Optic nerve head morphology in glaucoma patients of African descent is strongly correlated to retinal blood flow

BACKGROUND/AIMS: To examine the relationship between change in optic nerve head (ONH) morphology and retinal blood flow in patients with open-angle glaucoma (OAG) of African (AD) and European descent (ED) over 3 years. METHODS: 112 patients with OAG (29 AD; 83 ED) underwent assessment of ONH morphology using Heidelberg retinal tomography (HRT-III), and retinal blood flow using confocal scanning laser Doppler. Repeated-measures analysis of covariance was used to compare baseline and 3-year measurements, and Pearson correlations were calculated to evaluate the relationships. RESULTS: In OAG patients of AD, change in superior mean retinal blood flow was strongly, negatively correlated with change in cup/disc (C/D) area ratio (r=-0.78, p=0.020) and cup area (r=-0.75, p=0.0283) and strongly, positively correlated with change in rim area (r=0.74, p=0.0328) over 3 years. In OAG patients of AD, change in inferior mean retinal blood flow was strongly, negatively correlated with changes in C/D area ratio (r=-0.88, p=0.0156) and linear C/D ratio (r=-0.86, p=0.0265) over 3 years. In OAG patients of ED, these correlations were weak and did not reach statistical significance. DISCUSSION: OAG patients of AD may have a stronger vascular component to their glaucoma pathophysiology than patients of ED

Vascular considerations in glaucoma patients of African and European descent

Glaucoma is the leading cause of blindness in individuals of African descent (AD). While open-angle glaucoma (OAG) disproportionately affects individuals of AD compared with persons of European descent (ED), the physiological mechanisms behind this disparity are largely unknown. The more rapid progression and greater severity of the disease in persons of AD further raise the concern for identifying these underlying differences in disease pathophysiology between AD and ED glaucoma patients. Ocular structural differences between AD and ED patients, including larger optic disc area, cup:disc ratio and thinner corneas, have been found. AD individuals are also disproportionately affected by systemic vascular diseases, including hypertension, cardiovascular disease, stroke and diabetes mellitus. Abnormal ocular blood flow has been implicated as a risk factor for glaucoma, and pilot research is beginning to identify localized ocular vascular differences between AD and ED OAG patients. Given the known systemic vascular deficits and the relationship between glaucoma and ocular blood flow, exploring these concepts in terms of glaucoma risk factors may have a significant impact in elucidating the mechanisms behind the disease disparity in the AD population

Differences in Ocular Blood Flow Between People of African and European Descent With Healthy Eyes

Purpose: To investigate differences in ocular blood flow between people of African descent (AD) and European descent (ED) with healthy eyes. Materials and Methods: Retrobulbar and retinal capillary blood flow was assessed in 1 eye of 58 participants (24 AD, 34 ED) with healthy eyes with systemic blood pressure lower than 140/90. Retrobulbar blood flow was measured in the ophthalmic artery (OA), central retinal artery (CRA), nasal posterior ciliary artery (NPCA) and temporal posterior ciliary artery (TPCA). Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistive index (RI) were assessed. Retinal capillary blood flow was assessed using mean retinal flow and avascular space defined as the percent of area measured with no blood flow. Groups were compared using t tests and Pearson correlations were compared using Fisher r-to-z transformation. Results: Compared with people of ED, people of AD had significantly lower EDV in the NPCA (P=0.01), and higher RI in the CRA (P=0.04) and TPCA (P=0.01). No significant differences were observed in mean retinal capillary flow or avascular area. In the CRA, a significant negative correlation was observed between pattern standard deviation and peak systolic velocity (P=0.02) in the AD group and this correlation was significantly different from that observed in the ED group (P=0.01). A significant correlation was also observed between pattern standard deviation and EDV (0.04) in the AD group. Conclusions: This study suggests that retrobulbar blood flow is lower in healthy eyes in persons of AD compared with ED. This may provide a mechanism through which people of AD are at increased risk for ophthalmic diseases such as glaucoma

Racial differences in correlations between optic nerve head morphology and ocular blood flow in healthy eyes

poster abstractPurpose: To assess differences in the relationship between optic nerve head (ONH) morphology and ocular blood flow between persons of African descent (AD) and European descent (ED) with healthy eyes. Methods: 46 participants (20 AD, 26 ED) with normal fundoscopic exam and intraocular pressure were included. Each participant was assessed for disc area (DA), rim area (RA), linear cup to disc ratio (CDR), mean retinal nerve fiber layer (RNFL) thickness by Heidelberg retina tomograph. Retrobulbar blood flow was assessed by color Doppler imaging in the ophthalmic (OA), central retinal (CRA), nasal short posterior ciliary (NPCA) and temporal short posterior ciliary (TPCA) arteries. Peak systolic velocity (PSV), end diastolic velocity (EDV) and the resistive index (RI) were assessed in each artery. Mean retinal capillary blood flow and % of the area with no blood flow in both hemifields were measured with Heidelberg retinal flowmeter. Correlations between ONH morphology and ocular blood flow were derived using Pearson correlations. Differences between the correlations in the AD and ED groups were assessed using the Fisher r-to-z transformation method. Results: Age, gender, IOP and blood pressure were not significantly different between groups. Significant differences in correlations were observed between groups in the CRA. In this artery, PSV and DA were positively correlated in AD (r=0.43) and negatively correlated in ED (r=-0.35) (Δr=0.78; p=0.01). A similar finding was observed for PSV and RA (AD: r=0.39; ED: r=-0.22; Δr=0.61; p=0.04). Significant negative correlations between RI and CDR were observed in all arteries in the ED group (r coefficients range=-0.48 to -0.39), but not in the AD group (r coefficients range=-0.14 to 0.17). No significant differences were observed in the correlations of ONH morphology and capillary blood flow. Conclusion: ONH morphology and ocular blood flow relationship was significantly different in the healthy eyes of AD compared to ED

Differences in ocular blood flow in glaucoma between patients of African and European descent

PURPOSE: To investigate differences in ocular blood flow in individuals of African descent (AD) and European descent (ED) with open angle glaucoma (OAG). PATIENTS AND METHODS: A retrospective data analysis was performed on OAG patients of AD and ED who were previously examined for ocular blood flow within the Department of Ophthalmology at Indiana University School of Medicine. Data analysis included blood pressure, heart rate, visual fields, intraocular pressure, ocular perfusion pressure, and color Doppler imaging of retrobulbar vessels. Color Doppler imaging measurements were performed on ophthalmic, central retinal, and nasal and temporal short posterior ciliary arteries, with peak systolic (PSV) and end diastolic velocities (EDV) as well as the Pourcelot vascular resistive index calculated for each vessel. Two-sample t tests of unequal variance were performed with P values <0.05 considered statistically significant. RESULTS: OAG patients of AD had statistically significant lower retrobulbar blood flow values than patients of ED including lower ophthalmic artery PSV (P=0.0001), ophthalmic artery EDV (P=0.0008), central retinal artery PSV (P=0.01), temporal short posterior ciliary artery PSV (P=0.0037), and nasal short posterior ciliary artery PSV (P<0.0001). No significant differences were found in terms of intraocular pressure or visual field parameters. CONCLUSIONS: Significantly lower blood flow values were identified in all retrobulbar blood vessels in AD compared with ED OAG patients. These findings suggest that the contribution of ocular blood flow to the disease process may be different in AD compared with ED OAG patients

Effects of Sex Hormones on Ocular Blood Flow and Intraocular Pressure in Primary Open Angle Glaucoma: A Review

Primary open-angle glaucoma (POAG) is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell death and visual field loss. Some speculate that gender plays a role in the risk of developing POAG and that the physiologic differences between men and women may be attributed to the variable effects of sex hormones on intraocular pressure (IOP), ocular blood flow, and/or neuroprotection. Estrogen, in the form of premenopausal status, pregnancy, and post-menopausal hormone therapy is associated with increase in ocular blood flow, decrease in IOP and neuroprotective properties. The vasodilation caused by estrogen and its effects on aqueous humor outflow may contribute. On the other hand, although testosterone may have known effects in the cardiovascular and cerebrovascular systems, there is no consensus as to its effects in ocular health or POAG. With better understanding of sex hormones in POAG, sex hormone-derived preventative and therapeutic considerations in disease management may provide for improved gender-specific patient care

Accurate Prediction of Secreted Substrates and Identification of a Conserved Putative Secretion Signal for Type III Secretion Systems

The type III secretion system is an essential component for virulence in many Gram-negative bacteria. Though components of the secretion system apparatus are conserved, its substrates—effector proteins—are not. We have used a novel computational approach to confidently identify new secreted effectors by integrating protein sequence-based features, including evolutionary measures such as the pattern of homologs in a range of other organisms, G+C content, amino acid composition, and the N-terminal 30 residues of the protein sequence. The method was trained on known effectors from the plant pathogen Pseudomonas syringae and validated on a set of effectors from the animal pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) after eliminating effectors with detectable sequence similarity. We show that this approach can predict known secreted effectors with high specificity and sensitivity. Furthermore, by considering a large set of effectors from multiple organisms, we computationally identify a common putative secretion signal in the N-terminal 20 residues of secreted effectors. This signal can be used to discriminate 46 out of 68 total known effectors from both organisms, suggesting that it is a real, shared signal applicable to many type III secreted effectors. We use the method to make novel predictions of secreted effectors in S. Typhimurium, some of which have been experimentally validated. We also apply the method to predict secreted effectors in the genetically intractable human pathogen Chlamydia trachomatis, identifying the majority of known secreted proteins in addition to providing a number of novel predictions. This approach provides a new way to identify secreted effectors in a broad range of pathogenic bacteria for further experimental characterization and provides insight into the nature of the type III secretion signal

Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Global development goals increasingly rely on country-specific estimates for benchmarking a nation's progress. To meet this need, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 estimated global, regional, national, and, for selected locations, subnational cause-specific mortality beginning in the year 1980. Here we report an update to that study, making use of newly available data and improved methods. GBD 2017 provides a comprehensive assessment of cause-specific mortality for 282 causes in 195 countries and territories from 1980 to 2017. Methods The causes of death database is composed of vital registration (VR), verbal autopsy (VA), registry, survey, police, and surveillance data. GBD 2017 added ten VA studies, 127 country-years of VR data, 502 cancer-registry country-years, and an additional surveillance country-year. Expansions of the GBD cause of death hierarchy resulted in 18 additional causes estimated for GBD 2017. Newly available data led to subnational estimates for five additional countries Ethiopia, Iran, New Zealand, Norway, and Russia. Deaths assigned International Classification of Diseases (ICD) codes for non-specific, implausible, or intermediate causes of death were reassigned to underlying causes by redistribution algorithms that were incorporated into uncertainty estimation. We used statistical modelling tools developed for GBD, including the Cause of Death Ensemble model (CODErn), to generate cause fractions and cause specific death rates for each location, year, age, and sex. Instead of using UN estimates as in previous versions, GBD 2017 independently estimated population size and fertility rate for all locations. Years of life lost (YLLs) were then calculated as the sum of each death multiplied by the standard life expectancy at each age. All rates reported here are age-standardised. Findings At the broadest grouping of causes of death (Level 1), non-communicable diseases (NC Ds) comprised the greatest fraction of deaths, contributing to 73.4% (95% uncertainty interval [UI] 72.5-74.1) of total deaths in 2017, while communicable, maternal, neonatal, and nutritional (CMNN) causes accounted for 186% (17.9-19.6), and injuries 8.0% (7.7-8.2). Total numbers of deaths from NCD causes increased from 2007 to 2017 by 22.7% (21.5-23.9), representing an additional 7.61 million (7. 20-8.01) deaths estimated in 2017 versus 2007. The death rate from NCDs decreased globally by 7.9% (7.08.8). The number of deaths for CMNN causes decreased by 222% (20.0-24.0) and the death rate by 31.8% (30.1-33.3). Total deaths from injuries increased by 2.3% (0-5-4-0) between 2007 and 2017, and the death rate from injuries decreased by 13.7% (12.2-15.1) to 57.9 deaths (55.9-59.2) per 100 000 in 2017. Deaths from substance use disorders also increased, rising from 284 000 deaths (268 000-289 000) globally in 2007 to 352 000 (334 000-363 000) in 2017. Between 2007 and 2017, total deaths from conflict and terrorism increased by 118.0% (88.8-148.6). A greater reduction in total deaths and death rates was observed for some CMNN causes among children younger than 5 years than for older adults, such as a 36.4% (32.2-40.6) reduction in deaths from lower respiratory infections for children younger than 5 years compared with a 33.6% (31.2-36.1) increase in adults older than 70 years. Globally, the number of deaths was greater for men than for women at most ages in 2017, except at ages older than 85 years. Trends in global YLLs reflect an epidemiological transition, with decreases in total YLLs from enteric infections, respirator}, infections and tuberculosis, and maternal and neonatal disorders between 1990 and 2017; these were generally greater in magnitude at the lowest levels of the Socio-demographic Index (SDI). At the same time, there were large increases in YLLs from neoplasms and cardiovascular diseases. YLL rates decreased across the five leading Level 2 causes in all SDI quintiles. The leading causes of YLLs in 1990 neonatal disorders, lower respiratory infections, and diarrhoeal diseases were ranked second, fourth, and fifth, in 2017. Meanwhile, estimated YLLs increased for ischaemic heart disease (ranked first in 2017) and stroke (ranked third), even though YLL rates decreased. Population growth contributed to increased total deaths across the 20 leading Level 2 causes of mortality between 2007 and 2017. Decreases in the cause-specific mortality rate reduced the effect of population growth for all but three causes: substance use disorders, neurological disorders, and skin and subcutaneous diseases. Interpretation Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade. Copyright (C) 2018 The Author(s). Published by Elsevier Ltd.Peer reviewe

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2\ub75th percentile and 100 as the 97\ub75th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59\ub74 (IQR 35\ub74–67\ub73), ranging from a low of 11\ub76 (95% uncertainty interval 9\ub76–14\ub70) to a high of 84\ub79 (83\ub71–86\ub77). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97\ub71 (95% UI 95\ub78-98\ub71) in Iceland, followed by 96\ub76 (94\ub79-97\ub79) in Norway and 96\ub71 (94\ub75-97\ub73) in the Netherlands, to values as low as 18\ub76 (13\ub71-24\ub74) in the Central African Republic, 19\ub70 (14\ub73-23\ub77) in Somalia, and 23\ub74 (20\ub72-26\ub78) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91\ub75 (89\ub71-93\ub76) in Beijing to 48\ub70 (43\ub74-53\ub72) in Tibet (a 43\ub75-point difference), while India saw a 30\ub78-point disparity, from 64\ub78 (59\ub76-68\ub78) in Goa to 34\ub70 (30\ub73-38\ub71) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4\ub78-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20\ub79-point to 17\ub70-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17\ub72-point to 20\ub74-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations