Antiviral Efficacies of FDA-Approved Drugs against SARS-CoV-2 Infection in Ferrets.

Due to the urgent need of a therapeutic treatment for coronavirus (CoV) disease 2019 (COVID-19) patients, a number of FDA-approved/repurposed drugs have been suggested as antiviral candidates at clinics, without sufficient information. Furthermore, there have been extensive debates over antiviral candidates for their effectiveness and safety against severe acute respiratory syndrome CoV 2 (SARS-CoV-2), suggesting that rapid preclinical animal studies are required to identify potential antiviral candidates for human trials. To this end, the antiviral efficacies of lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir for SARS-CoV-2 infection were assessed in the ferret infection model. While the lopinavir-ritonavir-, hydroxychloroquine sulfate-, or emtricitabine-tenofovir-treated group exhibited lower overall clinical scores than the phosphate-buffered saline (PBS)-treated control group, the virus titers in nasal washes, stool specimens, and respiratory tissues were similar between all three antiviral-candidate-treated groups and the PBS-treated control group. Only the emtricitabine-tenofovir-treated group showed lower virus titers in nasal washes at 8 days postinfection (dpi) than the PBS-treated control group. To further explore the effect of immune suppression on viral infection and clinical outcome, ferrets were treated with azathioprine, an immunosuppressive drug. Compared to the PBS-treated control group, azathioprine-immunosuppressed ferrets exhibited a longer period of clinical illness, higher virus titers in nasal turbinate, delayed virus clearance, and significantly lower serum neutralization (SN) antibody titers. Taken together, all antiviral drugs tested marginally reduced the overall clinical scores of infected ferrets but did not significantly affect in vivo virus titers. Despite the potential discrepancy of drug efficacies between animals and humans, these preclinical ferret data should be highly informative to future therapeutic treatment of COVID-19 patients.IMPORTANCE The SARS-CoV-2 pandemic continues to spread worldwide, with rapidly increasing numbers of mortalities, placing increasing strain on health care systems. Despite serious public health concerns, no effective vaccines or therapeutics have been approved by regulatory agencies. In this study, we tested the FDA-approved drugs lopinavir-ritonavir, hydroxychloroquine sulfate, and emtricitabine-tenofovir against SARS-CoV-2 infection in a highly susceptible ferret infection model. While most of the drug treatments marginally reduced clinical symptoms, they did not reduce virus titers, with the exception of emtricitabine-tenofovir treatment, which led to diminished virus titers in nasal washes at 8 dpi. Further, the azathioprine-treated immunosuppressed ferrets showed delayed virus clearance and low SN titers, resulting in a prolonged infection. As several FDA-approved or repurposed drugs are being tested as antiviral candidates at clinics without sufficient information, rapid preclinical animal studies should proceed to identify therapeutic drug candidates with strong antiviral potential and high safety prior to a human efficacy trial.

Prevalence and risk characteristics of COVID-19 in outpatients: A cross-sectional study of New York-area clinics.

Outpatients can be at heightened risk of COVID-19 due to interaction between existing non-communicable diseases in outpatients and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study measured the magnitude of COVID-19 prevalence and explored related risk characteristics among adult outpatients visiting medicine clinics within a New York state-based tertiary hospital system. Data were compiled from 63,476 adult patients visiting outpatient medicine clinics within a New York-area hospital system between March 1, 2020, and August 28, 2020. The outcome was a clinical diagnosis of COVID-19. Crude and adjusted prevalence ratios (PR) of a COVID-19 were analyzed using univariable and multivariable Poisson regression with robust standard errors. The prevalence of COVID-19 was higher among these outpatients (3.0%) than in the total population in New York State (2.2%) as of August 28, 2020. Multivariable analysis revealed adjusted prevalence ratios significantly greater than one for male sex (PR=1.10), age 40 to 64 compared to <40 (PR=1.19), and racial/ethnic minorities in comparison to White patients (Hispanic: PR=2.76; Black: PR=1.89; and Asian/others: PR=1.56). Nonetheless, factors including the advanced age of ≥65 compared to <40 (PR=0.69) and current smoking compared to non-smoking (PR=0.60) were related to significantly lower prevalence. Therefore, the prevalence of COVID-19 in outpatients was higher than that of the general population. The findings also enabled hypothesis generation that routine clinical measures comprising sex, age, race/ethnicity, and smoking were candidate risk characteristics of COVID-19 in outpatients to be further verified by designs capable of assessing temporal association.

Age-dependent pathogenic characteristics of SARS-CoV-2 infection in ferrets.

While the seroprevalence of SARS-CoV-2 in healthy people does not differ significantly among age groups, those aged 65 years or older exhibit strikingly higher COVID-19 mortality compared to younger individuals. To further understand differing COVID-19 manifestations in patients of different ages, three age groups of ferrets are infected with SARS-CoV-2. Although SARS-CoV-2 is isolated from all ferrets regardless of age, aged ferrets (≥3 years old) show higher viral loads, longer nasal virus shedding, and more severe lung inflammatory cell infiltration, and clinical symptoms compared to juvenile (≤6 months) and young adult (1-2 years) groups. Furthermore, direct contact ferrets co-housed with the virus-infected aged group shed more virus than direct-contact ferrets co-housed with virus-infected juvenile or young adult ferrets. Transcriptome analysis of aged ferret lungs reveals strong enrichment of gene sets related to type I interferon, activated T cells, and M1 macrophage responses, mimicking the gene expression profile of severe COVID-19 patients. Thus, SARS-CoV-2-infected aged ferrets highly recapitulate COVID-19 patients with severe symptoms and are useful for understanding age-associated infection, transmission, and pathogenesis of SARS-CoV-2.

Source Analysis and Effective Control of a COVID-19 Outbreak in a University Teaching Hospital during a Period of Increasing Community Prevalence of COVID-19.

BACKGROUND: South Korea has been experiencing a third wave of coronavirus disease 2019 (COVID-19) since mid-November 2020. Our hospital in Gwangju metropolitan city experienced a healthcare-associated COVID-19 outbreak early in the third wave. The first confirmed COVID-19 patient was a symptomatic neurosurgery resident with high mobility throughout the hospital. We analyzed the transmission routes of nosocomial COVID-19 and discussed infection control strategies. METHODS: We retrospectively analyzed the severe acute respiratory syndrome coronavirus 2 reverse transcription-polymerase chain reaction (RT-PCR) testing results according to time point and evaluated transmission routes. RESULTS: Since COVID-19 was first confirmed in a healthcare worker (HCW) on 11/13/2020, we performed RT-PCR tests for all patients and caregivers and four complete enumeration surveys for all HCWs. We detected three clusters of nosocomial spread and several sporadic cases. The first cluster originated from the community outbreak spot, where an asymptomatic HCW visited, which led to a total of 22 cases. The second cluster, which included patient-to-patient transmission, originated from a COVID-19 positive caregiver before diagnosis and the third cluster involved a radiologist and a banker. We took measures to isolate Building 1 of the hospital for 17 days and controlled the outbreak during a period of increasing community COVID-19 prevalence. Universal screening of all inpatients upon admission and resident caregivers was made mandatory and hospital-related employees are now screened monthly. CONCLUSION: Infection control strategies to prevent the nosocomial transmission of emerging infectious diseases must correspond with community disease prevalence. Our data reinforce the importance of multi-time point surveillance of asymptomatic HCWs and routine surveillance of patients and caregivers during an epidemic.

Global citizenship education through curriculum-as-relations.

The Covid-19 pandemic was a reminder of the importance of increasing connectivity amidst the accelerated rate of changes and disruptive events of our era. The need and the rationale for global citizenship education (GCED) were ever more emphasized by many educational organizations, including UNESCO. This article reviews the GCED discourses conceptualizing global competence as instrumental action and a binary view of global-local relations. In turn, the article proposes the idea of curriculum-as-relations for GCED. Curriculum-as-relations conceptualizes competence as situated praxis and focuses on providing authentic critical-translocal learning. Authentic critical-translocal learning through the strategy of comparison offers an alternative view of global-local relations as "articulated moments created by situated praxis". This new understanding of global-local relations may help different stakeholders to imagine GCED curricula beyond a Tylerian instrumentalist, ends-means orientation of curriculum.

Differences in seroprevalence between epicenter and non-epicenter areas of the COVID-19 outbreak in South Korea.

To compare the standardized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence of high epicenter region with non-epicenter region, serological studies were performed with a total of 3,268 sera from Daegu City and 3,981 sera from Chungbuk Province. Indirect immunofluorescence assay (IFA) for SARS-CoV-2 IgG results showed a high seroprevalence rate in the Daegu City (epicenter) compared with a non-epicenter area (Chungbuk Province) (1.27% vs. 0.91%, P = 0.0358). It is noteworthy that the highest seroprevalence in Daegu City was found in elderly patients (70's) whereas young adult patients (20's) in Chungbuk Province showed the highest seroprevalence. Neutralizing antibody (NAb) titers were found in three samples from Daegu City (3/3, 268, 0.09%) while none of the samples from Chungbuk Province were NAb positive. These results demonstrated that even following the large outbreak, the seropositive rate of SARS-CoV-2 in the general population remained low in South Korea.

Examination of patient characteristics and hydroxychloroquine use based on the US Food and Drug Administration's recommendation: a cross-sectional analysis in New York.

OBJECTIVE: To describe the pattern of hydroxychloroquine use and examine the association between hydroxychloroquine use and clinical outcomes arising from changes in the US Food and Drug Administration (FDA)'s recommendation during the coronavirus disease 2019 (COVID-19) pandemic. DESIGN: A retrospective cross-sectional analysis. SETTING AND PARTICIPANTS: We included hospitalised adult patients at Northwell Health hospitals with confirmed COVID-19 infections between 1 March 2020 and 11 May 2020. We categorised changes in the FDA's recommendation as pre-FDA approval (1 March 2020-27 March 2020), FDA approval (28 March 2020-23 April 2020), and FDA warning (24 April 2020-11 May 2020). The hydroxychloroquine-treated group received at least one dose within 48 hours of hospital admission. PRIMARY OUTCOME: A composite of intubation and inpatient death. RESULTS: The percentages of patients who were treated with hydroxychloroquine were 192/2202 (8.7%) pre-FDA approval, 2902/6741 (43.0%) FDA approval, and 176/1066 (16.5%) FDA warning period (p<0.001). Using propensity score matching, there was a higher rate of the composite outcome among patients treated with hydroxychloroquine (49/192, 25.5%) compared with no hydroxychloroquine (66/384, 17.2%) in the pre-FDA approval period (p=0.03) but not in the FDA approval period (25.5% vs 22.6%, p=0.08) or the FDA warning (21.0% vs 15.1%, p=0.11) periods. Coincidently, there was an increase in number of patients with COVID-19 and disease severity during the FDA approval period (24.1% during FDA approval vs 21.4% during pre-FDA approval period had the composite outcome). Hydroxychloroquine use was associated with increased odds of the composite outcome during the pre-FDA approval period (OR=1.65 (95% CI 1.09 to 2.51)) but not during the FDA approval (OR=1.17 (95% CI 0.99 to 1.39)) and FDA warning (OR=1.50 (95% CI 0.94 to 2.39)) periods. CONCLUSIONS: Hydroxychloroquine use was associated with adverse clinical outcomes only during the pre-FDA approval period but not during the FDA approval and warning periods, even after adjusting for concurrent changes in the percentage of patients with COVID-19 treated with hydroxychloroquine and the number (and disease severity) of hospitalised patients with COVID-19 infections.

Critical role of neutralizing antibody for SARS-CoV-2 reinfection and transmission.

Cases of laboratory-confirmed SARS-CoV-2 reinfection have been reported in a number of countries. Further, the level of natural immunity induced by SARS-CoV-2 infection is not fully clear, nor is it clear if a primary infection is protective against reinfection. To investigate the potential association between serum antibody titres and reinfection of SARS-CoV-2, ferrets with different levels of NAb titres after primary SARS-CoV-2 infection were subjected to reinfection with a heterologous SARS-CoV-2 strain. All heterologous SARS-CoV-2 reinfected ferrets showed active virus replication in the upper respiratory and gastro-intestinal tracts. However, the high NAb titre group showed attenuated viral replication and rapid viral clearance. In addition, direct-contact transmission was observed only from reinfected ferrets with low NAb titres (<20), and not from other groups. Further, lung histopathology demonstrated the presence of limited inflammatory regions in the high NAb titre groups compared with control and low NAb groups. This study demonstrates a close correlation between a low NAb titre and SARS-CoV-2 reinfection in a recovered ferret reinfection model.

BMI as a Risk Factor for Clinical Outcomes in Patients Hospitalized with COVID-19 in New York.

OBJECTIVE: This study examined the association between BMI and clinical outcomes among patients with coronavirus disease 2019 (COVID-19) infection. METHODS: A total of 10,861 patients with COVID-19 infection who were admitted to the Northwell Health system hospitals between March 1, 2020, and April 27, 2020, were included in this study. BMI was classified as underweight, normal weight, overweight, and obesity classes I, II, and III. Primary outcomes were invasive mechanical ventilation (IMV) and death. RESULTS: A total of 243 (2.2%) patients were underweight, 2,507 (23.1%) were normal weight, 4,021 (37.0%) had overweight, 2,345 (21.6%) had obesity class I, 990 (9.1%) had obesity class II, and 755 (7.0%) had obesity class III. Patients who had overweight (odds ratio [OR] = 1.27 [95% CI: 1.11-1.46]), obesity class I (OR = 1.48 [95% CI: 1.27-1.72]), obesity class II (OR = 1.89 [95% CI: 1.56-2.28]), and obesity class III (OR = 2.31 [95% CI: 1.88-2.85]) had an increased risk of requiring IMV. Underweight and obesity classes II and III were statistically associated with death (OR = 1.44 [95% CI: 1.08-1.92]; OR = 1.25 [95% CI: 1.03-1.52]; OR = 1.61 [95% CI: 1.30-2.00], respectively). Among patients who were on IMV, BMI was not associated with inpatient deaths. CONCLUSIONS: Patients who are underweight or who have obesity are at risk for mechanical ventilation and death, suggesting that pulmonary complications (indicated by IMV) are a significant contributor for poor outcomes in COVID-19 infection.

Machine learning to assist clinical decision-making during the COVID-19 pandemic.

BACKGROUND: The number of cases from the coronavirus disease 2019 (COVID-19) global pandemic has overwhelmed existing medical facilities and forced clinicians, patients, and families to make pivotal decisions with limited time and information. MAIN BODY: While machine learning (ML) methods have been previously used to augment clinical decisions, there is now a demand for "Emergency ML." Throughout the patient care pathway, there are opportunities for ML-supported decisions based on collected vitals, laboratory results, medication orders, and comorbidities. With rapidly growing datasets, there also remain important considerations when developing and validating ML models. CONCLUSION: This perspective highlights the utility of evidence-based prediction tools in a number of clinical settings, and how similar models can be deployed during the COVID-19 pandemic to guide hospital frontlines and healthcare administrators to make informed decisions about patient care and managing hospital volume.

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area.

Importance: There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). Objective: To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Design, Setting, and Participants: Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Exposures: Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Main Outcomes and Measures: Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. Results: A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). Conclusions and Relevance: This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.

Infection and Rapid Transmission of SARS-CoV-2 in Ferrets.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and rapidly spread worldwide. To prevent SARS-CoV-2 dissemination, understanding the in vivo characteristics of SARS-CoV-2 is a high priority. We report a ferret model of SARS-CoV-2 infection and transmission that recapitulates aspects of human disease. SARS-CoV-2-infected ferrets exhibit elevated body temperatures and virus replication. Although fatalities were not observed, SARS-CoV-2-infected ferrets shed virus in nasal washes, saliva, urine, and feces up to 8 days post-infection. At 2 days post-contact, SARS-CoV-2 was detected in all naive direct contact ferrets. Furthermore, a few naive indirect contact ferrets were positive for viral RNA, suggesting airborne transmission. Viral antigens were detected in nasal turbinate, trachea, lungs, and intestine with acute bronchiolitis present in infected lungs. Thus, ferrets represent an infection and transmission animal model of COVID-19 that may facilitate development of SARS-CoV-2 therapeutics and vaccines.