Ophthalmic and Systemic Factors of Acute Nonarteritic Anterior Ischemic Optic Neuropathy in the Quark207 Treatment Trial.

PURPOSE: We describe the baseline ophthalmic and cardiovascular risk factors across countries, race, and sex for the Quark207 treatment trial for acute nonarteritic anterior ischemic optic neuropathy (NAION). DESIGN: Prospective, randomized controlled clinical trial. PARTICIPANTS: Adults 50 to 80 years of age with acute NAION recruited from 80 sites across 8 countries. MAIN OUTCOME MEASURES: Ophthalmic features of NAION and cardiovascular risk factors. METHODS: We evaluated demographics and clinical and ophthalmologic data, including best-corrected visual acuity (BCVA) and average visual field total deviation (TD), in affected eyes and cup-to-disc ratio in fellow eyes at enrollment. We report the prevalence (mean and standard devition, and median and interquartile range [IQR]) of ophthalmic features and cardiovascular risk factors, stratified by country, race, and sex. We corrected for multiple comparisons using Dunn's test with Bonferroni correction for continuous variables and chi-square testing with Holm-Bonferroni correction for categorical variables. RESULTS: The study enrolled 500 men and 229 women with a median age of 60 and 61 years (P = 0.027), respectively. Participants were predominantly White (n = 570) and Asian (n = 149). The study eye BCVA was 71 characters (IQR, 53-84 characters; approximately 0.4 logarithm of the minimum angle of resolution), and the TD was -16.5 dB (IQR, -22.2 to -12.6 dB) for stimulus III and -15.7 dB (IQR, -20.8 to -10.9 dB) for stimulus V. The vertical and horizontal cup-to-disc ratio was 0.1 (IQR, 0.1-0.3) for unaffected fellow eyes. The prevalence of cardiovascular risk factors varied among countries. The most notable differences were in the baseline comorbidities and ophthalmologic features, which differed between Asian and White races. Men and women differed with respect to a few clinically meaningful features. CONCLUSIONS: The cardiovascular risk factors in the NAION cohort varied among the 7 countries, race, and sex, but were not typically more prevalent than in the general population. Ophthalmic features, typical of NAION, generally were consistent across countries, race, and sex, except for worse BCVA and TD in China. Men have a frequency of NAION twice that of women. Having a small cup-to-disc ratio in the fellow eye was the most prevalent risk factor across all demographics. This study suggests that factors, not yet identified, may contribute to the development of NAION. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Maculopapillary Bundle Degeneration in Optic Neuropathies.

PURPOSE OF REVIEW: Degeneration of the maculopapillary bundle (MPB) is a prominent feature in a spectrum of optic neuropathies. MPB-selective degeneration is seen in specific conditions, such as nutritional and toxic optic neuropathies, Leber hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA). Despite their distinct etiologies and clinical presentations, which encompass variations in age of incidence and monocular or binocular onset, these disorders share a core molecular mechanism: compromised mitochondrial homeostasis. This disruption is characterized by dysfunctions in mitochondrial metabolism, biogenesis, and protein synthesis. This article provides a comprehensive understanding of the MPB's role in optic neuropathies, emphasizing the importance of mitochondrial mechanisms in the pathogenesis of these conditions. RECENT FINDINGS: Optical coherence tomography studies have characterized the retinal nerve fiber layer changes accompanying mitochondrial-affiliated optic neuropathies. Selective thinning of the temporal optic nerve head is preceded by thickening in early stages of these disorders which correlates with reductions in macular ganglion cell layer thinning and vascular atrophy. A recently proposed mechanism underpinning the selective atrophy of the MPB involves the positive feedback of reactive oxygen species generation as a common consequence of mitochondrial dysfunction. Additionally, new research has revealed that the MPB can undergo degeneration in the early stages of glaucoma, challenging the historically held belief that this area was not involved in this common optic neuropathy. A variety of anatomical risk factors influence the propensity of glaucomatous MPB degeneration, and cases present distinct patterns of ganglion cell degeneration that are distinct from those observed in mitochondria-associated diseases. This review synthesizes clinical and molecular research on primary MPB disorders, highlighting the commonalities and differences in their pathogenesis. KEY POINTS (BOX): 1. Temporal degeneration of optic nerve fibers accompanied by cecocentral scotoma is a hallmark of maculopapillary bundle (MPB) degeneration. 2. Mechanisms of MPB degeneration commonly implicate mitochondrial dysfunction. 3. Recent research challenges the traditional belief that the MPB is uninvolved in glaucoma by showing degeneration in the early stages of this common optic neuropathy, yet with features distinct from other MPB-selective neuropathies. 4. Reactive oxygen species generation is a mechanism linking mitochondrial mechanisms of MPB-selective optic neuropathies, but in-vivo and in-vitro studies are needed to validate this hypothesis.

Canadian Stroke Best Practice Recommendations, 7th Edition: Cerebral Venous Thrombosis, 2024.

The 7th edition of the Canadian Stroke Best Practice Recommendations (CSBPR) is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners, and intended to drive healthcare excellence, improved outcomes and more integrated health systems. This edition includes a new module on the management of cerebral venous thrombosis (CVT). Cerebral venous thrombosis is defined as thrombosis of the veins of the brain, including the dural venous sinuses and/or cortical or deep veins. Cerebral venous thrombosis is a rare but potentially life-threatening type of stroke, representing 0.5-1.0% of all stroke admissions. The reported rates of CVT are approximately 10-20 per million and appear to be increasing over time. The risk of CVT is higher in women and often associated with oral contraceptive use and with pregnancy and the puerperium. This guideline addresses care for adult individuals who present to the healthcare system with current or recent symptoms of CVT. The recommendations cover the continuum of care from diagnosis and initial clinical assessment of symptomatic CVT, to acute treatment of symptomatic CVT, post-acute management, person-centered care, special considerations in the long-term management of CVT, including pregnancy and considerations related to CVT in special circumstances such as trauma and vaccination. This module also includes supporting materials such as implementation resources to facilitate the adoption of evidence into practice and performance measures to enable monitoring of uptake and effectiveness of recommendations.

Association between visceral adipose tissue and major depressive disorder across the lifespan: A scoping review.

OBJECTIVES: Increasing evidence supports a bidirectional relationship between major depressive disorder (MDD) and obesity, but the role of visceral adipose tissue (VAT) as a measure of obesity in relation to MDD is not well understood. Here we review literature investigating the link between MDD and VAT in terms of biomarkers, sex differences, and aging. METHODS: PubMed, EMBASE, PsycINFO, and CINAHL searches were conducted on December 11, 2020. No date or language limits were imposed. Major concepts searched were Depressive Disorder linked with Adipose Tissue, White, Hypothalmo-Hypophyseal System, and Pituitary-Adrenal System in addition to keywords. A final set of 32 items meeting criteria for inclusion. RESULTS: Converging biological evidence suggests a significant bidirectional relationship between VAT and MDD across the lifespan. In adulthood, greater VAT was associated with increased risk for depression, especially in vulnerable groups such as individuals who are overweight/obese, postmenopausal women, and individuals with comorbid medical or psychiatric illness. In older adults, sarcopenia had an impact on the relationship between abnormal VAT and risk of depression. Additionally, sex differences emerged as a potential factor affecting the strength of the association between VAT and depression. CONCLUSIONS: Elucidating the pathophysiological mechanisms associated with increased rates of depression in obese individuals will be crucial for developing specific treatment strategies that seek to improve outcomes in individuals with comorbid depression and obesity. Moreover, identifying age- and sex-specific risk factors may contribute to a more personalized medicine approach, thereby improving the quality of clinical care.

A Scoping Review of Interventions for Spousal Bereavement in Older Adults.

The loss of a spouse is a common and natural life event for older adults. Nearly one of four older bereaved spouses experience prolonged grief, impaired function or chronic depression. Mechanisms underlying these and other long-term health risks are not well understood. We conducted a scoping literature review to examine the interventions and outcomes that have been studied for late-life spousal bereavement to date. We identified 22 studies of group and individual-level interventions with most studies concerning grief processes within the first year. Nearly all studies evaluated emotional and psychological symptoms of loss and a small number evaluated the restoration of adaptive functioning. Four interventions addressed the treatment of complicated grief or grief with major depressive disorder. Qualitative studies explored themes of spirituality and mindfulness. There were 17 controlled studies, including 13 randomized controlled trials. Findings were eclectic, with evidence supporting mindfulness techniques in a group format for emotional and life satisfaction outcomes; an individual, function-based therapy addressing sleep to improve emotion and function; an individual, writing-based emotional expression therapy for short-term improvement in emotion and function; nortriptyline for the treatment of bereavement-related major depressive disorder; a group-based, complicated grief therapy for this condition; an internet-based CBT intervention for prolonged grief; and pharmacotherapy for cardiovascular changes during bereavement. These findings highlight the small literature of methodologically strong intervention studies addressing spousal bereavement in older adults and the need for greater exploration of relevant biological, social, cognitive and behavioral factors to improve short and long term health outcomes.

The State of Point-of-Care Teleultrasound Use for Educational Purposes: A Scoping Review.

Bedside ultrasound has been shown to change and direct patient management in the emergent setting. Demand, use, and diagnostic potential of point-of-care ultrasound (POCUS) has continually increased throughout the years. The ongoing COVID-19 pandemic and physical distancing have necessitated further POCUS innovation. With the advent of affordable portable ultrasound devices, teleultrasound teaching has become a more viable method of POCUS education, especially in resource-limited settings. Here, we provide a scoping review of the current state of teleultrasound, specifically its use for educational purposes.

Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning.

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

An assessment of temporal trends in mercury concentrations in fish.

The importance of fish consumption as the primary pathway of human exposure to mercury and the establishment of fish consumption advisories to protect human health have led to large fish tissue monitoring programs worldwide. Data on fish tissue mercury concentrations collected by state, tribal, and provincial governments via contaminant monitoring programs have been compiled into large data bases by the U.S. Environmental Protection Agency's Great Lakes National Monitoring Program Office (GLNPO), the Ontario Ministry of the Environment's Fish Contaminants Monitoring and Surveillance Program (FMSP), and many others. These data have been used by a wide range of governmental and academic investigators worldwide to examine long-term and recent trends in fish tissue mercury concentrations. The largest component of the trend literature is for North American freshwater species important in recreational fisheries. This review of temporal trends in fish tissue mercury concentrations focused on published results from freshwater fisheries of North America as well as marine fisheries worldwide. Trends in fish tissue mercury concentrations in North American lakes with marked overall decreases were reported over the period 1972-2016. These trends are consistent with reported mercury emission declines as well as trends in wet deposition across the U.S. and Canada. More recently, a leveling-off in the rate of decreases or increases in fish tissue mercury concentrations has been reported. Increased emissions of mercury from global sources beginning between 1990 and 1995, despite a decrease in North American emissions, have been advanced as an explanation for the observed changes in fish tissue trends. In addition to increased atmospheric deposition, the other factors identified to explain the observed mercury increases in the affected fish species include a systematic shift in the food-web structure with the introduction of non-native species, creating a new or expanding role for sediments as a net source for mercury. The influences of climate change have also been identified as contributing factors, including considerations such as increases in temperature (resulting in metabolic changes and higher uptake rates of methylmercury), increased rainfall intensity and runoff (hydrologic export of organic matter carrying HgII from watersheds to surface water), and water level fluctuations that alter either the methylation of mercury or the mobilization of monomethylmercury. The primary source of mercury exposure in the human diet in North America is from the commercial fish and seafood market which is dominated (>90%) by marine species. However, very little information is available on mercury trends in marine fisheries. Most of the data used in the published marine trend studies are assembled from earlier reports. The data collection efforts are generally intermittent, and the spatial and fish-size distribution of the target species vary widely. As a result, convincing evidence for the existence of fish tissue mercury trends in marine fish is generally lacking. However, there is some evidence from sampling of large, long-lived commercially-important fish showing both lower mercury concentrations in the North Atlantic in response to reduced anthropogenic mercury emission rates in North America and increases in fish tissue mercury concentrations over time in the North Pacific in response to increased mercury loading.

Cobalamin-Associated Superoxide Scavenging in Neuronal Cells Is a Potential Mechanism for Vitamin B12-Deprivation Optic Neuropathy.

Chronic deficiency of vitamin B12 is the only nutritional deficiency definitively proved to cause optic neuropathy and loss of vision. The mechanism by which this occurs is unknown. Optic neuropathies are associated with death of retinal ganglion cells (RGCs), neurons that project their axons along the optic nerve to the brain. Injury to RGC axons causes a burst of intracellular superoxide, which then signals RGC apoptosis. Vitamin B12 (cobalamin) was recently shown to be a superoxide scavenger, with a rate constant similar to superoxide dismutase. Given that vitamin B12 deficiency causes an optic neuropathy through unknown mechanisms and that it is a potent superoxide scavenger, we tested whether cobalamin, a vitamin B12 vitamer, would be neuroprotective in vitro and in vivo. We found that cobalamin scavenged superoxide in neuronal cells in vitro treated with the reduction-oxidation cycling agent menadione. In vivo confocal scanning laser ophthalmoscopy demonstrated that optic nerve transection in Long-Evans rats increased superoxide levels in RGCs. The RGC superoxide burst was significantly reduced by intravitreal cobalamin and resulted in increased RGC survival. These data demonstrate that cobalamin may function as an endogenous neuroprotectant for RGCs through a superoxide-associated mechanism.

Perinatal depression care pathway for obstetric settings.

Perinatal depression is common and can have deleterious effects on mothers, infants, children, partners, and families. Despite this, few women who screen positive for depression receive psychiatric treatment. A comprehensive perinatal depression care pathway includes: (1) screening, (2) assessment, (3) triage and referral, (4) treatment access, (5) treatment initiation, (6) symptom monitoring, and (7) adaptation of treatment based on measurement until symptoms remit. This depression care pathway provides a scaffold on which to frame the challenges encountered when, and the opportunities that exist for, addressing depression in obstetric settings. Comprehensive interventions that address each step on the care pathway are needed to support obstetric practices in providing high-quality, evidence-based, effective treatment including pro-active follow-up for depression management. Despite recent attention being brought to, and significant progress in the field of maternal mental health, gaps in care persist. Ultimately, depression care needs to be fully integrated into obstetric care. Additionally, more targeted maternal mental health support and structure are needed for integration to occur and ultimately be optimized. Specific areas requiring more attention include consistency of screening, evaluation of patients with a positive depression screen for bipolar disorder, anxiety or substance use disorders, and monitoring of symptom improvement.

Randomized Controlled Phase 2a Study of RPh201 in Previous Nonarteritic Anterior Ischemic Optic Neuropathy.

BACKGROUND: No proven treatment exists for nonarteritic anterior ischemic optic neuropathy (NAION), either in the acute or late phase. OBJECTIVE: To assess safety and changes in visual function and structure after RPh201/placebo treatment in participants with previous NAION. DESIGN AND SETTING: Phase 2a, single-site, prospective, randomized, placebo-controlled, double-masked trial (registration NCT02045212). MAIN OUTCOMES MEASURES: Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA), visual fields, retinal nerve fiber layer, and visual evoked potential at weeks 13, 26, and after a 13-week wash-out ("off-drug") period; and safety. STUDY POPULATION: Twenty-two participants aged 18 years or older with previous NAION. INTERVENTION(S): RPh201 (20 mg) or placebo (cottonseed oil vehicle) administered subcutaneously twice weekly at the study site. RESULTS: Thirteen men and 9 women were randomized, of which 20 completed all visits. The mean (±SD) age was 61.0 ± 7.6 years. In a post hoc analysis, after 26 weeks of treatment, BCVA improved by ≥15 letters in 4/11 (36.4%) eyes with RPh201, compared to 1/8 (12.5%) eyes with placebo (P = 0.24). Overall, 7/11 (63.6%) of participants on RPh201 showed some improvement in BCVA, compared with 3/8 (37.5%) on placebo (P = 0.26). Improvement in BCVA from a calculated baseline was 14.8 ± 15.8 letters for RPh201 and 6.6 ± 15.3 for placebo (P = 0.27). Of the 154 adverse effects (AEs), 52 were considered related to the study procedures/treatment. Across the study and 1,017 injections, the most frequently reported AE was injection site pain (23 events in 5 participants). There were no clinically significant changes in vital signs or laboratory values. CONCLUSIONS: This Phase 2a was designed to assess safety, feasibility, and explore potential efficacy signals in treating previous NAION with RPh201. No safety concerns were raised. The results support a larger trial in patients with previous NAION.

Smartphone Apps to Support Coordinated Specialty Care for Prodromal and Early Course Schizophrenia Disorders: Systematic Review.

BACKGROUND: Demand for mental health services, especially for clinical high-risk and early psychosis, has increased, creating a need for new solutions to increase access to and quality of care. Smartphones and mobile technology are potential tools to support coordinated specialty care for early psychosis, given their potential to augment the six core roles of care: case management and team leadership, recovery-oriented psychotherapy, medication management, support for employment and education, coordination with primary care services, and family education and support. However, the services smartphones are actually offering specifically for coordinated specialty care and the level of evidence are unknown. OBJECTIVE: This study aimed to review the published literature on smartphone technology to enhance care for patients with prodromal and early course psychosis and schizophrenia and to analyze studies by type, aligned with coordinated specialty care domains. METHODS: A systematic literature search was conducted on August 16 and 17, 2019, using the PubMed, EMBASE, Web of Sciences, and PsycINFO electronic databases. The eligible studies were reviewed and screened based on inclusion and exclusion criteria. RESULTS: The search uncovered 388 unique results, of which 32 articles met the initial inclusion criteria; 21 eligible studies on 16 unique app platforms were identified. Feasibility studies showed a high user engagement and interest among patients, monitoring studies demonstrated a correlation between app assessments and clinical outcomes, and intervention studies indicated that these apps have the potential to advance care. Eighteen studies reported on app use for the case management roles of coordinated specialty care. No app studies focused on employment and education, coordination with primary care services, and family education and support. CONCLUSIONS: Although the published literature on smartphone apps for prodromal and first-episode psychosis is small, it is growing exponentially and holds promise to augment both monitoring and interventions. Although the research results and protocols for app studies are not well aligned with all coordinated specialty care roles today, high rates of adoption and feasibility suggest the potential for future efforts. These results will be used to develop coordinated specialty care-specific app evaluation scales and toolkits.

Axonal Degeneration in Retinal Ganglion Cells Is Associated with a Membrane Polarity-Sensitive Redox Process.

Axonal degeneration is a pathophysiological mechanism common to several neurodegenerative diseases. The slow Wallerian degeneration (WldS) mutation, which results in reduced axonal degeneration in the central and peripheral nervous systems, has provided insight into a redox-dependent mechanism by which axons undergo self-destruction. We studied early molecular events in axonal degeneration with single-axon laser axotomy and time-lapse imaging, monitoring the initial changes in transected axons of purified retinal ganglion cells (RGCs) from wild-type and WldS rat retinas using a polarity-sensitive annexin-based biosensor (annexin B12-Cys101,Cys260-N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethylenediamine). Transected axons demonstrated a rapid and progressive change in membrane phospholipid polarity, manifested as phosphatidylserine externalization, which was significantly delayed and propagated more slowly in axotomized WldS RGCs compared with wild-type axons. Delivery of bis(3-propionic acid methyl ester)phenylphosphine borane complex, a cell-permeable intracellular disulfide-reducing drug, slowed the onset and velocity of phosphatidylserine externalization in wild-type axons significantly, replicating the WldS phenotype, whereas extracellular redox modulation reversed the WldS phenotype. These findings are consistent with an intra-axonal redox mechanism for axonal degeneration associated with the initiation and propagation of phosphatidylserine externalization after axotomy.SIGNIFICANCE STATEMENT Axonal degeneration is a neuronal process independent of somal apoptosis, the propagation of which is unclear. We combined single-cell laser axotomy with time-lapse imaging to study the dynamics of phosphatidylserine externalization immediately after axonal injury in purified retinal ganglion cells. The extension of phosphatidylserine externalization was slowed and delayed in Wallerian degeneration slow (WldS) axons and this phenotype could be reproduced by intra-axonal disulfide reduction in wild-type axons and reversed by extra-axonal reduction in WldS axons. These results are consistent with a redox mechanism for propagation of membrane polarity asymmetry in axonal degeneration.

Six Landmark Case Reports Essential for Neuropsychiatric Literacy.

Well-described clinical case reports have been a core component of the neuropsychiatry literature and have led to: a deepened understanding of brain-behavior relationships and neuropsychiatric phenomenology, new paths for research, and compelling material for physicians who are studying neurology and psychiatry. Six landmark neuropsychiatry cases were selected for being well described, paradigmatic, and illuminating of brain-behavior correlations: Phineas Gage, Louis Victor Leborgne ("Tan"), Auguste Deter, Solomon Shereshevsky ("S"), "JP," and Henry Gustav Molaison ("HM"). Each case and its neuropsychiatric lessons are summarized from primary sources, highlighting some less appreciated aspects. Case reports continue to be a valuable resource for neuropsychiatric education. Yet only four of the 10 highest impact factor psychiatry journals accept case reports for publication.

A Systematic Review of Integrated Care Interventions Addressing Perinatal Depression Care in Ambulatory Obstetric Care Settings.

This systematic review searched 4 databases (PubMed/MEDLINE, Scopus, CINAHL, and PsychINFO) and identified 21 articles eligible to evaluate the extent to which interventions that integrate depression care into outpatient obstetric practice are feasible, effective, acceptable, and sustainable. Despite limitations among the available studies including marked heterogeneity, there is evidence supporting feasibility, effectiveness, and acceptability. In general, this is an emerging field with promise that requires additional research. Critical to its real-world success will be consideration for practice workflow and logistics, and sustainability through novel reimbursement mechanisms.

Polyester-based microdisc systems for sustained release of neuroprotective phosphine-borane complexes.

Phosphine-borane complexes are recently developed redox-active drugs that are neuroprotective in models of optic nerve injury and radioprotective in endothelial cells. However, a single dose of these compounds is short-lived, necessitating the development of sustained-release formulations of these novel molecules. We screened a library of biodegradable co- and non-block polyester polymer systems for release of incorporated phosphine-borane complexes to evaluate them as drug delivery systems for use in chronic disease. Bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1) was combined with biodegradable polymers based on poly(D,L-lactide) (PDLLA), poly(L-lactide) (PLLA), poly(caprolactone) (PCL), poly(lactide-co-glycide) (PLGA), or poly(dioxanone-co-caprolactone) (PDOCL) to make polymer microdiscs, and release over time quantified. Of 22 polymer-PB1 formulations tested, 17 formed rigid polymers. Rates of release differed significantly based on the chemical structure of the polymer. PB1 released from PLGA microdiscs released most slowly, with the most linear release in polymers of 60:40 LA:GA, acid endcap, Mn 15 000-25 000 and 75:25 LA:GA, acid endcap, Mn 45 000-55 000. Biodegradable polymer systems can, therefore, be used to produce sustained-release formulations for redox-active phosphine-borane complexes, with PLGA-based systems most suitable for very slow release. The sustained release could enable translation to a clinical neuroprotective strategy for chronic diseases such as glaucoma.

Special Commentary: Early Clinical Development of Cell Replacement Therapy: Considerations for the National Eye Institute Audacious Goals Initiative.

The National Eye Institute launched the Audacious Goals Initiative (AGI) in 2013 with the aim "to restore vision through the regeneration of neurons and neural connections in the eye and visual system." An AGI Town Hall held at the Association for Research in Vision and Ophthalmology Annual Meeting in 2016 brought together basic, translational, and clinical scientists to address the clinical implications of the AGI, with a particular emphasis on diseases amenable to regenerative medicine and strategies to deal with barriers to progess. An example of such a barrier is that replacement of lost neurons may be insufficient because damage to other neurons and non-neuronal cells is common in retinal and optic nerve disease. Reparative processes such as gliosis and fibrosis also can make it difficult to replenish and regenerate neurons. Other issues include choice of animal models, selecting appropriate endpoints, ethics of informed consent, and regulatory issues. Another area critical to next steps in the AGI is the choice of target diseases and the stage at which early development studies should be focused. For example, an advantage of doing clinical trials in patients with early disease is that supporting cellular and structural constituents are still likely to be present. However, regenerative studies in patients with late disease make it easier to detect the effects of replacement therapy against the background of severe visual loss, whereas it may be harder to detect incremental improvement in visual function in those with early disease and considerable remaining visual function. Achieving the goals of the AGI also requires preclinical advances, new imaging techniques, and optimizing translational issues. The work of the AGI is expected to take at least 10 years but should eventually result in therapies to restore some degree of vision to the blind.

Neuroprotection for glaucoma: Requirements for clinical translation.

Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular pressure. There is currently a great potential for research surrounding neuroprotection as it relates to glaucoma. Anatomical targets for neuroprotection should focus on upstream rather than downstream factors, and could include any part of the retinal ganglion cell, the glia, especially astrocytes or Muller cells, and vasculature. The great number of anatomical targets is exceeded only by the number of possible biochemical pathways and potential treatments. Successful treatment may be accomplished through the targeting of one or even a combination of multiple pathways. Once a treatment is shown effective in vitro, it should be evaluated in vivo with carefully chosen animal models and studied in sufficient numbers to detect statistically and clinically significant effects. Such a drug should have few systemic side effects and its delivery should be optimized so as to encourage compliance. There are still a multitude of possible screens available to test the efficacy of a neuroprotective drug and a single gold standard is ideal for the accurate assessment and comparison of new drugs. Future studies in neuroprotection should investigate the genetic component of the disease, novel pharmaceutical agents for new or known pathways, modulations of scleral biomechanics, and relation to research of other complex disorders of the central nervous system.

Total Mercury Released to the Environment by Human Activities.

We estimate that a cumulative total of 1540 (1060-2800) Gg (gigagrams, 109 grams or thousand tonnes) of mercury (Hg) have been released by human activities up to 2010, 73% of which was released after 1850. Of this liberated Hg, 470 Gg were emitted directly into the atmosphere, and 74% of the air emissions were elemental Hg. Cumulatively, about 1070 Gg were released to land and water bodies. Though annual releases of Hg have been relatively stable since 1880 at 8 ± 2 Gg, except for wartime, the distributions of those releases among source types, world regions, and environmental media have changed dramatically. Production of Hg accounts for 27% of cumulative Hg releases to the environment, followed by silver production (24%) and chemicals manufacturing (12%). North America (30%), Europe (27%), and Asia (16%) have experienced the largest releases. Biogeochemical modeling shows a 3.2-fold increase in the atmospheric burden relative to 1850 and a contemporary atmospheric reservoir of 4.57 Gg, both of which agree well with observational constraints. We find that approximately 40% (390 Gg) of the Hg discarded to land and water must be sequestered at contaminated sites to maintain consistency with recent declines in atmospheric Hg concentrations.

Translational Pharmacology in Glaucoma Neuroprotection.

Glaucoma is both the most common optic neuropathy worldwide and the most common cause of irreversible blindness in the world. The only proven treatment for glaucomatous optic neuropathy is lowering the intraocular pressure, achieved with a variety of pharmacological, laser, and surgical approaches. Over the past 2 decades there has been much basic and clinical research into achieving treatment of the underlying optic nerve damage with neuroprotective approaches. However, none has resulted in regulatory approval based on successful phase 3 studies. This chapter discusses the reasons for this "lost in translation" aspect of glaucoma neuroprotection, and outlines issues at the laboratory and clinical trial level that need to be addressed for successful development of neuroprotective therapies.