Sustained Reductions in Online Search Interest for Communicable Eye and Other Conditions During the COVID-19 Pandemic: Infodemiology Study.

Background: In a prior study at the start of the pandemic, we reported reduced numbers of Google searches for the term "conjunctivitis" in the United States in March and April 2020 compared with prior years. As one explanation, we conjectured that reduced information-seeking may have resulted from social distancing reducing contagious conjunctivitis cases. Here, after 1 year of continued implementation of social distancing, we asked if there have been persistent reductions in searches for "conjunctivitis," and similarly for other communicable disease terms, compared to control terms. Objective: The aim of this study was to determine if reduction in searches in the United States for terms related to conjunctivitis and other common communicable diseases occurred in the spring-winter season of the COVID-19 pandemic, and to compare this outcome to searches for terms representing noncommunicable conditions, COVID-19, and to seasonality. Methods: Weekly relative search frequency volume data from Google Trends for 68 search terms in English for the United States were obtained for the weeks of March 2011 through February 2021. Terms were classified a priori as 16 terms related to COVID-19, 29 terms representing communicable conditions, and 23 terms representing control noncommunicable conditions. To reduce bias, all analyses were performed while masked to term names, classifications, and locations. To test for the significance of changes during the pandemic, we detrended and compared postpandemic values to those expected based on prepandemic trends, per season, computing one- and two-sided P values. We then compared these P values between term groups using Wilcoxon rank-sum and Fisher exact tests to assess if non-COVID-19 terms representing communicable diseases were more likely to show significant reductions in searches in 2020-2021 than terms not representing such diseases. We also assessed any relationship between a term's seasonality and a reduced search trend for the term in 2020-2021 seasons. P values were subjected to false discovery rate correction prior to reporting. Data were then unmasked. Results: Terms representing conjunctivitis and other communicable conditions showed a sustained reduced search trend in the first 4 seasons of the 2020-2021 COVID-19 pandemic compared to prior years. In comparison, the search for noncommunicable condition terms was significantly less reduced (Wilcoxon and Fisher exact tests, P<.001; summer, autumn, winter). A significant correlation was also found between reduced search for a term in 2020-2021 and seasonality of that term (Theil-Sen, P<.001; summer, autumn, winter). Searches for COVID-19-related conditions were significantly elevated compared to those in prior years, and searches for influenza-related terms were significantly lower than those for prior years in winter 2020-2021 (P<.001). Conclusions: We demonstrate the low-cost and unbiased use of online search data to study how a wide range of conditions may be affected by large-scale interventions or events such as social distancing during the COVID-19 pandemic. Our findings support emerging clinical evidence implicating social distancing and the COVID-19 pandemic in the reduction of communicable disease and on ocular conditions.

A Google Trends Approach to Identify Distinct Diurnal and Day-of-Week Web-Based Search Patterns Related to Conjunctivitis and Other Common Eye Conditions: Infodemiology Study.

BACKGROUND: Studies suggest diurnal patterns of occurrence of some eye conditions. Leveraging new information sources such as web-based search data to learn more about such patterns could improve the understanding of patients' eye-related conditions and well-being, better inform timing of clinical and remote eye care, and improve precision when targeting web-based public health campaigns toward underserved populations. OBJECTIVE: To investigate our hypothesis that the public is likely to consistently search about different ophthalmologic conditions at different hours of the day or days of week, we conducted an observational study using search data for terms related to ophthalmologic conditions such as conjunctivitis. We assessed whether search volumes reflected diurnal or day-of-week patterns and if those patterns were distinct from each other. METHODS: We designed a study to analyze and compare hourly search data for eye-related and control search terms, using time series regression models with trend and periodicity terms to remove outliers and then estimate diurnal effects. We planned a Google Trends setting, extracting data from 10 US states for the entire year of 2018. The exposure was internet search, and the participants were populations who searched through Google's search engine using our chosen study terms. Our main outcome measures included cyclical hourly and day-of-week web-based search patterns. For statistical analyses, we considered P<.001 to be statistically significant. RESULTS: Distinct diurnal (P<.001 for all search terms) and day-of-week search patterns for eye-related terms were observed but with differing peak time periods and cyclic strengths. Some diurnal patterns represented those reported from prior clinical studies. Of the eye-related terms, "pink eye" showed the largest diurnal amplitude-to-mean ratios. Stronger signal was restricted to and peaked in mornings, and amplitude was higher on weekdays. By contrast, "dry eyes" had a higher amplitude diurnal pattern on weekends, with stronger signal occurring over a broader evening-to-morning period and peaking in early morning. CONCLUSIONS: The frequency of web-based searches for various eye conditions can show cyclic patterns according to time of the day or week. Further studies to understand the reasons for these variations may help supplement the current clinical understanding of ophthalmologic symptom presentation and improve the timeliness of patient messaging and care interventions.

RANBP2 and USP9x regulate nuclear import of adenovirus minor coat protein IIIa.

As intracellular parasites, viruses exploit cellular proteins at every stage of infection. Adenovirus outbreaks are associated with severe acute respiratory illnesses and conjunctivitis, with no specific antiviral therapy available. An adenoviral vaccine based on human adenovirus species D (HAdV-D) is currently in use for COVID-19. Herein, we investigate host interactions of HAdV-D type 37 (HAdV-D37) protein IIIa (pIIIa), identified by affinity purification and mass spectrometry (AP-MS) screens. We demonstrate that viral pIIIa interacts with ubiquitin-specific protease 9x (USP9x) and Ran-binding protein 2 (RANBP2). USP9x binding did not invoke its signature deubiquitination function but rather deregulated pIIIa-RANBP2 interactions. In USP9x-knockout cells, viral genome replication and viral protein expression increased compared to wild type cells, supporting a host-favored mechanism for USP9x. Conversely, RANBP2-knock down reduced pIIIa transport to the nucleus, viral genome replication, and viral protein expression. Also, RANBP2-siRNA pretreated cells appeared to contain fewer mature viral particles. Transmission electron microscopy of USP9x-siRNA pretreated, virus-infected cells revealed larger than typical paracrystalline viral arrays. RANBP2-siRNA pretreatment led to the accumulation of defective assembly products at an early maturation stage. CRM1 nuclear export blockade by leptomycin B led to the retention of pIIIa within cell nuclei and hindered pIIIa-RANBP2 interactions. In-vitro binding analyses indicated that USP9x and RANBP2 bind to C-terminus of pIIIa amino acids 386-563 and 386-510, respectively. Surface plasmon resonance testing showed direct pIIIa interaction with recombinant USP9x and RANBP2 proteins, without competition. Using an alternative and genetically disparate adenovirus type (HAdV-C5), we show that the demonstrated pIIIa interaction is also important for a severe respiratory pathogen. Together, our results suggest that pIIIa hijacks RANBP2 for nuclear import and subsequent virion assembly. USP9x counteracts this interaction and negatively regulates virion synthesis. This analysis extends the scope of known adenovirus-host interactions and has potential implications in designing new antiviral therapeutics.

COVID-19 and the eye: alternative facts The 2022 Bowman Club, David L. Easty lecture.

In addition to catastrophic loss of life, and dramatic and unwanted alterations to the daily lives of those left behind, the COVID-19 pandemic has fostered the publication and dissemination of an unprecedented quantity of peer-reviewed medical and scientific publications on a single subject. In particular, the ophthalmic literature is now replete with clinical and laboratory studies on putative eye involvement by SARS-CoV-2, the aetiologic agent of COVID-19. In this review, we critically appraise the published literature on COVID-19, and suggest that the quality of scientific peer review and editorial decision-making also suffered during the COVID-19 pandemic.

Tracking SARS-CoV-2 Omicron diverse spike gene mutations identifies multiple inter-variant recombination events.

The current pandemic of COVID-19 is fueled by more infectious emergent Omicron variants. Ongoing concerns of emergent variants include possible recombinants, as genome recombination is an important evolutionary mechanism for the emergence and re-emergence of human viral pathogens. In this study, we identified diverse recombination events between two Omicron major subvariants (BA.1 and BA.2) and other variants of concern (VOCs) and variants of interest (VOIs), suggesting that co-infection and subsequent genome recombination play important roles in the ongoing evolution of SARS-CoV-2. Through scanning high-quality completed Omicron spike gene sequences, 18 core mutations of BA.1 (frequency >99%) and 27 core mutations of BA.2 (nine more than BA.1) were identified, of which 15 are specific to Omicron. BA.1 subvariants share nine common amino acid mutations (three more than BA.2) in the spike protein with most VOCs, suggesting a possible recombination origin of Omicron from these VOCs. There are three more Alpha-related mutations in BA.1 than BA.2, and BA.1 is phylogenetically closer to Alpha than other variants. Revertant mutations are found in some dominant mutations (frequency >95%) in the BA.1. Most notably, multiple characteristic amino acid mutations in the Delta spike protein have been also identified in the "Deltacron"-like Omicron Variants isolated since November 11, 2021 in South Africa, which implies the recombination events occurring between the Omicron and Delta variants. Monitoring the evolving SARS-CoV-2 genomes especially for recombination is critically important for recognition of abrupt changes to viral attributes including its epitopes which may call for vaccine modifications.

V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity.

The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.

Impact of SARS-CoV-2 on Ocular Surface Pathology and Treatment Practices: a Review.

PURPOSE OF REVIEW: The ocular surface is a potential site of ocular involvement by SARS-CoV-2 infection. We performed a review of the literature to understand the pathogenesis of SARS-CoV-2 disease manifestations on the ocular surface as well as to elucidate emerging treatment patterns and practice changes during the COVID-19 pandemic. RECENT FINDINGS: The ocular manifestations of SARS-CoV-2 are likely limited to a mild and transient conjunctivitis. Other manifestations have not been validated in larger cohorts. Ocular surface tissue should be considered potentially infectious due to the presence of host receptors on surface tissues. The availability of donor tissue in lower-middle income countries has been greatly impacted by the pandemic and would benefit from further investigation into transmissibility through donor tissue. SUMMARY: Transmission of SARS-CoV-2 through the ocular surface has yet to be confirmed. The most common ocular manifestation is a mild conjunctivitis. Ocular surface surgeons face specific challenges in the use of donor tissues and aerosolizing procedures and have adapted practice patterns accordingly.

Towards global control of parasitic diseases in the Covid-19 era: One Health and the future of multisectoral global health governance.

Human parasitic infections-including malaria, and many neglected tropical diseases (NTDs)-have long represented a Gordian knot in global public health: ancient, persistent, and exceedingly difficult to control. With the coronavirus disease (Covid-19) pandemic substantially interrupting control programmes worldwide, there are now mounting fears that decades of progress in controlling global parasitic infections will be undone. With Covid-19 moreover exposing deep vulnerabilities in the global health system, the current moment presents a watershed opportunity to plan future efforts to reduce the global morbidity and mortality associated with human parasitic infections. In this chapter, we first provide a brief epidemiologic overview of the progress that has been made towards the control of parasitic diseases between 1990 and 2019, contrasting these fragile gains with the anticipated losses as a result of Covid-19. We then argue that the complementary aspirations of the United Nations Sustainable Development Goals (SDGs) and the World Health Organization (WHO)'s 2030 targets for parasitic disease control may be achieved by aligning programme objectives within the One Health paradigm, recognizing the interdependence between humans, animals, and the environment. In so doing, we note that while the WHO remains the preeminent international institution to address some of these transdisciplinary concerns, its underlying challenges with funding, authority, and capacity are likely to reverberate if left unaddressed. To this end, we conclude by reimagining how models of multisectoral global health governance-combining the WHO's normative and technical leadership with greater support in allied policy-making areas-can help sustain future malaria and NTD elimination efforts.

The era of artificial intelligence and virtual reality: transforming surgical education in ophthalmology.

Training the modern ophthalmic surgeon is a challenging process. Microsurgical education can benefit from innovative methods to practice surgery in low-risk simulations, assess and refine skills in the operating room through video content analytics, and learn at a distance from experienced surgeons. Developments in emerging technologies may allow us to pursue novel forms of instruction and build on current educational models. Artificial intelligence, which has already seen numerous applications in ophthalmology, may be used to facilitate surgical tracking and evaluation. Within immersive technology, growth in the space of virtual reality head-mounted displays has created intriguing possibilities for operating room simulation and observation. Here, we explore the applications of these technologies and comment on their future in ophthalmic surgical education.

COVID-19: Coronavirus Vaccine Development Updates.

Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a newly emerged coronavirus, and has been pandemic since March 2020 and led to many fatalities. Vaccines represent the most efficient means to control and stop the pandemic of COVID-19. However, currently there is no effective COVID-19 vaccine approved to use worldwide except for two human adenovirus vector vaccines, three inactivated vaccines, and one peptide vaccine for early or limited use in China and Russia. Safe and effective vaccines against COVID-19 are in urgent need. Researchers around the world are developing 213 COVID-19 candidate vaccines, among which 44 are in human trials. In this review, we summarize and analyze vaccine progress against SARS-CoV, Middle-East respiratory syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, including inactivated vaccines, live attenuated vaccines, subunit vaccines, virus like particles, nucleic acid vaccines, and viral vector vaccines. As SARS-CoV-2, SARS-CoV, and MERS-CoV share the common genus, Betacoronavirus, this review of the major research progress will provide a reference and new insights into the COVID-19 vaccine design and development.

COVID-19 and the Unfinished Agenda of VISION 2020.

PURPOSE: To critically evaluate the potential impact of the coronavirus disease (COVID-19) pandemic on global ophthalmology and VISION 2020. DESIGN: Perspective supplemented with epidemiologic insights from available online databases. METHODS: We extracted data from the Global Vision Database (2017) and Global Burden of Disease Study (2017) to highlight temporal trends in global blindness since 1990, and provide a narrative overview of how COVID-19 may derail progress toward the goals of VISION 2020. RESULTS: Over 2 decades of VISION 2020 advocacy and program implementation have culminated in a universal reduction of combined age-standardized prevalence of moderate-to-severe vision impairment (MSVI) across all world regions since 1990. Between 1990 and 2017, low-income countries observed large reductions in the age-standardized prevalence per 100,000 persons of vitamin A deficiency (25,155 to 19,187), undercorrected refractive disorders (2,286 to 2,040), cataract (1,846 to 1,690), onchocerciasis (5,577 to 2,871), trachoma (506 to 159), and leprosy (36 to 26). Despite these reductions, crude projections suggest that more than 700 million persons will experience MSVI or blindness by 2050, principally owing to our growing and ageing global population. CONCLUSIONS: Despite the many resounding successes of VISION 2020, the burden of global blindness and vision impairment is set to reach historic levels in the coming years. The impact of COVID-19, while yet to be fully determined, now threatens the hard-fought gains of global ophthalmology. The postpandemic years will require renewed effort and focus on vision advocacy and expanding eye care services worldwide.

SARS-CoV-2 and the Eye: Implications for the Retina Specialist from Human Coronavirus Outbreaks and Animal Models.

PURPOSE: The current SARS-CoV-2 pandemic has escalated rapidly since December 2019. Understanding the ophthalmic manifestations in patients and animal models of the novel coronavirus may have implications for disease surveillance. Recognition of the potential for viral transmission through the tear film has ramification for protection of patients, physicians, and the public. METHODS: Information from relevant published journal articles was surveyed using a computerized PubMed search and public health websites. We summarize current knowledge of ophthalmic manifestations of SARS-CoV-2 infection in patients and animal models, risk mitigation measures for patients and their providers, and implications for retina specialists. RESULTS: SARS-CoV-2 is efficiently transmitted among humans, and while the clinical course is mild in the majority of infected patients, severe complications including pneumonia, acute respiratory distress syndrome, and death can ensue, most often in elderly patients and individuals with co-morbidities. Conjunctivitis occurs in a small minority of patients with COVID-19 and SARS-CoV-2 RNA has been identified primarily in association with conjunctivitis. Uveitis has been observed in animal models of coronavirus infection and cotton-wool spots have been reported recently. CONCLUSION: SARS-CoV-2 and other coronaviruses have been rarely associated with conjunctivitis. The identification of SARS-CoV and SARS-CoV-2 RNA in the tear film of patients and its highly efficient transmission via respiratory aerosols supports eye protection, mask and gloves as part of infection prevention and control recommendations for retina providers. Disease surveillance during the COVID-19 pandemic outbreak may also include ongoing evaluation for uveitis and retinal disease given prior findings observed in animal models and a recent report of retinal manifestations.