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Abstract Background Stem cell-derived secreted factors could protect neurons in neurodegenerative disease or after injury. The exact neuroprotective components in the secretome remain challenging to discover. Here we developed a cell-to-cell interaction model to identify a retinal ganglion cell (RGC)-protective factor derived from induced pluripotent stem cells (iPSCs). Methods Primary RGCs were co-cultured with iPSCs or treated with iPSC-conditioned media in vitro. Cell viability were assayed using live-cell staining, and culture supernatant were analyzed via multiplexed antibody-based assays and ELISA. In vivo tests were carried out under mouse optic nerve crush model and RGC transplantation study in rats. Paired t-tests were used for data analysis between two groups. Results RGC viability was significantly enhanced when iPSCs were first stimulated with RGC-derived supernatant before iPSC-conditioned medium was collected and added into RGC culture. A significant increase of stem cell growth factor-beta (SCGF-β) concentration was detected in the latter conditioned medium. SCGF-β enhanced RGC survival in vitro and in vivo, and RGC-derived interleukin-12(p70) (IL-12[p70]) promotes secretion of iPSC-derived SCGF-β. Downstream of this IL-12(p70)-to-SCGF-β axis, ngn2 was significantly upregulated, and was found both necessary and sufficient for RGC survival. Conclusion This study addresses a longstanding question of how neurons and stem cells interact to promote neuroprotection, and define a novel molecular interaction pathway whereby RGC’s secretion of IL-12(p70) enhances iPSCs’ secretion of SCGF-β, and SCGF-β protects RGCs via upregulating ngn2, suggesting that neurons may call on stem cells for their own protection.

Abstract Mammalian central nervous system (CNS) axons cannot spontaneously regenerate after injury, creating an unmet need to identify molecular regulators to promote axon regeneration and reduce the lasting impact of CNS injuries. While tubulin polymerization promoting protein family member 3 (Tppp3) is known to promote axon outgrowth in amphibians, its role in mammalian axon regeneration remains unknown. Here we investigated Tppp3 in retinal ganglion cells (RGCs) neuroprotection and axonal regeneration using an optic nerve crush (ONC) model in the rodent. Single-cell RNA sequencing identified the expression of Tppp3 in RGCs of mice, macaques, and humans. Tppp3 overexpression enhanced neurite outgrowth in mouse primary RGCs in vitro, promoted axon regeneration, and improved RGC survival after ONC. Bulk RNA sequencing indicated that Tppp3 overexpression upregulates axon regeneration genes such as Bmp4 and neuroinflammatory pathways. Our findings advance regenerative medicine by developing a new therapeutic strategy for RGC neuroprotection and axon regeneration.

Abstract Regulators, environmental advocates, and community groups in the United States (U.S.) are concerned about air pollution associated with the proliferating e-commerce and warehousing industries. Nationwide datasets of warehouse locations, traffic, and satellite observations of the traffic-related pollutant nitrogen dioxide (NO2) provide a unique capability to evaluate the air quality and environmental equity impacts of these geographically-dispersed emission sources. Here, we show that the nearly 150,000 warehouses in the U.S. worsen local traffic-related air pollution with an average near-warehouse NO2 enhancement of nearly 20% and are disproportionately located in marginalized and minoritized communities. Near-warehouse truck traffic and NO2 significantly increase as warehouse density and the number of warehouse loading docks and parking spaces increase. Increased satellite-observed NO2 near warehouses underscores the need for indirect source rules, incentives for replacing old trucks, and corporate commitments towards electrification. Future ground-based monitoring campaigns may help track impacts of individual or small clusters of facilities.

The use of immunohistochemistry (IHC) and molecular pathology has been widely adopted over the past 3 decades and has aided in the precision of diagnosing gynecologic tumors. While many tumors can be diagnosed by histologic appearance on routine hematoxylin and eosin stained slides, the use of IHC has dramatically changed practice, leading to a better understanding and subtyping of gynecologic tumors. This detailed classification of tumors has aided in the implementation and development of targeted therapies. Available IHC stains and their applications continue to rapidly evolve. Our review aims to provide updated information on the use of IHC in gynecologic tumors. We will also address the rationale for preferred therapeutic regimens that are personalized based on IHC.

Purpose Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique.Methods Different strategies to approach the optic nerve head were investigated, including standard intravitreal and retroorbital injections. A novel SupraChoroidal-to-Optic-NervE (SCONE) delivery was optimized by creating a sclerotomy and introducing a catheter into the suprachoroidal space. Under direct visualization, the catheter was guided to the optic nerve head. India ink was injected. The suprachoroidal approach was performed in New Zealand White rabbit eyes in vivo (25 animals total). Parameters, including microneedle size and design, catheter design, and catheter tip angle, were optimized ex vivo and in vivo.Results Out of the candidate optic nerve head approaches, intravitreal, retroorbital, and suprachoroidal approaches were able to localize India ink to within 2 mm of the optic nerve. The suprachoroidal approach was further investigated, and after optimization, was able to deposit India ink directly within the optic nerve head in up to 80% of attempts. In eyes with successful SCONE delivery, latency and amplitude of visual evoked potentials was not different than the naïve untreated eye.Conclusions SCONE delivery can be used for targeted drug delivery to the optic nerve head of rabbits without measurable toxicity measured anatomically or functionally. Successful development of this system may yield novel opportunities to study optic nerve head-specific drug delivery in animal models, and paradigm-shifting management strategies for treating optic neuropathies.Translational Relevance Here we demonstrate data on a new method for targeted delivery to the optic nerve head, addressing a significant unmet need in therapeutics for optic neuropathies.

Nitrogen dioxide (NO2) is a precursor of ozone (O3) and fine particulate matter (PM2.5) – two pollutants that are above regulatory guidelines in many cities. Bringing urban areas into compliance of these regulatory standards motivates an understanding of the distribution and sources of NO2 through observations and simulations. The TRACER-AQ campaign, conducted in Houston, Texas, in September 2021, provided a unique opportunity to compare observed NO2 columns from ground-, airborne-, and satellite-based spectrometers. In this study, we investigate how these observational datasets compare and simulate column NO2 using WRF–CAMx with fine resolution (444 × 444 m2) comparable to the airborne column measurements. We compare WRF-simulated meteorology to ground-level monitors and find good agreement. We find that observations from the GEOstationary Coastal and Air Pollution Events (GEO-CAPE) Airborne Simulator (GCAS) instrument were strongly correlated (r2 = 0.79) to observations from Pandora spectrometers with a slight high bias (normalized mean bias (NMB) = 3.4 %). Remote sensing observations from the TROPOspheric Monitoring Instrument (TROPOMI) were generally well correlated with Pandora observations (r2 = 0.73) with a negative bias (NMB = −22.8 %). We intercompare different versions of TROPOMI data and find similar correlations across three versions but slightly different biases (from −22.8 % in v2.4.0 to −18.2 % in the NASA MINDS product). Compared with Pandora observations, the WRF–CAMx simulation had reduced correlation (r2 = 0.34) and a low bias (−21.2 %) over the entire study region. We find particularly poor agreement between simulated NO2 columns and GCAS-observed NO2 columns in downtown Houston, an area of high population and roadway densities. These findings point to a potential underestimate of NOx emissions (NOx = NO + NO2) from sources associated with the urban core of Houston, such as mobile sources, in the WRF–CAMx simulation driven by the Texas state inventory, and further investigation is recommended.

Abstract Reverse zoonotic respiratory diseases threaten great apes across Sub-Saharan Africa. Studies of wild chimpanzees have identified the causative agents of most respiratory disease outbreaks as “common cold” paediatric human pathogens, but reverse zoonotic transmission pathways have remained unclear. Between May 2019 and August 2021, we conducted a prospective cohort study of 234 children aged 3–11 years in communities bordering Kibale National Park, Uganda, and 30 adults who were forest workers and regularly entered the park. We collected 2047 respiratory symptoms surveys to quantify clinical severity and simultaneously collected 1989 nasopharyngeal swabs approximately monthly for multiplex viral diagnostics. Throughout the course of the study, we also collected 445 faecal samples from 55 wild chimpanzees living nearby in Kibale in social groups that have experienced repeated, and sometimes lethal, epidemics of human-origin respiratory viral disease. We characterized respiratory pathogens in each cohort and examined statistical associations between PCR positivity for detected pathogens and potential risk factors. Children exhibited high incidence rates of respiratory infections, whereas incidence rates in adults were far lower. COVID-19 lockdown in 2020–2021 significantly decreased respiratory disease incidence in both people and chimpanzees. Human respiratory infections peaked in June and September, corresponding to when children returned to school. Rhinovirus, which caused a 2013 outbreak that killed 10% of chimpanzees in a Kibale community, was the most prevalent human pathogen throughout the study and the only pathogen present at each monthly sampling, even during COVID-19 lockdown. Rhinovirus was also most likely to be carried asymptomatically by adults. Although we did not detect human respiratory pathogens in the chimpanzees during the cohort study, we detected human metapneumovirus in two chimpanzees from a February 2023 outbreak that were genetically similar to viruses detected in study participants in 2019. Our data suggest that respiratory pathogens circulate in children and that adults become asymptomatically infected during high-transmission times of year. These asymptomatic adults may then unknowingly carry the pathogens into forest and infect chimpanzees. This conclusion, in turn, implies that intervention strategies based on respiratory symptoms in adults are unlikely to be effective for reducing reverse zoonotic transmission of respiratory viruses to chimpanzees.

Abstract Proposed mechanisms of zoonotic virus spillover often posit that wildlife transmission and amplification precede human outbreaks. Between 2006 and 2012, the palm Raphia farinifera, a rich source of dietary minerals for wildlife, was nearly extirpated from Budongo Forest, Uganda. Since then, chimpanzees, black-and-white colobus, and red duiker were observed feeding on bat guano, a behavior not previously observed. Here we show that guano consumption may be a response to dietary mineral scarcity and may expose wildlife to bat-borne viruses. Videos from 2017–2019 recorded 839 instances of guano consumption by the aforementioned species. Nutritional analysis of the guano revealed high concentrations of sodium, potassium, magnesium and phosphorus. Metagenomic analyses of the guano identified 27 eukaryotic viruses, including a novel betacoronavirus. Our findings illustrate how “upstream” drivers such as socioeconomics and resource extraction can initiate elaborate chains of causation, ultimately increasing virus spillover risk.

Abstract Protocols for characterizing taxonomic assemblages by deep sequencing of short DNA barcode regions (metabarcoding) have revolutionized our understanding of microbial communities and are standardized for bacteria, archaea, and fungi. Unfortunately, comparable methods for host-associated eukaryotes have lagged due to technical challenges. Despite 54 published studies, issues remain with primer complementarity, off-target amplification, and lack of external validation. Here, we present VESPA (Vertebrate Eukaryotic endoSymbiont and Parasite Analysis) primers and optimized metabarcoding protocol for host-associated eukaryotic community analysis. Using in silico prediction, panel PCR, engineered mock community standards, and clinical samples, we demonstrate VESPA to be more effective at resolving host-associated eukaryotic assemblages than previously published methods and to minimize off-target amplification. When applied to human and non-human primate samples, VESPA enables reconstruction of host-associated eukaryotic endosymbiont communities more accurately and at finer taxonomic resolution than microscopy. VESPA has the potential to advance basic and translational science on vertebrate eukaryotic endosymbiont communities, similar to achievements made for bacterial, archaeal, and fungal microbiomes.

Recreational fisheries involve an intimate connection between people, individual fish, and the environment. Recreational fishers and their health crucially depend on healthy fish and ecosystems. Similarly, fish and ecosystems can be impacted by the activities of people including recreational fishers. Thus, amplified by the global interest in recreational fishing, we posit that recreational fishing is particularly suited as an empirical system to explore a One Health perspective, with a goal of creating pathways to better manage such socio-ecological systems for the benefit of people, fish, and the environment. Although zoonoses are uncommon in fishes, fish can carry pathogens, biotoxins, or contaminants that are harmful to people. When captured and released, fish can experience stress and injuries that may promote pathogen development. Similarly, when humans contribute to environmental degradation, not only are fish impacted but so are the humans that depend on them for nutrition, livelihoods, culture, and well-being. Failure to embrace the One Health perspective for recreational fisheries has the potential to negatively impact the health of fish, fisheries, people, society, and the aquatic environment—especially important since these complex social–ecological systems are undergoing rapid change.

Background: To determine if take home laparoscopic trainer boxes with only self-directed learning can develop laparoscopic skills in surgically naive learners. Methods: 74 starting PGY1 OB/Gyn residents and OB/Gyn clerkship medical students volunteered for the study. Learners performed a laparoscopic peg transfer task with only task instructions and no additional training. Initial tasks were recorded and scored. The participants took home a laparoscopic trainer box for 3 weeks to practice without guidance and returned to perform the same task for a second/final score. Initial and final scores were compared for improvement. This improvement was compared to practice and variables such as demographics, surgical interest, comfort with laparoscopy, and past experiences. Results: Mean peg transfer task scores improved from 287 (SD = 136) seconds to 193 (SD = 79) seconds (p

The spread of COVID-19 led to a lockdown in New York in March of 2020. Nonemergent surgeries were postponed, including oncologic procedures. The backlog of surgeries was addressed starting May 2020. Our goal was to examine the change in waiting times for endometrial cancer surgeries during the COVID-19 pandemic in our institution. Data on surgery incidence and waiting time was gathered for patients diagnosed with endometrial intraepithelial neoplasia and endometrial cancer. The association between days from diagnosis to surgery was adjusted for age, obesity, presence of comorbid conditions, race, smoking history and diagnosis and was examined using a general linear model. A total of 190 patients were identified for this retrospective study. Five subjects were missing information on race and were excluded from all analyses, resulting in 185 subjects in the final analyses. Mean waiting time during COVID-19 was 70.9 days (95%CI 55.0, 91.3), compared to 49.3 (95%CI 49.8, 63.8) days during the reference period. No significant associations were seen between the time and any of the clinical or demographic factors.

Summary: Retinal ganglion cell (RGC) differentiation is tightly controlled by extrinsic and intrinsic factors. Growth and differentiation factor 15 (GDF-15) promotes RGC differentiation, opposite to GDF-11 which inhibits RGC differentiation, both in the mouse retina and in human stem cells. To deepen our understanding of how these two closely related molecules confer opposing effects on retinal development, here we assess the transcriptional profiles of mouse retinal progenitors exposed to exogenous GDF-11 or -15. We find a dichotomous effect of GDF-15 on RGC differentiation, decreasing RGCs expressing residual pro-proliferative genes and increasing RGCs expressing non-proliferative genes, suggestive of greater RGC maturation. Furthermore, GDF-11 promoted the differentiation of photoreceptors and amacrine cells. These data enhance our understanding of the mechanisms underlying the differentiation of RGCs and photoreceptors from retinal progenitors and suggest new approaches to the optimization of protocols for the differentiation of these cell types.

IntroductionRespiratory illness is the most common childhood disease globally, especially in developing countries. Previous studies have detected viruses in approximately 70-80% of respiratory illnesses.MethodsIn a prospective cohort study of 234 young children (ages 3-11 years) and 30 adults (ages 22-51 years) in rural Western Uganda sampled monthly from May 2019 to August 2021, only 24.2% of nasopharyngeal swabs collected during symptomatic disease had viruses detectable by multiplex PCR diagnostics and metagenomic sequencing. In the remaining 75.8% of swabs from symptomatic participants, we measured detection rates of respiratory bacteria Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae by quantitative PCR.Results100% of children tested positive for at least one bacterial species. Detection rates were 87.2%, 96.8%, and 77.6% in children and 10.0%, 36.7%, and 13.3% for adults for H. influenzae, M. catarrhalis, and S. pneumoniae, respectively. In children, 20.8% and 70.4% were coinfected with two and three pathogens, respectively, and in adults 6.7% were coinfected with three pathogens but none were coinfected with two. Detection of any of the three pathogens was not associated with season or respiratory symptoms severity, although parsing detection status by symptoms was challenged by children experiencing symptoms in 80.3% of monthly samplings, whereas adults only reported symptoms 26.6% of the time. Pathobiont colonization in children in Western Uganda was significantly more frequent than in children living in high-income countries, including in a study of age-matched US children that utilized identical diagnostic methods. Detection rates were, however, comparable to rates in children living in other Sub-Saharan African countries.DiscussionOverall, our results demonstrate that nonviral colds contribute significantly to respiratory disease burden among children in rural Uganda and that high rates of respiratory pathobiont colonization may play a role. These conclusions have implications for respiratory health interventions in the area, such as increasing childhood immunization rates and decreasing air pollutant exposure.

Purpose: Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery. Design: Preclinical study using a rabbit model of glaucoma filtration surgery. Subjects: Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes. Methods: Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring. Main Outcome Measures: The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology. Results: Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank P = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank P = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, P

IntroductionRespiratory disease is a major cause of morbidity and mortality in the developing world, but prospective studies of temporal patterns and risk factors are rare.MethodsWe studied people in rural Western Uganda, where respiratory disease is pervasive. We followed 30 adults (ages 22–51 years; 534 observations) and 234 children (ages 3–11 years; 1,513 observations) between May 2019 and July 2022 and collected monthly data on their respiratory symptoms, for a total of 2,047 case records. We examined associations between demographic and temporal factors and respiratory symptoms severity.ResultsThe timing of our study (before, during, and after the emergence of COVID-19) allowed us to document the effects of public health measures instituted in the region. Incidence rates of respiratory symptoms before COVID-19 lockdown were 568.4 cases per 1,000 person-months in children and 254.2 cases per 1,000 person-months in adults. These rates were 2.6 times higher than the 2019 global average for children but comparable for adults. Younger children (ages 3–6 years) had the highest frequencies and severities of respiratory symptoms. Study participants were most likely to experience symptoms in February, which is a seasonal pattern not previously documented. Incidence and severity of symptoms in children decreased markedly during COVID-19 lockdown, illustrating the broad effects of public health measures on the incidence of respiratory disease.DiscussionOur results demonstrate that patterns of respiratory disease in settings such as Western Uganda resemble patterns in developed economies in some ways (age-related factors) but not in others (increased incidence in children and seasonal pattern). Factors such as indoor air quality, health care access, timing of school trimesters, and seasonal effects (rainy/dry seasons) likely contribute to the differences observed.

Abstract Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

Freshwater mussels (order: Unionida) are highly imperiled globally and are increasingly the focus of captive propagation efforts to protect and restore wild populations. The Upper Tennessee River Basin (UTRB) in Virginia is a freshwater biodiversity hotspot hosting at least 45 of North America’s ~300 species of freshwater mussels, including 21 threatened and endangered species listed under the U.S. Endangered Species Act. Recent studies have documented that viruses and other microbes have contributed to freshwater mussel population declines in the UTRB. We conducted a multi-year longitudinal study of captive-reared hatchery mussels released to restoration sites throughout the UTRB to evaluate their viromes and compare them to captive hatchery environments. We documented 681 viruses from 27 families. The hatchery mussels had significantly less viruses than those deployed to wild sites, with only 20 viruses unique to the hatchery mussels. After the hatchery mussels were released into the wild, their number of viruses initially spiked and then increased steadily over time, with 451 viruses in total unique to the mussels in the wild. We found Clinch densovirus 1 (CDNV-1), a virus previously associated with mass mortality events in the Clinch River, in all samples, but the wild site mussels consistently had significantly higher CDNV-1 levels than those held in the hatchery. Our data document substantial differences between the viruses in the mussels in the hatchery and wild environments and rapid virome shifts after the mussels are released to the wild sites. These findings indicate that mussel release programs might benefit from acclimatization periods or other measures to mitigate the potential negative effects of rapid exposure to infectious agents found in natural environments.

Abstract Subduction zones are fundamental features of Earth's mantle convection and plate tectonics, but mantle flow and pressure around slabs are poorly understood because of the lack of direct observational constraints on subsurface flow. To characterize the linkages between slabs and mantle flow, we integrate high‐resolution representations of Earth's lithosphere and slabs into a suite of global mantle convection models to produce physically plausible present‐day flow fields for Earth's mantle. We find that subduction zones containing wide, thick, and long slabs dominate regional mantle flow in the neighboring regions and this flow conforms to patterns predicted by simpler regional subduction models. These subduction zones, such as Kuril‐Japan‐Izu‐Bonin‐Mariana, feature prismatic poloidal flow coupled to the downgoing slab that rotates toward toroidal slab‐parallel flow near the slab edge. However, other subduction zones, such as Sumatra, deviate from this pattern because of the competing influence of other slabs or longer‐wavelength mantle flow, showing that upper mantle flow can link separate subduction zones and how flow at subduction zones is influenced by broader scale mantle flow. We find that the non‐linear dislocation creep reduces the coupling between slab motion and asthenospheric flow and increases the occurrence of non‐ideal flow, in line with inferences derived from seismological constraints on mantle anisotropy.

Objective: To describe visual acuity data representation in the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) Registry and present a data-cleaning strategy Design: Reliability and validity study. Participants: Patients with visual acuity records from 2018 in the IRIS Registry. Methods: Visual acuity measurements and metadata were identified and characterized from 2018 IRIS Registry records. Metadata, including laterality, assessment method (distance, near, and unspecified), correction (corrected, uncorrected, and unspecified), and flags for refraction or pinhole assessment were compared between Rome (frozen April 20, 2020) and Chicago (frozen December 24, 2021) versions. We developed a data-cleaning strategy to infer patients’ corrected distance visual acuity in their better-seeing eye. Main Outcome Measures: Visual acuity data characteristics in the IRIS Registry. Results: The IRIS Registry Chicago data set contains 168 920 049 visual acuity records among 23 001 531 unique patients and 49 968 974 unique patient visit dates in 2018. Visual acuity records were associated with refraction in 5.3% of cases, and with pinhole in 11.0%. Mean (standard deviation) of all measurements was 0.26 (0.41) logarithm of the minimum angle of resolution (logMAR), with a range of − 0.3 to 4.0 A plurality of visual acuity records were labeled corrected (corrected visual acuity [CVA], 39.1%), followed by unspecified (37.6%) and uncorrected (uncorrected visual acuity [UCVA], 23.4%). Corrected visual acuity measurements were paradoxically worse than same day UCVA 15% of the time. In aggregate, mean and median values were similar for CVA and unspecified visual acuity. Most visual acuity measurements were at distance (59.8%, vs. 32.1% unspecified and 8.2% near). Rome contained more duplicate visual acuity records than Chicago (10.8% vs. 1.4%). Near visual acuity was classified with Jaeger notation and (in Chicago only) also assigned logMAR values by Verana Health. LogMAR values for hand motion and light perception visual acuity were lower in Chicago than in Rome. The impact of data entry errors or outliers on analyses may be reduced by filtering and averaging visual acuity per eye over time. Conclusions: The IRIS Registry includes similar visual acuity metadata in Rome and Chicago. Although fewer duplicate records were found in Chicago, both versions include duplicate and atypical measurements (i.e., CVA worse than UCVA on the same day). Analyses may benefit from using algorithms to filter outliers and average visual acuity measurements over time. Financial Disclosure(s): Proprietary or commercial disclosure may be found found in the Footnotes and Disclosures at the end of this article.

Abstract Despite improvements in ambient air quality in the US in recent decades, many people still experience unhealthy levels of pollution. At present, national‐level alert‐day identification relies predominately on surface monitor networks and forecasters. Satellite‐based estimates of surface air quality have rapidly advanced and have the capability to inform exposure‐reducing actions to protect public health. At present, we lack a robust framework to quantify public health benefits of these advances in applications of satellite‐based atmospheric composition data. Here, we assess possible health benefits of using geostationary satellite data, over polar orbiting satellite data, for identifying particulate air quality alert days (24hr PM2.5 > 35 μg m−3) in 2020. We find the more extensive spatiotemporal coverage of geostationary satellite data leads to a 60% increase in identification of person‐alerts (alert days × population) in 2020 over polar‐orbiting satellite data. We apply pre‐existing estimates of PM2.5 exposure reduction by individual behavior modification and find these additional person‐alerts may lead to 1,200 (800–1,500) or 54% more averted PM2.5‐attributable premature deaths per year, if geostationary, instead of polar orbiting, satellite data alone are used to identify alert days. These health benefits have an associated economic value of 13 (8.8–17) billion dollars ($2019) per year. Our results highlight one of many potential applications of atmospheric composition data from geostationary satellites for improving public health. Identifying these applications has important implications for guiding use of current satellite data and planning future geostationary satellite missions.

Abstract An impressive number of COVID-19 data catalogs exist. However, none are fully optimized for data science applications. Inconsistent naming and data conventions, uneven quality control, and lack of alignment between disease data and potential predictors pose barriers to robust modeling and analysis. To address this gap, we generated a unified dataset that integrates and implements quality checks of the data from numerous leading sources of COVID-19 epidemiological and environmental data. We use a globally consistent hierarchy of administrative units to facilitate analysis within and across countries. The dataset applies this unified hierarchy to align COVID-19 epidemiological data with a number of other data types relevant to understanding and predicting COVID-19 risk, including hydrometeorological data, air quality, information on COVID-19 control policies, vaccine data, and key demographic characteristics.

Abstract As part of the central nervous system (CNS), retinal ganglion cells (RGCs) and their axons are the only neurons in the retina that transmit visual signals from the eye to the brain via the optic nerve (ON). Unfortunately, they do not regenerate upon injury in mammals. In ON trauma, retinal microglia (RMG) become activated, inducing inflammatory responses and resulting in axon degeneration and RGC loss. Since aldose reductase (AR) is an inflammatory response mediator highly expressed in RMG, we investigated if pharmacological inhibition of AR can attenuate ocular inflammation and thereby promote RGC survival and axon regeneration after ON crush (ONC). In vitro, we discovered that Sorbinil, an AR inhibitor, attenuates BV2 microglia activation and migration in the lipopolysaccharide (LPS) and monocyte chemoattractant protein-1 (MCP-1) treatments. In vivo, Sorbinil suppressed ONC-induced Iba1 + microglia/macrophage infiltration in the retina and ON and promoted RGC survival. Moreover, Sorbinil restored RGC function and delayed axon degeneration one week after ONC. RNA sequencing data revealed that Sorbinil protects the retina from ONC-induced degeneration by suppressing inflammatory signaling. In summary, we report the first study demonstrating that AR inhibition transiently protects RGC and axon from degeneration, providing a potential therapeutic strategy for optic neuropathies.

Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators. Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds. Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants. Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science. Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background Tissue‐engineered intervertebral disc (TE‐IVD) constructs are an attractive therapy for treating degenerative disc disease and have previously been investigated in vivo in both large and small animal models. The mechanical environment of the spine is notably challenging, in part due to its complex anatomy, and implants may require additional mechanical support to avoid failure in the early stages of implantation. As such, the design of suitable support implants requires rigorous validation. Methods We created a FE model to simulate the behavior of the IVD cages under compression specific to the anatomy of the porcine cervical spine, validated the FE model using an animal model, and predicted the effects of implant location and vertebral angle of the motion segment on implant behavior. Specifically, we tested anatomical positioning of the superior vertebra and placement of the implant. We analyzed corresponding stress and strain distributions. Results Results demonstrated that the anatomical geometry of the porcine cervical spine led to concentrated stress and strain on the posterior side of the cage. This stress concentration was associated with the location of failure of the cages reported in vivo, despite superior mechanical properties of the implant. Furthermore, placement of the cage was found to have profound effects on migration, while the angle of the superior vertebra affected stress concentration of the cage. Conclusions This model can be utilized both to inform surgical procedures and provide insight on future cage designs and can be adopted to models without the use of in vivo animal models.

Empirical models aim to predict spatial variability in concentrations of outdoor air pollution. For year-2010 concentrations of PM~2.5~ in the US, we intercompared six national-scale empirical models, each generated by a different research group. Despite differences in methods and independent variables for the models, we find a relatively high degree of agreement among model predictions (e.g., correlations of 0.84 to 0.92, RMSD (root-mean-square-difference; units: μg/m^3^) of 0.8 to 1.4, or on average \~12% of the average concentration; many best-fit lines are near the 1:1 line).

Abstract Background The prevalence estimates of burnout among residents vary widely. Resident physicians working overnight have additional stressors and therefore, may be at higher risk of developing burnout. Objective To determine the rates of burnout among residents working night rotations versus day rotations. Methods This is a prospective, cross sectional, survey-based assessment of the prevalence of burnout among Obstetrics and Gynecology (OBGYN) residents on nights versus days rotations conducted at a large academic residency program that spans two separate hospitals in New York. All residents in the residency program were asked to complete the Maslach Burnout Inventory – Human Services Survey for Medical Personnel (MBI-HSS (MP)) after the first rotation of the academic year in 2018, 2019, and 2020. The results for each of the three aspects of the MBI-HSS (MP): emotional exhaustion, depersonalization, and personal accomplishment, were then compared for those on nights versus day rotations using students t-test. Results A total of 76 responses were received, 13 from residents on night rotations and 63 from residents on day rotations with a response rate of 61.8%. Comparing resident responses for a night versus day rotation, the residents averaged a low level of emotional exhaustion (a score of 17 ± 9) on day shift, compared to a moderate level of emotional exhaustion (a score of 18 ± 14) on nights (p = 0.37). Similarly, 55.6% of respondents reports low personal accomplishment on days, compared to 76.9% while on nights. Conclusions Emotional exhaustion scores were lower for residents on daytime rotations (mean score 17, SD 9), compared to those on nights rotations (mean 18, SD 14). Although there was no difference in depersonalization when comparing the day and night shift, 45% of the responses indicated high levels of depersonalization regardless of the type of shift. These results highlight the need to continue efforts to minimize burnout in medical training.

Abstract Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS.

Purpose: To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma. Design: Open-label, prospective, phase I clinical trial. Participants: A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye. Methods: The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics. Main Outcome Measures: Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome. Results: All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA, −5.82 vs. −0.82 letters; and contrast sensitivity, −1.82 vs. −0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (−13.0%, −3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 μm vs. 10.16 μm; and GDx VCC, 1.58 μm vs. 8.36 μm in fellow vs. study eyes, respectively). Conclusions: The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Background: Amid the height of the COVID-19 pandemic in the US, the US Surgeon General ordered hospitals and healthcare systems to stop all elective surgical procedures. The aim of our study was to evaluate the additional mental health impact of surgical delay on patients awaiting surgery for benign, pre-malignant and malignant conditions within the context of the COVID-19 pandemic. Study design: All patients over the age of 18 awaiting surgery for benign, pre-malignant or malignant conditions within the gynecologic oncology, surgical oncology and colorectal services across Northwell Health were eligible for participation. Upon successful enrollment, participants completed a baseline questionnaire consisting of the Generalized Anxiety Disorder Questionnaire, the Penn State Worry Questionnaire, and Brief-Illness Patient Questionnaire. Results: The surgical delay was considered moderately to extremely concerning by 72 % of survey respondents, with one third indicating the highest (10/10) level of concern. Fifty-five percent of patients with a pre-operatively suspected/confirmed cancer or pre-malignant condition demonstrated mild to severe anxiety in their completion of the GAD-7 scale. The average time awaiting surgery was 117 days (range 8–292); and 63 % of respondents indicated that the delay had a moderate to severe impact on their daily life. Conclusions: Patients awaiting surgery for confirmed, suspected or pre-malignant conditions expressed decreased sense of control and increased levels of distress compared to patients awaiting procedures for benign conditions (p

Summary: Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody.

Objective Minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) is a highly reproducible procedure for the fusion of spinal segments. We recently introduced the concept of “total navigation” to improve workflow and eliminate fluoroscopy. Image-guided surgery incorporating augmented reality (AR) may further facilitate workflow. In this study, we developed and evaluated a protocol to integrate AR into the workflow of MIS-TLIF. Methods A case series of 10 patients was the basis for the evaluation of a protocol to facilitate tubular MIS-TLIF by the application of AR. Surgical TLIF landmarks were marked on a preoperative computed tomography (CT)-scan using dedicated software. This marked CT scan was fused intraoperatively with the low-dose navigation CT scan using elastic image fusion, and the markers were transferred to the intraoperative scan. Our experience with this workflow and the surgical outcomes were collected. Results Our AR protocol was safely implemented in all cases. The TLIF landmarks could be preoperatively planned and transferred to the intraoperative imaging. Of the 10 cases, 1 case had additionally a synovial cyst resection and in 2 cases an additional bony decompression was performed due to central stenosis. The average procedure time was 160.6±31.9 minutes. The AR implementation added 1.72±0.37 minutes to the overall procedure time. No complications occurred. Conclusion Our findings support the idea that total navigation with AR may further facilitate the workflow, especially in cases with more complex anatomy and for teaching and training purposes. More work is needed to simplify the software and make AR integration more user-friendly.

The Tropospheric Monitoring Instrument (TROPOMI) on the Sentinel-5 Precursor (S5P) satellite is a valuable source of information to monitor the NOx emissions that adversely affect air quality. We conduct a series of experiments using a 4×4 km2 Comprehensive Air Quality Model with Extensions (CAMx) simulation during April–September 2019 in eastern Texas to evaluate the multiple challenges that arise from reconciling the NOx emissions in model simulations with TROPOMI. We find an increase in NO2 (+17 % in urban areas) when transitioning from the TROPOMI NO2 version 1.3 algorithm to the version 2.3.1 algorithm in eastern Texas, with the greatest difference (+25 %) in the city centers and smaller differences (+5 %) in less polluted areas. We find that lightning NOx emissions in the model simulation contribute up to 24 % of the column NO2 in the areas over the Gulf of Mexico and 8% in Texas urban areas. NOx emissions inventories, when using locally resolved inputs, agree with NOx emissions derived from TROPOMI NO2 version 2.3.1 to within 20 % in most circumstances, with a small NOx underestimate in Dallas–Fort Worth (−13 %) and Houston (−20 %). In the vicinity of large power plant plumes (e.g., Martin Lake and Limestone) we find larger disagreements, i.e., the satellite NO2 is consistently smaller by 40 %–60 % than the modeled NO2, which incorporates measured stack emissions. We find that TROPOMI is having difficulty distinguishing NO2 attributed to power plants from the background NO2 concentrations in Texas – an area with atmospheric conditions that cause short NO2 lifetimes. Second, the NOx/NO2 ratio in the model may be underestimated due to the 4 km grid cell size. To understand ozone formation regimes in the area, we combine NO2 column information with formaldehyde (HCHO) column information. We find modest low biases in the model relative to TROPOMI HCHO, with −9 % underestimate in eastern Texas and −21 % in areas of central Texas with lower biogenic volatile organic compound (VOC) emissions. Ozone formation regimes at the time of the early afternoon overpass are NOx limited almost everywhere in the domain, except along the Houston Ship Channel, near the Dallas/Fort Worth International airport, and in the presence of undiluted power plant plumes. There are likely NOx-saturated ozone formation conditions in the early morning hours that TROPOMI cannot observe and would be well-suited for analysis with NO2 and HCHO from the upcoming TEMPO (Tropospheric Emissions: Monitoring Pollution) mission. This study highlights that TROPOMI measurements offer a valuable means to validate emissions inventories and ozone formation regimes, with important limitations.

Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.

Studies of marine fish have revealed distant relatives of viruses important to global fish and animal health, but few such studies exist for freshwater fish. To investigate whether freshwater fish also host such viruses, we characterized the viromes of five wild species of freshwater fish in Wisconsin, USA: bluegill (Lepomis macrochirus), brown trout (Salmo trutta), lake sturgeon (Acipenser fulvescens), northern pike (Esox lucius), and walleye (Sander vitreus). We analyzed 103 blood serum samples collected during a state-wide survey from 2016 to 2020 and used a metagenomic approach for virus detection to identify known and previously uncharacterized virus sequences. We then characterized viruses phylogenetically and quantified prevalence, richness, and relative abundance for each virus. Within these viromes, we identified 19 viruses from 11 viral families: Amnoonviridae, Circoviridae, Coronaviridae, Hepadnaviridae, Peribunyaviridae, Picobirnaviridae, Picornaviridae, Matonaviridae, Narnaviridae, Nudnaviridae, and Spinareoviridae, 17 of which were previously undescribed. Among these viruses was the first fish-associated coronavirus from the Gammacoronavirus genus, which was present in 11/15 (73%) of S. vitreus. These results demonstrate that, similar to marine fish, freshwater fish also harbor diverse relatives of viruses important to the health of fish and other animals, although it currently remains unknown what effect, if any, the viruses we identified may have on fish health.

Over the past decade several studies have reported that the gut microbiomes of mammals with similar dietary niches exhibit similar compositional and functional traits. However, these studies rely heavily on samples from captive individuals and often confound host phylogeny, gut morphology, and diet. To more explicitly test the influence of host dietary niche on the mammalian gut microbiome we use 16S rRNA gene amplicon sequencing and shotgun metagenomics to compare the gut microbiota of 18 species of wild non-human primates classified as either folivores or closely related non-folivores, evenly distributed throughout the primate order and representing a range of gut morphological specializations. While folivory results in some convergent microbial traits, collectively we show that the influence of host phylogeny on both gut microbial composition and function is much stronger than that of host dietary niche. This pattern does not result from differences in host geographic location or actual dietary intake at the time of sampling, but instead appears to result from differences in host physiology. These findings indicate that mammalian gut microbiome plasticity in response to dietary shifts over both the lifespan of an individual host and the evolutionary history of a given host species is constrained by host physiological evolution. Therefore, the gut microbiome cannot be considered separately from host physiology when describing host nutritional strategies and the emergence of host dietary niches.

We report an unknown taxon of bot fly (Diptera: Oestridae: Oestrinae) in red river hogs (Potamochoerus porcus Linnaeus, 1758) in Cross River State, Nigeria. From direct observation and interviews with local hunters, we document that, remarkably, the parasite typically occurs within the intracranial supra-meningeal space – i.e., between the inner wall of the skull and the brain – but without causing visible inflammation or clinical signs. The parasite is most similar (up to 87.9%) to Rhinoestrus usbekistanicus based on cytochrome oxidase subunit 1 DNA sequencing but is sufficiently divergent phylogenetically to represent a new or previously un-sequenced taxon. Morphologically, the parasite shares some, but not all, features with R. nivarleti. Local cultural belief systems attribute aspects of red river hog behavior (e.g. intelligence, elusiveness) to the parasite, suggesting a prolonged presence in the red river hog population. The parasite's unusual anatomic location may be aberrant, or it may be a protective adaptation to life in red river hogs, which forage vigorously with their snouts.

As deforestation progresses in the tropics, wildlife populations are increasingly restricted to forest fragments. Here we study genetic population structure in the endangered Ashy red colobus (Piliocolobus tephrosceles) population in the forest fragments surrounding Kibale National Park, Uganda. Subsequently, we use landscape features (elevation, road data and distance to the park) to design a feasible strategy to restore forest in a fashion suitable for both the dispersal patterns of the species and land use practices of the local people. A lack of association between geographic distance and pairwise genetic relatedness among localities, the presence of first degree relatives across localities, and a low global Fst value suggest that red colobus individuals have migrated across this landscape in the recent past. Thus, a series of “stepping stone” forests from the fragments to the park will likely maintain viability of red colobus fragment populations. In this area, low-lying valleys are legally protected to prevent flooding and are considered of low-economic value to local people. We identify such valleys for development of community-based forest restoration efforts that will aid in red colobus conservation and provide various ecosystem services. Our study outlines how genetics and community-based restoration can be integrated to provide realistic conservation solutions.

Purpose: Complement C1q, the initiating molecule of the classical complement cascade, is involved in synapse elimination and neuronal loss in neurodegenerative diseases including glaucoma. Here we report an evaluation of the safety, tolerability, and ocular pharmacokinetics (PK) and pharmacodynamics of intravitreal (IVT) injections of ANX007, an anti-C1q monoclonal antibody fragment that blocks activation of the classical complement cascade. Design: An open-label, single-dose-escalation phase Ia study followed by a double-masked, randomized, sham-controlled, repeat-injection phase Ib study. Participants: A total of 26 patients with primary open-angle glaucoma. Methods: Nine patients with primary open-angle glaucoma (mean Humphrey visual field deviation between −3 and −18 decibels [dB]) were enrolled in phase Ia and received single doses of ANX007 (1.0 mg, n = 3; 2.5 mg, n = 3; or 5.0 mg, n = 3). Seventeen patients (mean Humphrey visual field deviation between −3 and −24 dB) were enrolled in phase Ib and randomized to 2 monthly doses of ANX007 (sham, n = 6; 2.5 mg ANX007, n = 6; or 5 mg ANX007, n = 5). Main Outcome Measures: Safety and tolerability (including laboratory evaluation of urinalysis, complete blood count, and serum chemistries), ANX007 PK, target engagement, and immunogenicity. Results: The mean age overall was 70 years in phase Ia and 68 years in phase Ib. In both studies, no serious adverse events were observed, no non-ocular treatment-emergent adverse events (TEAEs) attributable to study drug were reported, and ocular TEAEs were mild. Intraocular pressure returned to normal levels for all patients within 45 minutes of IVT injection. No clinically significant deviations in laboratory results were observed. In the phase Ib study, C1q in the aqueous humor was reduced to undetectable levels in both the 2.5 mg and 5 mg cohorts 4 weeks after the first ANX007 dose. Conclusions: In these studies, single and repeat IVT ANX007 injections were well tolerated and demonstrated full target engagement 4 weeks after dosing with both low and high doses, supporting monthly or less-frequent dosing. Further investigation in neurodegenerative ocular diseases is warranted. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Endometrial cancer is the most common gynecologic malignancy in the United States and is one of the few malignancies that had an increasing incidence and mortality rate over the last 10 years. Current research models fail to recapitulate actual characteristics of the tumor that are necessary for the proper understanding and treatment of this heterogenous disease. Patient-derived organoids provide a durable and versatile culture system that can capture patient-specific characteristics such as the mutational profile and response to therapy of the primary tumor. Here we describe the methods for establishing, expansion and banking of endometrial cancer organoids to develop a living biobank. Samples of both endometrial tumor tissue and matched normal endometrium were collected from 10 patients. The tissue was digested into single cells and then cultured in optimized media to establish matched patient endometrial cancer and normal endometrial tissue organoids. Organoids were created from all major endometrial cancer histologic subtypes. These organoids are passaged long term, banked and can be utilized for downstream histological and genomic characterization as well as functional assays such as assessing the response to therapeutic drugs.

Introduction: The World Health Organization (WHO) recently revised its health guidelines for Nitrogen dioxide (NO2) air pollution, reducing the annual mean NO2 level to 10 μg/m3 (5.3 ppb) and the 24-h mean to 25 μg/m3 (13.3 ppb). NO2 is a pollutant of global concern, but it is also a criteria air pollutant that varies spatiotemporally at fine resolutions due to its relatively short lifetime (~hours). Current models have limited ability to capture both temporal and spatial NO2 variation and none are available with global coverage. Land use regression (LUR) models that incorporate timevarying predictors (e.g., meteorology and satellite NO2 measures) and land use characteristics (e.g., road density, emission sources) have significant potential to address this need.Methods: We created a daily Land use regression model with 50 × 50 m2 spatial resolution using 5.7 million daily air monitor averages collected from 8,250 monitor locations.Results: In cross-validation, the model captured 47%, 59%, and 63% of daily, monthly, and annual global NO2 variation. Daily, monthly, and annual root mean square error were 6.8, 5.0, and 4.4 ppb and absolute bias were 46%, 30%, and 21%, respectively. The final model has 11 variables, including road density and built environments with fine (30 m or less) spatial resolution and meteorological and satellite data with daily temporal resolution. Major roads and satellite-based estimates of NO2 were consistently the strongest predictors of NO2 measurements in all regions.Discussion: Daily model estimates from 2005–2019 are available and can be used for global risk assessments and health studies, particularly in countries without NO2 monitoring.

Abstract Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

Abstract Background Understanding how and why people interact with animals is important for the prevention and control of zoonoses. To date, studies have primarily focused on the most visible forms of human-animal contact (e.g., hunting and consumption), thereby blinding One Health researchers and practitioners to the broader range of human-animal interactions that can serve as cryptic sources of zoonotic diseases. Zootherapy, the use of animal products for traditional medicine and cultural practices, is widespread and can generate opportunities for human exposure to zoonoses. Existing research examining zootherapies omits details necessary to adequately assess potential zoonotic risks. Methods We used a mixed-methods approach, combining quantitative and qualitative data from questionnaires, key informant interviews, and field notes to examine the use of zootherapy in nine villages engaged in wildlife hunting, consumption, and trade in Cross River State, Nigeria. We analyzed medicinal and cultural practices involving animals from a zoonotic disease perspective, by including details of animal use that may generate pathways for zoonotic transmission. We also examined the sociodemographic, cultural, and environmental contexts of zootherapeutic practices that can further shape the nature and frequency of human-animal interactions. Results Within our study population, people reported using 44 different animal species for zootherapeutic practices, including taxonomic groups considered to be “high risk” for zoonoses and threatened with extinction. Variation in use of animal parts, preparation norms, and administration practices generated a highly diverse set of zootherapeutic practices (n = 292) and potential zoonotic exposure risks. Use of zootherapy was patterned by demographic and environmental contexts, with zootherapy more commonly practiced by hunting households (OR = 2.47, p

Introduction Treatment of non‐acute subdural hematoma (NASDH) remains challenging due to recurrence ranging from 2–37%. Middle meningeal artery embolization (MMAe) has emerged as a minimally invasive procedure uniquely poised to improve outcomes in NASDH. The goal of this study is to evaluate the clinical and radiographic characteristics of patients undergoing MMAe for NASDH, and how outcomes for MMAe differ when utilized upfront, prophylactically, or as a salvage modality after surgical evacuation. Furthermore, we investigated how independent patient risk factors, such as oncologic history and anticoagulant/antiplatelet (ACAP) medication use, may impact MMAe and NASDH outcomes. Methods This prospective study followed patients undergoing MMAe for NASDH from 2016–2021. All patients were diagnosed with a NASDH on non‐contrast CT imaging and underwent MMAe by the lead neurosurgeon. The primary outcome was NASDH recurrence post‐MMAe requiring surgical evacuation, repeat MMAe, or both within the one‐year follow up period. Additional radiographic outcomes included reduction of hematoma width and midline shift at longest follow‐up. Subgroup analyses stratified outcomes by MMAe indication: upfront (previously untreated and nonoperative NASDH), prophylactic (MMAe 1–5 days after surgical evacuation), or salvage (individuals with radiographic and clinical NASDH recurrence). Outcomes among oncologic, coagulopathic, and ACAP patients were also assessed. The modified Rankin scale (mRS) quantified post‐MMAe clinical outcomes. Results A total of 236 NASDH patients underwent 294 MMAe. Of these, 115 (48.7%), 92 (39.0%), and 29 (12.3%) patients received upfront, prophylactic, and salvage MMAe, respectively. Upfront MMAe was performed more frequently than prophylactic and salvage for patients with co‐existing malignancy (29.6%, 12.0%, 20.7%; P < 0.01) and coagulopathy (17.4%, 4.3%, 10.3%; P = 0.01). Prophylactic MMAe was more commonly performed for subacute SDH compared with upfront or salvage (15.2%, 2.6%, 0%; P < 0.001); no differences in utilization were seen for chronic or acute on chronic SDH. Sixteen (5.4%) patients presented with hematoma recurrence after MMAe requiring repeat intervention, of which 5 (1.7%) received a craniotomy, 7 (2.4%) received repeat MMAe, and 4 (1.3%) underwent both MMAe and surgical evacuation. Risk of overall NASDH recurrence requiring re‐intervention did not differ among prophylactic, upfront, and salvage groups (6.5%, 7.0%, 6.9%; P > 0.99). Clinical outcomes did not differ between MMAe indications at longest follow‐up. Within the prophylactic group, radiographic and clinical outcomes were similar between MMAe paired with twist‐drill craniostomy or with craniotomy. Subgroup analysis revealed MMAe also effectively decreased NASDH recurrence in ACAP, oncologic, and coagulopathic patients. However, patients with both an oncologic history and concurrent ACAP use less frequently achieved improved clinical status at follow‐up compared with those harboring ACAP/coagulopathic history alone, oncologic history alone, or neither (31.4%, 45.9%, 50.0%, 57.3%; P = 0.049). Conclusions MMAe is emerging as a viable treatment for curtailing recurrence and improving NASDH outcomes, with similar clinical outcomes when performed prophylactically, upfront, or as salvage treatment. NASDH patients presenting with an oncologic history and concurrent ACAP use may be less likely to achieve improved clinical status after MMAe.

As the world becomes increasingly urbanized, growing populations are exposed to poor ambient air quality and at risk of the associated health outcomes. Urban air quality is affected both by local sources of air pollution and sources outside city borders. Policy-makers who develop air quality policies need to know whether it is most effective to focus on local policies or to spend resources fostering larger regional air quality management cooperation. Identifying the fraction of air pollution exposure from emissions as a function of distance from the city is a critical element of air quality management design. We estimate the health burden associated with exposure to fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) from county-level anthropogenic sources in and around 14 US cities; this analysis is a test-bed to conduct future global analyses. We use adjoint sensitivities calculated from the chemical transport model GEOS-Chem, high resolution satellite-derived surface concentrations of PM2.5 and NO2, and health impact assessment methods. For the 70.2 million people living in these cities, we estimate that 27,740 PM2.5- and O3-related premature deaths and 126,600 NO2-related new asthma cases were attributable to air pollution exposure in 2011. Development within the GEOS-Chem adjoint framework enables sectoral attribution and policy analysis in addition to the rote assessment of impact. We find that 70% of deaths and nearly 100% of these asthma cases were attributable to anthropogenic emissions. There is great variability in the sources of the anthropogenically-related health impacts; within-urban emissions make up 5% in Austin to 56% in Los Angeles and Phoenix (median: 31%) of urban premature deaths and 18% in Austin to 82% in Los Angeles (median: 59.5%) of new asthma cases, with the remaining portions attributable to emissions from outside the urban area. For each city, we estimate the air quality related health benefits associated with the adoption of a vehicle-miles-traveled fee in that city and in multiple spatial regions surrounding the city. The findings suggest that the proportion of urban air pollution that is regional is greater for premature deaths than new asthma cases and for the eastern US than the western US.

Pathogen surveillance for great ape health monitoring has typically been performed on non-invasive samples, primarily feces, in wild apes and blood in sanctuary-housed apes. However, many important primate pathogens, including known zoonoses, are shed in saliva and transmitted via oral fluids. Using metagenomic methods, we identified viruses in saliva samples from 46 wild-born, sanctuary-housed chimpanzees at two African sanctuaries in Republic of Congo and Uganda. In total, we identified 20 viruses. All but one, an unclassified CRESS DNA virus, are classified in five families: Circoviridae, Herpesviridae, Papillomaviridae, Picobirnaviridae, and Retroviridae. Overall, viral prevalence ranged from 4.2% to 87.5%. Many of these viruses are ubiquitous in primates and known to replicate in the oral cavity (simian foamy viruses, Retroviridae; a cytomegalovirus and lymphocryptovirus; Herpesviridae; and alpha and gamma papillomaviruses, Papillomaviridae). None of the viruses identified have been shown to cause disease in chimpanzees or, to our knowledge, in humans. These data suggest that the risk of zoonotic viral disease from chimpanzee oral fluids in sanctuaries may be lower than commonly assumed.

Objectives. Primary cilia are conserved organelles found in polarized mammalian cells that regulate neuronal growth, migration, and differentiation. Proper cilia formation is essential during eye development. Our previous reports found that both amacrine and retinal ganglion cells (RGCs) contain primary cilia in primate and rodent retinas. However, whether primary cilia are present in the inner retina of human retinal organoids remains unknown. The purpose of this study is to characterize the primary cilia distribution in human embryonic stem cell (hESC-derived retinal organoid development. Materials and Methods. Retinal organoids were differentiated from a hESC line, harvested at various developmental timepoints (day 44-day 266), and immunostained with antibodies for primary cilia, including Arl13b (for the axoneme), AC3, and Centrin3 (for the basal body). AP2α, Prox1, GAD67, Calretinin, GFAP, PKCα, and Chx10 antibodies as well as Brn3b-promoted tdTomato expression were used to visualize retinal cell types. Results. A group of ciliated cells were present in the inner aspects of retinal organoids from day 44 to day 266 in culture. Ciliated Chx10-positive retinal progenitor cells, GFAP-positive astrocytes, and PKCα-positive rod-bipolar cells were detected later during development (day 176 to day 266). Ciliation persisted during all stages of retinal developmental in AP2α-positive amacrine cells, but it was decreased in Brn3b-positive retinal ganglion cells (RGCs) at later time points. Additionally, AC3-positive astrocytes significantly decreased during the later stages of organoid formation. Conclusions. Amacrine cells in retinal organoids retain cilia throughout development, whereas RGC ciliation gradually and progressively decreases with organoid maturation.

Freshwater mussels (Unionida) are globally imperiled, in part due to largely unexplained mass mortality events (MMEs). While recent studies have begun to investigate the possibility that mussel MMEs in the Eastern USA may be caused by infectious diseases, mussels in the Western USA have received relatively little attention in this regard. We conducted a two-year epidemiologic investigation of the role of viruses in ongoing MMEs of the Western pearlshell (Margaritifera falcata) and the Western ridged mussel (Gonidea angulata) in the Chehalis River and Columbia River watersheds in the Western USA. We characterized viromes of mussel hemolymph from 5 locations in 2018 and 2020 using metagenomic methods and identified 557 viruses based on assembled contiguous sequences, most of which are novel. We also characterized the distribution and diversity of a previously identified mussel Gammarhabdovirus related to pathogenic finfish viruses. Overall, we found few consistent associations between viruses and mussel health status. Variation in mussel viromes was most strongly driven by location, with little influence from date, species, or health status, though these variables together only explained ~1/3 of variation in virome composition. Our results demonstrate that Western freshwater mussels host remarkably diverse viromes, but no single virus or combination of viruses appears to be associated with morbidity or mortality during MMEs. Our findings have implications for the conservation of imperiled freshwater mussels, including efforts to enhance natural populations through captive propagation.