Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk

Modeling causes of death: an integrated approach using CODEm

Background: Data on causes of death by age and sex are a critical input into health decision-making. Priority setting in public health should be informed not only by the current magnitude of health problems but by trends in them. However, cause of death data are often not available or are subject to substantial problems of comparability. We propose five general principles for cause of death model development, validation, and reporting.Methods: We detail a specific implementation of these principles that is embodied in an analytical tool - the Cause of Death Ensemble model (CODEm) - which explores a large variety of possible models to estimate trends in causes of death. Possible models are identified using a covariate selection algorithm that yields many plausible combinations of covariates, which are then run through four model classes. The model classes include mixed effects linear models and spatial-temporal Gaussian Process Regression models for cause fractions and death rates. All models for each cause of death are then assessed using out-of-sample predictive validity and combined into an ensemble with optimal out-of-sample predictive performance.Results: Ensemble models for cause of death estimation outperform any single component model in tests of root mean square error, frequency of predicting correct temporal trends, and achieving 95% coverage of the prediction interval. We present detailed results for CODEm applied to maternal mortality and summary results for several other causes of death, including cardiovascular disease and several cancers.Conclusions: CODEm produces better estimates of cause of death trends than previous methods and is less susceptible to bias in model specification. We demonstrate the utility of CODEm for the estimation of several major causes of death

Effect of prostaglandin analogs on matrix metalloproteinases and tissue inhibitor of metalloproteinases in eyelid muscle specimens

Sapir Karli, Juan Alfredo Ayala-Haedo, William J Feuer, Maria Fernandez, Sander Dubovy, Sara T Wester Bascom Palmer Eye Institute, Miami, FL, USA Purpose: To characterize the effect of prostaglandin analogs (PAs) on tissue specific expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in levator aponeurosis resections (LAR) and conjunctiva-Muller muscle resections (CMMR).Methods: Specimens from LAR and CMMR of PA users and non-users were analyzed for tissue specific expression of MMP-3, MMP-7, MMP-9 and TIMP-2 using immunohistochemistry. PA use, marginal reflex distances, levator function and palpebral fissure were documented through chart review. The associations between MMP expression, PA exposure time and ocular characteristics were evaluated with a two-factor analysis of variance and multiple correlation analysis.Results: We observed a tissue specific pattern of expression of MMPs and TIMP-2 in relation to PA exposure between CMMR and LAR specimens. There was increased MMP-7 and TIMP-2 expression in muscle compared to collagen and adipose tissue (P≤0.005), as well as a statistically significant difference in the relationship of MMP-3, MMP-9 and TIMP-2 levels to PA exposure in the two types of muscles (all P≤0.011). Adipose tissue had a PA-dependent reduced expression of MMP-3 (P<0.022), which was seen in both LAR and CMMR. Decreased expression of MMP-3 in collagen correlated with increased dermatochalasis (P<0.045) and steatoblepharon (P<0.018).Conclusion: PA exposure may affect MMP and TIMP expression in a tissue specific manner, and decreased expression of certain MMPs in collagen correlates to increased clinical measures of prostaglandin associated periorbitopathy (PAP). Further studies with larger samples are needed to ascertain if the changes associated with PAP are due to MMP/TIMP changes or to structural changes. Keywords: MMP, matrix metalloproteinase, prostaglandin associated periorbitopathy, PAP, prostaglandin analog, periorbitopath

Effects of temperature and fluid media on the scroll width size of the Descemet’s membrane endothelial keratoplasty (DMEK) donor graft

Ellen H Koo,1 Allen O Eghrari,2 Ryan S Meshkin,2 Wei Shi,1 William J Feuer,1 Karen G DeMarco,3 Arthur C Kurz3 1Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 2Wilmer Eye Institute, Johns Hopkins University School of Medicine, 3KeraLink International, Baltimore, MD, USA Aim: Our study was conducted to evaluate whether higher temperature leads to increased – or wider – scroll widths of the Descemet’s membrane endothelial keratoplasty (DMEK) donor graft.Purpose: To investigate the effects of temperature and fluid media on the DMEK donor graft scroll widths.Materials and methods: This research work was a laboratory investigation. Baseline cell count was taken via specular microscopy for the donor corneas at room temperature (20°C–25°C). The endothelium sides of the donor corneas were stained with Trypan Blue Solution 0.4% for 30 s, and the Descemet’s membranes were stripped. The DMEK donor grafts were placed into three different fluid media – Optisol®, Balanced Salt Solution (BSS), and BSS PLUS® (BSS Plus). The DMEK donor grafts were then transferred into cold temperature (4°C) for 60 min, after which the donor grafts’ scroll widths were examined and measured. The donor grafts were then warmed in the incubator and brought to physiological temperature (35°C–37°C), and their scroll widths were examined and measured again.Results: In 30 measurements of ten tissues across three temperature and fluid conditions, the average scroll width measured 1.73 mm, ranging from 1.1 to 2.9 mm. In a mixed linear model, the scroll widths increased with temperature (P=0.02). There was no significant difference in scroll widths among the three solutions (P=0.84, mixed linear model).Conclusion: We observed an increase in DMEK donor graft scroll widths with higher temperatures. The usage of BSS Plus as media solution could also lead to smaller DMEK donor graft scroll widths, compared with BSS, but our study does not establish this. Keywords: DMEK, graft scroll, graft conformation, DMEK scroll, DMEK graft&nbsp

Visual function and quality of life among patients with glaucoma.

This study determines the relation between visual field impairment, visual functioning, and global quality of life in patients with glaucoma. Binocular visual field impairment was calculated from simultaneous Esterman visual field testing using the Humphrey automated perimeter. Visual acuity impairment, defined with the American Medical Association's Guides to the Evaluation of Permanent Impairment; visual functioning, measured with the VF-14 and the field test version of the National Eye Institute-Visual Functioning Questionnaire; and global quality of life, assessed with the Medical Outcomes Study 36-Item Short Form Health Survey, were determined in 147 consecutive patients with glaucoma. None of the Medical Outcomes Study 36-Item Short Form Health Survey domains demonstrated more than a weak correlation with visual field impairment. The VF-14 scores were moderately correlated (r = -0.58). Of the National Eye Institute-Visual Functioning Questionnaire scales, peripheral vision (r = -0.60), distance activities (r = -0.56), and vision-specific dependency (r = -0.56) were moderately correlated with visual field impairment; vision-specific social functioning, near activities, vision-specific role difficulties, general vision, vision-specific mental health, color vision, and driving were modestly correlated with visual field impairment (r value between -0.32 and -0.55); visual pain was weakly correlated with visual field impairment; and general health and vision-specific expectations were not notably correlated with visual field impairment. Statistically adjusting for visual acuity weakened the correlations. The Medical Outcomes Study 36-Item Short Form Health Survey indicated that our patients with glaucoma were comparable with previously studied patients without severe systemic medical problems. However, the Medical Outcomes Study 36-Item Short Form Health Survey scores did not correlate with visual field impairment in our study. Based on the moderate correlation between binocular visual field impairment with the VF-14 and the National Eye Institute-Visual Functioning Questionnaire, these questionnaires may be useful among patients with glaucoma

Treatment Outcomes in the Ahmed Baerveldt Comparison Study after 1 Year of Follow-up

Purpose: To determine the relative efficacy and complications of the Ahmed glaucoma valve (AGV) model FP7 (New World Medical, Ranchos Cucamonga, CA) and the Baerveldt glaucoma implant (BGI) model 101-350 (Abbott Medical Optics, Abbott Park, IL) in refractory glaucoma. Design: Multicenter, randomized, controlled clinical trial. Participants: Two hundred seventy-six patients, including 143 in the AGV group and 133 in the BGI group. Methods: Patients 18 to 85 years of age with refractory glaucoma having intraocular pressure (IOP) of 18 mmHg or more in whom an aqueous shunt was planned were randomized to undergo implantation of either an AGV or a BGI. Main Outcome Measures: The primary outcome was failure, defined as IOP > 21 mmHg or not reduced by 20% from baseline, IOP 2 Snellen lines, or both occurred in 29 patients (20%) in the AGV group and in 45 patients (34%) in the BGI group (P = 0.014). Conclusions: Although the average IOP after 1 year was slightly higher in patients who received an AGV, there were fewer early and serious postoperative complications associated with the use of the AGV than the BGI.1183443452National Institutes of Health, Bethesda, Maryland [P30 EY014801]New World Medical, Rancho Cucamonga, CaliforniaResearch to Prevent Blindness, Inc., New York, New YorkNational Institutes of Health, Bethesda, Maryland [P30 EY014801

Strategies to overcome myelotoxic therapy for the treatment of Burkitt's and AIDS- related non-Hodgkin's lymphoma

Background: Strategies to circumvent or lessen the myelotoxicity associated with combination chemotherapy may improve the overall outcome of the management of patients particularly in resource poor settings. Objectives: To develop effective non-myelotoxic therapies for Burkitt's Lymphoma (BL) and AIDS-related non-Hodgkin's lymphoma. Data sources: Publications, original and review articles, conference abstracts searched mainly on Pubmed indexed for medline. Data extraction: A systematic review of the clinical problem of combination chemotherapy. Identification of clinical strategies that circumvent or lessen the myelotoxicity of combination cytotoxic chemotherapy. Length of survival, lack of clinically significant (> grade 3) myelosuppression and weight loss were used as markers of myelotoxicity. Data synthesis: Review of published experience with some of these strategies including dose-modification of multi-agent chemotherapy; rationale for targeted therapies, and the preclinical development of a mouse model exploring the role of metronomic scheduling substantiate pragmatism and feasibility of these approaches. Conclusion: Myelotoxic death rates using multi-agent induction chemotherapy approach 25% for endemic Burkitt's lymphoma and range between 20% to 60% for AIDS-related malignancy. This is mostly explained by the paucity of supportive care compounded by wasting and inanition attributable to advanced cancer and HIV infection making patients more susceptible to myelosuppressive side effects of cytotoxic chemotherapy. Investigations and alternative approaches that lessen or circumvent myelotoxicity of traditional cytotoxic chemotherapy for the management of Burkitt's lymphoma and AIDS-related non- Hodgkin's lymphoma in the resource-constrained setting are warranted. Pertinent preclinical and clinical data are emerging to support the need for abrograting the myelosuppressive effects of traditional cytotoxic chemotherapy. This can be achieved by developing targeted anti-viral and other strategies, such as the use of bryostatin 1 and vincristine, and by developing a preclinical mouse model to frame the clinical rationale for a pilot trial of metronomic therapy for the treatment of Burkitt's and AIDS-related lymphoma. Implementation of these investigational approaches must be encouraged as viable anti-cancer therapeutic strategies particularly in the resource-constrained settings. East African Medical Journal Vol. 82(9) 2005: S155-S16