Background: Understanding the impact of the COVID-19 pandemic on healthcare workers (HCW) is crucial. Objective: Utilizing a health system COVID-19 research registry, we assessed HCW risk for COVID-19 infection, hospitalization and intensive care unit (ICU) admission. Design: Retrospective cohort study with overlap propensity score weighting. Participants: Individuals tested for SARS-CoV-2 infection in a large academic healthcare system (N=72,909) from March 8-June 9 2020 stratified by HCW and patient-facing status. Main Measures: SARS-CoV-2 test result, hospitalization, and ICU admission for COVID-19 infection. Key Results: Of 72,909 individuals tested, 9.0% (551) of 6,145 HCW tested positive for SARS-CoV-2 compared to 6.5% (4353) of 66,764 non-HCW. The HCW were younger than non-HCW (median age 39.7 vs. 57.5, p<0.001) with more females (proportion of males 21.5 vs. 44.9%, p<0.001), higher reporting of COVID-19 exposure (72 vs. 17 %, p<0.001) and fewer comorbidities. However, the overlap propensity score weighted proportions were 8.9 vs. 7.7 for HCW vs. non-HCW having a positive test with weighted odds ratio (OR) 1.17, 95% confidence interval (CI) 0.99-1.38. Among those testing positive, weighted proportions for hospitalization were 7.4 vs.15.9 for HCW vs. non-HCW with OR of 0.42 (CI 0.26-0.66) and for ICU admission: 2.2 vs.4.5 for HCW vs. non-HCW with OR of 0.48 (CI 0.20 -1.04). Those HCW identified as patient-facing compared to not had increased odds of a positive SARS-CoV-2 test (OR 1.60, CI 1.08-2.39, proportions 8.6 vs. 5.5), but no statistically significant increase in hospitalization (OR 0.88, CI 0.20-3.66, proportions 10.2 vs. 11.4) and ICU admission (OR 0.34, CI 0.01-3.97, proportions 1.8 vs. 5.2). Conclusions: In a large healthcare system, HCW had similar odds for testing SARS-CoV-2 positive, but lower odds of hospitalization compared to non-HCW. Patient-facing HCW had higher odds of a positive test. These results are key to understanding HCW risk mitigation during the COVID-19 pandemic.

We recently reported the development of the first African green monkey (AGM) model for COVID-19 based on a combined liquid intranasal (i.n.) and intratracheal (i.t.) exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we followed up on this work by assessing an i.n. particle only route of exposure using the LMA mucosal atomization device (MAD). Six AGMs were infected with SARS-CoV-2; three animals were euthanized near the peak stage of virus replication (day 5) and three animals were euthanized during the early convalescence period (day 34). All six AGMs supported robust SARS-CoV-2 replication and developed respiratory disease. Evidence of coagulation dysfunction as noted by a transient increases in aPTT and circulating levels of fibrinogen was observed in all AGMs. The level of SARS-CoV-2 replication and lung pathology was not quite as pronounced as previously reported with AGMs exposed by the combined i.n. and i.t. routes; however, SARS-CoV-2 RNA was detected in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge. Of particular importance to this study, all three AGMs that were followed until the early convalescence stage of COVID-19 showed substantial lung pathology at necropsy as evidenced by multifocal chronic interstitial pneumonia and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. These findings are consistent with human COVID-19 further demonstrating that the AGM faithfully reproduces the human condition.

Coronavirus infection is associated to life-threatening respiratory failure. The aryl hydrocarbon receptor (AHR) was recently identified as a host factor for Zika and dengue viruses; AHR antagonists decrease viral titers and ameliorate ZIKV-induced pathology in vivo. Here we report that AHR is activated during coronavirus infection, impacting anti-viral immunity and lung basal cells associated to tissue repair. Hence, AHR antagonists are candidate therapeutics for the management of coronavirus-infected patients.

The coronavirus (CoV) severe acute respiratory syndrome (SARS)-CoV-2 (COVID-19) pandemic has received rapid response by the research community to offer suggestions for repurposing of approved drugs as well as to improve our understanding of the COVID-19 viral life cycle molecular mechanisms. In a short period, tens of thousands of research preprints and other publications have emerged including those that report lists of experimentally validated drugs and compounds as potential COVID-19 therapies. In addition, gene sets from interacting COVID-19 virus-host proteins and differentially expressed genes when comparing infected to uninfected cells are being published at a fast rate. To organize this rapidly accumulating knowledge, we developed the COVID-19 Gene and Drug Set Library (https://amp.pharm.mssm.edu/covid19/), a collection of gene and drug sets related to COVID-19 research from multiple sources. The COVID-19 Gene and Drug Set Library is delivered as a web-based interface that enables users to view, download, analyze, visualize, and contribute gene and drug sets related to COVID-19 research. To evaluate the content of the library, we performed several analyses including comparing the results from 6 in-vitro drug screens for COVID-19 repurposing candidates. Surprisingly, we observe little overlap across these initial screens. The most common and unique hit across these screen is mefloquine, a malaria drug that should receive more attention as a potential therapeutic for COVID-19. Overall, the library of gene and drug sets can be used to identify community consensus, make researchers and clinicians aware of the development of new potential therapies, as well as allow the research community to work together towards a cure for COVID-19.

Cancer patients are particularly vulnerable to COVID-19, partially owing to their compromised immune systems and curbed or cut cancer healthcare services caused by the pandemic. As a result, cancer caregivers may have to shoulder triple crises: the COVID-19 pandemic, pronounced healthcare needs from the patient, and elevated need for care from within. While technology-based health interventions have the potential to address unique challenges cancer caregivers face amid COVID-19, limited insights are available. Thus, to bridge this gap, we aim to identify technology-based interventions designed for cancer caregivers and report the characteristics and effects of these interventions concerning cancer caregivers' distinctive challenges amid COVID-19.

Background: Coronavirus disease (COVID-19) is currently the main public health problem worldwide. The administration of neutral electrolyzed saline, a solution that contains reactive species of chlorine and oxygen (ROS), may be an effective therapeutic alternative due to its immunomodulating characteristics, in systemic inflammation control, as well as in immune response improvement, promoting control of the viral infection. The present study evaluated the efficacy of treatment with intravenous and/or nebulized neutral electrolyzed saline combined with usual medical care versus usual medical care alone, in ambulatory patients with COVID-19. Methods: A prospective, 2-arm, parallel group, randomized, open-label, phase I-II clinical trial included 39 patients in the control group (usual medical care alone) and 45 patients in the experimental group (usual medical care + intravenous and/or nebulized electrolyzed saline, with dose escalation). Two aspects were evaluated during the twenty-day follow-up: i) the number of patients with disease progression (hospitalization or death); and ii) the Patient Acceptable Symptom State (PASS), a single-question outcome that determines patient well-being thresholds for pain and function. Biochemical and hematologic parameters, as well as adverse effects, were evaluated in the experimental group. Results: The experimental treatment decreased the risk for hospitalization by 92% (adjusted RR=0.08, 95% CI: 0.01-0.50, P=0.007), with a 43-fold increase in the probability of achieving an acceptable symptom state on day 5 (adjusted RR= 42.96, 95% CI: 9.22-200.0, P<0.001). Intravenous + nebulized administration was better than nebulized administration alone, but nebulized administration was better than usual medical care alone. Clinical improvement correlated with a decrease in C-reactive protein, and aberrant monocytes and an increase of lymphocytes, and platelets. Cortisol and testosterone levels were also evaluated, observing a decrease in cortisol levels and an increment of testosterone-cortisol ratio, on days 2 and 4. Conclusions: The experimental treatment produced no serious adverse effects. In conclusion, intravenous and/or nebulized neutral electrolyzed saline importantly reduced the symptomatology and risk of progression (hospitalization and death), in ambulatory patients with COVID-19. Trial registration: Cuban Public Registry of Clinical Trials (RPCEC) Database RPCEC00000309. Registered: 05. May 2020. https://rpcec.sld.cu/en/trials/RPCEC00000309-En.

The pathogenesis of severe COVID-19 remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (77%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM), and only infrequently auto-reactive IgG or IgA. Importantly, these auto-IgM preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, LDH-release assays, and analytical proteome microarray technology, we identified high-affinity, complement-fixing, auto-reactive IgM directed against 263 candidate auto-antigens, including numerous molecules preferentially expressed on cellular membranes in pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for novel therapeutic interventions.

Infection or vaccination induces a population of long-lived bone marrow plasma cells (BMPCs) that are a persistent and essential source of protective antibodies1-5. Whether this population is induced in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unknown. Recent reports have suggested that SARS-CoV-2 convalescent patients experience a rapid decay in their antigen-specific serum antibodies, raising concerns that humoral immunity against this virus may be short-lived6-8. Here we show that in patients who experienced mild infections (n=73), serum anti-SARS-CoV-2 spike (S) antibodies indeed decline rapidly in the first 3 to 4 months after infection. However, this is followed by a more stable phase between 4- and 8-months after infection with a slower serum anti-S antibody decay rate. The level of serum antibodies correlated with the frequency of S-specific long-lived BMPCs obtained from 18 SARS-CoV-2 convalescent patients 7 to 8 months after infection. S-specific BMPCs were not detected in aspirates from 11 healthy subjects with no history of SARS-CoV-2 infection. Comparable frequencies of BMPCs specific to contemporary influenza virus antigens or tetanus and diphtheria vaccine antigens were present in aspirates in both groups. Circulating memory B cells (MBCs) directed against the S protein were detected in the SARS-CoV-2 convalescent patients but not in uninfected controls, whereas both groups had MBCs against influenza virus hemagglutinin. Overall, we show that robust antigen specific long-lived BMPCs and MBCs are induced after mild SARS-CoV-2 infection of humans.

The COVID-19 pandemic has become an immense global health crisis. However, the lack of efficient and sensitive on-site testing methods limits early detection for timely isolation and intervention. Here, we present a Quantitative and Ultrasensitive in-situ Immunoassay Technology for SARS-CoV-2 detection in saliva (QUIT SARS-CoV-2). Our nanoporous membrane resonator generates a rapid oscillating flow to purify and concentrate SARS-CoV-2 virus in saliva by 40 folds for in-situ detection of viral antigens based on chemiluminescent immunoassay within 20 min. This method achieved a detection sensitivity below 10 0 copies/mL viral load, comparable to the bench-top PCR equipment. The portable QUIT SARS-CoV-2 system, allowing rapid and accurate on-site viral screen with high-throughput sample pooling strategy, can be performed at the primary care settings and substantially improve the detection and prevention of COVID-19.

Background The unprecedented outbreak of a contagious respiratory disease caused by a novel coronavirus has led to a pandemic since December 2019, claiming millions of lives. The study systematically reviews and summarizes COVID-19's impact based on symptoms, demographics, comorbidities, and demonstrates the association of demographics in cases and mortality in the United States.Methods PubMed and Google Scholar were searched from December 2019- August 2020, and articles restricted to the English language were collected following PRISMA guidelines. US CDC data was used for establishing statistical significance of age, sex, and race.Results• Among 3745 patients in China, mean age is 50.63 (95% CI: 36.84, 64.42) years, and 55.7 % (95% CI: 52.2, 59.2) were males. Symptoms included fever 86.5% (82.7, 90.0), fatigue 41.9% (32.7, 51.4), dyspnea 29.0% (21.2, 37.5), cough 66.0% (61.3, 70.6), mucus 66% (61.3, 70.6), lymphopenia 18.9% (5.2, 38.0). Prevalent comorbidities were hypertension 16.4% (12.5, 20.8), diabetes 8.9% (7.0, 11.1), CVD 10.9% (6.1, 16.7), ARDS 14.6% (4.9, 27.8), malignancy 1.5 ( 0.05, 2.8), 1.3% (0.08, 1.9), COPD 1.3 (0.08, 1.9). 63.5 % (33.5, 88.7) received oxygen therapy, 20.8% (8.9, 35.7) were in ventilation, 23.5% (5.9, 47.8) were at the ICU. 86.5% (76.8, 94) had antiviral, 73.9% (55.3, 89.0) had antibiotics, 30% (20.6, 40.2) corticosteroids treatment.• In the US, the odds ratio of infection in males to females is 0.873 (CI: 0.052,14.791), while the odds of dying from infection is 1.378 (CI: 0.081, 23.528) for males. The prevalence of infection is higher in females; case and death rates are higher in whites and Hispanics than other races; the death rate is higher in males irrespective of race and age; death rate per 100,000 population increases monotonically with age.Conclusion Results showed that metabolic diseases comprising CVD, diabetes, hypertension, and respiratory diseases, including COPD, ARDS, are the most common comorbidities to severe condition and poor prognosis in covid-19 patients. Following the recent FDA's guidance for designing Covid-19 vaccine trials, stratification factors of age, race, sex, and comorbidities need consideration in allocation. This study aimed to provide clinical researchers, health policy planners a detailed insight into the coronavirus disease.

Background: While the coronavirus (COVID-19) has had far-reaching consequences on society and health care providers, there is a paucity of research exploring emergency medicine (EM) provider wellness over the course of a pandemic. The objective of this study was to assess the well-being, resilience, burnout, and wellness factors and needs of EM physicians and advanced practice providers (APPs) during the initial phase of the COVID-19 pandemic. Methods: A longitudinal, descriptive, prospective cohort survey study of 213 EM physicians and APPs was performed across ten emergency departments in a single state, including academic and community settings. Participants were recruited via email to complete four weekly, voluntary, anonymous questionnaires comprised of customized and validated tools for assessing wellness (Well Being Index), burnout (Physician Work Life Study item), and resilience (Brief Resilience Scale) during the initial acceleration phase of COVID-19. Univariate and multivariate analysis with Chi-squared, Fisher’s Exact, and logistic regression was performed. Results: Of 213 eligible participants, response rates ranged from 31 to 53% over four weeks. Women comprised 54 to 60% of responses. Nonrespondent characteristics were similar to respondents. Concern for personal safety decreased from 85% to 61% (p<0.001). Impact on basic self-care declined from 66% to 32% (p<0.001). Symptoms of stress, anxiety or fear was initially 83% and reduced to 66% (p=0.009). Reported strain on relationships and feelings of isolation affected >50% of respondents initially without significant change (p=0.05 and p=0.30 respectively). Women were nearly twice as likely to report feelings of isolation as men (OR 1.95; 95%CI 1.82-5.88). Working part-time carried twice the risk of burnout (OR, 2.45; 95% CI, 1.10-5.47). Baseline resilience was normal to high. Provider well-being improved over the four-weeks (30% to 14%; p=0.01), but burnout did not significantly change (30% to 22%; p=0.39). Conclusion: This survey of frontline EM providers during the initial surge of COVID-19 found that despite being a resilient group, the majority experienced stress, anxiety, fear, and concerns about personal safety due to COVID-19, with many at risk for burnout. The sustained impact of the pandemic on EM provider wellness deserves further investigation to guide targeted interventions.

Background: COVID-19 is a global pandemic caused by a new coronavirus strain. Innovative tests have been developed to diagnose and characterize the spread of COVID-19. Only a few studies have reported the diagnostic value of currently available tests. The diagnostic performance of the tests is a major concern after the recent resurgence in COVID-19. Methods: Published papers and FDA data on the currently available tests were used for analysis. Likelihood ratios, and predictive values of tests were computed. Only FDA approved tests were included. RT-PCR performance among different specimen types were also explored. Main results: All the published reports on the COVID-19 tests reported RT-PCR as the validation tool for their results. Not all available COVID-19 tests reported their sensitivity and specificity. Among the publications which reported, the positive likelihood ratio ranged between 0.15 to 0.88 and tests had high negative likelihood ratio (0.99). Conclusion: Although most recent publications showed high positive and negative likelihood ratios and high predictive values, the publications on test accuracy and validity have limited scope primarily due to their small sample size and insufficiencies in methodology and published data. Although most lab tests reported high sensitivity and specificity, false omission and false discovery rates were found notable in several COVID-19 lab tests. These results suggest need for caution on test results’ interpretation. Practitioners also need to integrate evidence that is evolving rapidly.

We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection ( ACE2, TMPRSS2, DPP4 , and LY6E ). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. At ACE2 , we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function. However, three non-synonymous variants were common among Central African hunter-gatherers from Cameroon and are on haplotypes that exhibit signatures of positive selection. We identify strong signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2 , we identified 13 amino acid changes that are adaptive and specific to the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.

While inhibition of T cell co-inhibitory receptors has revolutionized cancer therapy, the mechanisms governing their expression on human T cells have not been elucidated. Type 1 interferon (IFN-I) modulates T cell immunity in viral infection, autoimmunity, and cancer, and may facilitate induction of T cell exhaustion in chronic viral infection. Here we show that IFN-I regulates co-inhibitory receptor expression on human T cells, inducing PD-1/TIM-3/LAG-3 while surprisingly inhibiting TIGIT expression. High-temporal-resolution mRNA profiling of IFN-I responses enabled the construction of dynamic transcriptional regulatory networks uncovering three temporal transcriptional waves. Perturbation of key transcription factors on human primary T cells revealed unique regulators that control expression of co-inhibitory receptors. We found that the dynamic IFN-I response in vitro closely mirrored T cell features with IFN-I linked acute SARS-CoV-2 infection in human, with high LAG3 and decreased TIGIT expression. Finally, our gene regulatory network identified SP140 as a key regulator for differential LAG3 and TIGIT expression, which were validated at the level of protein expression. The construction of IFN-I regulatory networks with identification of unique transcription factors controlling co-inhibitory receptor expression may provide targets for enhancement of immunotherapy in cancer, infectious diseases, and autoimmunity.

Socioeconomic disadvantage is associated with larger COVID-19 disease burdens and pandemic-related economic impacts. We utilized the longitudinal Adolescent Brain Cognitive Development Study to understand how family- and neighborhood-level socioeconomic disadvantage relate to disease burden, family communication, and preventative responses to the pandemic in over 6,000 youth-parent/caregiver dyads. Data were collected at three timepoints (May to August 2020). Here, we show that both family- and neighborhood-level disadvantage were associated with parents’ reports of greater family COVID-19 exposure risk and diagnoses, less perceived exposure risk, more frequent parent-youth conversations about COVID-19 risk/prevention and reassurance, and greater youth preventative behaviors. More disadvantaged families may be adaptively incorporating more protective strategies to reduce emotional distress and likelihood of COVID-19 infection. The results highlight the importance of parent-youth communication and disease-preventative practices for buffering the economic and disease burdens of COVID-19, along with policies and programs that reduce these burdens for families with socioeconomic disadvantage.

Pregnant women are a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Herein, we report that SARS-CoV-2 infection during pregnancy primarily induced specific maternal inflammatory responses in the circulation and at the maternal-fetal interface, the latter being governed by T cells and macrophages. SARS-CoV-2 infection during pregnancy was also associated with a cytokine response in the fetal circulation (i.e. umbilical cord blood) without compromising the cellular immune repertoire. Moreover, SARS-CoV-2 infection neither altered fetal cellular immune responses in the placenta nor induced elevated cord blood levels of IgM. Importantly, SARS-CoV-2 was not detected in the placental tissues, nor was the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and further emphasizes the rarity of placental infection.

The role that in-person schooling contributes to community incidence of SARS-CoV-2 infections and deaths remains unknown. We conducted an event study evaluating the effect of in-person school on SARS-CoV-2 cases and deaths per 100,000 persons during the 12-weeks following school opening, stratified by US Census region. There was no impact of in-person school opening and COVID-19 deaths. In most regions, COVID-19 incidence rates were not statistically different in counties with in-person versus remote school modes. However, in the South, there was a significant and sustained increase in cases per week among counties that opened for in-person learning versus remote learning, with weekly effects ranging from 7.8 (95% CI: 1.2-14.5) to 18.9 (95% CI: 7.9-29.9) additional cases per 100,000, driven by increases among 0-9 year olds and adults.

Increasing evidence of new-onset diabetes during the COVID19 pandemic indicates that the SARS-CoV2 virus may drive beta-cell dysfunction leading to diabetes, but it is unclear if it is a primary or secondary effect. Here, we present evidence of SARS-CoV-2 infection of pancreatic beta cells in vivo using a robust and reproducible non-human primates model of mild to moderate COVID19 pathogenesis. Pancreas from SARS-CoV-2 infected subjects were positive for the SARS-CoV2 spike protein by immunohistochemistry and structures indicative of viral replication were evident by electron microscopy. Total beta cell area was decreased in SARS-CoV-2-infected pancreas, attributable to beta cell atrophy. Beta cell granularity was decreased. These histologic phenotypes persisted beyond the duration of the clinical disease course. Detailed electron microscopy of SARS-CoV-2 infected beta-cells revealed ultrastructural hallmarks of beta cell stress that are seen in islets of patients with Type 2 diabetes, including disrupted mitochondria and dilated endoplasmic reticulum. To assess the metabolic status of beta cells from SARS-CoV-2-infected subjects, we used fluorescence life-time imaging to measure the ratio of free and bound NADH as a surrogate of glycolytic and oxidative metabolism. We report an increase in free NADH levels, suggesting that beta cells from SARS-CoV-2-infected subjects adopt a more glycolytic metabolic profile. Taken together, we conclude that SARS-CoV-2 infection induces beta cell stress that may compromise beta-cell function beyond the duration of the disease course. This raises the possibility that the beta cell stress and injury may have clinical implications of the long-term future health of patients that have recovered from COVID19.

PurposeOlder cancer survivors required medical care during the COVID-19 pandemic despite infection risks, but there are limited data on medical care in this age group.