Intravitreal Neuroglobin Mitigates Primate Experimental Glaucomatous Structural Damage in Association with Reduced Optic Nerve Microglial and Complement 3-Astrocyte Activation.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans.

Determinants of lamina cribrosa depth in healthy Asian eyes: the Singapore Epidemiology Eye Study.

AIM: To investigate the determinants of lamina cribrosa depth (LCD) in healthy eyes of Chinese and Indian Singaporean adults. METHODS: The optic nerve head (ONH) of the right eye of 1396 subjects (628 Chinese and 768 Indian subjects) was imaged with optical coherence tomography (OCT, Spectralis, Heidelberg, Germany). LCD was defined as the distance from the Bruch's membrane opening (LCD-BMO) or the peripapillary sclera (LCD-PPS) reference plane to the laminar surface. A linear regression model was used to evaluate the relationship between the LCD and its determinants. RESULTS: Both LCDs were significantly different between the two races (LCD-BMO: 421.95 (95% CI 365.32 to 491.79) µm in Chinese vs 430.39 (367.46-509.81) µm in Indians, p=0.021; and LCD-PPS: 353.34 (300.98-421.45) µm in Chinese vs 376.76 (313.39-459.78) µm in Indians, p<0.001). In the multivariable regression analysis, the LCD-PPS of the whole cohort was independently associated with females (ß=-31.93, p<0.001), Indians subjects (ß=21.39, p=0.004) (Chinese as the reference), axial length (Axl) (ß=-6.68, p=0.032), retinal nerve fibre layer thickness (RNFL) (ß=0.71, p=0.019), choroidal thickness (ChT) (ß=0.41, p<0.001), vertical cup disc ratio (VCDR) (ß=24.42, p<0.001) and disc size (ß=-60.75, p=0.001). For every 1 year older in age, the LCD-PPS was deeper on average by 1.95 µm in Chinese subjects (p=0.01) but there was no association in Indians subjects (p=0.851). CONCLUSIONS: The LCD was influenced by age, gender, race, Axl, RNFL, ChT, VCDR and disc size. This normative LCD database may facilitate a more accurate assessment of ONH cupping using OCT in Asian populations.

Longitudinal assessment of optic nerve head changes using optical coherence tomography in a primate microbead model of ocular hypertension.

In humans, the longitudinal characterisation of early optic nerve head (ONH) damage in ocular hypertension (OHT) is difficult as patients with glaucoma usually have structural ONH damage at the time of diagnosis. Previous studies assessed glaucomatous ONH cupping by measuring the anterior lamina cribrosa depth (LCD) and minimal rim width (MRW) using optical coherence tomography (OCT). In this study, we induced OHT by repeated intracameral microbead injections in 16 cynomolgus primates (10 unilateral; 6 bilateral) and assessed the structural changes of the ONH longitudinally to observe early changes. Elevated intraocular pressure (IOP) in OHT eyes was maintained for 7 months and serial OCT measurements were performed during this period. The mean IOP was significantly elevated in OHT eyes when compared to baseline and compared to the control eyes. Thinner MRW and deeper LCD values from baseline were observed in OHT eyes with the greatest changes seen between month 1 and month 2 of OHT. Both the mean and maximum IOP values were significant predictors of MRW and LCD changes, although the maximum IOP was a slightly better predictor. We believe that this model could be useful to study IOP-induced early ONH structural damage which is important for understanding glaucoma pathogenesis.

Asian-specific vertical cup-to-disc ratio cut-off for glaucoma screening: An evidence-based recommendation from a multi-ethnic Asian population.

IMPORTANCE: Evidence-based guidelines are essential for glaucoma screening to work effectively. BACKGROUND: To derive a vertical cup-to-disc ratio (VCDR) cut-off for glaucoma screening in a multi-ethnic Asian population. DESIGN: The Singapore Epidemiology of Eye Diseases (SEED) study is a population-based study conducted from 2004 to 2011 in a single tertiary care research institute. PARTICIPANTS: SEED comprised of 10 033 Chinese, Malay and Indian adults aged ≥40 (response rate 75.6%). After excluding participants with a history of glaucoma medication or surgery, 9673 participants were included for analysis. METHODS: A systematic eye examination, which included applanation tonometry, visual field testing, gonioscopy and dilated fundus examination was conducted. MAIN OUTCOME MEASURE: Diagnosis of glaucoma. RESULTS: The distribution of VCDR and VCDR asymmetry were relatively homogenous in this multi-ethnic Asian population, with a 97.5th percentile value of 0.67 and 0.17, respectively. In the absence of more definite signs of glaucoma, VCDR ≥0.60 and VCDR asymmetry ≥0.20 provided the best balance between sensitivity (95.1%) and specificity (90.9%) in detecting glaucoma. For larger optic disc (≥2.0 mm), VCDR ≥0.65 with VCDR asymmetry ≥0.20 provided the best balance between sensitivity (84.8%) and specificity (93.2%). CONCLUSION AND RELEVANCE: Overall, VCDR ≥0.60 with VCDR ≥0.20 asymmetry provides a good balance between sensitivity and specificity in detecting glaucoma. For larger optic disc, VCDR ≥0.65 should be considered instead to mitigate against false-referrals due to larger physiological disc cupping. Our findings may act as a reference to populations with similar VCDR distribution.

Changes in the Anterior Lamina Cribrosa Morphology with Glaucoma Severity.

This study was designed to evaluate if primary open angle glaucoma (POAG) and its severity are associated with the shape of the lamina cribrosa (LC) as measured by a global shape index (LC-GSI), or other indices of LC curvature or depth. Optical coherence tomography (OCT) scans of the optic nerve head (OHN) were obtained from subjects with POAG (n = 99) and non-glaucomatous controls (n = 76). ONH structures were delineated, the anterior LC morphology reconstructed in 3D, and the LC-GSI calculated (more negative values denote greater posterior concavity). Anterior LC depth and 2D-curvature were also measured. Severity of glaucoma was defined by the extent of visual field loss, based on the Hodapp-Parrish-Anderson grading. Linear regression analyses compared LC characteristics between controls, mild-moderate, and advanced POAG groups. After adjusting for age, gender, ethnicity, intraocular pressure, axial length and corneal curvature, the LC-GSI was most negative in the advanced POAG group (mean [standard error] = -0.34 [0.05]), followed by the mild-moderate POAG group (-0.31 [0.02]) and then controls (-0.23 [0.02], PTrend = 0.01). There was also a significant trend of increasing LC depth and greater LC horizontal curvature with increasing severity of glaucoma (PTrend = 0.04 and 0.02, respectively). Therefore, with more severe glaucoma, the LC-GSI was increasingly more negative, and the anterior LC depth and curvature greater. These observations collectively correspond to greater cupping of the ONH at the level of the LC. As the LC-GSI describes the 3D anterior LC morphology, its potential usage may be complementary to existing ONH parameters measured on OCT.

Feeding practices and nutritional status of children age 6-23 months in Myanmar: A secondary analysis of the 2015-16 Demographic and Health Survey.

Nutritional deficiencies are a major problem among developing countries including Myanmar. They can occur in all age groups, but the impact is more severe among children age 6-23 months as this period is critical for child development, and irreversible damages can occur due to nutritional deficiencies. Proper infant and young child feeding practices are pivotal to tackle nutritional problems and to prevent irreversible consequences among children. To assess the current feeding practices and associations with nutritional status, we conducted a secondary data analysis using the 2015-16 Myanmar Demographic and Health Survey. Multiple logistic regression analysis was done adjusting for covariates and the results were presented by adjusted odds ratios with 95% confidence intervals. A total of 1,222 children age 6-23 months were included in this analysis. Twenty percent were stunted and 43% were moderately anemic. Only 16% of children received a minimum acceptable diet, 25% received diverse food groups, 58% were fed with minimum meal frequency, 85% currently breastfed, and 59% consumed iron-rich foods. Breastfeeding reduced the odds of being stunted. Male sex, perceived small birth size, mother with short stature, and working mother were significant predictors of stunting. Iron-rich food consumption was inversely associated with moderate anemia. Male sex and maternal anemia were also significant predictors of moderate anemia. The study concluded that stunting and anemia among young children in Myanmar are major public health challenges that need urgent action. While further prospective research is needed to determine the effect of feeding practice on linear growth, interventions such as iron supplementation, and nutritional education programs according to the World Health Organization complementary feeding guidelines could help prevent stunting and childhood anemia and might reduce their prevalence in Myanmar.

Glaucoma.

Glaucoma is a heterogeneous group of diseases characterised by cupping of the optic nerve head and visual-field damage. It is the most frequent cause of irreversible blindness worldwide. Progression usually stops if the intraocular pressure is lowered by 30-50% from baseline. Its worldwide age-standardised prevalence in the population aged 40 years or older is about 3·5%. Chronic forms of glaucoma are painless and symptomatic visual-field defects occur late. Early detection by ophthalmological examination is mandatory. Risk factors for primary open-angle glaucoma-the most common form of glaucoma-include older age, elevated intraocular pressure, sub-Saharan African ethnic origin, positive family history, and high myopia. Older age, hyperopia, and east Asian ethnic origin are the main risk factors for primary angle-closure glaucoma. Glaucoma is diagnosed using ophthalmoscopy, tonometry, and perimetry. Treatment to lower intraocular pressure is based on topical drugs, laser therapy, and surgical intervention if other therapeutic modalities fail to prevent progression.

Auxiliary midwives in hard to reach rural areas of Myanmar: filling MCH gaps.

BACKGROUND: Auxiliary Midwives (AMWs) are community health volunteers supporting the work of midwives, especially maternal and child health services in hard to-reach areas in Myanmar. This paper assessed the contributions of AMW to maternal and child health services, factors influencing their productivity and their willingness to serve the community. METHOD: The study applied quantitative cross-sectional survey using census method. Total of 1,185 AMWs belonging to three batches: trained prior to 2000, between 2000 and 2011, and in 2012, from 21 townships of 17 states and regions in Myanmar participated in the study. Multiple logit regression was used to examine the impact of age, marital status, education, domicile, recruitment pattern and 'batch of training', on AMW's confidence level in providing care, and their intention to serve the community more than 5 years. RESULTS: All AMWs were able to provide essential maternal and child health services including antenatal care, normal delivery and post-natal care. They could identify and refer high-risk pregnancies to larger health facilities for proper management. On average, 9 deliveries, 11 antenatal and 9 postnatal cases were performed by an AMW during the six months prior to this study. AMWs had a comparative advantage for longer service in hard-to-reach villages where they lived, spoke the same dialect as the locals, understood the socio-cultural dimensions, and were well accepted by the community. Despite these contributions, 90 % of the respondents expressed receiving no adequate supervision, refresher training, replenishment of the AMW kits and transportation cost. AMWs in the elder age group are significantly more confident in taking care of the patients than those in the younger groups. Over 90 % of the respondents intended to stay more than five years in the community. The confidence in catering services appeared to have significant association with a longer period of stay in AMW jobs as evidenced by the odds ratio of 3.5, compared to those reporting unconfident. CONCLUSIONS: Comprehensive support system and national policy are needed to sustain and strengthen the contributions of AMWs, in sharing the workload of midwives, particularly in hard-to-reach areas of Myanmar.

Pupillary Responses to High-Irradiance Blue Light Correlate with Glaucoma Severity.

PURPOSE: To evaluate whether a chromatic pupillometry test can be used to detect impaired function of intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with primary open-angle glaucoma (POAG) and to determine if pupillary responses correlate with optic nerve damage and visual loss. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred sixty-one healthy controls recruited from a community polyclinic (55 men; 151 ethnic Chinese) and 40 POAG patients recruited from a glaucoma clinic (22 men; 35 ethnic Chinese) 50 years of age or older. METHODS: Subjects underwent monocular exposure to narrowband blue light (469 nm) or red light (631 nm) using a modified Ganzfeld dome. Each light stimulus was increased gradually over 2 minutes to activate sequentially the rods, cones, and ipRGCs that mediate the pupillary light reflex. Pupil diameter was recorded using an infrared pupillography system. MAIN OUTCOME MEASURES: Pupillary responses to blue light and red light were compared between control subjects and those with POAG by constructing dose-response curves across a wide range of corneal irradiances (7-14 log photons/cm(2) per second). In patients with POAG, pupillary responses were evaluated relative to standard automated perimetry testing (Humphrey Visual Field [HVF]; Carl Zeiss Meditec, Dublin, CA) and scanning laser ophthalmoscopy parameters (Heidelberg Retinal Tomography [HRT]; Heidelberg Engineering, Heidelberg, Germany). RESULTS: The pupillary light reflex was reduced in patients with POAG only at higher irradiance levels, corresponding to the range of activation of ipRGCs. Pupillary responses to high-irradiance blue light associated more strongly with disease severity compared with responses to red light, with a significant linear correlation observed between pupil diameter and HVF mean deviation (r = -0.44; P = 0.005) as well as HRT linear cup-to-disc ratio (r = 0.61; P < 0.001) and several other optic nerve head parameters. CONCLUSIONS: In glaucomatous eyes, reduced pupillary responses to high-irradiance blue light were associated with greater visual field loss and optic disc cupping. In POAG, a short chromatic pupillometry test that evaluates the function of ipRGCs can be used to estimate the degree of damage to retinal ganglion cells that mediate image-forming vision. This approach could prove useful in detecting glaucoma.

Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma.

OBJECTIVES: Vitamin D is involved in visual health and function. Our objective was to determine whether age-related vitamin D insufficiency was associated with the presence and the severity of primary open angle glaucoma (POAG) in a case-control study of older adults. STUDY DESIGN: Case-control study. MAIN OUTCOME MEASURES: One hundred fifty cases diagnosed with moderate-to-severe POAG (mean, 75.1 ± 8.5 years; 42.0% female) and 164 healthy controls (mean, 73.0 ± 7.9 years; 59.8% female) were included. POAG diagnosis was based on classical diagnostic criteria of optic nerve cupping and/or RNFL thinning, measured with optical coherence tomography. Severe POAG was defined as Humphrey visual field mean deviation (MD) worse than -12 dB. Vitamin D insufficiency was defined as serum 25OHD ≤ 75 nmol/L. Age, gender, mean arterial pressure, vitamin D supplementation, visual acuity, and intraocular pressure were used as potential confounders. RESULTS: POAG cases had lower mean serum 25OHD concentration than controls (42.9 ± 25.7 nmol/L versus 49.4 ± 29.5 nmol/L, P=0.039) and a greater prevalence of vitamin D insufficiency (90.7% versus 82.3%, P=0.032). Increased mean serum 25OHD concentrations were associated with lower POAG frequency, even after adjustment for potential confounders (OR=0.89 per 10 nmol/L of 25OHD, P=0.045). Similarly, vitamin D insufficiency was associated with POAG (OR=2.09, P=0.034). Among POAG cases, no 25OHD difference was observed between moderate and severe POAG cases (respectively, 39.2 ± 23.3 nmol/L versus 45.1 ± 26.7 nmol/L, P=0.188); and no between-group difference regarding the prevalence of vitamin D insufficiency (88.9% versus 94.0%, P=0.313). CONCLUSIONS: Decreased serum 25OHD concentration was associated with POAG. There was no 25OHD difference between moderate and severe POAG.

Cost-effectiveness of using a social franchise network to increase uptake of oral rehydration salts and zinc for childhood diarrhea in rural Myanmar.

INTRODUCTION: This paper examines the cost-effectiveness of achieving increases in the use of oral rehydration solution and zinc supplementation in the management of acute diarrhea in children under 5 years through social franchising. The study uses cost and outcome data from an initiative by Population Services International (PSI) in 3 townships of Myanmar in 2010 to promote an ORS-Zinc product called ORASEL. BACKGROUND: The objective of this study was to determine the incremental cost-effectiveness of a strategy to promote ORS-Z use through private sector franchising compared to standard government and private sector practices. METHODS: Costing from a societal perspective included program, provider, and household costs for the 2010 calendar year. Program costs including ORASEL program launch, distribution, and administration costs were obtained through a retrospective review of financial records and key informant interviews with staff in the central Yangon office. Household out of pocket payments for diarrheal episodes were obtained from a household survey conducted in the study area and additional estimates of household income lost due to parental care-giving time for a sick child were estimated. Incremental cost-effectiveness relative to status quo conditions was calculated per child death and DALY averted in 2010. Health effects included deaths and DALYs averted; the former modeled based on coverage estimates from a household survey that were entered into the Lives Saved Tool (LiST). Uncertainty was modeled with Monte Carlo methods. FINDINGS: Based on the model, the promotional strategy would translate to 2.85 (SD 0.29) deaths averted in a community population of 1 million where there would be 81,000 children under 5 expecting 48,373 cases of diarrhea. The incremental cost effectiveness of the franchised approach to improving ORASEL coverage is estimated at a median $5,955 (IQR: $3437-$7589) per death averted and $214 (IQR: $127-$287) per discounted DALY averted. INTERPRETATION: Investing in developing a network of private sector providers and keeping them stocked with ORS-Z as is done in a social franchise can be a highly cost-effective in terms of dollars per DALY averted.

National survey of ophthalmologists in Singapore for the assessment and management of asymptomatic angle closure.

PURPOSE: Approximately 10% of Chinese people older than 50 years in Singapore have asymptomatic narrow angles [also termed primary angle closure suspects (PACS)]. The aim of this study was to determine the attitudes and practices of ophthalmologists in Singapore regarding the management of these patients. METHODS: A nation wide questionnaire-based survey was conducted on all registered, practicing ophthalmologists in Singapore by electronic mail and post. An ophthalmologist was defined as a doctor who had completed at least 3 years of specialist training in ophthalmology and had passed the Master's Degree in Ophthalmology or equivalent examinations. The survey asked the ophthalmologists about the methods and criteria used for the diagnosis of angle closure. It also inquired about the management of PACS and opinions on the effectiveness of prophylactic laser peripheral iridotomy (LPI) in preventing both acute and chronic angle closure. RESULTS: A total of 126 out of 158 ophthalmologists responded (79.7% response rate). Of the respondents, 84.9% would advise prophylactic LPI for asymptomatic PACS; 84.9% believed that prophylactic LPI would prevent acute angle closure but only 44% thought that it could prevent the development of glaucomatous optic nerve damage. The preferred method of prophylactic LPI was sequential argon-YAG LPI. In assessing patients for angle closure, 85.4% used gonioscopy, 92.9% assessed anterior chamber depth, and 17.5% performed provocative tests. CONCLUSIONS: Ophthalmologists in Singapore vary in the method of assessment of patients with angle closure. Most believe that prophylactic LPI should be performed for asymptomatic PACS.

Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene.

PURPOSE: To investigate the clinical features of subjects with glaucoma with the E50K mutation in the optineurin (OPTN) gene and to compare the onset, severity, and clinical course of these patients with a control group of subjects with glaucoma without this mutation. METHODS: The phenotype of well-characterized subjects from Moorfields Eye Hospital, London, who had been identified as carrying the OPTN E50K mutation was examined. A wide range of structural, psychophysical, and demographic factors were then compared with those in a control group of subjects with glaucoma without this mutation. RESULTS: Eleven subjects with glaucoma with the E50K mutation (nine in two families and two sporadic cases) were studied. All 11 subjects had normal tension glaucoma (NTG), with presenting and highest IOP of 15.3 +/- 3.0 and 16.5 +/- 2.5 mm Hg (+/-SD) on diurnal testing. Compared with 87 NTG control subjects who did not have this mutation, subjects with E50K presented at a younger age (40.8 +/- 15 years, P = 0.0001) and had more advanced optic disc cupping (mean cup-disc ratio +/- SD 0.86 +/- 0.1, P = 0.001) and smaller neuroretinal rim area (+/-SD; 0.5 +/- 0.28 mm2, P = 0.001) at diagnosis. The rate of filtration surgery performed for progressive visual field loss in those with and without the E50K mutation was 72.7% and 25.3%, respectively (P = 0.003), and all subjects with E50K were found to have progressing visual fields. In addition, seven E50K mutation-carrying individuals in two families (age range, 23-58 years) presented with normal optic discs and visual fields and, as yet, no signs of glaucoma. CONCLUSIONS: In this study, subjects with glaucoma who had the OPTN E50K mutation were found to have NTG that appeared to be more severe than that in a control group of subjects with NTG without this mutation. The findings emphasize the importance of early detection and treatment of glaucoma in such individuals, to minimize visual loss.

Configuration of the drainage angle, intraocular pressure, and optic disc cupping in subjects with chronic angle-closure glaucoma.

OBJECTIVE: To investigate the relationship between drainage angle configuration with untreated intraocular pressure (IOP) and optic disc cupping in subjects with chronic angle-closure glaucoma (CACG). DESIGN: Prospective, observational study. PARTICIPANTS: Two hundred seventy-five Asian subjects with CACG who participated in a randomized controlled trial that investigated the IOP-reducing effect of latanoprost and timolol. METHODS: Chronic angle-closure glaucoma was defined as the presence of glaucomatous optic neuropathy (with or without a visual field defect), an anterior chamber angle in which the pigmented trabecular meshwork was not visible for at least 180 degrees on gonioscopy, and evidence of peripheral anterior synechiae (PAS) in association with elevated IOP of 21 mmHg or more. Static and dynamic gonioscopy were performed, the angles were graded in each quadrant according to the Shaffer scheme, and the number of clock hours of PAS was recorded. The untreated IOP and vertical cup-to-disc ratio were correlated with mean angle width and extent of PAS. MAIN OUTCOME MEASURES: Mean angle width, clock hours of PAS, IOP, and vertical cup-to-disc ratio. RESULTS: Most subjects were female (75%), and the mean age was 62.9+/-9.4 years. The mean angle width was 0.77+/-0.53 and the mean number of clock hours of PAS was 4.77+/-3.2 hours. Untreated IOP correlated with angle width (r = -0.23; P<0.001) and clock hours of PAS (r = 0.22; P<0.001). Vertical cup-to-disc ratio also correlated with angle width (r = -0.17; P = 0.004) and PAS (r = 0.28; P<0.001). Performing a multiple linear regression using baseline IOP as the outcome variable with age, gender, clock hours of PAS, and angle width as predictors, there was a 0.39-mmHg (95% confidence interval, 0.15-0.63) increase in baseline untreated IOP for each unit increase in clock hours of PAS (P = 0.002). CONCLUSIONS: In subjects with CACG, the extent of PAS and a narrower width of the drainage angle were associated with higher untreated IOP and a larger vertical cup-to-disc ratio.