Harmonizing ophthalmic residency surgical training across Europe: A proposed surgical curriculum.

BACKGROUND: One of the core aims of the European Union of Medical Specialists is to harmonize training across Europe by creating European Training Requirements for all medical specialties including Ophthalmology. The theoretical part is already defined by the EBO, however as ophthalmology also includes surgical skills, we herein propose a surgical minimum curriculum for ophthalmology residents in Europe. METHODS: National and international ophthalmic training curricula which are publicly available in English were reviewed and compared. The final proposal was created from 5 criteria: 1. Disease prevalence; 2. Patient safety; 3. Case-trainee ratio; 4. Skill transfer; and 5. Technical difficulty. RESULTS: In total 7 different training curricula from across the world were compared. Among the surgical procedures, cataract surgery has the highest median number of procedures required to be completed during residency: 86 procedures (50-350). Followed by oculoplastics: 28 procedures (10-40) and panretinal photocoagulation: 27.5 procedures (10-49) Full procedural competence is proposed in 9 surgical skills, including YAG laser posterior capsulotomy, retinal argon laser, intravitreal injection, corneal foreign body removal, removal of corneal sutures, facial and periocular laceration repair, eyelid laceration repair, minor eyelid procedures, and punctal occlusion. These procedures are deemed essential and feasible for all ophthalmology residents in Europe to perform independently upon completion of their training. CONCLUSION: This proposal should be regarded as a recommendation based on comparable surgical curricula in use worldwide to establish standards across European countries and may serve as valuable insight to those responsible for compiling ETRs for ophthalmology, or their national curriculums.

Cellular morphological changes detected by laser scanning in vivo confocal microscopy associated with clinical outcome in fungal keratitis.

HRT3 in vivo confocal microscopy (IVCM) images may indicate clinical outcome, but few studies have analysed this in fungal keratitis (FK). Adults with FK (diameter ≥3 mm) presenting to Aravind Eye Hospital, India from 2012-3 were enrolled prospectively. IVCM was performed at baseline, days 7, 14 and 21 post-enrolment (+/- 3 days where possible). Specific morphologies were identified in IVCM images by a grader masked to microbiology and clinical outcome (defined as good: healed/improving, or poor: enlarged ulcer, perforation or transplant/glue). Associations with final visit outcome assessed using logistic regression. 143 FK participants were enrolled; 87 had good outcome, 56 had poor outcome. Poor outcomes were associated with stellate interconnected cellular processes with no visible nuclei (OR 2.28, 95% CI: 1.03-5.06, p = 0.043) in baseline IVCM images, and fungal filaments (OR 6.48, 95% CI:2.50-16.78, p < 0.001) or honeycomb distribution of inflammatory cells (OR 5.24, 95% CI: 1.44-19.06, p = 0.012) in final visit images. Fungal filaments (OR 3.61, 95% CI:1.64-7.95, p = 0.001), stromal dendritiform cells (OR 2.88, 95% CI:1.17-7.11, p = 0.022), or stellate cellular processes with no visible nuclei (OR 2.09, 95% CI:1.14-3.82, p = 0.017) were associated with poor outcome if not in baseline but present in final visit images. IVCM can reveal morphological changes associated with clinical outcome.

Association Between Season, Temperature and Causative Organism in Microbial Keratitis in the UK.

PURPOSE: Microbial keratitis (MK) is a major cause of corneal blindness worldwide. Variations in season and temperature can affect MK incidence due to specific causative organisms; however, few studies have examined these factors in the UK. METHODS: Retrospective review of all corneal scrapes from patients with MK presenting to Manchester Royal Eye Hospital, UK, between January 2004 and December 2015. Manchester's monthly temperature data were obtained from Met Office UK. Analysis was performed using logistic regression. RESULTS: From 4229 corneal scrapes, 1539 organisms grew (90.6% bacteria, 7.1% fungi, and 2.3% Acanthamoebae sp.). Gram-positive bacteria grew with increasing temperature [odds ratio (OR) 1.62, 95% CI: 1.11-2.39, P = 0.014], and fungi grew with decreasing temperature (OR 0.29, 95% CI: 0.16-0.51, P < 0.001). Moraxella sp. grew with decreasing temperature (OR 0.91, 95% CI: 0.86-0.96, P = 0.001). Compared with winter, overall culture positivity was significantly less likely in summer (OR 0.57, 95% CI: 0.38-0.87, P = 0.008) and spring (OR 0.65, 95% CI: 0.43-0.99, P = 0.045). Gram-negative bacteria were more likely in summer (OR 1.48, 95% CI: 1.06-2.09, P = 0.022) and autumn (OR 1.75, 95% CI: 1.24-2.47, P = 0.001). Candida sp. were less likely in summer (OR 0.25, 95% CI: 0.07-0.82, P = 0.027) and autumn (OR 0.18, 95% CI: 0.05-0.62, P = 0.009), and Acanthamoeba sp. were less likely in summer (OR 0.39, 95% CI: 0.15-0.92, P = 0.037) and spring (OR 0.26, 95% CI: 0.08-0.69, P = 0.011). CONCLUSIONS: Herein we report variation in the incidence of MK-causing organisms by season and temperature; this finding may aid clinicians in predicting possible causative organisms for MK at differing times of the year.

In Vivo Confocal Microscopy Cellular Features of Host and Organism in Bacterial, Fungal, and Acanthamoeba Keratitis.

PURPOSE: To determine cellular features of fungal (FK), Acanthamoeba (AK), and bacterial keratitis (BK) using HRT3 in vivo confocal microscopy (IVCM). DESIGN: Prospective observational cross-sectional study. METHODS: Eligible participants were adults with microbiologically positive FK, AK, or BK, of size ≥ 3 mm, attending Aravind Eye Hospital from February 2012 to February 2013. Exclusion criteria were descemetocele or perforation. At presentation, IVCM imaging was performed, then corneal scrapes were obtained for culture/light microscopy. An experienced grader (masked to microbiology/clinical features) assessed IVCM images for presence/absence of normal keratocyte-like morphology, stellate interconnected cells with/without visible nuclei, dendritiform cells (DFCs), inflammatory cells in a honeycomb distribution, and organism features. Statistical significance was assessed by logistic regression, adjusted for age, sex, ulcer size, and symptom duration. Main outcome measures were presence/absence of IVCM features in FK, AK, BK. RESULTS: A total of 183 participants had FK, 18 AK, 17 BK. Acanthamoeba appeared as bright spots (16/18, 89%), double-walled cysts (15/18, 83%), or signet rings (3/18, 17%), and often formed clusters after topical steroid use (univariable odds ratio [OR] 9.98, 95% confidence interval [CI] 1.02-97.96, P = .048). BK was associated with bullae in anterior stroma (OR 9.99, 95% CI: 3.11-32.06, P < .001). Honeycomb distribution of anterior stromal inflammatory cells was associated with FK (univariable OR 2.74, 95% CI: 1.01-7.40, P = .047). Aspergillus ulcers were associated with stromal DFCs (OR 11.05, 95% CI: 1.49-82.13, P = .019) and Fusarium ulcers with stellate appearance of interconnected cell processes with nuclei (OR 0.24, 95% CI: 0.09-0.65, P = .005). CONCLUSION: Specific cellular and structural features observed using IVCM in microbial keratitis may be associated with organism.

Persistence of Innate Immune Pathways in Late Stage Human Bacterial and Fungal Keratitis: Results from a Comparative Transcriptome Analysis.

Microbial keratitis (MK) is a major cause of blindness worldwide. Despite adequate antimicrobial treatment, tissue damage can ensue. We compared the human corneal transcriptional profile in late stage MK to normal corneal tissue to identify pathways involved in pathogenesis. Total RNA from MK tissue and normal cadaver corneas was used to determine transcriptome profiles with Illumina HumanHT-12 v4 beadchips. We performed differential expression and network analysis of genes in bacterial keratitis (BK) and fungal keratitis (FK) compared with control (C) samples. Results were validated by RTqPCR for 45 genes in an independent series of 183 MK patients. For the microarray transcriptome analysis, 27 samples were used: 12 controls, 7 BK culture positive for Streptococcus pneumoniae (n = 6), Pseudomonas aeruginosa (n = 1), and 8 FK, culture positive for Fusarium sp. (n = 5), Aspergillus sp. (n = 2), or Lasiodiplodia sp. (n = 1). There were 185 unique differentially expressed genes in BK, 50 in FK, and 339 common to both [i.e., genes with fold-change (FC) < -4 or ≥4 and false discovery rate (FDR) adjusted P < 0.05]. MMP9 had the highest FC in BK (91 FC, adj p = 3.64 E-12) and FK (FC 64, adj. p = 6.10 E-11), along with other MMPs (MMP1, MMP7, MMP10, MMP12), pro-inflammatory cytokines (IL1B, TNF), and PRRs (TLR2, TLR4). HIF1A and its induced genes were upregulated uniquely in BK. Immune/defense response and extracellular matrix terms were the most enriched Gene Ontology terms in both BK and FK. In the network analysis, chemokines were prominent for FK, and actin filament reorganization for BK. Microarray and RTqPCR results were highly correlated for the same samples tested with both assays, and with the larger RTqPCR series. In conclusion, we found a great deal of overlap in the gene expression profile of late stage BK and FK, however genes unique to fungal infection highlighted a corneal epithelial wound healing response and for bacterial infection the prominence of HIF1A-induced genes. These sets of genes may provide new targets for future research into therapeutic agents.

Prospective Study of the Diagnostic Accuracy of the In Vivo Laser Scanning Confocal Microscope for Severe Microbial Keratitis.

PURPOSE: To determine the diagnostic accuracy of in vivo confocal microscopy (IVCM) for moderate to severe microbial keratitis (MK). DESIGN: Double-masked prospective cohort study. PARTICIPANTS: Consecutive patients presenting to Aravind Eye Hospital, Madurai, India, between February 2012 and February 2013 with MK (diameter ≥3 mm, excluding descemetocele, perforation, or herpetic keratitis). METHODS: Following examination, the corneal ulcer was scanned by IVCM (HRT3/RCM, Heidelberg Engineering, Heidelberg, Germany). Images were graded for the presence or absence of fungal hyphae or Acanthamoeba cysts by the confocal microscopist who performed the scan (masked to microbial diagnosis) and 4 other experienced confocal graders (masked to clinical features and microbiology). The regrading of the shuffled image set was performed by 3 graders, 3 weeks later. Corneal-scrape samples were collected for microscopy and culture. MAIN OUTCOME MEASURES: The main outcome measures were sensitivity, specificity, and positive and negative predictive values of IVCM compared with those of a reference standard of positive culture or light microscopy. Sensitivities and specificities for multiple graders were pooled and 95% confidence intervals calculated using a bivariate random-effects regression model. RESULTS: The study enrolled 239 patients with MK. Fungal infection was detected in 176 (74%) and Acanthamoeba in 17 (7%) by microbiological methods. IVCM had an overall pooled (5 graders) sensitivity of 85.7% (95% confidence interval [CI]: 82.2%-88.6%) and pooled specificity of 81.4% (95% CI: 76.0%-85.9%) for fungal filament detection. For Acanthamoeba, the pooled sensitivity was 88.2% (95% CI: 76.2%-94.6%) and pooled specificity was 98.2% (95% CI: 94.9%-99.3%). Intergrader agreement was good: κ was 0.88 for definite fungus; κ was 0.72 for definite Acanthamoeba. Intragrader repeatability was high for both definite fungus (κ: 0.88-0.95) and definite Acanthamoeba classification (κ: 0.63-0.90). IVCM images from 11 patients were considered by all 5 graders to have a specific organism present (10 fungus, 1 Acanthamoeba) but had negative results via culture and light microscopy. CONCLUSIONS: Laser scanning IVCM performed with experienced confocal graders has high sensitivity, specificity, and test reproducibility for detecting fungal filaments and Acanthamoeba cysts in moderate to large corneal ulcers in India. This imaging modality was particularly useful for detecting organisms in deep ulcers in which culture and light microscopy results were negative.

Association of conjunctival bacterial infection and female sex in cicatricial trachoma.

PURPOSE: Conjunctival infection with non-chlamydial bacteria may play an important role in the progression of trachoma, especially with regard to the development of corneal opacity and blindness. To further characterize the microbiological profile of bacterial conjunctival infections in cicatricial trachoma, a conjunctival swabbing of adults in rural Ethiopia was performed. METHODS: In a cross-sectional study conducted in nine Ethiopian villages with hyperendemic trachoma, persons 40 years of age or older with signs or symptoms consistent with trichiasis were recruited and conjunctival swabbing for bacterial pathogens was performed. RESULTS: Conjunctival examination and swabbing on 112 females and 36 males were performed. Of the 148 study participants, 101 (68.2%) were confirmed to have trichiasis, and 118 (80%) had conjunctival swabs positive for bacteria. In multivariate analyses, growth of pathogenic conjunctival bacteria was independently associated with trichiasis (odds ratio [OR] 6.93; 95% confidence interval [CI] 2.71-17.7) and female sex (OR 5.90; 95% CI 2.09-16.7). Females were more likely to have swabs positive for Streptococcus pneumoniae or Haemophilus influenzae than were males (OR 9.09; 95% CI 1.17-70.8). CONCLUSIONS: In a region of Ethiopia with endemic trachoma, conjunctival bacterial growth was more common in females than that in males. S. pneumoniae and H. influenzae, both of which frequently colonize the nasopharynx of children, were more common in females, suggesting that the preponderance of infection in females may be attributable to close contact with children. This finding is consistent with the theory that childcare activities may preferentially expose females to ocular chlamydial infection. (ClinicalTrials.gov number, NCT00221364.).

Prospective comparison of microbial culture and polymerase chain reaction in the diagnosis of corneal ulcer.

PURPOSE: To compare polymerase chain reaction (PCR) to microbial culture for the detection and identification of bacterial and fungal pathogens in microbial keratitis. DESIGN: Prospective cohort study. METHODS: A total of 108 consecutive corneal ulcers were cultured and analyzed by PCR using pan-bacterial and pan-fungal primers. PCR products were cloned, sequenced, and compared to culture results using standard bioinformatics tools. RESULTS: Of the 108 samples, 56 were culture-positive, 25 for bacteria and 31 for fungi; 52 were culture-negative. After eliminating false-positive PCR products, 94 of 108 were positive by PCR, 37 for bacteria and 57 for fungi. Nineteen of 25 bacterial culture-positive samples were positive by PCR, and 29 of 31 samples culture-positive for fungi were positive by PCR. The majority of sequenced PCR products matched the positive culture results. Of the 52 culture-negative samples, 46 (88%) yielded pathogen deoxyribonucleic acid (DNA) PCR products, 18 bacterial and 28 fungal. These represented a variety of species, including at least three novel previously uncultured microbes. CONCLUSIONS: PCR detects microbial DNA in the majority of bacterial and fungal corneal ulcers, and identifies potentially pathogenic organisms in a high proportion of culture-negative cases. Yield and concordance with culture are higher for fungal than bacterial ulcers. Practical use of the technique is limited by artefactual amplification of nonpathogenic organisms. PCR may be used as an adjunct to culture to identify potential pathogens in microbial keratitis.

Comparison of annual and biannual mass antibiotic administration for elimination of infectious trachoma.

CONTEXT: Treatment recommendations assume that repeated mass antibiotic distributions can control, but not eradicate or even locally eliminate, the ocular strains of chlamydia that cause trachoma. Elimination may be an important end point because of concern that infection will return to communities that have lost immunity to chlamydia after antibiotics are discontinued. OBJECTIVE: To determine whether biannual treatment can eliminate ocular chlamydial infection from preschool children and to compare results with the World Health Organization-recommended annual treatment. DESIGN, SETTING, AND PARTICIPANTS: A cluster-randomized clinical trial of biannual vs annual mass azithromycin administrations to all residents of 16 rural villages in the Gurage Zone, Ethiopia, from March 2003 to April 2005. INTERVENTIONS: At scheduled treatments, all individuals aged 1 year or older were offered a single dose of oral azithromycin either annually or biannually. MAIN OUTCOME MEASURE: Village prevalence of ocular chlamydial infection and presence of elimination at 24 months in preschool children determined by polymerase chain reaction, correcting for baseline prevalence. Antibiotic treatments were performed after sample collections. RESULTS: Overall, 14,897 of 16,403 eligible individuals (90.8%) received their scheduled treatment. In the villages in which residents were treated annually, the prevalence of infection in preschool children was reduced from a mean of 42.6% (range, 14.7%-56.4%) to 6.8% (range, 0.0%-22.0%) at 24 months. In the villages in which residents were treated biannually, infection was reduced from 31.6% pretreatment (range, 6.1%-48.6%) to 0.9% (range, 0.0%-4.8%) at 24 months. Biannual treatment was associated with a lower prevalence at 24 months (P = .03, adjusting for baseline prevalence). At 24 months, no infection could be identified in 6 of 8 of those treated biannually and in 1 of 8 of those treated annually (P = .049, adjusting for baseline prevalence). CONCLUSION: Local elimination of ocular chlamydial infection appears feasible even in the most severely affected areas, although it may require biannual mass antibiotic distributions at a high coverage level. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00221364.

A rationale for continuing mass antibiotic distributions for trachoma.

BACKGROUND: The World Health Organization recommends periodic mass antibiotic distributions to reduce the ocular strains of chlamydia that cause trachoma, the world's leading cause of infectious blindness. Their stated goal is to control infection, not to completely eliminate it. A single mass distribution can dramatically reduce the prevalence of infection. However, if infection is not eliminated in every individual in the community, it may gradually return back into the community, so often repeated treatments are necessary. Since public health groups are reluctant to distribute antibiotics indefinitely, we are still in need of a proven long-term rationale. Here we use mathematical models to demonstrate that repeated antibiotic distributions can eliminate infection in a reasonable time period. METHODS: We fit parameters of a stochastic epidemiological transmission model to data collected before and 6 months after a mass antibiotic distribution in a region of Ethiopia that is one of the most severely affected areas in the world. We validate the model by comparing our predicted results to Ethiopian data which was collected biannually for two years past the initial mass antibiotic distribution. We use the model to simulate the effect of different treatment programs in terms of local elimination of infection. RESULTS: Simulations show that the average prevalence of infection across all villages progressively decreases after each treatment, as long as the frequency and coverage of antibiotics are high enough. Infection can be eliminated in more villages with each round of treatment. However, in the communities where infection is not eliminated, it returns to the same average level, forming the same stationary distribution. This phenomenon is also seen in subsequent epidemiological data from Ethiopia. Simulations suggest that a biannual treatment plan implemented for 5 years will lead to elimination in 95% of all villages. CONCLUSION: Local elimination from a community is theoretically possible, even in the most severely infected communities. However, elimination from larger areas may require repeated biannual treatments and prevention of re-introduction from outside to treated areas.

Antimicrobial susceptibility of Fusarium, Aspergillus, and other filamentous fungi isolated from keratitis.

OBJECTIVE: To characterize the susceptibility of filamentous fungi isolated from keratitis to amphotericin B, natamycin, caspofungin acetate, itraconazole, voriconazole, and posaconazole. METHODS: Ninety isolates from fungal keratitis cases at Aravind Eye Hospital in South India were tested using macrobroth dilution for susceptibility to amphotericin B, natamycin, caspofungin, itraconazole, voriconazole, and posaconazole. The minimum inhibitory concentration (MIC) median and 90th percentile were determined. RESULTS: The 90 isolates included 41 Aspergillus species, 38 Fusarium species, and 11 others. The triazoles and caspofungin had the lowest MICs against Aspergillus species; voriconazole, amphotericin B, and posaconazole had the lowest MICs against Fusarium species, and none of the Fusarium species were inhibited by itraconazole or caspofungin. Amphotericin B had significantly lower MICs compared with natamycin, but after correcting for the typical prescription dose, natamycin was superior. CONCLUSION: No single agent was universally most effective, but voriconazole and other triazoles demonstrated the broadest spectrum. Itraconazole and caspofungin were not effective against Fusarium species. CLINICAL RELEVANCE: Fungal ulcers are commonly treated empirically; drugs are typically selected without regard to susceptibility data. The nonocular infectious disease literature suggests modern fungal susceptibility methods are clinically relevant, but ocular studies are limited. Our results suggest antifungal therapy might be tailored to individual organisms.

Chlamydia on children and flies after mass antibiotic treatment for trachoma.

There are various approaches to control trachoma. These include the elimination of the ocular strains of Chlamydia trachomatis that cause the disease and to decrease the spread of infection by other measures such as fly control. Here, we examined how these two are related (i.e., how treating children with antibiotics affects carriage of Chlamydia by flies). Flies were collected in villages that had received mass oral azithromycin distribution and were compared with flies in untreated villages. Polymerase chain reaction (PCR) was performed to detect chlamydial DNA on the flies. Conjunctival swabs were also taken to assay for chlamydial prevalence in the children. Chlamydia was found on 23% of the flies in the untreated villages but only 0.3% in treated villages. Prevalence of trachoma in children proved to be an excellent predictor of the prevalence on flies (correlation coefficient, 0.89). Thus, treating children with antibiotics may drastically reduce the role of flies as a vector.

Effect of a single mass antibiotic distribution on the prevalence of infectious trachoma.

CONTEXT: The World Health Organization recommends mass antibiotic distributions in its strategy to eliminate blinding trachoma as a public health concern. Some hypothesize that a single distribution is sufficient to control the ocular strains of chlamydia that cause trachoma. Others believe infection will inevitably return and periodic treatments or other measures are essential. OBJECTIVE: To determine whether ocular chlamydial infection returns to the community up to 24 months after a single mass antibiotic distribution in a hyperendemic region of Ethiopia. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study conducted March 2003 to March 2005 in the Gurage Zone of Ethiopia. Eight randomly selected villages were assessed for ocular chlamydial infection. Fifteen untreated villages were randomly chosen at 12 months to allow assessment of a secular trend. INTERVENTION: A single dose of oral azithromycin was offered to all residents of the 8 selected villages who were aged 1 year or older. MAIN OUTCOME MEASURE: Prevalence of ocular chlamydial infection in all children aged 1 to 5 years from each intervention village prior to treatment and 2, 6, 12, 18, and 24 months after mass antibiotic treatment, and also in untreated villages enrolled at 12 months. RESULTS: Five hundred fifteen children were examined for ocular chlamydial infection at baseline. For the follow-up examinations, the mean participation rate was 83%. The mean prevalence of infection in children aged 1 to 5 years decreased from 43.5% (95% confidence interval [CI], 35.0%-52.0%) to 5.1% (95% CI, 1.1%-9.2%) after treatment. On average, infection returned gradually over 24 months to 11.3% (95% CI, 4.5%-18.1%; P = .001). In 7 of 8 villages, infection was higher at 24 months than at 2 months. In the remaining village, no infection could be identified at any point after treatment. Villages enrolled at 12 months had significantly fewer infections than those enrolled 12 months earlier, suggesting a secular trend (P<.001). CONCLUSIONS: Ocular chlamydial infection was not eliminated in children aged 1 to 5 years after a single mass azithromycin distribution; it slowly returned over 24 months, although not to baseline levels. Repeated treatments or other effective measures will be necessary for elimination.

Seasonal effects in the elimination of trachoma.

The World Health Organization currently recommends annual mass antibiotic treatment to eliminate the ocular chlamydia that cause blinding trachoma. Active trachoma is believed to be seasonal in many areas of the world, and the optimal season in which to treat has not as yet been established. Here we use mathematical models of disease transmission to demonstrate that ideally, treatment should be administered before the low season to have the greatest chance of locally eliminating infection.

Trachoma decline and widespread use of antimicrobial drugs.

Trachoma is disappearing in many parts of the world, even in the absence of specific control programs. Following mass antimicrobial drug treatments for trachoma in western Nepal, the prevalence of trachoma declined far more rapidly than could be attributed to the control program alone. Pharmacy surveys in the same region found that children received more antichlamydial drugs from sources outside the trachoma program than they did from the program itself. We demonstrate that high background antimicrobial drug use may be responsible for much of the observed decline in trachoma and discuss its potential role in eliminating this infectious disease.

Mass antibiotic treatment and community protection in trachoma control programs.

Azithromycin is highly effective against trachoma, but the practical difficulties of community-wide distribution often leave many individuals untreated. We demonstrate, after mass azithromycin treatment of a population in Ethiopia, an indirect protective effect that occurred among untreated children who resided in villages in which most individuals had been treated. Similarities with the indirect protection within a treated community (i.e., "herd protection") that has been observed in vaccination programs are discussed.