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Infection by Coronavirus SARS-CoV2 is a severe and often deadly disease that has implications for the respiratory system and multiple organs across the human body. While the effects in the lung have been extensively studied, less is known about COVID-19s cellular impact across other organs. Here we contribute a single-nuclei RNA sequencing atlas comprising six human organs across 20 autopsies where we analyzed the transcriptional changes due to COVID-19 in multiple cell types. Computational cross-organ analysis for endothelial cells and macrophages identified systemic transcriptional changes in these cell types in COVID-19 samples. In addition, analysis of signaling pathways from multiple datasets showed several systemic dysregulations of signaling interaction in different cell types. Altogether, the COVID Tissue Atlas enables the investigation of both cell type-specific and cross-organ transcriptional responses to COVID-19, providing insights into the molecular networks affected by the disease and highlighting novel potential targets for therapies and drug development.

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To develop a universal strategy to block SARS-CoV-2 cellular entry and infection represents a central aim for effective COVID-19 therapy. The growing impact of emerging variants of concern increases the urgency for development of effective interventions. Since ACE2 is the critical SARS-CoV-2 receptor and all tested variants bind to ACE2, some even at much increased affinity (see accompanying paper), we hypothesized that aerosol administration of clinical grade soluble human recombinant ACE2 (APN01) will neutralize SARS-CoV-2 in the airways, limit spread of infection in the lung and mitigate lung damage caused by deregulated signaling in the renin-angiotensin (RAS) and Kinin pathways. Here we show that intranasal administration of APN01 in a mouse model of SARS-CoV-2 infection dramatically reduced weight loss and prevented animal death. As a prerequisite to a clinical trial, we evaluated both virus binding activity and enzymatic activity for cleavage of Ang II following aerosolization. We report successful aerosolization for APN01, retaining viral binding as well as catalytic RAS activity. Dose range-finding and IND-enabling repeat-dose aerosol toxicology testing were conducted in dogs. Twice daily aerosol administration for two weeks at the maximum feasible concentration revealed no notable toxicities. Based on these results, a Phase I clinical trial in healthy volunteers can now be initiated, with subsequent Phase II testing in individuals with SARS-CoV-2 infection. This strategy could be used to develop a viable and rapidly actionable therapy to prevent and treat COVID-19, against all current and future SARS-CoV-2 variants. One Sentence SummaryPreclinical development and evaluation of aerosolized soluble recombinant human ACE2 (APN01) administered as a COVID-19 intervention is reported.

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Males and certain racial/ethnic minority groups have borne a disproportionate burden of COVID-19 mortality in the United States, and substantial scientific research has sought to quantify and characterize population-level disparities in COVID-19 mortality outcomes by sex and across categories of race/ethnicity. However, there has not yet been a national population-level study to quantify disparities in COVID-19 mortality outcomes across the intersection of these demographic dimensions. Here, we analyze a publicly available dataset from the National Center for Health Statistics comprising COVID-19 death counts stratified by race/ethnicity, sex, and age for the year 2020, calculating mortality rates for each race/ethnicity-sex-age stratum and age-adjusted mortality rates for each race/ethnicity-sex stratum, quantifying disparities in terms of mortality rate ratios and rate differences. Our results reveal persistently higher COVID-19 age-adjusted mortality rates for males compared to females within every racial/ethnic group, with notable variation in the magnitudes of the sex disparity by race/ethnicity. However, non-Hispanic Black, Hispanic, and non-Hispanic American Indian or Alaska Native females have higher age-adjusted mortality rates than non-Hispanic White and non-Hispanic Asian/Pacific Islander males. Moreover, persistent racial/ethnic disparities are observed among both males and females, with higher COVID-19 age-adjusted mortality rates observed for non-Hispanic Blacks, Hispanics, and non-Hispanic American Indian or Alaska Natives relative to non-Hispanic Whites.

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A damaging inflammatory response is strongly implicated in the pathogenesis of severe COVID-19 but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated, anti-SARS-CoV-2 IgG predicted progression from mild, to more severe COVID-19. In contrast to the antibody structures that predicted disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were low in Fc afucosylation and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model which revealed that human IgG-Fc{gamma}R interactions can regulate inflammation in the lung. Afucosylated IgG immune complexes induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine elicited IgG did not promote an inflammatory lung response. Here, we show that IgG-Fc{gamma}R interactions can regulate inflammation in the lung and define distinct lung activities associated with the IgG that predict severe COVID-19 and protection against SARS-CoV-2. One Sentence SummaryDivergent early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response and are functionally distinct in vivo.

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Males are at higher risk relative to females of severe outcomes following COVID-19 infection. Focusing on COVID-19-attributable mortality in the United States (U.S.), we quantify and contrast years of potential life lost (YPLL) attributable to COVID-19 by sex based on data from the U.S. National Center for Health Statistics as of 31 March 2021, specifically by contrasting male and female percentages of total YPLL with their respective percent population shares and calculating age-adjusted male-to-female YPLL rate ratios both nationally and for each of the 50 states and the District of Columbia. Using YPLL before age 75 to anchor comparisons between males and females and a novel Monte Carlo simulation procedure to perform estimation and uncertainty quantification, our results reveal a near-universal pattern across states of higher COVID-19-attributable YPLL among males compared to females. Furthermore, the disproportionately high COVID-19 mortality burden among males is generally more pronounced when measuring mortality in terms of YPLL compared to age-irrespective death counts, reflecting dual phenomena of males dying from COVID-19 at higher rates and at systematically younger ages relative to females. The U.S. COVID-19 epidemic also offers lessons underscoring the importance of a public health environment that recognizes sex-specific needs as well as different patterns in risk factors, health behaviors, and responses to interventions between men and women. Public health strategies incorporating focused efforts to increase COVID-19 vaccinations among men are particularly urged.

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The coronavirus disease 2019 (COVID-19) epidemic in the United States has disproportionately impacted communities of color across the country. Focusing on COVID-19-attributable mortality, we expand upon a national comparative analysis of years of potential life lost (YPLL) attributable to COVID-19 by race/ethnicity (Bassett et al., 2020), estimating percentages of total YPLL for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, non-Hispanic Asians, and non-Hispanic American Indian or Alaska Natives, contrasting them with their respective percent population shares, as well as age-adjusted YPLL rate ratios - anchoring comparisons to non-Hispanic Whites - in each of 45 states and the District of Columbia using data from the National Center for Health Statistics as of December 30, 2020. Using a novel Monte Carlo simulation procedure to quantify estimation uncertainty, our results reveal substantial racial/ethnic disparities in COVID-19-attributable YPLL across states, with a prevailing pattern of non-Hispanic Blacks and Hispanics experiencing disproportionately high and non-Hispanic Whites experiencing disproportionately low COVID-19-attributable YPLL. Furthermore, observed disparities are generally more pronounced when measuring mortality in terms of YPLL compared to death counts, reflecting the greater intensity of the disparities at younger ages. We also find substantial state-to-state variability in the magnitudes of the estimated racial/ethnic disparities, suggesting that they are driven in large part by social determinants of health whose degree of association with race/ethnicity varies by state.

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Introduction@#Non-Langerhans cell histiocytoses (non-LCH) are a group of rare diseases with varied clinical manifestations and overlapping features seen among the subtypes. Here, we present a case of Rosai-Dorfman disease with features of necrobiotic xanthogranuloma. @*Case@#A 45-year-old female presented with a 10-year history of an enlarging neck mass with normal overlying skin accompanied by dysphagia and multiple asymptomatic pink to yellowish-brown papules, nodules, and plaques on the face, trunk and extremities. Biopsies of a skin nodule and plaque revealed granulomatous dermal infiltrates (lymphocytes, foamy histiocytes, and Touton giant cells), emperipolesis and areas of necrosis. CD1A and Fite-Faraco staining showed negative results while CD68 and S100 positively stained the tissues of interest. Histopathology of the neck mass paralleled these findings in addition to being negative for lymphoid markers. Patient had monoclonal gammopathy and thyromegaly with enlarged cervical lymph nodes on further tests and imaging. Intralesional and systemic steroids were given which led to flattening of skin lesions and improvement in dysphagia, respectively. @*Conclusion@#Diagnosis and classification of a particular type of non-LCH may be difficult due to similarities across its subtypes. Hence, it is our belief that these diseases may occur on a spectrum. Treatment involves a multidisciplinary approach for the best possible care.

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Identifying areas with high COVID-19 burden and their characteristics can help improve vaccine distribution and uptake, reduce burdens on health care systems, and allow for better allocation of public health intervention resources. Synthesizing data from various government and nonprofit institutions of 3,142 United States (US) counties as of 12/21/2020, we studied county-level characteristics that are associated with cumulative case and death rates using regression analyses. Our results showed counties that are more rural, counties with more White/non-White segregation, and counties with higher percentages of people of color, in poverty, with no high school diploma, and with medical comorbidities such as diabetes and hypertension are associated with higher cumulative COVID-19 case and death rates. We identify the hardest hit counties in US using model-estimated case and death rates, which provide more reliable estimates of cumulative COVID-19 burdens than those using raw observed county-specific rates. Identification of counties with high disease burdens and understanding the characteristics of these counties can help inform policies to improve vaccine distribution, deployment and uptake, prevent overwhelming health care systems, and enhance testing access, personal protection equipment access, and other resource allocation efforts, all of which can help save more lives for vulnerable communities. Significance statementWe found counties that are more rural, counties with more White/non-White segregation, and counties with higher percentages of people of color, in poverty, with no high school diploma, and with medical comorbidities such as diabetes and hypertension are associated with higher cumulative COVID-19 case and death rates. We also identified individual counties with high cumulative COVID-19 burden. Identification of counties with high disease burdens and understanding the characteristics of these counties can help inform policies to improve vaccine distribution, deployment and uptake, prevent overwhelming health care systems, and enhance testing access, personal protection equipment access, and other resource allocation efforts, all of which can help save more lives for vulnerable communities.

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Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated the impact of GI infection on disease pathogenesis in three large cohorts of patients in the United States and Europe. Unexpectedly, we observed that GI involvement was associated with a significant reduction in disease severity and mortality, with an accompanying reduction in key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation. In a fourth cohort of COVID-19 patients in which GI biopsies were obtained, we identified severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) within small intestinal enterocytes for the first time in vivo but failed to obtain culturable virus. High dimensional analyses of GI tissues confirmed low levels of cellular inflammation in the GI lamina propria and an active downregulation of key inflammatory genes including IFNG, CXCL8, CXCL2 and IL1B among others. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit.

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BackgroundThe spread of Coronavirus Disease 2019 (COVID-19) across the United States confirms that not all Americans are equally at risk of infection, severe disease, or mortality. A range of intersecting biological, demographic, and socioeconomic factors are likely to determine an individuals susceptibility to COVID-19. These factors vary significantly across counties in the United States, and often reflect the structural inequities in our society. Recognizing this vast inter-county variation in risks will be critical to mounting an adequate response strategy. Methods and FindingsUsing publicly available county-specific data we identified key biological, demographic, and socioeconomic factors influencing susceptibility to COVID-19, guided by international experiences and consideration of epidemiological parameters of importance. We created bivariate county-level maps to summarize examples of key relationships across these categories, grouping age and poverty; comorbidities and lack of health insurance; proximity, density and bed capacity; and race and ethnicity, and premature death. We have also made available an interactive online tool that allows public health officials to query risk factors most relevant to their local context. Our data demonstrate significant inter-county variation in key epidemiological risk factors, with a clustering of counties in certain states, which will result in an increased demand on their public health system. While the East and West coast cities are particularly vulnerable owing to their densities (and travel routes), a large number of counties in the Southeastern states have a high proportion of at-risk populations, with high levels of poverty, comorbidities, and premature death at baseline, and low levels of health insurance coverage. The list of variables we have examined is by no means comprehensive, and several of them are interrelated and magnify underlying vulnerabilities. The online tool allows readers to explore additional combinations of risk factors, set categorical thresholds for each covariate, and filter counties above different population thresholds. ConclusionCOVID-19 responses and decision making in the United States remain decentralized. Both the federal and state governments will benefit from recognizing high intra-state, inter-county variation in population risks and response capacity. Many of the factors that are likely to exacerbate the burden of COVID-19 and the demand on healthcare systems are the compounded result of long-standing structural inequalities in US society. Strategies to protect those in the most vulnerable counties will require urgent measures to better support communities attempts at social distancing and to accelerate cooperation across jurisdictions to supply personnel and equipment to counties that will experience high demand.

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BACKGROUND: Human pancreata contain many types of cells, such as endocrine islets, acinar, ductal, fat, and mesenchymal stromal cells (MSCs). MSCs are important and shown to have a promising therapeutic potential to treat various disease conditions. METHODS: We investigated intra-pancreatic tissue-derived (IPTD) MSCs isolated from tissue fractions that are routinely discarded during pancreatic islet isolation of human cadaveric donors. Furthermore, whether pro-angiogenic and anti-inflammatory properties of these cells could be enhanced was investigated. RESULTS: IPTD-MSCs were expanded in GMP-compatible CMRL-1066 medium supplemented with 5% human platelet lysate (hPL). IPTD-MSCs were found to be highly pure, with > 95% positive for CD90, CD105, and CD73, and negative for CD45, CD34, CD14, and HLA-DR. Immunofluorescence staining of pancreas tissue demonstrated the presence of CD105+ cells in the vicinity of islets. IPTD-MSCs were capable of differentiation into adipocytes, chondrocytes, and osteoblasts in vitro, underscoring their multipotent features. When these cells were cultured in the presence of a low dose of TNF-α, gene expression of tumor necrosis factor alpha-stimulated gene-6 (TSG-6) was significantly increased, compared to control. In contrast, treating cells with dimethyloxallyl glycine (DMOG) (a prolyl 4-hydroxylase inhibitor) enhanced mRNA levels of nuclear factor erythroid 2-related factor 2 (NRF2) and vascular endothelial growth factor (VEGF). Interestingly, a combination of TNF-α and DMOG stimulated the optimal expression of all three genes in IPTD-MSCs. Conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α contained higher levels of pro-angiogenic (VEGF, IL-6, and IL-8) compared to controls, promoting angiogenesis of human endothelial cells in vitro. In contrast, levels of MCP-1, a pro-inflammatory cytokine, were reduced in the conditioned medium of IPTD-MSCs treated with a combination of DMOG and TNF-α. CONCLUSIONS: The results demonstrate that IPTD-MSCs reside within the pancreas and can be separated as part of a standard islet-isolation protocol. These IPTD-MSCs can be expanded and potentiated ex vivo to enhance their anti-inflammatory and pro-angiogenic profiles. The fact that IPTD-MSCs are generated in a GMP-compatible procedure implicates a direct clinical application.

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Influenza can be prevented through annual appropriate vaccination against the virus concerned. In China, influenza vaccine is categorized as "Class Ⅱ" infectious diseases which the cost is paid out of the user's pockets. The annual coverage of influenza vaccination had been 2%-3%. The main reasons for the low coverage would include the following factors: lacking awareness on both the disease and vaccine, poor accessibility of vaccination service, and the cost of vaccination. To reduce the health and economic burden associated with influenza, comprehensive policies should be improved, targeting the coverage of seasonal influenza vaccination. These items would include: ① Different financing reimbursement schemes and mechanisms to improve the aspiration on vaccination and on the vaccine coverage in high-risk groups, as young children, elderly, people with underlying medical conditions; ② to ameliorate equality of vaccination services; ③ to improve knowledge of the health care workers (HCWs) and the public on influenza and related vaccines; ④ to improve clinical and preventive medical practice and vaccination among HCWs through revising clinical guidelines, pathway and consensus of experts; ⑤ to provide more convenient, accessible and normative vaccination service system; ⑥ to strengthen research and development as well as marketing on novel influenza vaccines; ⑦ to revise items regarding the contraindication for influenza vaccine on pregnancy women, stated in the Chinese Pharmacopoeia.

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Objective: To analyze the reasons for the fluctuations in the percentage of outpatient or emergency visits for influenza-like illness (ILI) during the Spring Festival and National Day in 2014-2018 surveillance season. Methods: ILI surveillance data was collected during the period of Spring Festival and National Day in mainland China, and downloaded from Chinese Influenza Surveillance Information System, during the 2014-2018 surveillance season. Results: There was no significant difference noticed in the number of ILI reports in the festival week with weeks before or after in both the southern and northern provinces. The number of outpatient visits was much less than that of the week before and after, but the number of emergency visits was statistically significantly increased. Conclusion: In the holiday peak of ILI%, the major causes was the impact of holiday-off at sentinel hospitals, resulting in a large reduction in the number of outpatient visits in the consulting room during the festivals.

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Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and its complications. Currently, China has licensed trivalent (IIV3) and quadrivalent inactivated influenza vaccine (IIV4), including split-virus influenza vaccine and subunit vaccine. In most parts of China, influenza vaccine is a category Ⅱ vaccine, which means influenza vaccination is voluntary, and recipients need to pay for it. To strengthen the technical guidance for prevention and control of influenza and the operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC), Influenza Vaccine Technical Working Group (TWG), updated the 2014 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2018-2019)" , based on most recent existing scientific evidences. The main updates include: epidemiology and disease burden of influenza, types of influenza vaccines, northern hemisphere influenza vaccination composition for the 2018-2019 season, and, IIV3 and IIV4 vaccines'major immune responses, durability of immunity, immunogenicity, vaccine efficacy, effectiveness, safety, cost-effectiveness and cost-benefit. The recommendations include: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for any influenza vaccine product for persons who can accept ≥1 licensed, recommended, and appropriate products. To decrease the risk of severe infections and complications due to influenza virus infection among high risk groups, the recommendations prioritize seasonal influenza vaccination for children aged 6-60 months, adults ≥60 years of age, persons with specific chronic diseases, healthcare workers, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to pregnant during the influenza season. Children aged 6 months to 8 years old require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. If they were vaccinated in previous influenza season, 1 dose is recommended. People ≥ 9 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. Influenza vaccination should continue to be available for those unable to be vaccinated before the end of October during the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for CDC members who are working on influenza control and prevention, PoVs members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and members of maternity and child care institutions at all levels.

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While numerous herbal preparations have been used to treat human illnesses for extensive period of time in many different cultures, very few have been subject to rigorous clinical testing of modern scientific standards. To facilitate more clinical development of new drugs from botanical sources, the US FDA has published a draft Guidance for Industry: Botanical Drug Products in August 2000.<br>www.fda.gov/cder/guidance/1221dft.pdf. For herbal preparations with substantial marketing history, past human experiences may be taken into consideration for safety assessment and clinical studies may be initiated with less extensive product characterization and non-clinical testing. However, efficacy of almost all herbal products remains to be established with clinical trials that should be no different from those required for non-botanical new drugs. The objective of the regulatory approach is to confer the same degree of confidence in the clinical effectiveness of herbal medicines as that of modem non-botanical drugs. In this presentation, basic principles of clinical trial in all new drug development will be described, and unique issues related to studies of herbal medicines discussed.