Systemic and Laboratory Risk Factors for Retinopathy and Detection of Tear Film SARS-CoV-2 RNA

Purpose : Coronavirus-19 (COVID-19) has been associated with ophthalmic manifestations. The relationship between tear film SARS-CoV-2 RNA, timing of illness and eye disease are unknown. We evaluated hospitalized COVID-19 inpatients for retinopathy and tear film viral RNA. Methods : Hospitalized COVID-19 inpatients were offered enrollment from January-June 2021. Full dilated ophthalmic examination and conjunctival swabs were taken for triplex RT-PCR for SARS-CoV-2 RNA targeting N2, E and RNAse P. Demographic, clinical outcomes and laboratory data were collected. Univariate and multivariate analyses of systemic disease and laboratory risk factors for retinopathy and SARS-CoV-2 RNA detection were assessed. Results : Sixty patients were prospectively enrolled in this cross-sectional, observational study. The mean age was 58.8 years (Standard deviation [SD] 15.2 years) and 29 (48%) were female. Retinopathy associated with COVID-19 in 12 of 60 patients (20%). Univariate analyses revealed that younger age, greater body mass index (BMI) and extracorporeal membrane (ECMO) requirement were associated with increased odds of COVID-19 retinopathy. The mean age (SD) of patients with COVID-19 retinopathy was 49.0. (11.6) compared to 61.2 (15.1) years in individuals without retinopathy (p=0.01). The mean BMI was 38.8 (9.8) in patients with retinopathy compared to 31.8 (9.0) in those without retinal disease findings (p=0.04). ECMO requirement was observed in 33% of patients with retinopathy compared to 8% in those without retinopathy (p=0.04). Multivariate analyses trended towards increased risk of retinopathy with younger age (aOR 0.95 (95% CI 0.90- 1.01, p=0.095) and with increased BMI (aOR. 1.08, 95% CI 1.00-1.18, p=0.056). Fifteen of 60 patients (25%) tested positive in their tear film for SARS-CoV-2 RNA with a trend towards a shorter length of illness and hospitalization in patients who were positive. The N2 gene was particularly sensitive with 18 of 19 eyes (94.7%) showing N2-positivity (with or without E gene detection), including 2 patients in whom the B.117 / B.1.525 alpha or ?United Kingdom? variant was detected. Conclusions : A 20% rate of retinopathy was observed and SARS-CoV-2 RNA within tear film was detected in 25% of hospitalized COVID-19 patients. Continued infection control precautions are required given the risk of viral RNA in tear film, which may also be sensitive for the detection of COVID-19 variants.

Tourists’ travel intention: revisiting the TPB model with age and perceived risk as moderator and attitude as mediator

Purpose: This study aims to understand tourists’ travel intention during the COVID-19 pandemic by using the theory of planned behavior (TPB) with additional causal links and moderators. The three research objectives of this study are to explore basic causality, mediating effects of attitude and moderating effects of age and perceived risk, of the extended TPB model, respectively. Design/methodology/approach: An online survey was conducted in Taiwan during the COVID-19 pandemic. In total, the survey generated 351 responses. The structural model analysis was performed to test the cause-and-effect relationships in the traditional TPB model and the mediating role of an individual’s attitude regarding travel during the COVID-19 pandemic. The SmartPLS multi-group analysis procedure was applied to test the moderation effects of age and perceived risk. Findings: It is found that the perceived behavioral control is the main contributor of travel intention for the traditional TPB while attitude partially mediates the relationship between subjective norm and travel intention for the test of mediation. Also, moderation tests confirm that both age and perceived risk show significant moderating effect only on subjective norm to travel intention relationship. Originality/value: The novelty of this research is that this study proposed and verified the mediating influence of attitude and two additional paths, the moderating influence of age and perceived risk, which deepened the understanding of the TPB model and the impact of COVID-19 on travel intention. Because TPB model is context-dependent, using one mediating and two moderating variables allows the study to understand how TPB functions in a different situation. © 2022, Emerald Publishing Limited.

A VR-based Training and Intelligent Assessment System Integrated with Multi-modal Sensing for Children with Autism Spectrum Disorder

Autism Spectrum Disorder (ASD) exhibits social communication and social interaction disorders, and abnormal restrictive and repetitive behaviors. However, symptoms of infants less than 1-year-old are difficult to reliably predict subsequent diagnosis. Patients with mild ASD may not be discovered until school age, because schools have more opportunities for social activities. In addition, the therapist also needs to consider the labor cost. To provide effective treatment, it also needs to consume more resources. The current situation in Taiwan is that outlying islands and remote areas often have insufficient manpower for therapists. If VR technology can be applied, some of the problems may be solved. However, due to the global pandemic, COVID-19, early treatments or group treatments in many countries have been forced to stop. If VR technology can provide interpersonal interaction scenes, the training of ASD children can hardly be affected.This research uses Virtual Reality (VR) technology, combined with wearable multi-model sensing technology, including EEG, eye tracking, heart rate variability (HRV), and breath-sensing strap. Physiological signals and game performance data are collected while users are training, and integrate multiple evaluation scales such as ADOS, SRS, and CBCL. Statistical analysis of these data is performed to classify them through machine learning models to develop a VR assistance system that can be used to evaluate the diagnosis, severity, and social behavior treatment of ASD. This system presents assessment and therapy in a game-oriented way. In addition to enhancing the incentives for users to participate, it provides better training results than traditional training. It is also an effective and convenient tool for the therapist to use during evaluation and training. © 2021 IEEE.

COVID-19-related Versus Non-Viral Acute Respiratory Distress Syndrome: Comparison of Upper Airway Molecular Pathway and Drug Discovery Design based on Systems Biology and Deep Learning Methods

The coronavirus disease 2019 (COVID-19) epidemic is currently raging around the world with a rapid speed. Among the COVID-19 patients, SARS-CoV-2 associated acute respiratory distress syndrome (ARDS) is the main contribution to the high ratio of morbidity and mortality. However, clinical manifestations between SARS-CoV-2-caused-ARDS and non-SARS-CoV-2-caused-ARDS are quite common and their therapy is limited owing to the intricated pathophysiology are not fully understood. In this study, we constructed a candidate host-pathogen interspecies genome-wide genetic and epigenetic network (HPI-GWGEN) via database mining at first. With the help of host-pathogen microarray data, real HPI-GWGEN of COVID-19-ARDS and Non-Viral-ARDS were obtained by system modeling, system identification and Akaike information criterion (AIC) of model order selection method to delete the false positives in candidate HPI-GWGEN. Afterwards, principal network projection (PNP) approach is utilized to extract core HPI-GWGEN and their core signaling pathways of COVID-19-ARDS and Non-Viral-ARDS annotated by KEGG pathways. In order to design multiple-molecule drugs of COVID-19-ARDS and Non-Viral-ARDS, we identified essential biomarkers of pathogenesis by comparing the core signal pathways between COVID-19-ARDS and Non-Viral-ARDS. The deep neural network of drug-target interaction model (DNN-DTI) would be trained by drug-target interaction databases in advance to predict candidate drugs for the identified biomarkers. We further narrowed down these predicted drug candidates as potential multiple-molecule drug by filters of drug design specifications, including regulation ability, sensitivity, excretion, toxicity and drug-likeness. Taken together, we not only enlighten the etiologic mechanisms under COVID-19-ARDS but also provided novel therapeutic options for COVID-19-ARDS and Non-viral-ARDS. © 2021 IEEE

Targeting TMPRSS2 and ACE2 through AR degradation inhibits SARS-COV-2 pseudotype viral entry

Introduction: TMPRSS2 and ACE2 are critical surface proteins enabling cell infection by SARS-CoV-2 and some respiratory viruses. Androgen receptor regulates TMPRSS2 and ACE2 expression. Male gender is one of the risk factors in the increasing mortality and severe COVID-19 infection. Targeting androgen receptor degradation is a proposed strategy for therapy and prevention of SARS-CoV-2 infections. Objectives: We study the expression of AR, TMPRSS2 and ACE2 by treating with small molecule AR degradation enhancers, then examine the effect of supression SARS-CoV-2 pseudotyped viral particles entry after inducing AR degradation. Methods: Small molecule AR degradation enhencers Asc-JM-17 and Asc-JM-176 were obtained from ALLIANZ PHARMASCIENCE LTD. (Taipei, TWN). The expression of AR, TMPRSS2 and ACE2 were studied by western blotting. Small hairpin RNA lentivirus against AR and control lentivirus were tranfected to knockdown AR in A549, H1299 and CL1-5 cell lines. SARS-CoV-2 spike fusion protein pseudotyped viral particles were purchased from RNAi Core Lab in Academia Sinica. Peudotyped viral assay was performed in HEK293T/17 ACE2-pBsd cells. DHT, hydroxyflutamide, enzalutamide(MDV3100), Asc-JM-17, and Asc- JM-176 were applied to A549, H1299, CL1-5, HEK293T/17 ACE2-pBsd cells. Results: Asc-JM-17 and Asc-JM-176 rather than hydroxyflutamide and enzalutamide inhibits AR, TMPRSS2 and ACE2 in a dose- and timedependent manner. The suppression effect of Asc-JM-17 and Asc- JM-176 on TMPRSS2 expression was partially reversed by knockdown AR with shAR lentivirus infection. Asc-JM-17 and Asc-JM-176 rather then hydroxyflutamid and enzalutamide robustly prevent the pseudotyped viral particles in entry of HEK293T/17 ACE2-pBsd cells with EC50 at 1.2 μM and 3.3 μM respectively. Finally Asc-JM-17 and Asc-JM-176 were safely administered in mice for 35 days without obvious toxicity. Conclusion: Take together, our results support that application of Asc-JM-17 and Asc-JM-176 through targeting AR degradation is a novel strategy for therapy and prevention of respiratoy viral infection such as SARS-CoV-2. Suppression of SARS-CoV-2 viral culture and animal model with AR degradation enhancers merit further study. (Figure Presented).

COVID-19 associated retinopathy

Purpose : Coronavirus disease (COVID-19) has escalated to a global pandemic with increasing reports of ophthalmic disease. We report ophthalmic observations of hospitalized COVID-19 patients and correlate retinal disease findings with clinical and laboratory data. Methods : Retrospective review of COVID-19 patients who underwent ophthalmic exam during hospitalization within Emory Healthcare between April-July 2020. Results : Thirty-seven patients were examined with 23 (62%) females and a mean age of 54 years. 35 patients were admitted to the ICU. Ophthalmic manifestations included conjunctival injection in 12 eyes (17%), chemosis in 8 (11%) and retinopathy in 20 eyes (27%) with bilateral retinopathy in 6 patients (16%). No difference in baseline comorbidities or COVID-19 complication development was observed between patients with and without retinopathy. However, patients with retinopathy required ICU care for 1 week longer than those without retinopathy (27.6 vs 19.9 days p=0.19). The mean sequential organ failure assessment score at ICU admission was 6.18. All patients with retinopathy required both mechanical ventilation and vasopressors, while in patients without retinopathy, 15 (65%) and 12 (52%) required mechanical ventilation and vasopressors respectively (p=0.015, p=0.002). 6 patients with retinopathy required extracorporal membrane oxygenation compared to 1 without retinopathy (p=0.0070). While the mean peak D-Dimer was elevated at 18477, in the entire cohort, the peak D-Dimer was higher in patients with retinopathy (28,971 vs 12,575, p=0.0298). The fibrinogen nadir during hospitalization was on average 338 for the entire cohort, and reduced in patients with retinopathy (262 vs 381, p=0.029). Peak D-dimer analyses with a threshold of 16,508 showed an odds ratio of 16.7 (95% CI 3.11-89.3) for retinopathy. Fibrinogen nadir with a threshold of 367 showed odds ratio of 0.06 (95% CI 0.01-0.53) with 0.75 concordance. Conclusions : Retinopathy was the most common ophthalmic manifestation in a critically ill COVID-19 population, exceeding 25% of patients. Elevated D-dimers and a lower fibrinogen nadir in patients with retinopathy suggest a pathogenic relationship between coagulation pathways and retinal microangiopathy.

World Health Organization High Priority Pathogens: Ophthalmic Disease Findings and Vision Health Perspectives

Recent Ebola epidemics, the ongoing COVID-19 pandemic, and emerging infectious disease threats have highlighted the importance of global infectious diseases and responses to public health emergencies. Ophthalmologists are essential health care workers who provide urgent and emergent vision care services during outbreaks and address the ocular consequences of epidemic and pandemic infectious diseases. In 2017, the World Health Organization (WHO) identified high priority pathogens likely to cause a future epidemic with the goal of guiding research and development to improve diagnostic tests, vaccines, and medicines. These measures were necessary to better inform and respond to public health emergencies. Given the ocular complications associated with emerging infectious diseases, there is a need to recognize the ophthalmic sequelae for future vision health preparedness for potential future outbreaks. The WHO High Priority pathogens list provides a roadmap for ophthalmologists and subspecialty providers that will guide strategic areas of research for clinical care and preparedness for future pandemic threats. This review summarizes these key viral pathogens, summarizes major systemic disease findings, and delineates relevant ocular complications of the WHO High Priority pathogens list, including Crimean-Congo hemorrhagic fever, Filovirus diseases (Ebola virus disease and Marburg hemorrhagic fever), human Coronaviruses, Lassa Fever, Nipah virus infection, Zika, and Rift Valley fever.

Ebola, Emerging Infectious Diseases, and the Eye: Prepared for the Journal of the National Medical Association Special Issue Date of Presentation: August 2nd, 2020

Background: With the increasing impact of Ebola virus disease (EVD) in sub-Saharan Africa, the global health community has recognized that EVD survivors are at high risk for uveitis, an ocular inflammatory condition that may lead to vision loss. These findings have immediate relevance, particularly as the ongoing COVID-19 pandemic has heightened our awareness of emerging infectious diseases (EIDs). Key Findings and Results: A range of infectious diseases including Ebola, Zika, and COVID-19 may show ophthalmic manifestations, which may be associated with ocular viral RNA presence.1 We previously cared for a U.S. health care worker and EVD survivor who developed a severe, sight-threatening panuveitis during EVD convalescence, which was associated with ocular Ebola virus persistence.2 Our evaluation of EVD survivors in Liberia led to the identification of uveitis in over 20% of EVD survivors, with vision impairment in 60% of eyes.3 The subsequent EVICT Study in Sierra Leone was performed to determine the prevalence of Ebola virus within the ocular fluid of patients needing cataract surgery. Our study results showed negative EBOV ocular fluid results by RT-PCR in 50 patients at a median of 18-34 following acute EVD. Patients who underwent cataract surgery showed vision restoration, improving from hand motions to 20/30 at three-months (P<0.001).4 Infrastructural support, training and rapid response teams are opportunities to prepare health systems for future EVD and EID outbreaks.1 Conclusions: Ebola and EIDs have demonstrated the importance of understanding ocular complications. Vision health systems preparedness will be particularly relevant as data emerges from the ongoing COVID-19 pandemic. References: 1. Bavinger JC, Shantha JG, Yeh S. Ebola, COVID-19, and emerging infectious disease: lessons learned and future preparedness. Curr Opin Ophthalmol 2020;315: 416-422. 2. Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med 2015;372: 2423-2427. 3. Shantha JG, Crozier I, Hayek, et al Ophthalmic manifestations and causes of vision impairment in Ebola virus disease survivors in Monrovia, Liberia 2017;124: 170-177. 4. Shantha JG, Mattia JG, Goba A, et al. Ebola virus persistence in ocular tissues and fluids (EVICT) study: Reverse transcription-polymerase chain reaction and cataract surgery outcomes of Ebola survivors in Sierra Leone. EBioMedicine 2018;30: 217-224.