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Although reduced ambient lighting (“dim” light) can cause myopia in emmetropizing chicks, it does not necessarily lead to myopic changes in emmetropizing rhesus monkeys. Because myopia is rarely spontaneous, a question remained whether dim light would hasten the progression of visually induced myopia. To determine the effects of dim light on the development of and recovery from form-deprivation myopia (FDM), seven 3-week-old infant rhesus monkeys were reared under dim light (mean ± SD = 55 ± 9 lx) with monocular diffuser spectacles until ~154 days of age, then maintained in dim light with unrestricted vision until ~337 days of age to allow for recovery. Refractive errors, corneal powers, ocular axial dimensions and sub-foveal choroidal thicknesses were measured longitudinally and compared to those obtained from form-deprived monkeys reared under typical laboratory lighting (504 ± 168 lx). Five of the seven subjects developed FDMs that were similar to those observed among their normal-light-reared counterparts. The average degree of form-deprivation-induced myopic anisometropia did not differ significantly between dim-light subjects (−3.88 ± 3.26D) and normal-light subjects (−4.45 ± 3.75D). However, three of the five dim-light subjects that developed obvious FDM failed to exhibit any signs of recovery and the two monkeys that were isometropic at the end of the treatment period manifest abnormal refractive errors during the recovery period. All refractive changes were associated with alterations in vitreous chamber elongation rates. It appears that dim light is not a strong myopiagenic stimulus by itself, but it can impair the optical regulation of refractive development in primates.

Purpose To compare risks of interstitial lung disease (ILD) between patients treated with dronedarone versus other antiarrhythmics. Methods Parallel retrospective cohort studies were conducted in the United States Department of Defense Military Health System database (DoD) and the HealthCore Integrated Research Database (HIRD). Study patients were treated for atrial fibrillation (AF) with dronedarone, amiodarone, sotalol, or flecainide. Propensity score matching was employed to create analysis cohorts balanced on baseline variables considered potential confounders of treatment decisions. The study period of July 20, 2008 through September 30, 2014 included a 1‐year baseline and minimum 6 months of follow‐up, for patients with drugs dispensed between July 20, 2009 and March 31, 2014. Suspect ILD outcomes were reviewed by independent adjudicators. Cox proportional hazards regression compared risk of confirmed ILD between dronedarone and each comparator cohort. A sensitivity analysis examined the effect of broadening the outcome definition. Results A total 72 ILD cases (52 DoD; 20 HIRD) were confirmed among 27 892 patients. ILD risk was significantly higher among amiodarone than dronedarone initiators in DoD (HR = 2.5; 95% CI = 1.1–5.3, p = 0.02). No difference was detected in HIRD (HR = 1.0; 95% CI = 0.4–2.4). Corresponding risks in sotalol and flecainide exposure groups did not differ significantly from dronedarone in either database. Conclusions ILD risk among AF patients initiated on dronedarone therapy was comparable to or lower than that of amiodarone initiators, and similar to that of new sotalol or flecainide users. This finding suggests that elevated ILD risk associated with amiodarone does not necessarily extend to dronedarone or other antiarrhythmic drugs.

SIGNIFICANCE Planning for the effective delivery of eye care, on all levels, depends on an accurate and detailed knowledge of the optometric workforce and an understanding of demographic/behavioral trends to meet future needs of the public. PURPOSE The purposes of this study were to assess the current and future supply of doctors of optometry and to examine in-depth trends related to (1) demographic shifts, (2) sex-based differences, (3) differences in practice behaviors in between self-employed and employed optometrists, and (4) the concept of additional capacity within the profession. METHODS The 2017 National Optometry Workforce Survey (31 items) was distributed to 4050 optometrists, randomly sampled from a population of 45,033 currently licensed and practicing optometrists listed in the American Optometric Association's Optometry Master Data File. A stratified sampling method was applied to the population of optometrists using primary license state, age, and sex as variables to ensure a representative sample. RESULTS With a response rate of 29% (1158 responses), the sample ensured a 95% confidence interval with a margin of error of

Background. High-resolution estimates of HIV burden across space and time provide an important tool for tracking and monitoring the progress of prevention and control efforts and assist with improving the precision and efficiency of targeting efforts. We aimed to assess HIV incidence and HIV mortality for all second-level administrative units across sub-Saharan Africa. Methods. In this modelling study, we developed a framework that used the geographically specific HIV prevalence data collected in seroprevalence surveys and antenatal care clinics to train a model that estimates HIV incidence and mortality among individuals aged 15–49 years. We used a model-based geostatistical framework to estimate HIV prevalence at the second administrative level in 44 countries in sub-Saharan Africa for 2000–18 and sought data on the number of individuals on antiretroviral therapy (ART) by second-level administrative unit. We then modified the Estimation and Projection Package (EPP) to use these HIV prevalence and treatment estimates to estimate HIV incidence and mortality by second-level administrative unit. Findings. The estimates suggest substantial variation in HIV incidence and mortality rates both between and within countries in sub-Saharan Africa, with 15 countries having a ten-times or greater difference in estimated HIV incidence between the second-level administrative units with the lowest and highest estimated incidence levels. Across all 44 countries in 2018, HIV incidence ranged from 2·8 (95% uncertainty interval 2·1–3·8) in Mauritania to 1585·9 (1369·4–1824·8) cases per 100 000 people in Lesotho and HIV mortality ranged from 0·8 (0·7–0·9) in Mauritania to 676·5 (513·6–888·0) deaths per 100 000 people in Lesotho. Variation in both incidence and mortality was substantially greater at the subnational level than at the national level and the highest estimated rates were accordingly higher. Among second-level administrative units, Guijá District, Gaza Province, Mozambique, had the highest estimated HIV incidence (4661·7 [2544·8–8120·3]) cases per 100 000 people in 2018 and Inhassunge District, Zambezia Province, Mozambique, had the highest estimated HIV mortality rate (1163·0 [679·0–1866·8]) deaths per 100 000 people. Further, the rate of reduction in HIV incidence and mortality from 2000 to 2018, as well as the ratio of new infections to the number of people living with HIV was highly variable. Although most second-level administrative units had declines in the number of new cases (3316 [81·1%] of 4087 units) and number of deaths (3325 [81·4%]), nearly all appeared well short of the targeted 75% reduction in new cases and deaths between 2010 and 2020. Interpretation. Our estimates suggest that most second-level administrative units in sub-Saharan Africa are falling short of the targeted 75% reduction in new cases and deaths by 2020, which is further compounded by substantial within-country variability. These estimates will help decision makers and programme implementers expand access to ART and better target health resources to higher burden subnational areas. This work was primarily supported by the Bill & Melinda Gates Foundation (grant OPP1132415). Additionally, O Adetokunboh acknowledges the support of the Department of Science and Innovation, and National Research Foundation of South Africa. M Ausloos, A Pana, and C Herteliu are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, Executive Agency for Higher Education, Research, Development and Innovation Funding (Romania; project number PN-III-P4-ID-PCCF-2016-0084). T W Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. M J Bockarie is supported by the European and Developing Countries Clinical Trials Partnership. F Carvalho and E Fernandes acknowledge support from Portuguese national funds (Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior; UIDB/info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/50006/2020/PT, UIDB/04378/2020, and UIDP/04378/2020. K Deribe is supported by the Wellcome Trust (grant 201900/Z/16/Z) as part of his International Intermediate Fellowship. B-F Hwang was partially supported by China Medical University (CMU107-Z-04), Taichung, Taiwan. M Jakovljevic acknowledges support of the Serbia Ministry of Education Science and Technological Development (grant OI 175 014). M N Khan acknowledges the support of Jatiya Kabi Kazi Nazrul Islam University, Bangladesh. Y J Kim was supported by the Research Management Centre, Xiamen University Malaysia, Malaysia, (XMUMRF/2020-C6/ITCM/0004). K Krishnan is supported by University Grants Commission Centre of Advanced Study, (CAS II), awarded to the Department of Anthropology, Panjab University, Chandigarh, India. M Kumar would like to acknowledge National Institutes of Health and Fogarty International Cente (K43TW010716). I Landires is a member of the Sistema Nacional de Investigación, which is supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación, Panama. W Mendoza is a program analyst in population and development at the UN Population Fund Country Office in Peru, which does not necessarily endorse this study. M Phetole received institutional support from the Grants, Innovation and Product Development Unit, South African Medical Research Council. O Odukoya acknowledges support from the Fogarty International Center of the US National Institutes of Health (K43TW010704). The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. O Oladimeji is grateful for the support from Walter Sisulu University, Eastern Cape, South Africa, the University of Botswana, Botswana, and the University of Technology of Durban, Durban, South Africa. J R Padubidri acknowledges support from Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, India. G C Patton is supported by an Australian Government National Health and Medical Research Council research fellowship. P Rathi acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal India. A I Ribeiro was supported by National Funds through Fundação para a Ciência e Tecnologia, under the programme of Stimulus of Scientific Employment–Individual Support (info:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND/02386/2018/CP1538/CT0001/PT). A M Samy acknowledges the support of the Egyptian Fulbright Mission Program. F Sha was supported by the Shenzhen Social Science Fund (SZ2020C015) and the Shenzhen Science and Technology Program (KQTD20190929172835662). A Sheikh is supported by Health Data Research UK. N Taveira acknowledges partial funding by Fundação para a Ciência e Tecnologia, Portugal, and Aga Khan Development Network—Portugal Collaborative Research Network in Portuguese-speaking countries in Africa (332821690), and by the European and Developing Countries Clinical Trials Partnership (RIA2016MC-1615). C S Wiysonge is supported by the South African Medical Research Council. Y Zhang was supported by the Science and Technology Research Project of Hubei Provincial Department of Education (Q20201104) and Open Fund Project of Hubei Province Key Laboratory of Occupational Hazard Identification and Control (OHIC2020Y01).

Childhood malnutrition is associated with high morbidity and mortality globally1. Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood2. Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0–59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards3–5. The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z-score, respectively, that is more than two standard deviations below the World Health Organization’s median growth reference standards for a healthy population6. Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for example, states or provinces)7; the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes8. Building from our previous work mapping CGF in Africa9, here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live1, aggregated to policy-relevant first and second (for example, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries; our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications., High-resolution subnational mapping of child growth failure indicators for 105 low- and middle-income countries between 2000 and 2017 shows that, despite considerable progress, substantial geographical inequalities still exist in some countries.

Purpose: Light affects a variety of non-image forming processes, such as circadian rhythm entrainment and the pupillary light reflex, which are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). The purpose of this study was to assess the effects of long- and short-wavelength ambient lighting on activity patterns and pupil responses in rhesus monkeys.Methods: Infant rhesus monkeys were reared under either broadband “white” light (n = 14), long-wavelength “red” light (n = 20; 630 nm), or short-wavelength “blue” light (n = 21; 465 nm) on a 12-h light/dark cycle starting at 24.1 ± 2.6 days of age. Activity was measured for the first 4 months of the experimental period using a Fitbit activity tracking device and quantified as average step counts during the daytime (lights-on) and nighttime (lights-off) periods. Pupil responses to 1 s red (651 nm) and blue (456 nm) stimuli were measured after approximately 8 months. Pupil metrics included maximum constriction and the 6 s post-illumination pupil response (PIPR).Results: Activity during the lights-on period increased with age during the first 10 weeks (p < 0.001 for all) and was not significantly different for monkeys reared in white, red, or blue light (p = 0.07). Activity during the 12-h lights-off period was significantly greater for monkeys reared in blue light compared to those in white light (p = 0.02), but not compared to those in red light (p = 0.08). However, blue light reared monkeys exhibited significantly lower activity compared to both white and red light reared monkeys during the first hour of the lights-off period (p = 0.01 for both) and greater activity during the final hour of the lights-off period (p < 0.001 for both). Maximum pupil constriction and the 6 s PIPR to 1 s red and blue stimuli were not significantly different between groups (p > 0.05 for all).Conclusion: Findings suggest that long-term exposure to 12-h narrowband blue light results in greater disruption in nighttime behavioral patterns compared to narrowband red light. Normal pupil responses measured later in the rearing period suggest that ipRGCs adapt after long-term exposure to narrowband lighting.

Purpose We aimed to determine myopia control efficacy with novel contact lenses (CL) that (1) reduced both central and peripheral defocus, and (2) provided extended depth of focus with better global retinal image quality for points on, and anterior to, the retina and degraded for points posterior to the retina. Methods Children (n = 508, 8–13 years) with cycloplegic spherical equivalent (SE) −0.75 to −3.50D were enrolled in a prospective, double blind trial and randomised to one of five groups: (1) single vision, silicone hydrogel (SH) CL; (2) two groups wearing SH CL that imposed myopic defocus across peripheral and central retina (test CL I and II; +1.00D centrally and +2.50 and +1.50 for CL I and II at 3 mm semi‐chord respectively); and (3) two groups wearing extended depth of focus (EDOF) hydrogel CL incorporating higher order aberrations to modulate retinal image quality (test CL III and IV; extended depth of focus of up to +1.75D and +2.50D respectively). Cycloplegic autorefraction and axial length (AL) measurements were conducted at six monthly intervals. Compliance to lens wear was assessed with a diary and collected at each visit. Additionally, subjective responses to various aspects of lens wear were assessed. The trial commenced in February 2014 and was terminated in January 2017 due to site closure. Myopia progression over time between groups was compared using linear mixed models and where needed post hoc analysis with Bonferroni corrections conducted. Results Myopia progressed with control CL −1.12 ± 0.51D/0.58 ± 0.27 mm for SE/AL at 24 months. In comparison, all test CL had reduced progression with SE/AL ranging from −0.78D to −0.87D/0.41–0.46 mm at 24 months (AL: p

To evaluate the utility of magnetic resonance venography with time-resolved imaging (MRV TRI) in the diagnosis of pelvic vein insufficiency (PVI). A retrospective single-center review of N = 17 consecutive patients who underwent pelvic MRI for the assessment of PVI was performed. N = 8/17 (47%) studies were positive for PVI. TRI imaging demonstrated N = 6/8 patients with Grade 0–3 PVI and N = 2/8 patients with May–Thurner Syndrome. N = 4/8 patients underwent elective endovascular management, all of which were technically successful. In the assessment of PVI, MRV TRI provides a dynamic assessment of venous insufficiency, serving as an adjunct to the imaging diagnosis of this pathology.

With the growing prevalence of myopia, already at epidemic levels in some countries, there is an urgent need for new management approaches. However, with the increasing number of research publications on the topic of myopia control, there is also a clear necessity for agreement and guidance on key issues, including on how myopia should be defined and how interventions, validated by well-conducted clinical trials, should be appropriately and ethically applied. The International Myopia Institute (IMI) reports the critical review and synthesis of the research evidence to date, from animal models, genetics, clinical studies, and randomized controlled trials, by more than 85 multidisciplinary experts in the field, as the basis for the recommendations contained therein. As background to the need for myopia control, the risk factors for myopia onset and progression are reviewed. The seven generated reports are summarized: (1) Defining and Classifying Myopia, (2) Experimental Models of Emmetropization and Myopia, (3) Myopia Genetics, (4) Interventions for Myopia Onset and Progression, (5) Clinical Myopia Control Trials and Instrumentation, (6) Industry Guidelines and Ethical Considerations for Myopia Control, and (7) Clinical Myopia Management Guidelines.

Purpose Infantile strabismus impedes the development of stereopsis. In optically strabismic monkeys, 2 continuous hours of normal binocular vision per day has been shown to preserve near-normal stereopsis. In this study, we investigated whether, as in learning, multiple shorter periods of intervention would further boost performance. Methods To simulate infantile esotropia, infant monkeys were reared with 30 prism diopters base-in starting at 4 weeks of age. Daily periods of normal binocular vision were provided by replacing prisms with plano lenses. Altogether, 14 monkeys were prism reared: 2 with continuous prism, 2 with 2 continuous hours of normal binocular vision per day, 6 with 2 noncontinuous hours, and 4 with 1 noncontinuous hour of binocular vision each day. Seven normally reared monkeys provided control data. Behavioral methods were employed to measure spatial contrast sensitivity, eye alignment, and stereopsis. Results One monkey reared with continuous prism had poor stereopsis, and the other had no stereopsis. Ten of the 12 monkeys reared with periods of normal binocular vision had stereopsis, and those with longer and more continuous periods of binocular vision had stereopsis approaching that of normally reared monkeys. Conclusions During early development, multiple short periods of binocular vision were effective in preserving clinically significant stereopsis in monkeys. These results suggest that by providing relatively short multiple daily intervention periods, stereopsis may be preserved in strabismic human children.

The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs)1–4. Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19)5–8. Here we generated annual estimates of routine childhood MCV1 coverage at 5 × 5-km2 pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations; strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children., Although progress in the coverage of routine measles vaccination in children in low- and middle-income countries was made during 2000–2019, many countries remain far from the goal of 80% coverage in all districts by 2019.

Oral administration of the adenosine receptor (ADOR) antagonist, 7-methylxanthine (7-MX), reduces both form-deprivation and lens-induced myopia in mammalian animal models. We investigated whether topically instilled caffeine, another non-selective ADOR antagonist, retards vision-induced axial elongation in monkeys. Beginning at 24 days of age, a 1.4% caffeine solution was instilled in both eyes of 14 rhesus monkeys twice each day until the age of 135 days. Concurrent with the caffeine regimen, the monkeys were fitted with helmets that held either −3 D (-3D/pl caffeine, n = 8) or +3 D spectacle lenses (+3D/pl caffeine, n = 6) in front of their lens-treated eyes and zero-powered lenses in front of their fellow-control eyes. Refractive errors and ocular dimensions were measured at baseline and periodically throughout the lens-rearing period. Control data were obtained from 8 vehicle-treated animals also reared with monocular −3 D spectacles (-3D/pl vehicle). In addition, historical comparison data were available for otherwise untreated lens-reared controls (-3D/pl controls, n = 20; +3D/pl controls, n = 9) and 41 normal monkeys. The vehicle controls and the untreated lens-reared controls consistently developed compensating axial anisometropias (-3D/pl vehicle = −1.44 ± 1.04 D; -3D/pl controls = −1.85 ± 1.20 D; +3D/pl controls = +1.92 ± 0.56 D). The caffeine regime did not interfere with hyperopic compensation in response to +3 D of anisometropia (+1.93 ± 0.82 D), however, it reduced the likelihood that animals would compensate for −3 D of anisometropia (+0.58 ± 1.82 D). The caffeine regimen also promoted hyperopic shifts in both the lens-treated and fellow-control eyes; 26 of the 28 caffeine-treated eyes became more hyperopic than the median normal monkey (mean (±SD) relative hyperopia = +2.27 ± 1.65 D; range = +0.31 to +6.37 D). The effects of topical caffeine on refractive development, which were qualitatively similar to those produced by oral administration of 7-MX, indicate that ADOR antagonists have potential in treatment strategies for preventing and/or reducing myopia progression.

Citrus Black Spot (CBS), caused by the ascomycete, Phyllosticta citricarpa, is a fruit, foliar, and twig spotting fungal disease affecting the majority of commercial cultivars of citrus. The disease causes cosmetic lesions, may cause fruit drop and P. citricarpa is considered a quarantine pathogen by some countries, impacting domestic and international trade of citrus fruit. Regulatory requirements affecting fruit trade exist even though there is no documented case of disease spread via infected fruit into previously disease-free areas. To clarify the risk of fruit as a potential pathway for the spread of CBS, we developed a quantitative, probabilistic risk assessment model. The model provides an assessment of all steps in the fruit pathway, including production, packinghouse handling, transportation, export-import distribution channels, and consumer endpoints. The model is stochastic and uses Monte Carlo simulation to assess the risk of P. citricarpa moving through all steps in the pathway. We attempted to use all available literature and information to quantitate risk at each point in the potential pathway and by sequentially linking all steps to determine the overall quantitative risk. In addition, we assessed climatological effects on incidence of diseased fruit at production sites and on fungal reproduction and infection, as well as criteria for establishment at endpoints. We examined ten case studies between exporting and importing locations/countries. Model results indicated fruit to be an epidemiologically insignificant means for CBS spread, even between producing countries where CBS occurs and CBS-free importing countries with disease-conducive climates. We created a second model to examine the introduction of infected plant material from countries where CBS occurs. This model demonstrated significant probability of introduction via such infected material. However, pathogen establishment and disease development was still restricted only to areas with conducive climatological conditions. We created a tool to quantitatively explore the viability of various potential pathways via combinations of CBS-present production sites and corresponding pathway endpoints, including environments conducive and non-conducive to CBS. The tool is provided to aid decision makers on phytosanitary risk relative to international trade of citrus fruit.

The antiarrhythmic drug dronedarone was designed to reduce the extra-cardiac adverse effects associated with amiodarone use in treatment of patients with atrial fibrillation / atrial flutter (AF/AFL). This epidemiological study used a retrospective cohort design to compare risk of cardiovascular-related hospitalizations and death in AF/AFL patients treated with dronedarone versus other antiarrhythmic drugs (AADs). AF/AFL patients with incident dronedarone fills were matched by propensity score (PS) to incident users of other AADs. The primary study outcome was hospitalization for cardiovascular (CV) causes within 24 months after the first study drug fill. A secondary composite outcome comprised hospitalization for CV causes or all-cause mortality during follow-up. In the AF/AFL patient cohort meeting eligibility criteria, 6,964 incident users of dronedarone and 25 607 incident users of other AADs were identified. The PS-matched cohort comprised 6,349 Dronedarone users (91.2% of all eligible) and 12,698 other AAD users. Dronedarone patients had a significantly lower risk of hospitalization for a CV event compared to Other AAD users (hazard ratio = 0.87; 95% confidence interval = 0.79 to 0.96). This was consistent with results for the composite outcome (hazard ratio=0.86; 95% confidence interval = 0.78 to 0.95). In conclusion, AF/AFL patients initiated on dronedarone versus other AADs had significantly lower risk of CV hospitalizations as well as the composite CV hospitalization / death from any cause.

Dual-focus lenses that impose simultaneous competing myopic defocus over the entire visual field produce axial hyperopic shifts in refractive error. The purpose of this study was to characterize the effects of eccentricity on the ability of myopic defocus signals to influence central refractive development in infant monkeys. From 24 to 152 days of age, rhesus monkeys were reared with binocular, dual-focus lenses that had central, zero-powered zones surrounded by alternating concentric annular power zones of +3D and zero power. Between subject groups the diameter of the central, zero-powered zone was varied from 2 mm to 8 mm in 2 mm steps (+3D/pl 2 mm, n = 6; +3D/pl 4 mm, n = 6; +3D/pl 6 mm, n = 8, or + 3D/pl 8 mm, n = 6). For the treatment lens with 2, 4, 6 and 8 mm central zones, objects at eccentricities beyond 11°, 16°, 19° and 23°, respectively, were imaged exclusively through the dual-power peripheral zones. Refractive status (retinoscopy), corneal power (keratometry) and axial dimensions (ultrasonography) were measured at two-week intervals. Comparison data were obtained from monkeys reared with binocular, single-vision +3D full-field lenses (+3D FF, n = 6) and 41 normal control monkeys reared with unrestricted vision. At the end of the rearing period, with the exception of the +3D/pl 8 mm group (median = +3.64 D), the ametropias for the other lens-reared groups (medians: FF = +4.39 D, 2 mm = +5.19 D, 4 mm = +5.59 D, 6 mm = +3.50 D) were significantly more hyperopic than that for the normal monkeys (+2.50 D). These hyperopic errors were associated with shallower vitreous chambers. The key finding was that the extent and consistency of these hyperopic ametropias varied with the eccentricity of the dual-focus zones. The results confirm that myopic defocus in the near periphery can slow axial growth, but that imposed defocus beyond about 20° from the fovea does not consistently alter central refractive development.

Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this experiment was to examine the effects of low intensity ambient lighting (dim light) on normal refractive development in macaque monkeys. Seven infant rhesus monkeys were reared under dim light (room illumination level: ~55 lx) from 24 to ~310 days of age with otherwise unrestricted vision. Refractive error, corneal power, ocular axial dimensions, and choroidal thickness were measured in anesthetized animals at the onset of the experiment and periodically throughout the dim-light-rearing period, and were compared with those of normal-light-reared monkeys. We found that dim light did not produce myopia; instead, dim-light monkeys were hyperopic relative to normal-light monkeys (median refractive errors at ~155 days, OD: +3.13 D vs. +2.31 D; OS: +3.31D vs. +2.44 D; at ~310 days, OD: +2.75D vs. +1.78D, OS: +3.00D vs. +1.75D). In addition, dim-light rearing caused sustained thickening in the choroid, but it did not alter corneal power development, nor did it change the axial nature of the refractive errors. These results showed that, for rhesus monkeys and possibly other primates, low ambient lighting by itself is not necessarily myopiagenic, but might compromise the efficiency of emmetropization.

Purpose This study examined the potential risk of cardiovascular (CV) events associated with modafinil and the consistency of the risk estimates across databases. Methods A retrospective, inception cohort design of patients who initiated treatment with modafinil between 2006 and 2008 was used in three US health care claims databases. Modafinil users were matched with nonusers. Patients were further divided into two cohorts of obstructive sleep apnea (OSA) and non-OSA (NOSA) cohorts. Endpoints of interest, including myocardial infarction (MI), stroke, CV hospitalizations, and all-cause death, were assessed using incidence rates and Cox proportional hazard ratios (HRs), adjusted for potential confounding factors. Results The cohorts included a total of 175 524 patients in MarketScan CM; 77 266-in IMS LifeLink; and 8174-in MarketScan Medicaid. No increased risk for MI in the OSA and NOSA cohorts was observed across all three databases. The risks of CV hospitalization in the OSA and NOSA cohorts were not different between the modafinil users and nonusers, except for IMS LifeLink database where the HR was lower than one in the modafinil users compared with the nonusers (HR, 0.69; 95% confidence interval [CI], 0.54 to 0.87). For OSA patients with prior stroke, an adjusted HR of 1.96 (95% CI, 1.02 to 3.76) was observed for stroke among modafinil users compared with nonusers. Among the NOSA, the HRs for all-cause death in the OSA were inconsistent across databases. Conclusions Except for few CV outcomes, applying one common protocol generated consistent risk estimates of CV events following modafinil use across cohorts and databases.

Purpose To systematically analyse the differences between cycloplegic and noncycloplegic refractive errors (RE) in children and to determine if the predictive value of noncycloplegic RE in categorizing RE can be improved. Methods Random cluster sampling was used to select 6825 children aged 4–15 years. Autorefraction was performed under both noncycloplegic and cycloplegic (induced with 1% cyclopentolate drops) conditions. Paired differences between noncycloplegic and cycloplegic spherical equivalent (SE) RE were determined. A general linear model was developed to determine whether cycloplegic SE can be predicted using noncycloplegic SE, age and uncorrected visual acuity (UCVA). Results Compared to cycloplegia, noncycloplegia resulted in a more myopic SE (paired difference: −0.63 ± 0.65D, 95% CI: −0.612 to −0.65D, 6017 eligible right eyes) with greater differences observed in younger participants and in eyes with more hyperopic RE and smaller AL. Using raw noncycloplegic data resulted in only 61% of the eyes being correctly classified as myopic, emmetropic or hyperopic. Using age and uncorrected VA in the model, the association improved and 77% of the eyes were classified correctly. However, predicted cycloplegic SE continued to show large residual errors for low myopic to hyperopic RE. Applying the model to only those eyes with uncorrected VA

Importance Nearly half of children suffering vision impairment reside in China with myopia accounting for the vast majority. Background To describe the design and methodology of the Shanghai Child and Adolescent Large-scale Eye Study (SCALE). Design The SCALE was a city wide, school-based, prospective survey. Participants Children and adolescents aged 4 to 14 years from kindergarten (middle and senior), primary schools and junior high schools of all 17 districts and counties of the city of Shanghai, China were examined in 2012-2013. Methods Each enrolled child underwent vision assessment (distance visual acuity; uncorrected and with corrective device if worn) and their parent/carer completed a questionnaire designed to elicit risk factors associated with myopia. Additionally, non-cycloplegic autorefraction and ocular axial length was measured in a sub-set of the larger sample.. Main Outcome Measures Prevalence and the associated factors of vision impairment, myopia and high myopia in Shanghai. Results In 2012-2013, a total of 910,245 of the eligible 1,196,763 children and adolescents identified from census (76%, mean age 9.0 ± 2.7 years (4- 14 years)) were enrolled with visual acuity screened in the city of Shanghai. Of these, 610,952 children (67% of the entire sample) underwent non-cycloplegic autorefraction and 219,188 (24% of the entire sample) had both non-cycloplegic autorefraction and axial length measurements. Conclusions and Relevance The study results will provide insights on the burden of vision impairment, myopia and high myopia in children and adolescents in a metropolitan area of China, and contribute to the policies and strategies to address and limit the burden.

Encoding of visual information requires precisely timed spiking activity in the network of cortical neurons; irregular spiking can interfere with information processing especially for low-contrast images. The vision of newborn infants is impoverished. An infant's contrast sensitivity is low and the ability to discriminate complex stimuli is poor. The neural mechanisms that limit the visual capacities of infants are a matter of debate. Here we asked whether noisy spiking and/or crude information processing in visual cortex limit infant vision. Since neurons beyond the primary visual cortex (V1) have rarely been studied in neonates or infants, we focused on the firing pattern of neurons in visual area V2, the earliest extrastriate visual area of both male and female macaque monkeys (Maccaca mulatta). For eight stimulus contrasts ranging from 0% to 80%, we analyzed spiking irregularity by calculating the square of the coefficient of variation (CV(2)) in interspike intervals, the trial-to-trial fluctuation in spiking (Fano factor), and the amount of information on contrast conveyed by each spiking (information density). While the contrast sensitivity of infant neurons was reduced as expected, spiking noise, both the magnitude of spiking irregularity and the trial-to-trial fluctuations, was much lower in the spike trains of infant V2 neurons compared with those of adults. However, information density for V2 neurons was significantly lower in infants. Our results suggest that poor contrast sensitivity combined with lower information density of extrastriate neurons, despite their lower spiking noise, may limit behaviorally determined contrast sensitivity soon after birth. SIGNIFICANCE STATEMENT Despite >50 years of investigations on the postnatal development of the primary visual cortex (V1), cortical mechanisms that may limit infant vision are still unclear. We investigated the quality and strength of neuronal firing in primate visual area V2 by analyzing contrast sensitivity, spiking variability, and the amount of information on contrast conveyed by each action potential (information density). Here we demonstrate that the firing rate, contrast sensitivity, and dynamic range of V2 neurons were depressed in infants compared with adults. Although spiking noise was less, information density was lower in infant V2. Impoverished neuronal drive and lower information density in extrastriate visual areas, despite lower spiking noise, largely explain the impoverished visual sensitivity of primates near birth.

Item does not contain fulltext PURPOSE: The International Myopia Institute (IMI) Yearly Digest highlights new research considered to be of importance since the publication of the first series of IMI white papers. METHODS: A literature search was conducted for articles on myopia between 2019 and mid-2020 to inform definitions and classifications, experimental models, genetics, interventions, clinical trials, and clinical management. Conference abstracts from key meetings in the same period were also considered. RESULTS: One thousand articles on myopia have been published between 2019 and mid-2020. Key advances include the use of the definition of premyopia in studies currently under way to test interventions in myopia, new definitions in the field of pathologic myopia, the role of new pharmacologic treatments in experimental models such as intraocular pressure-lowering latanoprost, a large meta-analysis of refractive error identifying 336 new genetic loci, new clinical interventions such as the defocus incorporated multisegment spectacles and combination therapy with low-dose atropine and orthokeratology (OK), normative standards in refractive error, the ethical dilemma of a placebo control group when myopia control treatments are established, reporting the physical metric of myopia reduction versus a percentage reduction, comparison of the risk of pediatric OK wear with risk of vision impairment in myopia, the justification of preventing myopic and axial length increase versus quality of life, and future vision loss. CONCLUSIONS: Large amounts of research in myopia have been published since the IMI 2019 white papers were released. The yearly digest serves to highlight the latest research and advances in myopia.

The International Myopia Institute's (IMI) mission is to advance research, education, and management of myopia to decrease future vision impairment and blindness associated with increasing myopia. Its approach is to bring together scientists, clinicians, policymakers, government members, and educators into the field of myopia to stimulate collaboration and sharing of knowledge. The latest reports are on pathologic myopia, the impact of myopia, risk factors for myopia, accommodation and binocular vision in myopia development and progression, and the prevention of myopia and its progression. Together with the digest updating the 2019 International Myopia Institute white papers using the research published in the last 18 months, these evidence-based consensus white papers help to clarify the imperative for myopia control and the role of environmental modification initiatives, informing an evidence-based clinical approach. This guidance includes who to treat and when to start or stop treatment, and the advantages and limitations of different management approaches.

The prevalence of myopia has markedly increased in East and Southeast Asia, and pathologic consequences of myopia, including myopic maculopathy and high myopia-associated optic neuropathy, are now some of the most common causes of irreversible blindness. Hence, strategies are warranted to reduce the prevalence of myopia and the progression to high myopia because this is the main modifiable risk factor for pathologic myopia. On the basis of published population-based and interventional studies, an important strategy to reduce the development of myopia is encouraging schoolchildren to spend more time outdoors. As compared with other measures, spending more time outdoors is the safest strategy and aligns with other existing health initiatives, such as obesity prevention, by promoting a healthier lifestyle for children and adolescents. Useful clinical measures to reduce or slow the progression of myopia include the daily application of low-dose atropine eye drops, in concentrations ranging between 0.01% and 0.05%, despite the side effects of a slightly reduced amplitude of accommodation, slight mydriasis, and risk of an allergic reaction; multifocal spectacle design; contact lenses that have power profiles that produce peripheral myopic defocus; and orthokeratology using corneal gas-permeable contact lenses that are designed to flatten the central cornea, leading to midperipheral steeping and peripheral myopic defocus, during overnight wear to eliminate daytime myopia. The risk-to-benefit ratio needs to be weighed up for the individual on the basis of their age, health, and lifestyle. The measures listed above are not mutually exclusive and are beginning to be examined in combination. peerReviewed

Purpose Our objective was to highlight the importance of database selection in observational research and to determine the incidence of corticosteroid-related events in patients exposed to fluticasone propionate intranasal spray (FPNS) compared with other intranasal steroids (INS). Methods After a feasibility study using an electronic medical record database in the UK (1990–2002), a retrospective cohort study was conducted using a large administrative claims database in the USA from 1994 to 2002 comparing the incidence and rate ratios of steroid-related events among intermittent, sub-chronic, and chronic FPNS use and other INS use episodes. Results Most patients used INS intermittently; power was low to evaluate risk associated with chronic use. Significantly elevated adjusted rate ratios were observed in the US study comparing FPNS with other INS for hypercorticism, sinusitis, abscess, and empyema, as well as a significantly decreased rate ratio for cataracts. The US claims database provided greater granularity on covariates and markers of severity to improve control of confounding for this study and time period, but neither database was able to assess the indication for prescription and the UK study could not address the use of INS without a prescription. Conclusions The FPNS results were consistent with the risk profile for INS and did not raise any new safety signals at the time of study conduct, which is consistent with the current safety profile. We were not able to discern the extent of potential off-label use of FPNS or other INS. Differences in the available data and healthcare systems highlight important considerations for database selection in the feasibility phase to assess the precision and limitations prior to formal risk evaluation. Electronic supplementary material The online version of this article (doi:10.1007/s40801-015-0057-y) contains supplementary material, which is available to authorized users.

Asiatic citrus canker (ACC, caused by Xanthomonas citri subsp. citri, [Xcc]) is a serious disease of citrus, reducing yield and impacting marketability of fresh fruit. ACC has phytosanitary implications for fresh fruit trade. Lesions on fruit, leaves, and shoots in an orchard of ACC-susceptible grapefruit were monitored for production of Xcc from June to the following January in 2009 and 2010. Lesions on fruit post-harvest either packingline-treated or not treated were also monitored for production of Xcc on fruit harvested in November 2013 and January 2014. Shoot lesions generally produced fewer bacteria and had a smaller proportion of active lesions compared to leaf and fruit lesions. As the season progressed the proportion of active lesions on fruit and shoots gradually declined. Bacterial flux density (BFD) in surviving lesions was >103 on all organs at all sample times. A window-pane analysis revealed weather variables associated with bacterial survival within the lesion. The packingline treatment had no effect in reducing the proportion of active lesions, and had only a small, transient effect reducing BFD (~1.5 log units). Lesion size affected survival – small lesions (

Purpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin, and are primarily involved in non-image forming functions, such as the pupillary light reflex and circadian rhythm entrainment. The goal of this study was to develop and validate a targeted ipRGC immunotoxin to ultimately examine the role of ipRGCs in macaque monkeys. Methods: An immunotoxin for the macaque melanopsin gene (OPN4), consisting of a saporin-conjugated antibody directed at the N-terminus, was prepared in solutions of 0.316, 1, 3.16, 10, and 50 μg in vehicle, and delivered intravitreally to the right eye of six rhesus monkeys, respectively. Left eyes were injected with vehicle only. The pupillary light reflex (PLR), the ipRGC-driven post illumination pupil response (PIPR), and electroretinograms (ERGs) were recorded before and after injection. For pupil measurements, 1 and 5 s pulses of light were presented to the dilated right eye while the left pupil was imaged. Stimulation included 651 nm (133 cd/m2), and 4 intensities of 456 nm (16-500 cd/m2) light. Maximum pupil constriction and the 6 s PIPR were calculated. Retinal imaging was performed with optical coherence tomography (OCT), and eyes underwent OPN4 immunohistochemistry to evaluate immunotoxin specificity and ipRGC loss. Results: Before injection, animals showed robust pupil responses to 1 and 5 s blue light. After injection, baseline pupil size increased 12 ± 17%, maximum pupil constriction decreased, and the PIPR, a marker of ipRGC activity, was eliminated in all but the lowest immunotoxin concentration. For the highest concentrations, some inflammation and structural changes were observed with OCT, while eyes injected with lower concentrations appeared normal. ERG responses showed better preserved retinal function with lower concentrations. Immunohistochemistry showed 80-100% ipRGC elimination with the higher doses being more effective; however this could be partly due to inflammation that occurred at the higher concentrations. Conclusion: Findings demonstrated that the OPN4 macaque immunotoxin was specific for ipRGCs, and induced a graded reduction in the PLR, as well as, in ipRGC-driven pupil response with concentration. Further investigation of the effects of ipRGC ablation on ocular and systemic circadian rhythms and the pupil in rhesus monkeys will provide a better understanding of the role of ipRGCs in primates.

Adenosine receptor (ADOR) antagonists, such as 7-methylxanthine (7-MX), have been shown to slow myopia progression in humans and animal models. Adenosine receptors are found throughout the body, and regulate the release of neurotransmitters such as dopamine and glutamate. However, the role of adenosine in eye growth is unclear. Evidence suggests that 7-MX increases scleral collagen fibril diameter, hence preventing axial elongation. This study used immunohistochemistry (IHC) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) to examine the distribution of the four ADORs in the normal monkey eye to help elucidate potential mechanisms of action. Eyes were enucleated from six Rhesus monkeys. Anterior segments and eyecups were separated into components and flash-frozen for RNA extraction or fixed in 4% paraformaldehyde and processed for immunohistochemistry against ADORA1, ADORA2a, ADORA2b, and ADORA3. RNA was reverse-transcribed, and qPCR was performed using custom primers. Relative gene expression was calculated using the ΔΔCt method normalizing to liver expression, and statistical analysis was performed using Relative Expression Software Tool. ADORA1 immunostaining was highest in the iris sphincter muscle, trabecular meshwork, ciliary epithelium, and retinal nerve fiber layer. ADORA2a immunostaining was highest in the corneal epithelium, trabecular meshwork, ciliary epithelium, retinal nerve fiber layer, and scleral fibroblasts. ADORA2b immunostaining was highest in corneal basal epithelium, limbal stem cells, iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells and scattered scleral fibroblasts. ADORA3 immunostaining was highest in the iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells, and scleral fibroblasts. Compared to liver mRNA, ADORA1 mRNA was significantly higher in the brain, retina and choroid, and significantly lower in the iris/ciliary body. ADORA2a expression was higher in brain and retina, ADORA2b expression was higher in retina, and ADORA3 was higher in the choroid. In conclusion, immunohistochemistry and RT-qPCR indicated differential patterns of expression of the four adenosine receptors in the ocular tissues of the normal non-human primate. The presence of ADORs in scleral fibroblasts and the choroid may support mechanisms by which ADOR antagonists may prevent myopia. The potential effects of ADOR inhibition on both anterior and posterior ocular structures warrant investigation.

The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and form-deprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 ± 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), −3 D (−3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens- (+3D-NL, n = 9; −3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision-dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus.

Purpose Previous studies suggest that the adenosine receptor antagonist, 7-methylxanthine (7-MX), retards myopia progression. Our aim was to determine whether 7-MX alters the compensating refractive changes produced by defocus in rhesus monkeys. Methods Starting at age 3 weeks, monkeys were reared with -3 diopter (D; n = 10; 7-MX -3D/pl) or +3D (n = 6; 7-MX +3D/pl) spectacles over their treated eyes and zero-powered lenses over their fellow eyes. In addition, they were given 100 mg/kg of 7-MX orally twice daily throughout the lens-rearing period (age 147 ± 4 days). Comparison data were obtained from lens-reared controls (-3D/pl, n = 17; +3D/pl, n = 9) and normal monkeys (n = 37) maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. Results The -3D/pl and +3D/pl lens-reared controls developed compensating myopic (-2.10 ± 1.07 D) and hyperopic anisometropias (+1.86 ± 0.54 D), respectively. While the 7-MX +3D/pl monkeys developed hyperopic anisometropias (+1.79 ± 1.11 D) that were similar to those observed in +3D/pl controls, the 7-MX -3D/pl animals did not consistently exhibit compensating myopia in their treated eyes and were on average isometropic (+0.35 ± 1.96 D). The median refractive errors for both eyes of the 7-MX -3D/pl (+5.47 D and +4.38 D) and 7-MX +3D/pl (+5.28 and +3.84 D) monkeys were significantly more hyperopic than that for normal monkeys (+2.47 D). These 7-MX-induced hyperopic ametropias were associated with shorter vitreous chambers and thicker choroids. Conclusions In primates, 7-MX reduced the axial myopia produced by hyperopic defocus, augmented hyperopic shifts in response to myopic defocus, and induced hyperopia in control eyes. The results suggest that 7-MX has therapeutic potential in efforts to slow myopia progression.

N-glycosylation profoundly affects the biological stability and function of therapeutic proteins, which explains the recent interest in glycoengineering technologies as methods to develop biobetter therapeutics. In current manufacturing processes, N-glycosylation is host-specific and remains difficult to control in a production environment that changes with scale and production batches leading to glycosylation heterogeneity and inconsistency. On the other hand, in vitro chemoenzymatic glycan remodeling has been successful in producing homogeneous pre-defined protein glycoforms, but needs to be combined with a cost-effective and scalable production method. An efficient chemoenzymatic glycan remodeling technology using a plant expression system that combines in vivo deglycosylation with an in vitro chemoenzymatic glycosylation is described. Using the monoclonal antibody rituximab as a model therapeutic protein, a uniform Gal2GlcNAc2Man3GlcNAc2 (A2G2) glycoform without α-1,6-fucose, plant-specific α-1,3-fucose or β-1,2-xylose residues was produced. When compared with the innovator product Rituxan®, the plant-made remodeled afucosylated antibody showed similar binding affinity to the CD20 antigen but significantly enhanced cell cytotoxicity in vitro. Using a scalable plant expression system and reducing the in vitro deglycosylation burden creates the potential to eliminate glycan heterogeneity and provide affordable customization of therapeutics' glycosylation for maximal and targeted biological activity. This feature can reduce cost and provide an affordable platform to manufacture biobetter antibodies.

Background: Environmental manganese exposure has been associated with adverse neurodevelopmental outcomes among school-aged children; yet, few studies have evaluated prenatal exposure. Objectives: Our study examines associations between prenatal manganese concentrations and placental transfer of manganese with neurodevelopment in 224 2-y-old children residing near the Tar Creek Superfund Site. Methods: We collected maternal and cord blood at delivery, measured manganese using inductively coupled plasma mass spectrometry, and assessed neurodevelopment using the Bayley Scales of Infant Development-II. Associations between manganese and mental (MDI) and psychomotor (PDI) development indices were estimated in multivariable models. Placental transfer, approximated by cord/maternal manganese ratio, cord/total manganese ratio (total=maternal+cord), and by joint classification according to high or low (above or below median) maternal and cord manganese, was evaluated as a predictor of neurodevelopment. Results: Median levels [interquartile ranges (IQR)] of manganese in maternal and cord blood, respectively, were 24.0 (19.5–29.7) and 43.1 (33.5–52.1) μg/L. Adjusting for lead, arsenic, and other potential confounders, an IQR increase in maternal manganese was associated with −3.0 (95% CI: −5.3, −0.7) points on MDI and −2.3 (95% CI: −4.1, −0.4) points on PDI. Cord manganese concentrations were not associated with neurodevelopment scores. Cord/maternal and cord/total manganese ratios were positively associated with MDI [cord/maternal: β=2.6 (95% Cl: −0.04, 5.3); cord/total: β=22.0 (95% Cl: 3.2, 40.7)] and PDI (cord/maternal: β=1.7 (95% Cl: −0.5, 3.9); cord/total: β=15.6 (95% Cl: 0.3, 20.9)). Compared to mother–child pairs with low maternal and cord manganese, associations with neurodevelopment scores were negative for pairs with either high maternal, high cord, or high maternal and cord manganese. Conclusions: Maternal blood manganese concentrations were negatively associated with early childhood neurodevelopment scores in our study. Findings highlight the importance of understanding maternal exposures during pregnancy and factors influencing placental transfer. https://doi.org/10.1289/EHP925

Interocular decorrelation of input signals in developing visual cortex can cause impaired binocular vision and amblyopia. Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV2) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV2was pronounced in amblyopic neurons for high-contrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV2, and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys.SIGNIFICANCE STATEMENTAmblyopia is a common developmental vision disorder in humans. Despite the extensive animal studies on how amblyopia emerges, we know surprisingly little about the neural basis of amblyopia in humans and nonhuman primates. Although the vision of amblyopic humans is often described as being noisy by perceptual and modeling studies, the exact nature or origin of this elevated perceptual noise is not known. We show that elevated and noisy spontaneous activity and contrast-dependent noisy spiking (spiking irregularity and trial-to-trial fluctuations in spiking) in neurons of visual area V2 could limit the visual performance of amblyopic primates. Moreover, we discovered that the noisy spiking is linked to a high level of binocular suppression in visual cortex during development.

We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the co-existence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.

This research evaluates the connection between gambling and crime, simultaneously taking account of addiction-related mental health, alcohol, and drug use problems, using individual survey panel data collected on 4121 subjects over a period of 5 years. Pathological gambling is statistically significantly associated with elevated rates of crime and can be compared in its impact to substance abuse and mental health variables.

Vabicaserin, a potent 5-HT2C receptor agonist, decreases nucleus accumbens extracellular dopamine levels in rats, without affecting striatal dopamine, indicating mesolimbic selectivity. This is the first study of efficacy, safety and tolerability of vabicaserin in adults with acute schizophrenia. Three hundred fourteen hospitalized subjects were randomized to: Vabicaserin 200 or 400 mg/day, olanzapine 15 mg/day or placebo. Central raters assessed the PANSS and CGI-S. Site raters performed the BPRS and CGI-I. Central rated PANSS Positive (PANSS-PPS) was the primary endpoint. Two hundred eighty-nine subjects were included in the mITT efficacy analysis. Vabicaserin was well tolerated with no major safety concerns. Olanzapine, but not vabicaserin, caused weight gain. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement at week 6 vs. placebo on PANSS-PSS. A non-significant decrease vs. placebo was observed for 400 mg/day. Both vabicaserin groups demonstrated significant improvement over baseline on PANSS Negative while placebo worsened. Vabicaserin 200 mg/day and olanzapine demonstrated significantly greater improvement over placebo on PANSS Total whereas 400 mg/day showed a trend toward improvement. There was no significant improvement vs. placebo for either vabicaserin group on site-rated BPRS. Vabicaserin 200 mg/day and olanzapine demonstrated significant improvement vs. placebo on CGI-I and CGI-S but not 400 mg/day vabicaserin. Vabicaserin demonstrated efficacy on primary and secondary endpoints at 200 mg/day, but not at 400 mg/day which showed a trend for efficacy. The 200 mg/day vabicaserin group achieved proof of concept using central ratings. Both vabicaserin doses were well tolerated with no significant safety signals and no weight gain. Trial Registration: clinicaltrials.gov. Identifier: NCT00265551.

The results of many studies in a variety of species have significantly advanced our understanding of the role of visual experience and the mechanisms of postnatal eye growth, and the development of myopia. This paper surveys and reviews the major contributions that experimental studies using animal models have made to our thinking about emmetropization and development of myopia. These studies established important concepts informing our knowledge of the visual regulation of eye growth and refractive development and have transformed treatment strategies for myopia. Several major findings have come from studies of experimental animal models. These include the eye's ability to detect the sign of retinal defocus and undergo compensatory growth, the local retinal control of eye growth, regulatory changes in choroidal thickness, and the identification of components in the biochemistry of eye growth leading to the characterization of signal cascades regulating eye growth and refractive state. Several of these findings provided the proofs of concepts that form the scientific basis of new and effective clinical treatments for controlling myopia progression in humans. Experimental animal models continue to provide new insights into the cellular and molecular mechanisms of eye growth control, including the identification of potential new targets for drug development and future treatments needed to stem the increasing prevalence of myopia and the vision-threatening conditions associated with this disease.

Myopia is the most frequent cause of distance impairment in the world and is creating an alarming global epidemic with deleterious ramifications for the quality of life and economic health of individuals and nations as a whole. In addition to being immediately disadvantageous, myopia increases the risk of serious disorders such as myopic macular degeneration, retinal detachment, glaucoma, and cataract and is a leading cause of visual impairment and blindness across many countries. The reduction in age of onset of myopia is of great concern since the earlier the onset, the more myopic the individual will become, with all the attendant increased risks of accompanying debilitating eye conditions. The economic burden is great; both in consequences of uncorrected refractive error and also in the provision of devices for correcting visual acuity. Earlier onset of myopia increases the lifetime economic burden related to loss of productivity and independence, leading to a reduced quality of life. Recent data suggest addressing accommodation per se has little direct amelioration of myopia progression. Pharmacological interventions that effect changes in the sclera show promising efficacy, whereas optical interventions based on a myopic shift in the retinal image are proving to effect up to 55% reduction in the rate of progression of myopia. Early contact lens and spectacle interventions that reduce the rate of progression of myopia are able to significantly reduce the burden of myopia. These non-pharmacological interventions show profound promise in reducing the overall associated morbidity of myopia.

Visual signals that produce myopia are mediated by local, regionally selective mechanisms. However, little is known about spatial integration for signals that slow eye growth. The purpose of this study was to determine whether the effects of myopic defocus are integrated in a local manner in primates.Beginning at 24 ± 2 days of age, seven rhesus monkeys were reared with monocular spectacles that produced 3 diopters (D) of relative myopic defocus in the nasal visual field of the treated eye but allowed unrestricted vision in the temporal field (NF monkeys). Seven monkeys were reared with monocular +3 D lenses that produced relative myopic defocus across the entire field of view (FF monkeys). Comparison data from previous studies were available for 11 control monkeys, 8 monkeys that experienced 3 D of hyperopic defocus in the nasal field, and 6 monkeys exposed to 3 D of hyperopic defocus across the entire field. Refractive development, corneal power, and axial dimensions were assessed at 2- to 4-week intervals using retinoscopy, keratometry, and ultrasonography, respectively. Eye shape was assessed using magnetic resonance imaging.In response to full-field myopic defocus, the FF monkeys developed compensating hyperopic anisometropia, the degree of which was relatively constant across the horizontal meridian. In contrast, the NF monkeys exhibited compensating hyperopic changes in refractive error that were greatest in the nasal visual field. The changes in the pattern of peripheral refractions in the NF monkeys reflected interocular differences in vitreous chamber shape.As with form deprivation and hyperopic defocus, the effects of myopic defocus are mediated by mechanisms that integrate visual signals in a local, regionally selective manner in primates. These results are in agreement with the hypothesis that peripheral vision can influence eye shape and potentially central refractive error in a manner that is independent of central visual experience.

In order to develop effective optical treatment strategies for myopia, it is important to understand how visual experience influences refractive development. Beginning with the discovery of the phenomenon of form deprivation myopia, research involving many animal species has demonstrated that refractive development is regulated by visual feedback. In particular, animal studies have shown that optically imposed myopic defocus slows axial elongation, that the effects of vision are dominated by local retinal mechanisms, and that peripheral vision can dominate central refractive development. In this review, the results obtained from clinical trials of traditional optical treatment strategies employed in efforts to slow myopia progression in children are interpreted in light of the results from animal studies and are compared to the emerging results from preliminary clinical studies of optical treatment strategies that manipulate the effective focus of the peripheral retina. Overall, the results suggest that imposed myopic defocus can slow myopia progression in children and that the effectiveness of an optical treatment strategy in reducing myopia progression is influenced by the extent of the visual field that is manipulated.

In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors.

Objectives To describe rates of first significant infection of rheumatoid arthritis patients who switch between anti-tumor necrosis factor (aTNF) drugs. Methods Subjects with rheumatoid arthritis who received only aTNF drugs were observed in an insurance claims database from January 2001 to December 2007. Nonswitchers (NS) remained on one aTNF throughout the study period (date of the first aTNF claim was the index date); switchers (S) received at least one other aTNF (claim date for the 2nd agent was the index date). Significant infections included those that required intravenous antibiotics or hospitalization. Two attributable risk periods were used: (1) an infection occurring ≤90 days following a claim for an aTNF (90-day) and (2) an infection occurring after the index date (ever-treated). Follow-up was censored at the first occurrence of a significant infection event, end of eligibility, or end of study period. Data were analyzed using Cox regression. Results In 13,752 NS and 2293 S patients, time-stratified rates declined 2- to 3-fold between the first year versus ≥2 years. Risk of significant infection was not different for either attribution model [90-day hazard ratio (HR) = 0.93, 95CI: 0.74 to 1.17, P = 0.55; ever treated HR=0.94, 95CI: 0.78 to 1.15, P = 0.57]. First and second year rates were similar. Predictors included age ≥50 years; history of significant or opportunistic infection, diabetes, respiratory disease; Charlson score ≥2; or prior hospitalizations. Conclusions The risk of a significant infection was not different between NS and S patients. Regardless of switching status, the rate of infection was greater in the first year. This study was limited by the lack of clinical data to determine the reason for switching.

To characterize seasonal variation in the myopic progression of Chinese children.Myopia progression data are presented for a total of 85 Chinese children, aged 6 to 12 years, with baseline myopia of -0.75 D to -3.50 D sphere and astigmatism ≤-1.50 D, who wore traditional single-vision spectacles in two clinical trials (trial A: n = 37, trial B: n = 48). Refractive error and axial length data were obtained at 6-month intervals using cycloplegic autorefraction and partial coherence interferometry, respectively. Progression rates for right eyes were defined for the first and second 6 months of the studies and classified in terms of "summer," "autumn," "winter," or "spring" based on the mid-point of the 6-month period between visits.The mean 6-month spherical equivalent progression was -0.31 ± 0.25 D for summer, -0.40 ± 0.27 D for autumn, -0.53 ± 0.29 D for winter, and -0.42 ± 0.20 D for spring (p0.001). Mean axial elongation was 0.17 ± 0.10 mm for summer, 0.24 ± 0.09 mm for autumn, 0.24 ± 0.09 mm for winter, and 0.15 ± 0.08 mm for spring (p0.001). Post hoc analysis indicated that data for summer and winter were different from each other at p0.05 for both myopia progression and axial elongation after adjusting for age.Myopia progression in summer months was approximately 60% of that seen in winter, and axial elongation was likewise significantly less in summer. It is unclear whether more time spent outdoors in summer vs. winter is a contributing factor, or the difference in progression rates is a result of "seasonal" variations in the intensity or amount of close work performed. These results indicate that studies of potential myopia treatment strategies should be at least 12 months in duration to take seasonal variations into account.

Purpose To validate the administrative claims identification of a diagnosis of Stevens–Johnson syndrome (SJS) using medical records as the “gold standard” in a large, commercially insured US population. Methods Patients with >1 medical claim with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x between 1 July 2000 and 31 May 2007 were queried in the HealthCore Integrated Research DatabaseSM, which contains administrative claims data for 14 commercial health insurance plans. Trained nurses and pharmacists abstracted pertinent information from the identified patients' medical records, which were then reviewed by two independent dermatologists to identify criteria to determine SJS diagnosis. Positive predictive values (PPVs) based on the claims and chart data were computed for all the cases. Results Medical charts for 200 claims-identified cases, with the International Classification of Diseases, Ninth Revision, Clinical Modification code 695.1x, were abstracted and reviewed by the dermatologists. A total of five cases (PPV = 2.50%, 95%CI = 0.8%–5.7%) were determined to be SJS with clinical certainty. PPVs varied with data stratification: PPV for inpatient claims only (PPV = 2.00%, 95%CI = 0.24%–7.04%), inpatient claims with 695.1x in first diagnosis field (PPV = 4.11%, 95%CI = 0.86%–11.54%), and final decisions of either clinical certainty or probable cases of SJS (PPV = 6.00%, 95%CI = 3.14%–10.25%). Conclusion These findings demonstrate the difficulties associated with identifying rare disorders, which lack specific diagnostic criteria, within administrative claims databases. They underscore the challenges of using claims data to monitor ill-defined clinical conditions as well as the need to validate claims-identified cases with information from other sources, such as medical charts. Copyright © 2012 John Wiley & Sons, Ltd.

To conduct a meta-analysis on the rates of myopia progression in urban children of Asian and predominately European ethnicities who are corrected with traditional single-vision spectacles.A search of the National Library of Medicine's PubMed literature database for articles on myopia progression was conducted using the terms "myopi*progression" and MeSH terms "myopia" and "disease progression," and limited to publications from January 1990 and only for articles reporting data for humans16 years of age. Studies were excluded if they were non-randomized, did not use cycloplegic autorefraction, had a sample size30 individuals, examined high myopia (worse than -6.0 D) or special subject groups, presented myopia as part of a syndrome or condition, were retrospective, or used controls wearing optical corrections other than spectacles.Of 175 articles identified, 20 remained after applying the exclusion criteria. The estimated myopia progression at a mean age of 9.3 years after 1 year of follow-up was -0.55 D [95% confidence interval (CI), -0.39 to -0.72 D] for populations of predominantly European extraction and -0.82 D (95% CI, -0.71 to -0.93 D) for Asians. The estimated progression rates were dependent on baseline age, with decreasing progression as age increased. The rates also varied with gender. For an average baseline age of 8.8 years, estimated annual progression (combined ethnicities) was -0.80 D/yr for females (95% CI, -0.51 to -1.10), and a significantly slower (p0.01) -0.71 D/yr for males (95% CI, -0.42 to -1.00).In children wearing single-vision spectacles, higher myopia progression rates were found in urban Asians compared with urban populations of predominantly European descent. Younger children and females demonstrated greater annual rates of progression of myopia.