Team Science to maximize rapid collection and analyses of biosamples from patients with Covid-19

IMPACT: Indiana CTSI Team Science to maximize rapid collection, analyses and dissemination of biosamples collected from patients with Covid-19 to provide preliminary data for grant applications on the pathogenesis and outcomes of patients with Covid-19. OBJECTIVES/GOALS: When Covid-19 hit Indiana in April, there was an immediate need to respond rapidly to coordinate research across our healthcare systems. The CTSI became a point of contact for coordinating research endeavors including activation of clinical trials and use of precious samples from patients with Covid-19 to maximize preliminary data for grants. METHODS/STUDY POPULATION: The Indiana CTSI coordinated collection of biospecimens at multiple hospitals using in person and remote consenting via telephone or on a smartphone utilizing a QR code. We also retrieved existing samples from the Indiana Biobank previously collected for future research and from subject positive for Covid-19 by search of the linked electronic health record (EHR). A total of 224 subject samples (7 children, 36 previously collected, and 6 with both acute and recovered specimens) were obtained over a four month period. Our CTSI cores ran varied analyses collated to a single database, linked to the EMR for use as preliminary data for grant applications to avoid redundancy of measures on limited samples. RESULTS/ANTICIPATED RESULTS: The 224 subject samples were used for whole exome DNA sequencing, RNA seq, analyses of 48 plasma cytokine/chemokines by multiplex analyses, and PBMC isolated for culture and assessment of secreted cytokines. The clinical data were linked and included demographics, hospitalization length of stay and need for mechanical ventilation, max and min oxygen levels, liver function tests, IL-6, D-dimer, CRP, LDH, and ferritin, need for dialysis, and echocardiography. Additional clinical data were available upon request. A survey was sent to our CTSI email to query for potential interest in the data with 87 inquiries, and to date 46 investigators have requested data and/or additional samples. DISCUSSION/SIGNIFICANCE OF FINDINGS: During the first surge of Covid-19, the CTSI coordinated analyses for the dissemination of results for use by CTSI investigators to minimize duplication of assays and increase availability. The collaboration of research coordinators, biobank, research cores, and informatics demonstrates the power and agility of team science in the Indiana CTSI.

The Multi-Time Scale Changes in Air Pollutant Concentrations and Its Mechanism before and during the COVID-19 Periods: A Case Study from Guiyang, Guizhou Province

The lockdown during the coronavirus disease 2019 (COVID-19) pandemic provides a scarce opportunity to assess the efficiency of air pollution mitigation. Herein, the monitoring data of air pollutants were thoroughly analyzed together with meteorological parameters to explore the impact of human activity on the multi-time scale changes of air pollutant concentrations in Guiyang city, located in Southwest China. The results show that the COVID-19 lockdown had different effects on the criteria air pollutants, i.e., PM2.5 (diameter ≤ 2.5 μm), PM10 (diameter ≤ 10 μm), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) concentrations. The lockdown caused a significant drop in NO2 concentration. During the first-level lockdown period, the NO2 concentration declined sharply by 8.41 μg·m−3 (45.68%). The decrease in NO concentration caused the “titration effect” to weaken, leading to a sharp increase in O3 concentration. Although human activities resumed partially and the “titration effect” enhanced certainly during the second-level lockdown period, the meteorological conditions became more conducive to the formation of O3 by photochemical reactions. Atmosphere oxidation was enhanced to promote the generation of secondary aerosols through gas–particle transitions, thus compensating for the reduced primary emission of PM2.5. The implication of this study is that the appropriate air pollution control policies must be initiated to suppress the secondary generation of both PM2.5 and O3.

A Treatment to Eliminate SARS-CoV-2 Replication in Human Airway Epithelial Cells Is Safe for Inhalation as an Aerosol in Healthy Human Subjects.

BACKGROUND: Low airway surface pH is associated with many airway diseases, impairs antimicrobial host defense, and worsens airway inflammation. Inhaled Optate is designed to safely raise airway surface pH and is well tolerated in humans. Raising intracellular pH partially prevents activation of SARS-CoV-2 in primary normal human airway epithelial (NHAE) cells, decreasing viral replication by several mechanisms. METHODS: We grew primary NHAE cells from healthy subjects, infected them with SARS-CoV-2 (isolate USA-WA1/2020), and used clinical Optate at concentrations used in humans in vivo to determine whether Optate would prevent viral infection and replication. Cells were pretreated with Optate or placebo prior to infection (multiplicity of infection = 1), and viral replication was determined with plaque assay and nucleocapsid (N) protein levels. Healthy human subjects also inhaled Optate as part of a Phase 2a safety trial. RESULTS: Optate almost completely prevented viral replication at each time point between 24 h and 120 h, relative to placebo, on both plaque assay and N protein expression (P < .001). Mechanistically, Optate inhibited expression of major endosomal trafficking genes and raised NHAE intracellular pH. Optate had no effect on NHAE cell viability at any time point. Inhaled Optate was well tolerated in 10 normal subjects, with no change in lung function, vital signs, or oxygenation. CONCLUSIONS: Inhaled Optate may be well suited for a clinical trial in patients with pulmonary SARS-CoV-2 infection. However, it is vitally important for patient safety that formulations designed for inhalation with regard to pH, isotonicity, and osmolality be used. An inhalational treatment that safely prevents SARS-CoV-2 viral replication could be helpful for treating patients with pulmonary SARS-CoV-2 infection.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment.

BACKGROUND: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. METHODS: In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION: Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

Prevalence of Venous Thromboembolism in Critically Ill Patients With Coronavirus Disease 2019: A Meta-Analysis.

Background: Accumulating evidence suggests that coronavirus disease 2019 (COVID-19) is associated with hypercoagulative status, particularly for critically ill patients in the intensive care unit. However, the prevalence of venous thromboembolism (VTE) in these patients under routine prophylactic anticoagulation remains unknown. A meta-analysis was performed to evaluate the prevalence of VTE in these patients by pooling the results of these observational studies. Methods: Observational studies that reported the prevalence of VTE in critically ill patients with COVID-19 were identified by searching the PubMed and Embase databases. A random-effect model was used to pool the results by incorporating the potential heterogeneity. Results: A total of 19 studies with 1,599 patients were included. The pooled results revealed that the prevalence of VTE, deep venous thrombosis (DVT), and pulmonary embolism (PE) in critically ill patients with COVID-19 was 28.4% [95% confidence interval (CI): 20.0-36.8%], 25.6% (95% CI: 17.8-33.4%), and 16.4% (95% CI: 10.1-22.7%), respectively. Limited to studies, in which all patients received routine prophylactic anticoagulation, and the prevalence for VTE, DVT, and PE was 30.1% (95% CI: 19.4-40.8%), 27.2% (95% CI: 16.5-37.9%), and 18.3% (95% CI: 9.8%-26.7%), respectively. The prevalence of DVT was higher in studies with routine screening for all patients, when compared to studies with screening only in clinically suspected patients (47.5% vs. 15.1%, P < 0.001). Conclusion: Critically ill patients with COVID-19 have a high prevalence of VTE, despite the use of present routine prophylactic anticoagulation.

Impact of the COVID-19 Lockdown on Air Quality Trends in Guiyang, Southwestern China

The absence of motor vehicle traffic and suspended human activities during the COVID-19 lockdown period in China produced a unique experiment to assess the efficiency of air pollution mitigation. Herein, we synthetically analyzed monitoring data of atmospheric pollutants together with meteorological parameters to investigate the impact of human activity pattern changes on air quality in Guiyang, southwestern China. The results show that the Air Quality Index (AQI) during the lockdown period decreased by 7.4% and 23.48% compared to pre-lockdown levels and the identical lunar period during the past 3 years, respectively, which exhibited optimal air quality due to reduced emissions. The sharp decrease in NO2 concentration reduced the “titration” effect and elevated the O3 concentration by 31.94% during the lockdown period. Meteorological conditions significantly impacted air quality, and serious pollution events might also occur under emission reductions. Falling wind speeds and increasing relative humidity were the direct causes of the pollution event on February 1st. The “first rain” increases the hygroscopicity of atmospheric particulate matter and then elevate its concentration, while continuous rainfall significantly impacted the removal of atmospheric particulate matter. As impacted by the lockdown, the spatial distribution of the NO2 concentration sharply decreased on the whole, while the O3 concentration increased significantly. The implications of this study are as follows: Measures should be formulated to prevent O3 pollution when emission reduction measures are being adopted to improve air quality, and an emphasis should be placed on the impact of secondary aerosols formation by gas-particle conversion.