and NCT02570321.

The Prognostic Value of Persistent Culture Positivity in Fungal Keratitis in the Mycotic Antimicrobial Localized Injection Trial.

PURPOSE: To evaluate the utility of repeat cultures at days 3 and 7 after starting antifungal medications for predicting outcomes in fungal keratitis. DESIGN: Prespecified secondary analysis of the randomized clinical Mycotic Antimicrobial Localized Injection trial. METHODS: Patients presenting to Aravind Eye Hospital, Pondicherry, India, with fungal keratitis and visual acuity worse than 20/70 received topical natamycin and were randomized to either receive intrastromal injection of voriconazole or topical therapy alone. All subjects received corneal cultures at date of presentation, day 3, and day 7. Outcome measures included 3-week and 3-month visual acuity and scar size, corneal perforation, and/or the need for therapeutic penetrating keratoplasty (TPK). Visual acuity and scar size were analyzed with multiple linear regression controlling for baseline measures. Survival analysis was used to analyze the risk of corneal perforation and/or need for TPK. RESULTS: Of the 70 study subjects with fungal keratitis, 25 of 69 (36%) remained culture positive at day 3, and 20 of 62 (32%) were culture positive at day 7. Culture positivity at day 3 conferred a hazard ratio of 2.8 for requiring TPK (P = .03) but was not a statistically significant predictor of perforation, scar size, or final visual acuity. Culture positivity at day 7 had a hazard ratio of 3.5 for requiring TPK (P = .003). Those with positive cultures at day 7 had on average 3 logMAR lines worse visual acuity at 3 months (95% confidence interval 0.9 to 5.2 logMAR lines, P = .006) and 1.1 mm larger scar size at 3 months after controlling for baseline measures (95% confidence interval 0.1 to 2.2 mm; P = .03). CONCLUSIONS: While not as predictive as day 7 cultures, culture positivity at day 3 after starting treatment is a significant predictor of the need for TPK in patients with moderate-to-severe filamentous fungal keratitis. This has applications for risk stratification, and may facilitate earlier consideration of TPK in high-risk patients.

Genetic variants in a sodium-dependent vitamin C transporter gene and age-related cataract.

BACKGROUND: Cataract is a major health burden in many countries and a significant problem in India. While observational studies show lower cataract risk with increasing dietary or plasma vitamin C, randomised controlled trials of supplements have been negative. Genetic variants in vitamin C transporter proteins (SLC23A1), especially rs33972313, may provide evidence on a causal association of vitamin C with cataract. METHODS: We used data from a randomly selected population-based study in people aged 60 years and above in north and south India. Of 7518 sampled, 5428 (72%) were interviewed for socioeconomic and lifestyle factors, attended hospital for lens imaging and blood collection and were subsequently genotyped for rs33972313 and rs6596473. Mixed or pure types of cataract were graded by the Lens Opacity Classification System III as nuclear (2404), cortical (494) or posterior subcapsular cataract (PSC) (1026); 1462 had no significant cataract and no history of cataract surgery and 775 had bilateral aphakia/pseudophakia. RESULTS: rs33972313 was associated with cortical (OR 2.16; 95% CI 1.34 to 3.49, p=0.002) and PSC (OR 1.68; 95% CI 1.06 to 2.65, p=0.03) but not with nuclear cataract. In analyses of pure cataracts, associations were found only between rs33972313 and pure cortical cataracts (OR 2.29; 95% CI 1.12 to 4.65, p=0.03) and with a standardised cortical opacity score. There was no association with rs6596473 and any cataract outcomes. CONCLUSIONS: Using an established genetic variant as a proxy for lifetime ascorbate concentrations, our results support a causal association of vitamin C with cataract.

A retrospective study on the incidence of post-cataract surgery Descemet's membrane detachment and outcome of air descemetopexy.

PURPOSE: To study the anatomic and functional outcome of air descemetopexy in postcataract surgery Descemet's membrane detachment (DMD). DESIGN: Retrospective study. METHODS: Setting: Institutional. STUDY POPULATION: Records of 112 patients who underwent air descemetopexy for postcataract surgery sight-threatening DMD at Aravind Eye Hospital, Pondicherry, between January 2013 and December 2015 were studied. MAIN OUTCOME MEASURES: Anatomical outcome refers to reattachment of the Descemet's membrane (DM). Functional outcome was given by the best-corrected visual acuity. RESULTS: The mean age was 66.47±8.46 (SD) years, the male to female ratio was 45:67. The incidence of DMD was more in extracapsular cataract extraction (0.26%) and manual small incision cataract surgery (0.11%) than phacoemulsification (0.04%) (p=0.005 and p<0.0001). DMD was more common among surgical trainees (0.17%) than consultants (0.07%) (p≤0.0001). After primary air descemetopexy, 78 (71%) out of the 110 patients had DM reattachment. The complications noted after descemetopexy include persistent DMD (21.8%), corneal decompensation (7.3%), appositional angle closure (18%), pupillary block with air (2.7%) and uveitis (2.7%). Age, sex and timing of intervention did not influence the reattachment rate. Fifteen patients underwent repeat air descemetopexy for persistent DMD among whom nine (60%) had successful reattachment. Almost 75% of patients had vision better than 6/18 1 month after anatomically successful descemetopexy. CONCLUSION: Air descemetopexy is a safe and efficient modality of treatment of DMD and should be tried even in patients with severe DMD before planning a major surgery like endothelial keratoplasty.

Therapeutic Penetrating Keratoplasty Button Cultures in The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole Versus Placebo.

OBJECTIVE: To compare oral voriconazole vs placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. DESIGN: Non-prespecified, secondary case-control analysis from a multicenter, double-masked, randomized placebo-controlled clinical trial. METHODS: Study Participants: Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 or worse who eventuated to therapeutic penetrating keratoplasty (TPK). INTERVENTION: Study participants were randomized to oral voriconazole vs oral placebo; all received topical antifungal drops. MAIN OUTCOME MEASURES: TPK button culture positivity. RESULTS: A total of 95 of 194 (49.5%) study participants enrolled at Madurai, Coimbatore, or Pondicherry, India eventuated to TPK in an average of 20.9 days (standard deviation 15.2 days, range 2-71 days). TPK button cultures were available for 67 of 95 (71%) of the TPKs performed and were positive for filamentous fungus in 45 of 67 (67%) cases. For each 1-day increase in the time to TPK there was 0.94-fold decreased odds of fungal culture positivity (95% confidence interval [CI] 0.90-0.98, P = .005). Those randomized to oral voriconazole had 1.26-fold increased odds of TPK button culture positivity after controlling for time to TPK and baseline organism, but this was not statistically significant (95% CI 0.32-4.87; P = .74). Those who underwent TPK for lack of response to medical therapy were 10.64-fold more likely to be culture positive than if the indication for surgery was perforation and this was statistically significant (95% CI 2.16-51.70; P = .003). CONCLUSIONS: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. Infection rather than inflammation appears to be the reason for the worsening clinical picture in many of these patients.

The Significance of Repeat Cultures in the Treatment of Severe Fungal Keratitis.

PURPOSE: To identify fungal keratitis patients who are at risk of a poor outcome and may benefit from closer follow-up or more aggressive treatment. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: We compared the clinical outcomes of patients who had positive 6-day fungal cultures with those who did not, using backward stepwise regression with covariates for all baseline clinical characteristics. SUBJECTS: Patients presenting with a smear-positive filamentous fungal ulcer and visual acuity of 20/400 or worse, and who subsequently had a 6-day fungal culture performed at the Aravind Eye Care system (India), Lumbini Eye Hospital (Nepal), or Bharatpur Eye Hospital (Nepal). MAIN OUTCOME MEASURES: The primary outcome is rate of corneal perforation and/or the need for therapeutic penetrating keratoplasty. Secondary outcomes include 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate and/or scar size, and rate of re-epithelialization. RESULTS: Patients who tested positive at their 6-day culture had twice the hazard of experiencing a corneal perforation or the need for therapeutic penetrating keratoplasty (P = .002) than those who tested negative, even after controlling for baseline ulcer characteristics. These patients also had on average 0.26 logMAR lines worse BSCVA at 3 months (P = .001). Culture positivity at day 6 was not a statistically significant predictor of 3-month infiltrate/scar-size (-0.24 mm1; P = .45) or time to re-epithelialization (hazard ratio = .81; P = .31). CONCLUSIONS: Here we identify a uniquely valuable clinical tool, day 6 culture results, for the treatment of severe fungal keratitis. Risk stratification based on repeat culture positivity is an objective way to assess response to medical therapy and identify patients who are at high risk of a poor clinical outcome. This establishes a new standard of care for severe fungal keratitis management.

Regression Discontinuity and Randomized Controlled Trial Estimates: An Application to The Mycotic Ulcer Treatment Trials.

PURPOSE: We compare results from regression discontinuity (RD) analysis to primary results of a randomized controlled trial (RCT) utilizing data from two contemporaneous RCTs for treatment of fungal corneal ulcers. METHODS: Patients were enrolled in the Mycotic Ulcer Treatment Trials I and II (MUTT I & MUTT II) based on baseline visual acuity: patients with acuity ≤ 20/400 (logMAR 1.3) enrolled in MUTT I, and >20/400 in MUTT II. MUTT I investigated the effect of topical natamycin versus voriconazole on best spectacle-corrected visual acuity. MUTT II investigated the effect of topical voriconazole plus placebo versus topical voriconazole plus oral voriconazole. We compared the RD estimate (natamycin arm of MUTT I [N = 162] versus placebo arm of MUTT II [N = 54]) to the RCT estimate from MUTT I (topical natamycin [N = 162] versus topical voriconazole [N = 161]). RESULTS: In the RD, patients receiving natamycin had mean improvement of 4-lines of visual acuity at 3 months (logMAR -0.39, 95% CI: -0.61, -0.17) compared to topical voriconazole plus placebo, and 2-lines in the RCT (logMAR -0.18, 95% CI: -0.30, -0.05) compared to topical voriconazole. CONCLUSIONS: The RD and RCT estimates were similar, although the RD design overestimated effects compared to the RCT.

The Utility of Repeat Culture in Fungal Corneal Ulcer Management: A Secondary Analysis of the MUTT-I Randomized Clinical Trial.

PURPOSE: To determine whether patients who had a positive repeated culture was predictive of worse clinical outcome than those who achieved microbiological cure at 6 days in the Mycotic Ulcer Treatment Trial I (MUTT-I). DESIGN: Secondary analysis from a multicenter, double-masked, randomized clinical trial. METHODS: setting: Multiple hospital sites of the Aravind Eye Care System, India. STUDY POPULATION: Patients with culture-positive filamentous fungal ulcers and visual acuity of 20/40 to 20/400 reexamined 6 days after initiation of treatment. INTERVENTION: Corneal scraping and cultures were obtained from study participants at day 6 after enrollment. MAIN OUTCOME MEASURES: We assessed 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate/scar size, corneal perforation, and re-epithelialization rates stratified by culture positivity at day 6. RESULTS: Of the 323 patients with smear-positive ulcers enrolled in MUTT-I, 299 (92.6%) were scraped and cultured 6 days after enrollment. Repeat culture positivity was 31% (92/299). Among patients who tested positive at enrollment, those with positive 6-day cultures had significantly worse 3-month BSCVA (0.39 logMAR; 95% confidence interval [CI]: 0.24-0.44; P < .001), had larger 3-month scar size (0.39 mm; 95% CI: 0.06-0.73; P = .02), were more likely to perforate or require therapeutic penetrating keratoplasty (odds ratio: 6.27; 95% CI: 2.73-14.40; P < .001), and were slower to re-epithelialize (hazard ratio: 0.33; 95% CI: 0.21-0.50; P < .001) than those with a negative 6-day culture result. CONCLUSIONS: Early microbiological cure on culture is a predictor of clinical response to treatment.

Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II.

Importance: Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings. Objective: To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK). Design, Setting, and Participants: This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added. Main Outcomes and Measures: The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK. Results: The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis. Conclusions and Relevance: These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Adjunctive Oral Voriconazole Treatment of Fusarium Keratitis: A Secondary Analysis From the Mycotic Ulcer Treatment Trial II.

Importance: Fusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available. Objective: To explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis. Design, Setting, and Participants: In this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016. Main Outcomes and Measures: The primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months. Results: Of the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, -1.33 to -0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, -0.57 to 0.002; P = .052). Conclusions and Relevance: Although MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Spring-action Apparatus for Fixation of Eyeball (SAFE): a novel, cost-effective yet simple device for ophthalmic wet-lab training.

Achieving a formed and firm eyeball which is stably fixed in a holding device is a major challenge of surgical wet-lab training. Our innovation, the 'Spring-action Apparatus for Fixation of Eyeball (SAFE)' is a robust, simple and economical device to solve this problem. It consists of a hollow iron cylinder to which a spring-action syringe is attached. The spring-action syringe generates vacuum and enables reliable fixation of a human or animal cadaveric eye on the iron cylinder. The rise in intraocular pressure due to vacuum fixation can be varied as per need or nature of surgery being practised. A mask-fixed version of this device is also designed to train surgeons for appropriate hand positioning. An experienced surgeon performed various surgeries including manual small incision cataract surgery (MSICS), phacoemulsification, laser in situ keratomileusis (LASIK), femtosecond LASIK docking, Descemet's stripping endothelial keratoplasty, deep anterior lamellar keratoplasty, penetrating keratoplasty and trabeculectomy on this device, while a trainee surgeon practised MSICS and wound suturing. Skill-appropriate comfort level was much higher with SAFE than with conventional globe holders for both surgeons. Due to its stability, pressure adjustability, portability, cost-efficiency and simplicity, we recommend SAFE as the basic equipment for every wet lab.

Use of Cooking Fuels and Cataract in a Population-Based Study: The India Eye Disease Study.

BACKGROUND: Biomass cooking fuels are commonly used in Indian households, especially by the poorest socioeconomic groups. Cataract is highly prevalent in India and the major cause of vision loss. The evidence on biomass fuels and cataract is limited. OBJECTIVES: To examine the association of biomass cooking fuels with cataract and type of cataract. METHODS: We conducted a population-based study in north and south India using randomly sampled clusters to identify people ≥ 60 years old. Participants were interviewed and asked about cooking fuel use, socioeconomic and lifestyle factors and attended hospital for digital lens imaging (graded using the Lens Opacity Classification System III), anthropometry, and blood collection. Years of use of biomass fuels were estimated and transformed to a standardized normal distribution. RESULTS: Of the 7,518 people sampled, 94% were interviewed and 83% of these attended the hospital. Sex modified the association between years of biomass fuel use and cataract; the adjusted odds ratio (OR) for a 1-SD increase in years of biomass fuel use and nuclear cataract was 1.04 (95% CI: 0.88, 1.23) for men and 1.28 (95% CI: 1.10, 1.48) for women, p interaction = 0.07. Kerosene use was low (10%). Among women, kerosene use was associated with nuclear (OR = 1.76, 95% CI: 1.04, 2.97) and posterior subcapsular cataract (OR = 1.71, 95% CI: 1.10, 2.64). There was no association among men. CONCLUSIONS: Our results provide robust evidence for the association of biomass fuels with cataract for women but not for men. Our finding for kerosene and cataract among women is novel and requires confirmation in other studies. Citation: Ravilla TD, Gupta S, Ravindran RD, Vashist P, Krishnan T, Maraini G, Chakravarthy U, Fletcher AE. 2016. Use of cooking fuels and cataract in a population-based study: the India Eye Disease Study. Environ Health Perspect 124:1857-1862; http://dx.doi.org/10.1289/EHP193.

Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial.

IMPORTANCE: The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure. OBJECTIVE: To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a double-masked, multicenter, randomized clinical trial included patients with culture- or smear-positive filamentous fungal corneal ulcer and a baseline visual acuity of 20/40 to 20/400. Culture-positive samples with susceptibility testing were included in this analysis. The patients were treated at multiple locations of the Aravind Eye Care Hospital system in South India. Data were collected from April 3, 2010, to December 31, 2011, and analyzed from July 15 to September 1, 2015. INTERVENTIONS: Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen. MAIN OUTCOMES AND MEASURES: Minimum inhibitory concentration of voriconazole and natamycin in baseline cultures. RESULTS: Of 323 participants with smear-positive specimens (183 men [56.7%]; 140 women [43.3%]; median [interquartile range] age, 47 [38-56] years), fungal-positive cultures were obtained for 256 (79.3%). The MIC data were available for 221 of 323 participants (68.4%), because 35 samples had no growth during susceptibility testing. A 2.14-fold increase per year (95% CI, 1.13-4.56; P = .02) in voriconazole MICs after controlling for the infectious organism was found. This association was not found when looking at natamycin MICs of baseline cultures after controlling for the infectious organism (1.26; 95% CI, 0.13-12.55; P = .85). CONCLUSIONS AND RELEVANCE: Susceptibility to voriconazole appeared to decrease during the relatively short enrollment period of the clinical trial. This decrease may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, because presenting with azole treatment was not a risk factor for resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00996736.

Risk factors for low vision related functioning in the Mycotic Ulcer Treatment Trial: a randomised trial comparing natamycin with voriconazole.

BACKGROUND/AIMS: The Mycotic Ulcer Treatment Trial I (MUTT I) was a double-masked, multicentre, randomised controlled trial, which found that topical natamycin is superior to voriconazole for the treatment of filamentous fungal corneal ulcers. In this study, we determine risk factors for low vision-related quality of life in patients with fungal keratitis. METHODS: The Indian visual function questionnaire (IND-VFQ) was administered to MUTT I study participants at 3 months. Associations between patient and ulcer characteristics and IND-VFQ subscale score were assessed using generalised estimating equations. RESULTS: 323 patients were enrolled in the trial, and 292 (90.4%) completed the IND-VFQ at 3 months. Out of a total possible score of 100, the average VFQ score for all participants was 81.3 (range 0-100, SD 23.6). After correcting for treatment arm, each logMAR line of worse baseline visual acuity in the affected eye resulted in an average 1.2 points decrease on VFQ at 3 months (95% CI -1.8 to 0.6, p<0.001). Those who required therapeutic penetrating keratoplasty had an average of 25.2 points decrease on VFQ after correcting for treatment arm (95% CI -31.8 to -18.5, p<0.001). Study participants who were unemployed had on average 28.5 points decrease on VFQ (95% CI -46.9 to -10.2, p=0.002) after correcting for treatment arm. CONCLUSIONS: Monocular vision loss from corneal opacity due to fungal keratitis reduced vision-related quality of life. Given the relatively high worldwide burden of corneal opacity, improving treatment outcomes of corneal infections should be a public health priority. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov Identifier: NCT00996736.

Effect of Oral Voriconazole on Fungal Keratitis in the Mycotic Ulcer Treatment Trial II (MUTT II): A Randomized Clinical Trial.

Objective: To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. Design, Setting, and Participants: The Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis. Interventions: Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%. Main Outcomes and Measures: The primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use. Results: A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Sidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Sidák correction for multiple comparisons). Conclusions and Relevance: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world. Trial Registration: clinicaltrials.gov Identifier: NCT00996736.