Abstract

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.

Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is spreading globally (1, 2), and the World Health Organization (WHO) has declared it a pandemic. As of June 2, 2020, more than 6.1 million confirmed cases and more than 376,000 deaths have been reported worldwide (3).

SARS-CoV-2 infection usually results in a mild disease course with spontaneous resolution in the majority of infected individuals (4). However, some patients, particularly elderly patients develop severe COVID-19 infection that requires intensive care with mechanical ventilation (4, 5). The mortality rate for COVID-19 in Wuhan, China, is estimated to be 1.4% (5). Although this rate is lower than that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by other human pathogenic coronaviruses (6), it is much higher than that of influenza, a common respiratory viral disease requiring hospitalization and intensive care in severe cases.

In severe cases of COVID-19, a hyper-inflammatory response, also called a cytokine storm, has been observed and is suspected of causing the detrimental progression of COVID-19 (7). Circulating levels of pro-inflammatory cytokines, including TNF and IL-6, are increased in severe cases (8). Gene expression analyses have also shown that IL-1-related pro-inflammatory pathways are highly up-regulated in severe cases (9). In a murine model of SARS-CoV infection, a delayed, but considerable type I IFN (IFN-I) response promotes the accumulation of monocytes-macrophages and the production of pro-inflammatory cytokines, resulting in lethal pneumonia with vascular leakage and impaired virus-specific T-cell responses (10).

Immune dysfunction is also observed in patients with COVID-19. In severe cases, the absolute number of T cells is reduced (8, 11), and the T cells exhibit functional exhaustion with the expression of inhibitory receptors (12, 13). However, hyper-activation of T cells as reflected in the up-regulation of CD38, HLA-DR, and cytotoxic molecules was also reported in a lethal case of COVID-19 (14). Immune dysfunction in patients with severe COVID-19 has been attributed to pro-inflammatory cytokines (15).

In the present study, we performed single-cell RNA-seq (scRNA-seq) using peripheral blood mononuclear cells (PBMCs) to identify factors associated with the development of severe COVID-19 infection. By comparing COVID-19 and severe influenza, we report that the TNF/IL-1-driven inflammatory response was dominant in COVID-19 across all types of cells among PBMCs, whereas the up-regulation of various interferon-stimulated genes (ISGs) was prominent in severe influenza. When we compared the immune responses from patients with mild and severe COVID-19 infections, we found that classical monocytes from severe COVID-19 exhibit IFN-I-driven signatures in addition to TNF/IL-1-driven inflammation.

PBMCs were collected from healthy donors (n=4), hospitalized patients with severe influenza (n=5), and patients with COVID-19 of varying clinical severity, including severe, mild, and asymptomatic (n=8). PBMCs were obtained twice from three (the subject C3, C6, and C7) of the eight COVID-19 patients at different time points during hospitalization. PBMC specimens from COVID-19 patients were assigned to severe or mild COVID-19 groups according to the National Early Warning Score (NEWS; mild < 5, severe 5) evaluated on the day of whole blood sampling (16). In NEWS scoring, respiratory rate, oxygen saturation, oxygen supplement, body temperature, systolic blood pressure, heart rate, and consciousness were evaluated (16). Severe influenza was defined when hospitalization was required irrespective of NEWS score. Patients with severe influenza were enrolled from December 2015 to April 2016, prior to the emergence of COVID-19. The severe COVID-19 group was characterized by significantly lower lymphocyte count and higher serum level of C-reactive protein than the mild COVID-19 group on the day of blood sampling (Fig. S1A). Multiplex real-time PCR for N, RdRP, and E genes of SARS-CoV-2 was performed, and there was no statistical difference in Ct values for all three genes between two groups (Fig. S1B). Demographic information is provided with experimental batch of scRNA-seq in Table S1 and clinical data in Table S2 and S3.

Employing the 10X Genomics scRNA-seq platform, we analyzed a total of 59,572 cells in all patients after filtering the data with stringent high quality, yielding a mean of 6,900 UMIs per cell and detecting 1,900 genes per cell on average (Table S4). The transcriptome profiles of biological replicates (PBMC specimens in the same group) were highly reproducible (Fig. S1C), ensuring the high quality of the scRNA-seq data generated in this study.

To examine the host immune responses in a cell type-specific manner, we subjected 59,572 cells to t-distributed stochastic neighbor embedding (tSNE) based on highly variable genes using the Seurat package (17) and identified 22 different clusters unbiased by patients or experimental batches of scRNA-seq (Fig. 1A, Fig. S1D). These clusters were assigned to 13 different cell types based on well-known marker genes and two uncategorized clusters (Fig. 1B and C, and Table S5). In downstream analysis, we only focused on 11 different immune cell types, including IgG- B cell, IgG+ B cell, effector memory (EM)-like CD4+ T cell, non-EM-like CD4+ T cell, EM-like CD8+ T cell, non-EM-like CD8+ T cell, natural killer (NK) cell, classical monocyte, intermediate monocyte, non-classical monocyte, and dendritic cell (DC) after excluding platelets, red blood cells (RBCs), and two uncategorized clusters. The subject C8 (asymptomatic case) was also excluded due to a lack of replicates. In hierarchical clustering, most transcriptome profiles from the same cell type tended to cluster together, followed by disease groups, suggesting that both immune cell type and disease biology, rather than technical artifacts, are the main drivers of the variable immune transcriptome (Fig. S1E).

(A) tSNE projections of 59,572 PBMCs from healthy donors (HDs) (4 samples, 17,590 cells), severe influenza (FLU) patients (5 samples, 10,519 cells), COVID-19 patients (asymptomatic: 1 sample, 4,425 cells; mild COVID-19: 4 samples, 16,742 cells; severe COVID-19: 6 samples, 10,296 cells) colored by group information. (B) Normalized expression of known marker genes on a tSNE plot. (C) tSNE plot colored by annotated cell types. EM: effector memory, NK cell: natural killer cell, DC: dendritic cell, RBC: red blood cell. (D) Proportion of cell types in each group excluding Uncategorized 1, Uncategorized 2, RBC, and Platelet. The colors indicate cell type information. (E) Boxplots showing the fold enrichment in cell type proportions from mild COVID-19 (n=4), severe COVID-19 (n=6), and FLU (n=5) patients compared to the HD group (mild COVID-19 vs. HD: n=16, severe COVID-19 vs. HD: n=24, FLU vs. HD: n=20). For the boxplots, the box represents the interquartile range (IQR) and the whiskers correspond to the highest and lowest points within 1.5IQR. Uncategorized 1 (relatively high UMIs per cells and presence of multiple marker genes), Uncategorized 2 (B cell-like and high expression of ribosomal protein genes), RBC, and Platelet were excluded. Two-sided KolmogorovSmirnov (KS) tests were conducted for each cell type between the disease and HD group. *p<0.05, **p<0.01, and ***p<0.001.

As a feature of immunological changes, we investigated the relative proportions of immune cells among PBMCs in the disease groups compared to the healthy donor group (Fig. 1D and E, and Fig. S1F). Unlike the limited changes in mild COVID-19, significant changes were observed in both influenza and severe COVID-19 across multiple cell types among PBMCs. In severe COVID-19, the proportion of classical monocytes significantly increased whereas those of DCs, non-classical monocytes, intermediate monocytes, NK cells, EM-like CD8+ T cells, and EM-like CD4+ T cells significantly decreased (Fig. 1E). In severe influenza, the proportion of classical monocytes significantly increased whereas those of DCs, non-EM-like CD4+ T cells, EM-like CD4+ T cells, IgG+ B cells, and IgG- B cells significantly decreased. We validated the proportions of immune cell subsets from scRNA-seq by flow cytometry analysis. The relative proportions of total lymphocytes, B cells, CD4+ T cells, CD8+ T cells, NK cells, and total monocytes from scRNA-seq significantly correlated with those from flow cytometry analysis (Fig. S1G).

In order to compare the effect of infection between diseases, we performed hierarchical clustering based on relative gene expression changes against the healthy donor group. Unexpectedly, all types of cells among PBMCs were clustered together according to the disease groups instead of cell-types (Fig. 2A). Further investigation of the variable genes based on K-means clustering supported COVID-19-specific up- or down-regulated gene expression patterns across all types of cells among PBMCs (Fig. S2A). These results indicate that, in COVID-19, peripheral blood immune cells may be influenced by common inflammatory mediators regardless of cell type. Despite distinct transcriptional signatures between COVID-19 and influenza, severe COVID-19 and influenza shared transcriptional signatures in all types of monocytes and DCs (black boxed region in Fig. 2A), possibly reflecting common mechanisms underlying the innate immune responses in severe influenza and severe COVID-19.

(A) Hierarchical clustering using the Pearson correlation coefficient (PCC) of a normalized transcriptome between diseases in cell type resolution (n = 33). The color intensity of the heat map indicates the PCC values. The color bars above the heat map indicate the cell type and disease group. The black box indicates the cell types that highly correlate between the severe COVID-19 and FLU groups. (B) Illustration of the enrichment p-values for the select GO biological pathways (n = 49) of differentially expressed genes (DEGs) in COVID-19 and FLU patients (left 6 columns: DEGs for COVID-19 and FLU groups compared to HD, right 2 columns: DEGs between COVID-19 and FLU groups). (C) tSNE plot of representative gene expression patterns for GBP1 (FLU specific), CREM (COVID-19 specific), and CCL3 (COVID-19/FLU common). (D) Top, dendrogram from WGCNA analysis performed using relative normalized gene expression between the COVID-19 and FLU groups for the genes belonging to the select biological pathways in (B) (n=316). Bottom, heat map of relative normalized gene expression between the COVID-19 and FLU groups. The color bar (left) indicates cell type information clustered by hierarchical clustering based on the PCC for relative normalized gene expression. Modularized gene expression patterns by WGCNA are shown together (G1, n=10; G2, n=147; G3, n=27; G4, n=17; G5, n=12; G6, n=64; G7, n=34; G8, n=5).

Next, we sought to identify relevant biological functions in disease-specific up- or down-regulated genes in terms of the GO biological pathways. First, we combined both mild and severe COVID-19 as a COVID-19 group and identified disease-specific changes in genes for each cell type compared to the healthy donor group using model-based analysis of single cell transcriptomics (MAST) (18). NFKB1, NFKB2, IRF1, and CXCR3 were specifically up-regulated in COVID-19, and CXCL10, STAT1, TLR4, and genes for class II HLA and immunoproteasome subunits were specifically up-regulated in influenza (Table S6). TNF, TGFB1, IL1B, and IFNG were commonly up-regulated. When we directly compared COVID-19 and influenza, NFKB1, NFKB2, and TNF were up-regulated in COVID-19, whereas STAT1, TLR4, and genes for immunoproteasome subunits were up-regulated in influenza. For each group of differentially expressed genes (DEGs), we identified the top 10 enriched GO biological pathways and collected them to demonstrate p-value enrichment in each group of DEGs (Fig. 2B). Both distinct and common biological functions were identified as illustrated by inflammatory response genes being highly active in both COVID-19 and influenza, but genes for transcription factors, including inflammatory factors (i.e., NFKB1/2, and STAT4) were up-regulated in COVID-19. In contrast, a limited response in genes associated with the IFN-I and -II signaling pathways, T-cell receptor pathways, and adaptive immune response was observed in COVID-19 compared to influenza. Such disease-specific gene expression patterns were exemplified at single cell resolution by GBP1 (IFN--mediated signaling pathway) being specifically up-regulated in influenza, CREM (positive regulation of transcription) being specifically up-regulated in COVID-19, and CCL3 (inflammatory response) being commonly up-regulated (Fig. 2C and Table S7).

We expanded our analysis in a cell type specific manner by conducting weighted gene correlation network analysis (WGCNA) (19) for the collected genes associated with Fig. 2B. We identified several modular expression patterns (Fig. 2D and Table S8). In the COVID-19 group, NFKB1/2, JUN, and TNF were modularized in CD8+ T and NK cells (G6 and G7 in Fig. 2D), and IL1B, NFKBID, and OSM were modularized in all types of monocytes and DCs (G3 in Fig. 2D). In the influenza group, GBP1, TAP1, STAT1, IFITM3, OAS1, IRF3, and IFNG were modularized in all types of T cells and NK cells (G2 in Fig. 2D), and CXCL10 and TLR4 were modularized in all types of monocytes and DCs (G5 and part of G6 in Fig. 2D). Consistently, the DEGs between COVID-19 and influenza were dominant in CD8+ T cells and all types of monocytes (Fig. S2B).

To uncover disease-specific transcriptional signatures in CD8+ T cells, we performed sub-clustering analysis from EM-like and non-EM-like CD8+ T cell clusters using Seurat (17). Each disease group-specifically enriched sub-clusters compared to the two other groups were identified in the non-EM-like CD8+ T cell cluster (Fig. 3A). Of the six sub-clusters from the non-EM-like CD8+ T cell cluster, cluster 1 and cluster 3 were significantly enriched in the influenza and COVID-19 groups, respectively (Fig. 3B and C, and S3A). Clusters with the high expression of PPBP, a marker of platelets, were excluded in following analysis (e.g., cluster 6 in Fig. S3A). Intriguingly, up-regulated genes in cluster 1 and cluster 3 were associated with previously defined gene sets for influenza A virus infection and SARS-CoV infection, respectively (Fig. S3B) (20). We also found that the cluster 3-specific up-regulated genes reflect activation of immune response, including CD27, RGS1, CCL5, SELL, and RGS10 (Fig. S3C and Table S9). Protein interaction network analysis of selected top 30 up-regulated genes in each cluster based on STRING v11 (21) revealed the up-regulation of PRF1, GNLY, GZMB, and GZMH in cluster 1 and the up-regulation of GZMK, GZMA, CXCR3, and CCL5 in cluster 3 (Fig. 3D, green). STAT1, TAP1, PSMB9, and PSME2, which are up-regulated preferentially by IFN-, were overexpressed only in influenza-specific cluster 1 (Fig. 3D, blue). We validated these data by intracellular staining for granzyme B and PMA/ionomycin-stimulated intracellular cytokine staining for IFN-. The percentages of granzyme B+ and IFN-+ cells among CD8+ T cells were significantly higher in the influenza group than in the COVID-19 group (Fig. S3D). Of the seven representative GO biological pathways for the pro-inflammatory and IFN responses, pathways for responses to IFN-I and -II were more associated with influenza-specific cluster 1, whereas pathways for the response to TNF or IL-1 were more prominent in COVID-19-specific cluster 3 (Fig. 3E).

(A) tSNE plot of the non-EM-like CD8+ T cell subpopulations in all groups (left, n=6,253), COVID-19 (top right, n=2,653), FLU (middle right, n=1,452), and HD (bottom right, n=2,148) colored by cluster information. (B, C) Boxplots showing the proportion of individual sub-clusters from the non-EM-like CD8+ T cell cluster within each group (COVID-19, n=10; FLU, n=5; HD, n=4). The proportions follow normal distribution as tested by the Shapiro-Wilk normality test except the proportion of cluster 3 in the COVID-19 group (p=0.04). Cluster 1 and cluster 3 were highly enriched in the FLU and COVID-19 group, respectively. Two-sided Welchs t test p-values were 4.4E-03 between COVID-19 and FLU in cluster 1, 3.5E-02 between FLU and HD donor in cluster 1, 8.6E-03 between COVID-19 and FLU in cluster 3, and 5.8E-3 between COVID-19 and HD in cluster 3. *p<0.05, **p<0.01. (D) STRING analysis using the top 30 up-regulated genes in cluster 1 (left) and cluster 3 (right). (E) Bar plots showing enrichment p-values of eight representative GO biological pathways for pro-inflammation and interferon in cluster 1 or cluster 3-specific up-regulated genes (cluster 1, n=66; cluster 3, n=183).

We performed sub-clustering analysis from all three types of monocyte clusters to find COVID-19-specific sub-clusters. However, there was no COVID-19-specifically enriched sub-cluster (Fig. S4A and B). Next, we further focused on classical monocytes considering their crucial roles for inflammatory responses. We investigated DEGs between influenza and COVID-19 to seek COVID-19-specific transcriptional signatures in classical monocytes (Fig. 4A). Interestingly, TNF and IL1B, major genes in the inflammatory response, were identified as COVID-19-specific and commonly up-regulated genes, respectively. To better characterize the transcriptional signatures in classical monocytes, we performed K-means clustering of up-regulated genes in at least one disease group compared to the healthy donor group. We identified five different clusters of up-regulation (Fig. 4B and Table S10): genes in cluster 1 are commonly up-regulated in all disease groups, cluster 2 is influenza-specific, cluster 3 is associated with mild/severe COVID-19, cluster 4 is associated with influenza and severe COVID-19, and cluster 5 is severe COVID-19-specific.

(A) Venn diagram of differentially expressed genes (DEGs) in COVID-19 and FLU compared to HD. The representative genes are shown together. (B) K-means clustering of DEGs between all pairs of FLU, mild COVID-19, and severe COVID-19 (n=499). The color indicates the relative gene expression between the diseases and HD. The representative genes are shown together. (C) Bar plots showing the average log10(p-value) values in enrichment analysis using the perturbed genes of four different cell lines listed in L1000 LINCS for up-regulated genes in cluster 2 (C2, left) and cluster 3 (C3, right). Error bars indicate standard deviation. (D) Combined enrichment scores were compared between C2 and C3 for the gene sets of the type I IFN response (left; GSE26104) and TNF response (right; GSE2638, GSE2639). **p<0.01. Each dot indicates an individual subject. (E) Bar plots showing the average log10(p-value) values in the enrichment analysis using the perturbed genes listed of four different cell lines in L1000 LINCS for up-regulated genes in cluster 4 (C4, left) and cluster 5 (C5, right). Error bars indicate standard deviation (C and E).

We examined each cluster-specific genes by gene set enrichment analysis (GSEA) using cytokine-responsive gene sets originated from each cytokine-treated cells (LINCS L1000 ligand perturbation analysis in Enrichr) (22). COVID-19-specific cluster 3 genes were enriched by TNF/IL-1-responsive genes whereas influenza-specific cluster 2 genes were enriched by IFN-I-responsive genes in addition to TNF/IL-1-responsive genes (Fig. 4C), indicating that the IFN-I response is dominant in influenza compared to COVID-19. We confirmed this result by analyzing cluster-specific genes with cytokine-responsive gene sets originated from other sources (Fig. 4D). Unexpectedly, cluster 4 and 5 exhibited strong associations with IFN-I-responsive genes, in addition to TNF/IL-1-responsive genes (Fig. 4E), indicating that severe COVID-19 acquires IFN-I-responsive features in addition to TNF/IL-1-inflammatory features.

Next, we directly compared classical monocytes between mild and severe COVID-19. When we analyzed DEGs, severe COVID-19 was characterized by up-regulation of various ISGs, including ISG15, IFITM1/2/3, and ISG20 (Fig. 5A). Both TNF/IL-1-responsive genes and IFN-I-responsive genes were enriched in severe COVID-19-specific up-regulated genes (Fig. 5B). We measured plasma concentrations of TNF, IL-1, IL-6, IFN-, IFN-, and IL-18 in a larger cohort of COVID-19 patients. Among these cytokines, IL-6 and IL-18 were significantly increased in severe COVID-19 compared to mild COVID-19 whereas there was no difference in plasma concentrations of the other cytokines between the two groups (Fig. S5A). These results indicate that cytokine-responsive gene signatures cannot be simply explained by a few cytokines because of overlapped effects of cytokines.

(A) Volcano plot showing DEGs between mild and severe COVID-19 groups. Each dot indicates individual gene, colored by red when a gene is significant DEG. (B) Bar plot showing the average log10(p-value) values in enrichment analysis using the perturbed genes of four different cell lines listed in L1000 LINCS for up-regulated genes in the severe COVID-19 group. Error bars indicate standard deviation. (C) Trajectory analysis of classical monocytes from specimens obtained at two different time points in a single COVID-19 patient (mild: C7-2, 1,197 cells; severe: C7-1, 631 cells). The color indicates cluster information (left) or the severity of COVID-19 (right). (D) Relative expression patterns of representative genes in the trajectory analysis are plotted along the Pseudotime. The color indicates the relative gene expression calculated by Monocle 2. (E) Bar plots showing the average log10(p-value) values in the enrichment analysis using the perturbed genes of four different cell lines in L1000 LINCS for up-regulated genes in cluster 3 (left) and cluster 1 (right). Error bars indicate standard deviation. (F) Comparison of combined enrichment scores between cluster 3 and cluster 1 for the gene sets from systemic lupus erythematosus (SLE) (n=16) and rheumatoid arthritis (RA) (n=5). ***p<0.001; ns, not significant. (G) GSEA of up-regulated genes in cluster 3 (left) and cluster 1 (right) to the class 1 gene module of monocyte-derived macrophages by Park et al. (2017). NES: normalized enrichment score, FDR: false discovery rate.

To further investigate the characteristics of severe COVID-19, we performed a trajectory analysis with Monocle 2 (23) using two internally well-controlled specimens (one severe and one mild) in which both PBMC samples were collected from a single patient (the subject C7) with COVID-19. Trajectory analysis aligned classical monocytes along the disease severity with cluster 1 and cluster 3 corresponding to later and earlier Pseudotime, respectively (Fig. 5C). Representative genes in cluster 1 was enriched in the severe stage and highly associated with the both IFN-I and TNF/IL-1-associated inflammatory response (Fig. 5D, Fig. S5B, and Table S11). GSEA confirmed that both the IFN-I response and TNF/IL-1 inflammatory response were prominent in cluster 1, but not in cluster 3 (Fig. 5E). Cluster 1 exhibited a significantly higher association with a gene set from systemic lupus erythematosus, which is a representative inflammatory disease with IFN-I features, than cluster 3 (Fig. 5F, left), but was not significantly associated with a gene set from rheumatoid arthritis (Fig. 5F, right).

We obtained additional evidence of the IFN-I-potentiated TNF inflammatory response in severe COVID-19 by analyzing a gene module that is not responsive to IFN-I, but associated with TNF-induced tolerance to TLR stimulation. Park et al. previously demonstrated that TNF tolerizes TLR-induced gene expression in monocytes, though TNF itself is an inflammatory cytokine (24). They also showed that IFN-I induces a hyper-inflammatory response by abolishing the tolerance effects of TNF, and defined a gene module responsible for the IFN-I-potentiated TNF-NF-B inflammatory response as class 1 (24). This gene module was significantly enriched in cluster 1, but not in cluster 3 (Fig. 5G), which suggests that the IFN-I response may exacerbate hyper-inflammation by abolishing a negative feedback mechanism.

Finally, we validated IFN-I response and inflammatory features using bulk RNA-seq data obtained using post-mortem lung tissues from patients with lethal COVID-19 (25). Although the analysis was limited to only two patients without individual cell-type resolution, in genome browser, up-regulation of IFITM1, ISG15, and JAK3 and down-regulation of RPS18 were observed commonly in post-mortem COVID-19 lung tissues and classical monocytes of severe COVID-19 (Fig. 6A). In the analysis with cytokine-responsive gene sets, both the IFN-I response and TNF/IL-1-inflammatory response were prominent in the lung tissues (Fig. 6B). DEGs in the lung tissues were significantly associated with cluster 4, which is commonly up-regulated in both influenza and severe COVID-19, and cluster 5, which is specific to severe COVID-19 in Fig. 4B (Fig. 6C). These genes were also significantly associated with the cluster 1 identified in the trajectory analysis, but not with cluster 3 (Fig. 6D). When gene sets were defined by DEGs between mild and severe COVID-19, the DEGs in post-mortem lung tissues were significantly associated with genes up-regulated specifically in severe COVID-19 (Fig. 6E).

(A) UCSC Genome Browser snapshots of representative genes. (B) Bar plot showing the average log10(p-value) values from the enrichment analysis using the perturbed genes of four different cell lines in L1000 LINCS for up-regulated genes (n= 386) in post-mortem lung tissues compared to biopsied healthy lung tissue. Error bars indicate standard deviation. (C) GSEA of significantly up- and down-regulated genes in post-mortem lung tissues for gene sets originated from up-regulated genes in C2 (n=96), C3 (n=143), C4 (n=218), and C5 (n=30) of Fig. 4B. (D and E) GSEA of significantly up- and down-regulated genes in post-mortem lung tissues for gene sets originated from the top 200 up-regulated genes in cluster 3 (left) and cluster 1 (right) from the trajectory analysis in Fig. 5C (D), and from gene sets originated from the top 200 up-regulated genes in classical monocytes of mild (left) and severe (right) COVID-19 (E).

Severe COVID-19 has been shown to be caused by a hyper-inflammatory response (7). Particularly, inflammatory cytokines secreted by classical monocytes and macrophages are considered to play a crucial role in severe progression of COVID-19 (26). In the current study, we confirmed the results from previous studies by showing that the TNF/IL-1 inflammatory response is dominant in COVID-19 although a small number of patients were enrolled. However, we also found that severe COVID-19 is accompanied by the IFN-I response in addition to the TNF/IL-1 response. These results indicate that the IFN-I response might contribute to the hyper-inflammatory response by potentiating TNF/IL-1-driven inflammation in severe progression of COVID-19.

In the current study, we carried out scRNA-seq using PBMCs instead of specimens from the site of infection, e.g., lung tissues or bronchoalveolar lavage (BAL) fluids. However, hierarchical clustering based on relative changes to the healthy donor group showed that all types of cells among PBMCs were clustered together according to the disease groups as shown in Fig. 2A, indicating that there is disease-specific global impact across all types of cells among PBMCs. This finding suggests that peripheral blood immune cells are influenced by common inflammatory mediators regardless of cell type. However, we could not examine granulocytes in the current study because we used PBMCs, not whole blood samples for scRNA-seq.

In transcriptome studies for cytokine responses, we often analyze cytokine-responsive genes rather than cytokine genes themselves. However, we cannot exactly specify responsible cytokine(s) from the list of up-regulated genes because of overlapped effects of cytokines. For example, up-regulation of NF-B-regulated genes can be driven by TNF, IL-1 or other cytokines, and up-regulation of IFN-responsive genes can be driven by IFN-I or other interferons. In the current study, we designated the IFN-I response because many up-regulated IFN-responsive genes were typical ISGs.

Recently, Wilk et al. also performed scRNA-seq using PBMCs from COVID-19 patients and healthy controls (27). Similar to our study, they found IFN-I-driven inflammatory signatures in monocytes from COVID-19 patients. However, they did not find substantial expression of pro-inflammatory cytokine genes such as TNF, IL6, IL1B, CCL3, CCL4 and CXCL2 in peripheral monocytes from COVID-19 patients whereas we detected the up-regulation of TNF, IL1B, CCL3, CCL4 and CXCL2 in the current study. Moreover, they found a developing neutrophil population in COVID-19 patients that was not detected in our study. These discrepant results might be due to different platforms for scRNA-seq. Wilk et al. used the Seq-Well platform whereas we used the 10X Genomics platform that is more generally used. We also note that recent scRNA-seq analyses of COVID-19 sometimes lead to unrelated or contradictory conclusions to each other despite the same platform (28, 29). Although it often occurs in unsupervised analysis of highly multi-dimensional data, more caution will be required in designing scRNA-seq analysis of COVID-19, including definition of the severity and sampling time points.

Recently, Blanco-Melo et al. examined the transcriptional response to SARS-CoV-2 in in vitro infected cells, infected ferrets, and post-mortem lung samples from lethal COVID-19 patients and reported that IFN-I and -III responses are attenuated (25). However, we noted that IFN-I signaling pathway and innate immune response genes were relatively up-regulated in post-mortem lung samples from lethal COVID-19 patients compared to SARS-CoV-2-infected ferrets in their paper. Given that SARS-CoV-2 induces only mild disease without severe progression in ferrets (30), we interpret that IFN-I response is up-regulated in severe COVID-19 (e.g., post-mortem lung samples from lethal COVID-19 patients), but not in mild COVID-19 (e.g., SARS-CoV-2-infected ferrets). Indeed, severe COVID-19-specific signatures discovered in our current study were significantly enriched in the publically available data of post mortem lung tissues from the Blanco-Melo et al.s study although the analysis was limited to only two patients without individual cell-type resolution (Fig. 6). In a recent study, Zhou et al. also found a robust IFN-I response in addition to pro-inflammatory response in BAL fluid of COVID-19 patients (31). Moreover, up-regulation of IFN-I-responsive genes has been demonstrated in SARS-CoV-2-infected intestinal organoids (32).

Although IFN-I has direct antiviral activity, their immunopathological role was also reported previously (33). In particular, the detrimental role of the IFN-I response was elegantly demonstrated in a murine model of SARS (10). In SARS-CoV-infected BALB/c mice, the IFN-I response induced the accumulation of pathogenic inflammatory monocytes-macrophages and vascular leakage, leading to death. It was proposed that a delayed, but considerable IFN-I response is critical for the development of acute respiratory distress syndrome and increased lethality during pathogenic coronavirus infection (6, 34).

Currently, the management of patients with severe COVID-19 relies on intensive care and mechanical ventilation without a specific treatment because the pathogenic mechanisms of severe COVID-19 have not yet been clearly elucidated. In the current study, we demonstrated that severe COVID-19 is characterized by TNF/IL-1-inflammatory features combined with the IFN-I response. In a murine model of SARS-CoV infection, timing of the IFN-I response is a critical factor determining outcomes of infection (6, 10). Delayed IFN-I response contributes to pathological inflammation whereas early IFN-I response controls viral replication. Therefore, we propose that anti-inflammatory strategies targeting not only inflammatory cytokines, including TNF, IL-1, and IL-6, but also pathological IFN-I response needs to be investigated for the treatment of patients with severe COVID-19.

Patients diagnosed with COVID-19 were enrolled from Asan Medical Center, Severance Hospital, and Chungbuk National University Hospital. SARS-CoV-2 RNA was detected in patients nasopharyngeal swab and sputum specimens by multiplex real-time reverse-transcriptase PCR using the Allplex 2019-nCoV Assay kit (Seegene, Seoul, Republic of Korea). In this assay, N, RdRP, and E genes of SARS-CoV-2 were amplified, and Ct values were obtained for each gene. SARS-CoV-2-specific antibodies were examined using the SARS-CoV-2 Neutralization Antibody Detection kit (GenScript, Piscataway, NJ) and were positive in all COVID-19 patients in convalescent plasma samples or the last plasma sample in a lethal case. Hospitalized patients diagnosed with influenza A virus infection by a rapid antigen test of a nasopharyngeal swab were also enrolled from Asan Medical Center and Chungbuk National University Hospital from December 2015 to April 2016, prior to the emergence of COVID-19. Patients clinical features, laboratory findings, and chest radiographs were collected from their electronic medical records at each hospital. This study protocol was reviewed and approved by the institutional review boards of all participating institutions. Written informed consent was obtained from all patients.

Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral venous blood via standard Ficoll-Paque (GE Healthcare, Uppsala, Sweden) density gradient centrifugation, frozen in freezing media, and stored in liquid nitrogen until use. All samples showed a high viability of about 90% on average after thawing. Single-cell RNA-seq libraries were generated using the Chromium Single Cell 3 Library & Gel Bead Kit v3 (10X genomics, Pleasanton, CA) following the manufacturers instructions. Briefly, thousands of cells were separated into nanoliter-scale droplets. In each droplet, cDNA was generated through reverse transcription. As a result, a cell barcoding sequence and Unique Molecular Identifier (UMI) were added to each cDNA molecule. Libraries were constructed and sequenced as a depth of approximately 50,000 reads per cell using the Nextseq 550 or Novaseq 6000 platform (Illumina, San Diego, CA).

The sequenced data were de-multiplexed using mkfastq (cellranger 10X genomics, v3.0.2) to generate fastq files. After de-multiplexing, the reads were aligned to the human reference genome (GRCh38; 10x cellranger reference GRCh38 v3.0.0), feature-barcode matrices generated using the cellranger count, and then aggregated by cellranger aggr using default parameters. The following analysis was performed using Seurat R package v3.1.5 (17). After generating the feature-barcode matrix, we discarded cells that expressed <200 genes and genes not expressed in any cells. To exclude low-quality cells from our data, we filtered out the cells that express mitochondrial genes in >15% of their total gene expression as described in previous studies (29, 35, 36). Doublets were also excluded, which were dominant in the cluster Uncategorized 1. Although there was a high variability in the number of UMIs detected per cell, majority of cells (90.5%) were enriched in a reasonable range of the UMIs (1,000 - 25,000), and 59% of cells with less than 1,000 UMIs were platelet or RBC excluded in downstream analysis. In each cell, the gene expression was normalized based on the total read count and log-transformed. To align the cells originating from different samples, 2000 highly variable genes from each sample were identified by the vst method in Seurat R package v3.1.5 (17). Using the canonical correlation analysis (CCA), we found anchors and aligned the samples based on the top 15 canonical correlation vectors. The aligned samples were scaled and principal component analysis (PCA) conducted. Finally, the cells were clustered by unsupervised clustering (0.5 resolution) and visualized by tSNE using the top 15 principal components.

To identify marker genes, up-regulated genes in each cluster relative to the other clusters were selected based on the Wilcoxon rank sum test in Seurats implementation with >0.25 log fold change compared to the other clusters and a Bonferroni-adjusted p < 0.05 (Table S4). By manual inspection, among the 22 different clusters, 20 were assigned to 11 known immune cell types, RBCs which are characterized by HBA1, HBA2, and HBB, and platelets. The clusters characterized by similar marker genes were manually combined as one cell type. The two remaining clusters were assigned to Uncategorized 1 and Uncategorized 2 because they had no distinct features of known cell types. Based on the distribution of UMI counts, the cluster Uncategorized 1 was featured by relatively high UMIs per cell compared to other clusters and presence of higher expression of multiple cell type marker genes. The cluster Uncategorized 2 was featured by a B cell-like signatures and high expression of ribosomal protein genes, not recommended to be further analyzed according to the 10X platform guideline. In these aspects, RBCs, platelets, Uncategorized 1, and Uncategorized 2 were excluded in downstream analysis.

To check the reproducibility of biological replicates (individuals within a same group), we calculated the Spearmans rank correlation coefficient for UMI counts that were merged according to each individual. The correlation coefficients of all individual pairs within the same group were visualized by a boxplot (COVID-19, n=45; FLU, n=10; HD, n=6).

In Fig. S1E, to investigate the similarity of the transcriptomes between cell types across diseases, we merged the UMI counts of each cell type according to healthy donor, influenza, mild COVID-19, and severe COVID-19. Next, the UMI counts for each gene were divided by the total UMI count in each cell type and multiplied by 100,000 as the normalized gene expression. Based on a median expression value >0.5, we calculated the relative changes in gene expression divided by the median value for each gene. Hierarchical clustering analysis was performed based on the PCC of the relative change in gene expression.

In Fig. 2A and Fig. S2A, to compare the highly variable gene expression among mild and severe COVID-19 and influenza relative to healthy donors, the normalized gene expression used in Fig. S1E was divided by the values in the healthy donor group. We selected the highly variable genes in terms of the top 25% standard deviation followed by log2-transformation (pseudo-count =1). In Fig. 2A, hierarchical clustering analysis was performed based on the PCCs of the selected highly variable genes. For Fig. S2A, to investigate the expression patterns of the selected highly variable genes (n=6,052), K-means clustering (k=50) was performed based on Euclidean distance. We manually ordered the clusters and visualized them as a heat map, revealing four distinct patterns: influenza-specific (n=1,046), COVID-19 specific (n=1,215), influenza/COVID-19 common (n=1,483), and cell type-specific (n=2,308).

To investigate the dynamic changes in cell type composition, we calculated the proportion of cell types in each individual. As a control, we calculated the relative variation in each cell type composition between all pairs of healthy donors. Similarly, for each disease group, we calculated the relative variation in each cell type by dividing the fraction of the cell type in individual patient by that of individual healthy donor. After log2-transformation, we conducted statistical analysis using the relative variation in composition between the control and disease groups using a two-sided KolmogorovSmirnov test.

For any two transcriptome profiles, to identify DEGs, we utilized the model-based analysis of single cell transcriptomics (MAST) algorithm in Seurats implementation based on a Bonferroni-adjusted p<0.05 and a log2 fold change > 0.25.

In Fig. 2B, the DEGs in COVID-19 and influenza compared to healthy donors or COVID-19 compared to influenza were identified at cell type resolution. All DEGs were combined according to the disease groups for further analysis. The overlapping up or down DEGs between COVID-19 and influenza compared to healthy donors were defined as Common up or Common down. The specific DEGs in COVID-19 or influenza were assigned as COVID-19 up/down or FLU up/down, respectively. In addition, COVID-19-specific up- or down-regulated genes compared to influenza were assigned as COVID-19>FLU or FLU>COVID-19, respectively. The Gene Ontology analysis was performed by DAVID. For each group of DEGs, the top 10 enriched GO biological pathways were selected, resulting in 49 unique GO biological pathways across all groups. The -log10(p-values) are shown as a heat map in Fig. 2B.

The weighted gene correlation network analysis (WGCNA) was conducted with the genes listed in the top 10 GO biological pathways of COVID-19 up, FLU up, and Common up defined in Fig. 2B. The normalized gene expression values of the genes in COVID-19 were divided by the values in influenza and log2-transformed (pseudo-count =1). We used default parameters with the exception of soft threshold =10 and networkType = signed when we constructed a topological overlap matrix. The modular gene expression patterns were defined using cutreeDynamic with a minClusterSize of 5. We visualized the modular gene expression pattern as a heat map in which the cell types were ordered according to hierarchical clustering with the default parameters of hcluster in R.

To find disease-specific subpopulations, each immune cell type was subjected to the subclustering analysis using Seurat. Briefly, the highly variable genes (n=1000) were selected based on vst and then scaled by ScaleData in Seurat with the vars.to.regress option to eliminate variation between individuals. The subpopulations were identified by FindClusters with default parameters, except resolution (non-EM-like CD8+ T cells, 0.3; classical monocytes, 0.2); the inputs were the top eight principal components (PCs) obtained from PCA of the scaled expression of the highly variable genes. The subpopulations were visualized by tSNE using the top eight PCs.

The trajectory analysis was performed with 2000 highly variable genes in classical monocytes across mild (C7-2) and severe (C7-1) COVID-19 as defined by the vst method in Seurat. The following analysis was performed using Monocle2. Briefly, the input was created from the UMI count matrix of the highly variable genes using the newCellDataSet function with default parameters, except expressionFamily = negbinomial.size. The size factors and dispersion of gene expression were estimated. The dimension of the normalized data was reduced based on DDRTree using reduceDimension with default parameters, except scaling = FALSE, which aligned the cells to the trajectory with three distinct clusters.

To determine genes that gradually changed along the trajectory, we identified the DEGs using MAST between clusters 1 and 3, which represent the severe stage and mild stage, respectively. The expression patterns of representative DEGs were visualized along the Pseudotime after correction with estimated size factors and dispersion for all genes.

In Fig. 4B, we performed K-means clustering of DEGs among all pairs of mild COVID-19, severe COVID-19, and influenza. The log2-transformed relative gene expression of DEGs compared to healthy donors was subjected to K-means clustering (k=10). Here, we used up-regulated DEGs in at least one disease group compared to the healthy donor group. We manually assigned five clusters based on gene expression patterns.

The transcriptome profiles of post-mortem lung tissues from two lethal cases of COVID-19 and biopsied heathy lung tissues from two donors were downloaded from a public database (GSE147507). The DEGs were identified using DESeq2 based on a Bonferroni-adjusted p < 0.05 and a log2 fold change > 1.

Enrichr, the web-based software for gene set enrichment analysis (GSEA) was used for LINCS L1000 ligand perturbation analysis (22), virus perturbation analysis, and disease perturbation analysis from the GEO database. Combined score was calculated as a parameter of enrichment as the log(p-value) multiplied by the z-score from the Fisher exact test. GSEA 4.0.3 software was used to conduct the GSEA when a ranked list of genes was available (Fig. 5G, Fig. 6C-E) (37). Results for IFN--responsive genes were not presented because those were considerably overlapped with IFN--responsive genes, which are typical ISGs. The normalized enrichment score and FDR-q value were calculated to present the degree and significance of enrichment.

Cryopreserved PBMCs were thawed, and dead cells were stained using the Live/Dead Fixable Cell Stain kit (Invitrogen, Carlsbad, CA). Cells were stained with fluorochrome-conjugated antibodies, including anti-CD3 (BV605; BD Biosciences), anti-CD4 (BV510; BD Biosciences), anti-CD8 (BV421; BD Biosciences), anti-CD14 (PE-Cy7; BD Biosciences), anti-CD19 (Alexa Fluor 700; BD Biosciences), and anti-CD56 (VioBright FITC; Miltenyi Biotec). For staining with anti-granzyme B (BD Biosciences), cells were permeabilized using a Foxp3 staining buffer kit (eBioscience).

For intracellular cytokine staining of IFN-, PBMCs were stimulated with phorbol 12-myristate 13-acetate (PMA, 50 ng/ml) (Sigma Aldrich) and ionomycin (1 g/ml) (Sigma Aldrich). Brefeldin A (GolgiPlug, BD Biosciences) and monesin (GolgiStop, BD Biosciences) were added 1 hour later. After another 5 hours of incubation, cells were harvested for staining with the Live/Dead Fixable Cell Stain kit, anti-CD3, anti-CD4, and anti-CD8. Following cell permeabilization, cells were further stained with anti-IFN- (Alexa Fluor 488; eBioscience).

Flow cytometry was performed on an LSR II instrument using FACSDiva software (BD Biosciences) and the data analyzed using FlowJo software (Treestar, San Carlos, CA).

Cytokines were measured in plasma samples, including IFN-, IL-18 (ELISA, R&D Systems, Minneapolis, MN), IL-1 (Cytometric bead array flex kit, BD Biosciences, San Jose, CA), TNF, IL-6, and IFN- (LEGENDplex bead-based immunoassay kit, BioLegend, San Diego, CA).

We performed the KS test to compare the distributions of two groups without assuming that the distributions follow normality. Welchs t test was conducted to compare the two distributions after confirming the normality of the distributions using the Shapiro-Wilk normality test. A Wilcoxon signed rank test was conducted to compare the differences between two groups with paired subjects. The Mann-Whitney test was performed to compare the means of two groups. Statistical analyses were performed using Prism software version 5.0 (GraphPad, La Jolla, CA). p<0.05 was considered significant.

immunology.sciencemag.org/cgi/content/full/5/49/eabd1554/DC1

Fig. S1. Clinical characteristics and assessment of the quality of scRNA-seq results.

Fig. S2. Transcriptome features of highly variable genes.

Fig. S3. Characterization of disease-specific CD8+ T-cell subpopulations.

Fig. S4. Subpopulation analysis of classical monocytes.

Fig. S5. STRING analysis of up-regulated genes in cluster 1 obtained from the trajectory analysis of classical monocytes.

Table S1. Experimental batches of scRNA-seq.

Table S2. Clinical characteristics of severe influenza patients.

Table S3. Clinical characteristics of COVID-19 patients.

Table S4. The scRNA-seq results.

Table S5. A list of marker genes for each cluster.

Table S6. A list of DEGs and associated biological pathways in Fig. 2B.

Table S7. Cell types in which the GBP1, CREM, and CCL3 were upregulated in Fig. 2C.

Table S8. A list of genes in each module obtained from WGCNA in Fig. 2D.

Table S9. A list of up-regulated genes in non-EM-like CD8+ T-cell subpopulations.

Table S10. A list of genes included in each cluster defined by K-mean clustering of classical monocytes.

Table S11. A list of genes up-regulated in early and late Pseudotime.

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19 - Science

Georgia Gov. Brian Kemp holds a protective mask while speaking during a 'Wear A Mask' tour stop in Dalton, Georgia, earlier this month. Bloomberg/Bloomberg via Getty Images hide caption

Georgia Gov. Brian Kemp holds a protective mask while speaking during a 'Wear A Mask' tour stop in Dalton, Georgia, earlier this month.

Georgia's governor and the mayor of the state's capital and largest city are at odds over COVID-19 restrictions, with Atlanta Mayor Keisha Lance Bottoms announcing a return to tough measures to control a spike in coronavirus infections and Gov. Brian Kemp insisting that her order is "non-binding and legally unenforceable."

Bottoms, a Democrat, announced Friday that she was bringing Atlanta back to Phase 1 reopening the most restrictive post-lockdown measures that require all residents to stay home except for essential trips.

The mayor's order came on the same day that Georgia announced a record-breaking one-day spike in coronavirus, logging 4,400 new confirmed cases. Health authorities in Atlanta's Fulton County says about half of the new cases in Georgia in the past two weeks have occurred in the city.

But Kemp, a Republican, quickly dismissed the mayor's directive, saying on Friday that it didn't supersede his own, more relaxed, statewide order issued at the end of June.

"Mayor Bottoms' action today is merely guidance both non-binding and legally unenforceable," Kemp said in a statement.

"As clearly stated in the Governor's executive order, no local action can be more or less restrictive, and that rule applies statewide," the governor said.

"Once again, if the Mayor actually wants to flatten the curve in Atlanta, she should start enforcing state restrictions, which she has failed to do," he said. "We ask citizens and businesses alike to comply with the terms of the Governor's order, which was crafted in conjunction with state public health officials. These common-sense measures will help protect the lives and livelihoods of all Georgians."

Earlier this week, Bottoms had issued a directive for Atlanta residents to wear masks in public, and Kemp responded similarly to that order. Although the governor launched a "Wear A Mask" campaign to encourage their use, he has declined to make it mandatory.

Bottoms told the Atlanta Journal-Constitution on Wednesday that she had the authority to enforce the mask restrictions the way she would enforce any other city ordinance.

The cities of Savannah, East Point and Athens, Kemp's hometown, have enacted similar mask directives.

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Georgia Governor And The Mayor Of Atlanta In Turf War Over COVID-19 Restrictions - NPR

by: News Release & Posted By Staff | newsweb@everythinglubbock.com

(Nexstar Media Group/EverythingLubbock.com Staff)

LUBBOCK, Texas (NEWS RELEASE) The following is a news release from the City of Lubbock:

As of 4:00 p.m. on Saturday, July 11, 2020, the City of Lubbock confirmed 144 new cases of Coronavirus (COVID-19) and 8 recoveries. The total number of cases in Lubbock County is 3,668: 1,950 active, 1,650 listed as recovered and 60 deaths.

Walgreens, at602 Avenue Q, will operate a COVID-19 drive-thru testing sitestarting on Friday, July 17.The drive-thru will be openfrom 9:00 a.m. 5:00 p.m., seven days a week. Visitors need to take a COVID-19 assessment test before they will be given an appointment time to be tested. The assessment can be found atwww.walgreens.com/COVID19testing.

In a recent proclamation, Governor Greg Abbott limited outdoor gatherings to 10 people, unless approved by a mayor or county judge. If citizens, or organizations, would like to have their event considered for approval they can download a form atwww.mylubbock.us/lubbocksafe. They can then send the form toLubbockSafe@mylubbock.us. Those seeking approval are asked to submit their request at least 10 days before the event.

(News release from the City of Lubbock)

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COVID-19: City of Lubbock reports 144 new cases, 8 additional recoveries on Saturday - KLBK | KAMC | EverythingLubbock.com

It never ends. Another virus? A new pnuemonia? Kazakhstan disagrees with their Chinese counterparts. ... [+] Here, a Kazakh woman receives a swab test for Covid-19 on June 16, 2020. (Photo by Kalizhan Ospanov/Xinhua via Getty) (Xinhua/ via Getty Images)

China is panicking people the world over about viruses and here is another one: an unknown pneumonia sweeping Kazakhstan that was highlighted by the Chinese Embassy as a fair warning to their biggest Silk Road partner in Central Asia.

The story broke on Thursday. And on Friday, Kazakhstan rejected Chinas warning of a new bug circulating on its home turf.

The South China Morning Post reported yesterday that the Chinese embassy was getting nervous about a spike in pneumonia cases over the last five weeks.

The death rate of this disease is much higher than the novel coronavirus. The countrys health departments are conducting comparative research into the pneumonia virus, but have yet to identify it, the embassy said in a warning to Chinese citizens in the country.

Kazakhstan public health officials said it was standard pneumonia.

It was unclear why the Chinese embassy considered it a new type of pneumonia, but saying so hearkened back to December, when medical doctors from Hubei province, in the city of Wuhan, discovered an unknown pneumonia that acted a lot like SARS. Some of them were rounded up and jailed for spreading rumors about the outbreak, later to turn into a global pandemic that has infected 11.8 million people globally and killed over 545,000, according to the World Health Organizations statistics from yesterday.

On Friday, Kazakhstans health ministry officially dismissed the Chinese governments warning of a strange pneumonia, saying the information given by the Chinese embassy was incorrect.

The health ministry did say, however, that the pneumonia cases in the country all showed clinical symptoms of abnormalities. So, something is awry with this pneumonia, whatever that may mean.

George Gao Fu, director of Chinese Center for Disease Control and Prevention, was quoted by the China New Service today saying the Chinese authorities were still investigating it.

Aizhan Esmagambetova, chief sanitary doctor for Kazakhstan, was quoted in Informburo a state run news portal saying the death toll from pneumonia this year was 50% higher than it was last year.

And Alexei Tsoi, the Kazakhstan health minister, said that pneumonia of all types would be treated as if the patient had Covid-19, in an effort to avoid spreading it. Kazakhstan has reported more than 50,000 cases of the news SARS coronavirus. To date, of the roughly 28,000 people who have been hospitalized with pneumonia, all have tested negative for Covid-19, according to the Kazakhstan government.

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Worse Than Covid-19? China And Kazakhstan Disagree Over New Virus - Forbes

The West Virginia Department of Health andHuman Resources (DHHR) reports as of 5:00 p.m., on July 10,2020, there have been 201,092 total confirmatorylaboratory results received for COVID-19, with 3,983 totalcases and 95 deaths.

Inalignment with updated definitions from the Centers for Disease Control andPrevention, the dashboard includes probable cases which are individuals that havesymptoms and either serologic (antibody) or epidemiologic (e.g., a link to aconfirmed case) evidence of disease, but no confirmatory test.

CASESPER COUNTY (Case confirmed by lab test/Probable case):Barbour(18/0), Berkeley (504/19), Boone (31/0), Braxton (4/0), Brooke (24/1), Cabell(188/6), Calhoun (4/0), Clay (11/0), Fayette (79/0), Gilmer (13/0), Grant(18/1), Greenbrier (69/0), Hampshire (42/0), Hancock (35/3), Hardy (45/1),Harrison (109/0), Jackson (148/0), Jefferson (248/5), Kanawha (381/12), Lewis (19/1),Lincoln (10/0), Logan (35/0), Marion (95/3), Marshall (57/1), Mason (23/0),McDowell (8/0), Mercer (62/0), Mineral (62/2), Mingo (27/2), Monongalia(454/14), Monroe (14/1), Morgan (19/1), Nicholas (15/1), Ohio (138/0),Pendleton (15/1), Pleasants (4/1), Pocahontas (36/1), Preston (79/16), Putnam(78/1), Raleigh (68/3), Randolph (184/2), Ritchie (2/0), Roane (12/0), Summers(2/0), Taylor (22/1), Tucker (6/0), Tyler (9/0), Upshur (22/1), Wayne (121/1),Webster (1/0), Wetzel (30/0), Wirt (6/0), Wood (159/9), Wyoming (7/0).

Ascase surveillance continues at the local health department level, it may revealthat those tested in a certain county may not be a resident of that county, oreven the state as an individual in question may have crossed the state borderto be tested. Such is the case of Pleasants and Putnamcounties in this report.

Please visit the dashboard at http://www.coronavirus.wv.gov for more detailed information.

Additional report:

Toincrease COVID-19 testing opportunities, the Governor's Office, the HerbertHenderson Office of Minority Affairs, WV Department of Health and HumanResources, WV National Guard, local health departments,and community partners today provided freeCOVID-19 testing for residents in counties with high minority populations andevidence of COVID-19 transmission.

Todays testing resulted in 2,589 individuals tested: 323in Marshall County; 1,368 in Monongalia County; 407 in Preston County; 51 inWayne County; and 440 in Upshur County. Please note these are consideredpreliminary numbers.

Testingin the same counties will continue tomorrow in these locations.

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COVID-19 Daily Update 7-10-2020 - 5 PM - West Virginia Department of Health and Human Resources

A Lancaster County lab is helping test nursing home residents and staff for COVID-19, the Pennsylvania Department of Health said this week.

The department saidLancaster Laboratories Eurofins in Leola is being used as an overflow lab to assist the state's laboratory with testing it's requiring nursing homes to finish by July 24. It announced a similar partnership with Omnicare, a CVS Health company, about two weeks ago.

More than 300 of the state's 695 licensed nursing homes have completed the required testing, spokeswoman Maggi Mumma said in an email.

Lancaster Laboratories provides analytical testing services to the bio/pharmaceutical, food, environmental and medical device industries and is among the county's largest employers. It's owned by Eurofins Scientific, a Luxembourg-based firm that employs 25,000 people across 39 countries.

Pennsylvania has averaged 16,876 tests daily for the last two weeks, and the the state's lab can handle about 1,200 tests a day with 24-hour turnaround for results, according to the department.

The department did not say how much it's paying Eurofins per test, but noted that it has budgeted for roughly 40,750 tests, and the cost is being covered by a federal grant.

"Increased testing, especially in long-term care facilities, will help us determine the number of our most vulnerable Pennsylvanians who have been infected by COVID-19," Mumma wrote in an email. "Each individual who tests positive is followed through a case investigation and contact tracing."

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As of Wednesday, the Lancaster County coroner's office said 301 of the 359 local deaths caused by COVID-19 were residents of nursing or personal care homes.

The state's most recent report shows 1,128 cases among residents and 313 among staffers at 45 of the county's nursing and personal care homes.

Statewide, the figure is 18,092 resident and 3,396 staffer cases at 732 facilities. On June 1, those figures stood at 15,545 resident and 2,663 staff cases at 608 facilities.

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Hundreds of Pa. nursing homes haven't finished COVID-19 testing; local lab hired to help - LancasterOnline

Two more COVID-19-related deaths were reported Friday in Santa Barbara County after what Supervisor Gregg Hart called another very difficult week.

At the latest briefing, public health officials said the county has 75 COVID-19-related hospitalizations, including 23 people in intensive care units, which is a 25 percent increase in the past week.

Positive COVID-19 cases are rising significantly across all parts of Santa Barbara County, California and the nation, Hart said.

Because of the increase in local COVID-19 patients, Santa Barbara Cottage Hospital decided to reduce the number of elective procedures by half starting Monday.

This will ensure that we can provide lifesaving care for the predicted surge of COVID-positive cases while still safely caring for patients who require emergency and essential care for non-COVID conditions, Ron Werft, president and CEO of Cottage Health, said in a statement Friday.

Local hospitals previously postponed elective procedures and surgeries from mid-March until May.

Intensive care units across the county are collectively 56 percent full, including COVID-19 and non-COVID-19 patients, Public Health Director Van Do-Reynoso said. That is concerning because hospitalized COVID-19 patients can require intensive care with little warning, she said.

The two deaths reported Friday were Santa Maria residents in their 70s who lived in skilled nursing facilities experiencing outbreaks, she said. At least one of the people lived in the Country Oaks Care Center, where 10 other residents have died in the COVID-19 outbreak.

Do-Reynoso reported 75 more COVID-19 cases on Friday, and said that contact tracing investigations have linked recent cases, since July 1, to close contact exposures at family gatherings, Father's Day gatherings, Fourth of July parties, funeral services, church services, jail and bars.

You must assume that everyone you come into contact with may be infectious, she said.

Do-Reynoso urged everyone to not become complacent, telling people to keep social distancing, wearing face coverings, disinfecting surfaces and washing hands frequently.

Im taking this seriously and paying special attention to the details again because it's our best, and frankly, only defense, Hart said.

Nick Clay, director of the County Emergency Medical Services Agency, said the large demand for COVID-19 testing at the state-run community testing sites means the facilities are being booked to capacity. There has been a trend of missed appointments, and he asked people to cancel their appointments if they cannot make it, so someone else can get the testing slot.

Santa Barbara County is now asking community members to request a test through these state-run facilities only if they have symptoms or an exposure to someone who tested positive for COVID-19.

We adjusted our messaging several weeks ago from a want to get tested to a need to get tested message, Clay said.

Labs are overwhelmed with the increased demand for testing, and test results are taking up to a week, according to the Public Health Department.

The number of tests administered in the county has more than doubled from what it was a month ago, said Dr. Stewart Comer, who heads the county's public health laboratory. The county had conducted 54,000 tests as of Friday, he said.

Hart said the county will continue to use an educational approach to get compliance with public health orders, including the face coverings mandate.

Although he said that ticketing individual citizens who do not wear face coverings would be too hard to enforce, public health officials will continue to message, explain and urge residents to wear masks to "take care of all of us together."

He also said the county is developing cease-and-desist letters as a way to address noncompliance by businesses who are repeat offendersviolating public health orders.

We are not ultimately going to enforce our way out of this problem. Were going to encourage people to do the right thing,Hart said.I strongly believe were all going to get through this together by modeling proper behavior and setting the best possible example. We will be facing this pandemic for a longer period of time than we all initially hoped. This is not a sprint, it's a marathon, and perhaps even an ultra-marathon.

Noozhawk staff writer Jade Martinez-Pogue can be reached at .(JavaScript must be enabled to view this email address). Follow Noozhawk on Twitter: @noozhawk, @NoozhawkNews and @NoozhawkBiz. Connect with Noozhawk on Facebook.

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Public Health Reports 2 More COVID-19 Deaths, Says Many Recent Cases Linked to Gatherings, Parties - Noozhawk

Unlike the data from the C.D.C., pregnancy is the primary inclusion criteria, said Dr. Afshar, who is a co-principal investigator of the U.C.S.F. and U.C.L.A. study.

Women can register for the study themselves, regardless of where they are getting care, rather than relying on a clinician referral, she added. So far, more than 950 women have enrolled from across the country, and about 60 percent of them have Covid-19.

U.C.S.F. has also started another large, national study for pregnant women in their first trimester called ASPIRE that will follow about 10,000 women and their babies from the start of pregnancy through delivery and up to 18 months postpartum.

This data is vital given that there are gaping holes in the health information used by the C.D.C.

In the C.D.C. study, the researchers found that pregnant women with Covid-19 were more likely to be hospitalized than nonpregnant women who had the virus, but it did not say whether the pregnant women were hospitalized because of labor and delivery, or because of complications from Covid-19. Data sets that the researchers would have needed to make that distinction were not available, the study said.

The data on whether or not infected pregnant women were admitted to the I.C.U. or whether they required mechanical ventilation was missing for about 75 percent of the patients. Using the data that was available, the researchers determined that pregnant women with Covid-19 were more likely to be admitted to the I.C.U. than nonpregnant women (the numbers appeared to be slightly more than the percentage of pregnant women admitted in the past, when compared to data from a 2010 study). Similarly, the study found pregnant women with Covid-19 were more likely to end up on mechanical ventilators than infected nonpregnant women, though the differences were quite small.

Its really hard scientifically to know what that means unless you have an appropriate control group, Dr. Huddleston, one of the principal investigators of the ASPIRE study, said. In other words, researchers also need a control group of pregnant women who are not infected.

Despite the caveats of the C.D.C. study, it remains a signal that pregnant women could be more susceptible to severe Covid-19 symptoms, Dr. Bryant said, adding, its not super surprising given what we know about other respiratory illnesses like flu.

Continued here:

Why We Still Dont Know Enough About Covid-19 and Pregnancy - The New York Times

ITHACA, N.Y. (WSYR-TV) The Tompkins County Health Department announced that there have been positive COVID-19 cases related to some Fourth of July gatherings.

The cases are connected to out-of-state travel to states with significant increases in cases. Some of those cases are connected to local, social gatherings where social distancing was not practiced and masks were not worn.

We have come a long way, but we are not done with COVID-19. I strongly remind all residents to remain vigilant and take all precautions to prevent the spread of COVID-19. People traveling are still bringing the disease into our community, increasing the potential of spread. The Health Department is discouraging all non-essential travel to affected states. Masks are required in public spaces, especially indoors, where distance cannot be maintained. Masks and face-coverings are a simple measure we can all take to prevent exposing others to the virus.

If someone is infected when people come together for a social gathering and do not observe the recommendations for distancing and mask-wearing, everyone is exposed, said Frank Kruppa, the Tompkins County public health director.

If you travel to a state on the travel advisory list sent out by New York State, you are required to quarantine for 14 days once you return.

Completing the full 14 days of quarantine is critical to keeping the disease from spreading. Getting tested does not replace the full quarantine because a test is only one moment in time; you could test negative one day and positive a few days later as the disease incubates or you are exposed to a new source of COVID-19. We all have to stay vigilant.

Anyone who is experiencing symptoms or is concerned about being exposed should get tested.

You can get tested at the Cayuga Health Sampling Site Monday through Friday from 8:30 a.m. to 4 p.m.

To pre-register for an appointment, call (607) 319-5708 orclick here.

Everyone can take the following steps to help stop the spread of coronavirus:

If you would like to file a complaint about a business or social gathering, click here.

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Some positive COVID-19 cases in Tompkins Co. have been linked to Fourth of July gatherings - WETM - MyTwinTiers.com

Spokane County health officials announced 46 new cases of COVID-19 on Friday, bringing the weekly county total to 373 and the countys overall tally to 1,942.

Hospitalizations of county residents, which were predicted in mid-June to double, have done so.

About a dozen county residents were hospitalized in mid-June, and 27 residents were as of Friday. But Spokane hospitals are also treating another 15 COVID-19 patients total, including residents from outside the county.

With ballooning case counts, community spread and backlogged test results, Spokane County Health Officer Dr. Bob Lutz said the county is, in essence, truly back to where we were in March.

The health district continues to identify cases tied to local businesses as well as cases not connected to any other confirmed cases, which is a sign of community spread.

Lutz expressed concerns about residents not adhering to Phase 2 guidelines for gatherings, which should involve fewer than five people, with face coverings and physical distancing in place.

Processing of tests is backed up at national laboratories, causing wait times of up to a week for people awaiting test results. But Lutz reiterated that people waiting for test results must isolate at home until they get them back.

The presumptive diagnosis is that youre positive. Even if your symptoms lessen, you need to keep self-isolating, he said.

With case counts increasing in the Panhandle Health District of North Idaho and in some Eastern Washingtons rural counties, Lutz said he is concerned about the region in general.

The Northeast Tri County Health District confirmed seven new cases across all three counties in one day this week, which was a record.

Matt Schanz, administrator of the health district in the counties, said the increase is concerning because some of these cases were acquired locally, meaning the virus has spread within the three counties, even as some cases were acquired by traveling outside the tri-county region.

We know theres person-to-person transmission in our counties, Schanz said.

What is happening in Spokane County will impact what happens in nearby counties, Schanz said, especially when it comes to hospital capacity.

We are joined at the hip to Spokanes medical system through Providence and MultiCare, Schanz said, noting that patients who need intensive treatment for the virus in intensive care units will likely receive that care in the Lilac City.

A stressed Spokane hospital system would impact their ability to move ahead in the governors reopening phases, although all counties are frozen at the moment and not allowed to apply to advance further due to case counts increasing statewide.

The Northeast Tri County Health District announced that an employee of the Colville McDonalds tested positive for the virus on Thursday, and the restaurant closed for a deep cleaning. Employees identified as close contacts have been asked to complete a two-week quarantine before returning to work, and no customers were identified as close contacts.

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With 46 new COVID-19 cases Friday, Spokane is 'back to where we were in March' - The Spokesman-Review

Ulster County Commissioner of Health Dr. Carol Smith announced today that an employee at Mother Earths Storehouse in Kingston has tested positive this week for COVID-19. Anyone who has shopped at this Mother Earth store from July 1st to July 5 is urged to promptly contact their primary care physician and seek testing, or contact the Ulster County COVID-19 hotline at (845) 443-8888.

I urge anyone who has recently shopped at Mother Earth in Kingston to be alert and monitor their symptoms, said Smith. We are encouraging residents, who may have been in the Kingston Mother Earth store from July 1st through July 5th, to be tested for COVID-19 at one of the Countys many walk-in or mobile testing sites. We will continue to monitor the situation and take measures to minimize the spread of this disease including completing contact tracing to inform those who may have been in contact with this individual. As we see cases continue to rise across the country, we must continue to follow critical safety precautions including wearing masks, social distancing, and washing our hands to protect the health and safety of our community.

The Ulster County Department of Health has recommended the store is thoroughly cleaned and disinfected and is working with the New York State Department of Health to ensure they are following proper protocols.

Residents can find information about their nearest testing location and both walk-in testing sites and mobile testing sites by visitingulstercountyny.gov/get-tested.

There are currently 134 active cases of COVID-19 in Ulster County and 88 fatalities.

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Kingston health-food store worker tests positive for Covid-19: Shoppers urged to get tested - Hudson Valley One

Poverty is suddenly all over the front page. As coronavirus ravages the globe, its wholly disproportionate impact on poor people and marginalised communities is inescapable. Hundreds of millions of people are being pushed into poverty and unemployment, with woeful support in most places, alongside a huge expansion in hunger, homelessness, and dangerous work.

How could the poverty narrative have turned on a dime? Until just a few months ago, many were celebrating the imminent end of poverty; now its everywhere. The explanation is simple. Over the past decade, world leaders, philanthropists and pundits have embraced a deceptively optimistic narrative about the worlds progress against poverty. It has been lauded as one of the greatest human achievements, a feat seen never before in human history and an unprecedented accomplishment. But the success story was always highly misleading.

As I show in my final report as UN special rapporteur on extreme poverty and human rights, almost all of these rosy accounts rely on one measure the World Banks $1.90 (1.50) a day international poverty line which is widely misunderstood, flawed and yields a deceptively positive picture. It has generated an undue sense of satisfaction and a dangerous complacency with the status quo.

Under that line, the number of people in extreme poverty fell from 1.9 billion in 1990 to 736 million in 2015. But the dramatic drop is only possible with a scandalously unambitious benchmark, which aims to ensure a mere miserable subsistence. The best evidence shows it doesnt even cover the cost of food or housing in many countries. And it obscures poverty among women and those often excluded from official surveys, such as migrant workers and refugees. Much of the touted decline is due to rising incomes in a single country, China.

The consequences of this highly unrealistic picture of progress against poverty have been devastating.

First, it is attributed to economic growth, justifying a pro-growth agenda characterised by deregulation, privatisation, lower taxes for corporations and the wealthy, easy movement of money across borders and excessive legal protections for capital. In my six years investigating governments anti-poverty efforts for the UN, I encountered this convenient alibi time and time again. Everything from tax breaks for the super-rich to destructive mega-projects that extract wealth from the global south are lauded as efforts to reduce poverty, when they do no such thing.

Presenting the agenda of the wealthy as the best road to poverty alleviation has entirely upended the social contract and redefined the public good as helping the rich get richer.

Second, the progress narrative has been used to drown out the appalling results so often brought about by this perversion of pro-growth policies. Many of the countries that have achieved great growth in GDP have also experienced exploding inequality, rising hunger, unaffordable health and housing costs, persistent racial wealth gaps, the proliferation of jobs that dont pay a living wage, the dismantling of social safety nets and ecological devastation. These phenomena, directly related to neoliberal policies, are unaccounted for in the tale of heroic gains against poverty.

Third, the rosy picture painted by the World Banks most publicised poverty measure has encouraged complacency. Billions of people face few opportunities, preventable death and remain too poor to enjoy basic human rights. About half the world, 3.4 billion people, lives on less than $5.50 a day, and that number has barely declined since 1990. Even high-income countries with ample resources have failed to seriously reduce poverty rates.

The coronavirus has merely lifted the lid off the pre-existing pandemic of poverty. Covid-19 arrived in a world where poverty, extreme inequality and disregard for human life are thriving, and in which legal and economic policies are designed to create and sustain wealth for the powerful, but not end poverty. This is the political choice that has been made.

Nowhere are these problems more evident than the UNs sustainable development goals, which are clearly not going to be met without drastic recalibration. The SDG framework places immense and mistaken faith in growth and the private sector, rather than envisioning states as the key agents of change and embracing policies that will redistribute wealth and address precarity.

Until governments take seriously the human right to an adequate standard of living, the poverty pandemic will long outlive coronavirus. This requires them to stop hiding behind the World Banks miserable subsistence line and abandon triumphalism about the imminent end of poverty. Deeper social and economic transformation is imperative, to avert a climate catastrophe, provide universal social protection, achieve redistribution through tax justice and ultimately to really get on track to ending poverty.

Philip Alston is John Norton Pomeroy professor of law at New York University School of Law and co-chair of the Center for Human Rights and Global Justice. He was the UN special rapporteur on extreme poverty and human rights from 2014-2020

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Covid-19 has revealed a pre-existing pandemic of poverty that benefits the rich - The Guardian

In January, as a frightening new virus filled hospital wards in Wuhan, China, Stephanie Giordano, a 25-year-old researcher at the drugmaker Regeneron, in a suburb of New York City, began working on a treatment for the disease.

By March, the deadly coronavirus had hit home. Fearing she would get infected on the train that took her to the lab every day, she moved from her apartment in East Harlem to an Airbnb five minutes from the companys headquarters in Tarrytown, in Westchester County.

Then her mother, a nurses assistant who cared for newborn babies at a Long Island hospital, was reassigned to a Covid-19 ward where she tended to older people struggling to breathe. No drug could help these patients or her, if she were to get sick, too.

I had somebody on the line that I really cared about, Ms. Giordano said recently. And I wanted to see her make it through this.

Ms. Giordano, the youngest member of the companys five-person rapid response team for infectious diseases, helped develop what many consider one of the most promising new treatments for Covid-19, which has now infected more than 12 million people around the world, and killed more than 549,000.

She worked in the lab until 10 many nights and through weekends, screening thousands of antibodies the weapons of the immune system that seek out and destroy viruses in search of the most powerful ones. The result was a cocktail of two antibodies that might not only treat the virus, but prevent it by giving the body the same natural defenses that people infected with it produce on their own.

The Trump administration this week gave a major boost to Regenerons treatment, awarding the company $450 million to manufacture and supply as many as 300,000 doses as treatments or 1.3 million doses to prevent infection. Thats in addition to $160 million in federal money the company had already received to run clinical trials and ramp up manufacturing. After the treatment passed an initial safety study, Regenerons broader trials to evaluate the products efficacy got underway.

Dr. Francis S. Collins, the director of the National Institutes of Health, recently singled out the treatment as the most likely to pan out soon. If I had to pick one, I think the monoclonal antibody cocktails have a lot going for them, Dr. Collins said at a Senate hearing last week. Theres all kinds of reasons to think this is the kind of virus it should work for.

If the trials are successful, company executives have said the treatment could be available by the end of the summer. The hope is that it could serve as a stopgap until a vaccine arrives by providing temporary protection to people at high risk of getting infected.

Regeneron is making a significant gamble, ramping up manufacturing of the antibody cocktail before clinical trials have even proved that it works. The most lucrative drugs it makes for other diseases have been relocated to a factory in Ireland.

Regeneron is one of several companies pursuing monoclonal antibody treatments. The drug giant Eli Lilly has also begun clinical trials, and others working on antibody treatments include partnerships of Amgen and Adaptive Biotechnologies and also Vir Biotechnology and GlaxoSmithKline.

Its unclear which of these projects if any will succeed. Drug development is notoriously unpredictable: Just last week, Regeneron announced that an older monoclonal antibody drug, the rheumatoid arthritis treatment Kevzara, had failed to help patients critically ill with Covid-19.

Still, scientists and investors alike are closely watching Regeneron, which developed a treatment for Ebola with this same technology. That treatment was tested during the most recent Ebola outbreak in the Democratic Republic of Congo, which began in 2018 and ended in June. Together with a new Ebola vaccine, the treatment was credited with reducing the deadliness of the outbreak.

Regenerons track record of developing a similar treatment for Ebola doesnt mean they will have a better product, but it does make me relieved that they will not fumble, said Ronny Gal, an analyst for Bernstein, a Wall Street firm.

And Regeneron has taken this all-hands-on-deck approach to Covid-19 in one of the hardest-hit areas of the country. In Westchester County, more than 35,000 people have been infected and more than 1,500 people have died.

Its just a remarkable and unfortunate coincidence, said Dr. Leonard S. Schleifer, Regenerons chief executive.

Ms. Giordano, a research and development associate with a bachelors degree in chemistry from Fordham University, had just transferred to Regenerons viral infectious disease group in January when the researchers noticed a report about a new virus in Wuhan on an international alert system known as ProMED.

Christos Kyratsous, the companys vice president of research for infectious diseases, said his team ordered a synthetic genome of the virus from an outside company, but while they waited for it to arrive, the number of infections simply exploded. While Dr. Kyratsouss team closely watches any new viruses, the way it spread across Wuhan convinced us that this was something worth spending our resources and our time on.

Regeneron has built its business on what Dr. Schleifer, one of the companys founders, calls its magical mice animals that have been genetically engineered to have human immune systems. The mice are infected with harmless viruses that trigger the animals to produce human antibodies. Those antibodies can then be screened for the ones that work best, and then mass-produced in stainless steel vats known as bioreactors.

The technology drove one of the companys biggest blockbusters, the eczema drug Dupixent, as well as the treatment for Ebola.

Dr. Schleifer said he realized the company would need to turn its full attention to developing a treatment in late January, when a news program showed construction vehicles breaking ground on a vast hospital in Wuhan.

They said they were going to build a hospital in five days, he recalled. I said to myself, Holy cow, OK, this doesnt happen just for the fun of it.

In early February, Regeneron expanded a collaboration with the federal government to begin working on the coronavirus treatment. It also started ramping up manufacturing of the antibodies.

Usually, you dont scale it up until youve got something thats proven, Dr. Schleifer said. We knew that the ordinary course of business could not work here. We knew that we needed to get as much capacity as possible.

Dr. Schleifer said the company decided to move its existing products to its plant in Ireland to ensure that the antibody treatment would be made in the United States and available to treat Americans. The pandemic has already led some countries, such as India, to limit exports of drugs that might treat Covid-19, and the United States has snapped up the global supply of another treatment, remdesivir.

There was scary stuff going on in the world about, you know, countries closing borders, he said. We wanted to manufacture as much as we could as close to where the processes were being developed.

The company started its work by collecting as many coronavirus antibodies as possible, both through infecting its magic mice, and from the donated blood of coronavirus survivors.

Those antibodies were handed off to Ms. Giordanos team, which identified the ones that fought off the virus most powerfully.

Ms. Giordanos role was to help develop a phony coronavirus to test against the companys antibody candidates one that, though not harmful, would stand in for the real thing. It was like three years of work in I want to say maybe like a month and a half, she said.

By the end of February, she was clocking 90 hours a week. In March, as the coronavirus arrived in Westchester, she moved to the Airbnb apartment in White Plains the owners gave her a significant discount when she explained what she was working on.

As her mother began caring for Covid-19 patients, the two exchanged photos of each other in their protective gear.

You guys are heros!!!!!!! Ms. Giordano texted in April to her mother, who had sent photos of herself and her co-workers in protective gowns, gloves, face shields and masks. Love ur double glove technique.

Ms. Giordano said that thinking about her mother and her colleagues being at risk of infection kept her going during the grueling days. Because otherwise I think I would have broken down and cried a lot.

As the cases in Westchester County mounted and the state locked down, officials at Regeneron scrambled to keep their labs open without putting employees in danger.

We were truly petrified that we would have this cure that we knew we had to develop, but all of our scientists would get sick and we wouldnt be able to do it, Dr. Schleifer said.

Like many other businesses, the company sent nonessential workers home including Dr. Schleifer, who did conference calls and television appearances from a bedroom in his home. They redirected some cars used by sales representatives to workers who would otherwise rely on public transportation. They staggered researchers shifts so fewer people were in the labs at once.

In late April, the company set up a drive-through testing site in its parking lot, and now requires all employees to get tested at least once every two weeks.

Ms. Giordano and her colleagues, working long hours, took turns grocery shopping at Whole Foods, taking orders for the group. She recalled getting home late one night, eating a bag of defrosted broccoli and carrots for dinner, then collapsing.

In April, the scientists selected their lead candidates for the two-antibody cocktail that would eventually enter clinical trials.

Ms. Giordano turned 25. The group celebrated with a chocolate cake covered in sprinkles. She cut her own bangs. She downloaded the new album by the Strokes, and played it on tiny speakers next to her lab station. (Lana Del Rey was in heavier rotation earlier in the pandemic, she said, because I needed something melodramatic and just kind of soothing in the background.)

Ms. Giordano was listed as an author on two articles in the journal Science describing how Regenerons researchers had selected the antibody cocktail, including their reasoning that, by using two antibodies, they could help prevent resistance to the treatment.

So proud of you!!! her mother wrote in a text.

Now, like everyone else, Ms. Giordano is waiting to see if the antibody treatment will succeed in clinical trials.

While antibody treatments have shown promise in the past, the real question is how well will they work for Covid? said Angela Rasmussen, a virologist at Columbia University. And thats something thats really hard to say, because weve only known about this virus for seven months.

The clinical trials will test how well the antibodies work for three groups: people who are hospitalized, those who are mildly ill and those who have been exposed to someone with the virus. The product will be given as an infusion for people who are sick, and as a lower-dose injection when it is used for prevention. The preliminary results are expected by late summer.

The most intense phase of Ms. Giordanos work on the treatment is now over, and her work schedule has mainly returned to normal. She moved to a new apartment in Greenpoint, Brooklyn, and, as the outbreak ebbed in New York, her mother went back to caring for babies.

She knows the treatment may not ultimately work. Its so scary, she said. But she tries to focus on the science, not her fears.

We did our best, and we tried everything that we could to make something that works, she said. And I think thats enough for now.

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How Scientists Got Coronavirus While Trying to Find a Drug for the Disease - The New York Times

The U.S. is currently facing a shortage of ventilators. Here's how they work and why they are so important in fighting COVID-19. USA TODAY

When Dr. Carl June first heard about symptoms in seriously ill COVID-19 patients, his thoughts jumped to Emily Whitehead.Emily, 7, had endured the same kind of immune systemoverreaction when June treated her in 2012 with an experimental therapy against her leukemia.

Her immune system went into life-threatening overdrive, just like many of those with COVID-19.

In a last-ditch effort to save Emily's life, he had given her a drug,tocilizumab, that kept his own daughter's rheumatoid arthritis under control. To everyone's surprise, the drug worked. Emily is now a normal teenager.

Tocilizumab is one of hundreds of therapies being tested against COVID-19.

Four months ago when COVID-19 arrived in the USA, there were no therapies shown to treat it. Doctors relied solely on what's called supportive care, including intravenous fluids, fever reducersand ventilators, the bulky machines that allow people to breathe when they can't do it on their own.

There are two approved therapies shown to make a difference in COVID-19, and 150 treatments and more than 50 antivirals are being tested in people.

A treatment that kept people from falling seriously ill or even needing hospitalization could strip the fear from the coronavirus andallow people to resume their pre-COVID-19 lives.

Once somebody develops a treatment for the virus, everything will go away, said Daniel Batlle, a kidney expert from Northwestern Medicine and professor of medicine at Northwestern University in Chicago.

Even after a vaccine is developed, treatments that save lives and prevent hospitalization will be crucial.Vaccines might not work for everyone, and doses may initially be limited.

The majority of people diagnosed with COVID-19 more than 80% will recover without the need for hospitalization or significant treatment.

For those who do require care, treatments haveevolved as researchers learn more about the coronavirus and the infection it causes, as well as the damage it can do tovarious parts of the body.

Potential therapies being tested, experts said, fall into four major categories that are best used at different times:

Even as these different approaches are tested, many unanswered questions and challenges remain. One is how to treat patients who might have different responses to the virus, said Dr. John Wherry, director of the institute for immunology at the Perlman School of Medicine at the University of Pennsylvania.

At Penn, he and his colleagues have seen three types of patients: a large group whose immune system is overreacting, a small group whose immune system is underreacting, and others whose immune system is more balanced in the response.

Drugs are tested on all patients without making any distinction, Wherry said. That means ones that tamp down the immune system might help patients with an overactive immune systembut hurt those whose immune systems arent working hard enough, and do nothing for those with a balanced immune response.

Drugs that might be useful for patients with too little immune response might be seen as ineffectivebecause they don't help the larger number of people with immune overreactions, he said.

Wherry said researchers are getting closer to identifying which patients are likely to do better with which kind of therapy. We still need to be pushing very hard and thinking very creatively about how to match treatments to the right patient, he said.

Doctors learn other approaches simply by treating patients.

Batlle, the kidney expert, said that although COVID-19 has been considered a lung disease, as many as half of patients hospitalized with severe cases also suffer acute kidney injury. Its notclear how many patients will be left with long-term kidney problems after recovering from severe cases of COVID-19.

We dont want to scare anybody, but kidney damage was initially underreported, and now several studies have shown that it is extremely frequent in hospitalized patients," he said.

Treatment for acute kidney injury usually involves dialysis, which removes toxins from the blood that the kidneys can no longer address. Batlle hopes treatments that address COVID-19-related inflammation and formation of blood clots will eventually reduce such injuries.

We should be better prepared to help these patients and not rely (only)on supportive care, he said.

As coronavirus cases in some states start to rise again, make sure to remember these safety tips. USA TODAY

Since mid-May, dexamethasone and remdesivir have been shown useful for certain COVID-19 patients. Both are recommended by the National Institutes of Health and the Infectious Disease Society of America.

For hospitalized patients, these drugs are beginning to show an effect, said Dr. Rajesh Gandhi, an infectious disease specialist at Massachusetts General Hospital who sits on both panels.

Placing patients on their stomachs rather than their back when they have breathing problems may help, according to some experts.

Gandhi and other doctors said they are much more comfortable treating COVID-19s many symptoms, which can include blood clots, immune problems and organ failure, in addition to lung issues.

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Some said COVID-19 is a multi-system disease, targeting at times the lining of blood vessels. This would explain how it damages so many of the body's organs, all of which are fed by blood vessels.

A study by theRecovery Collaborative Group, still not fully vetted, showed that dexamethasone, at a dose of 6 mg per day for up to 10 days, can be lifesaving for patients with COVID-19 who are on ventilators. The evidence was weaker for patients who are hospitalized and receiving oxygen. The study found no support for giving the steroid to less seriously ill COVID-19 patients, but more research is underway.

According to a study in May in the New England Journal of Medicine,the drug remdesivir, developed to treat Ebola, shortened the recovery time of patients hospitalized with COVID-19 and lower respiratory tract infections.

Scientists said remdesivir might be even more effective in people who are notsick enough to require hospitalization, but because it can be delivered only intravenously, it has not been tested on outpatients. Its manufacturer, Gilead, is rushing to ramp up production and to develop an inhaled version of the drug.

Although remdesivir is helpful, it doesnt cure COVID-19 and is far from a home run, said Dr. Mark Rupp, an infectious disease expert at the University of Nebraska.

Its kind of like getting on base with a single, he said. Weve got a long way to go.

Although its tempting tothrow everything in the medicine cabinet at COVID-19, Rupp said he learned while fighting Ebola in 2014-2015 that its much more important to conduct high-quality clinical research during an outbreak.

Without such research, you throw the kitchen sink at everybody, and you dont know what helps and what hurts and thats a dangerous place to be, he said.

He cited the example of hydroxychloroquine,which was used early on to treat COVID-19 before research showed it was ineffective in very sick patients.

Everybody wants to do good, we want to help our patients, Rupp said. But sometimes well-meaning efforts really dont result in beneficial effects.

Its only by testing drugs and other therapies through clinical trials that doctors learn what works and what doesnt, he said. The more data and information we can gather, the better off were going to be.

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Health and patient safety coverage at USA TODAY is made possible in part by a grant from the Masimo Foundation for Ethics, Innovation and Competition in Healthcare. The Masimo Foundation does not provide editorial input.

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Medical care for very ill COVID-19 patients is getting better - USA TODAY

In early March, most doctors in the United States had never seen a person sick with COVID-19. Four months later, nearly every emergency room and intensive care physician in the country is intimately familiar with the disease. In that time, theyve learned a lot about how best to treat patients. But in some cases, theyre still taking the same approach they did in the spring.

Theres so much thats different, and so much thats the same, says Megan Ranney, an emergency physician and associate professor at the Brown University Department of Emergency Medicine.

For the first few months of the pandemic, recommendations for every incremental decision made in a hospital were changing faster than they ever have before. You almost couldnt keep up from one day to the next, your practice would change and your protocols would change. It was really disorienting for doctors and nurses, Ranney says.

Information spread between colleagues, through medical education blogs and podcasts, and on social media. Doctors talked about new research on Twitter and shared new strategies in Facebook groups and on WhatsApp. If a suggestion that floated by a doctor in a Facebook group was low-risk and seemed like it might be helpful, it could be put into practice immediately. If its a small change, they could start using it the next day, she says.

Thats how the now-common practice of asking patients with COVID-19 to flip onto their stomachs spread: through word-of-mouth and on social media. When someone is on their back, their organs squish their lungs and make it harder for their airways to fully expand. When someone is on their stomach, their lungs have more room to fill up with air. The advice started circulating through the medical community before there was a formal, published study on the practice.

Testing it out wouldnt have many downsides (it wasnt dangerous to patients), and it was easy to do. Theres this possibility that it could be positive, and there were a lot of stories about it having a positive effect, Ranney says. So, it spread in a much more organic and quick way, because it was something that we could do, but we werent worried it would hurt patients.

Doctors like Seth Trueger, an assistant professor of emergency medicine at Northwestern University, saw the position help patients get enough oxygen to avoid needing a ventilator. I started jokingly call it tummy time, he says. Studies are starting to validate those observations, finding that patients who spent time on their stomachs were, in fact, better off.

Since March, physicians have also figured out other ways to help severely ill patients avoid ventilation. We appreciate that its probably not a great thing for these patients, and weve developed other ways to get people high levels of oxygen, says James Hudspeth, the COVID response inpatient floor lead at Boston Medical Center. For example, doctors are turning to nasal cannulas, which are noninvasive prongs that blow oxygen into the nose, before a ventilator.

They have better medications for hospitalized patients now, too. Since March, doctors have cycled through a few different options like hydroxychloroquine, which turned out not to be effective. Now, theyre primarily using remdesivir, an antiviral drug that appears to help COVID-19 patients recover more quickly, and the steroid dexamethasone, which helps improve the survival rate for patients on ventilators. Many intensive care units and many hospitals have created their own standard order sets, or standard therapies, for people with COVID-19, Ranney says. Those shift as new evidence comes out around different medications.

Thats not unusual, Ranney says. Hospitals regularly change the drugs they use for conditions like flu and pneumonia as new data comes out. Whats unusual is to change practice so quickly, she says. Thats just the reality of a global pandemic, with a disease weve never seen before.

Most of the changes in doctors strategies over the past few months have been in patients who are severely ill. If someone is sick enough to be hospitalized with COVID-19 but doesnt need to be in intensive care, there still isnt much doctors can do for them. Theyll get fluids to make sure they stay hydrated and are given oxygen if they need it. Doctors will try to keep their fever down and monitor them to see if they get sicker, but thats about it.

Its just those basic things, Ranney says. Doctors now are more vigilant to the threat from blood clots, which have appeared in many COVID-19 patients over the past months. Because testing is more available in hospitals than it was earlier this year, theyll also confirm that a moderately ill patient actually does have COVID-19 and avoid giving them unnecessary treatments. But active interventions for patients with less severe symptoms are still around the same as they were back in March. Were still kind of in this watchful waiting, she says.

One lingering question, Hudspeth says, is figuring out how to keep those moderately ill patients from becoming severely ill. Steroids may be helpful earlier on, he says, as could artificial antibody treatments that block the virus, though those strategies are still under investigation. Part of the challenge we face at the present moment is that the moderate patients are often where we would want to intervene, he says.

Changes to treatment strategies for patients who are not severely sick have been harder to come by in part because its riskier to try something new in that group. If someone isnt dangerously sick, there isnt as much to gain from using an experimental treatment that may have a chance of causing harm, so doctors are less likely to take risks. Were more likely to try stuff with sicker patients, Ranney says. And their families are more likely to consent to a clinical trial.

Despite the open issues around COVID-19 treatments, the rate of new information is slowing down. Doctors arent shifting their practices as quickly as they were back in March and April, and Trueger says he thinks the next few months may be relatively stable. Doctors might get new information about which medications are more or less helpful, but other common best practices might be more entrenched. I dont think things are going to change as rapidly as the changes we had up front, when we were really flying half blind, he says.

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Doctors are better at treating COVID-19 patients now than they were in March - The Verge

26 March 2020 - Salt Lake City

While some missionaries will remain and complete their regular term of service, many others will be released early

The First Presidency and Quorum of the Twelve Apostles of The Church of Jesus Christ of Latter-day Saints sent the following letter March 26, 2020, to Church members around the globe. See the latest updates on how COVID-19 is impacting Saints worldwide.

Dear Brothers and Sisters,

In our letter of March 20, 2020, we indicated that the original term of service for missionaries brought back early to the United States would likely be reduced to accommodate the large number of missionaries returning from around the world.

As we evaluate changing conditions, further adjustments will be made.

To all missionaries who have served and are continuing to serve in these unique circumstances we express our deep gratitude. We love and pray for our missionaries and their families. We are grateful for the continued prayers and support of parents, loved ones, and Church members as we make every effort to help them remain safe and well in these challenging times.

Sincerely,

The First Presidency and Quorum of the Twelve Apostles

Style Guide Note:When reporting about The Church of Jesus Christ of Latter-day Saints, please use the complete name of the Church in the first reference. For more information on the use of the name of the Church, go to our online Style Guide.

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Further Adjustments to Missionary Service - The Church of ...

Contributed BySarah Jane Weaver, Church News editor

Sharing the gospel of Jesus Christ remains a sacred priority for The Church of Jesus Christ of Latter-day Saints, even in the current circumstances related to the COVID-19 pandemic. Church statement

In another response to the COVID-19 pandemic, temporary adjustments will be made to missionary work in The Church of Jesus Christ of Latter-day Saints, leaders announced Monday morning.

Missionaries will continue to be called to serve and assigned to labor in missions worldwide, according to a statement from Church leaders. Missionary recommendations will continue to be received, and missionary assignments for worldwide service will continue to be made.

However, in an effort to adapt to constantly changing conditions and out of an abundance of caution, Church leaders are implementing temporary adjustments to missionary service.

These changes include the following:

Young missionary elders currently serving in missions within the United States and Canada who would complete their mission on or before September 1, 2020 may be released after they have served for 21 months. The length of service for sister missionaries serving in the United States and Canada will not be impacted by the adjustments.

Young missionaries with health issues and senior missionaries may be released from service.

Some missionaries may be temporarily reassigned to another mission.

Sharing the gospel of Jesus Christ remains a sacred priority for The Church of Jesus Christ of Latter-day Saints, even in the current circumstances related to the COVID-19 pandemic, said Church leaders in a statement. We continue to monitor the spread of this condition and its impact on missionaries worldwide. We take very seriously the health and safety of our missionaries and of those they teach.

Young missionaries needing to work primarily from their apartments will continue teaching using technology, studying the scriptures, and Preach My Gospel, language learning, family history, online community service and other activities as identified by the mission president, according to the statement.

In addition, missionaries are encouraged to stay in contact with their families frequently and to take opportunities to leave their apartments for periods of exercise and fresh air, while observing wise guidelines for personal contact.

Church leaders will continue to monitor conditions and make further adjustments as needed. As a Church, we express our love and appreciation for all missionaries as they strive to teach the gospel of Jesus Christ and share His love wherever they serve, wrote leaders in the statement.

Family history missionaries work on computers and do paperwork.

Missionary work has been impacted by epidemics during other times in history.

Missionary work in Hong Kong was affected by theSARS outbreak in 2003.And following an outbreak of Ebola in Liberia, missionaries were moved out of the West African nation in August 2014; young missionaries returned in September 2015.Missionary work was also disrupted in Madagascarfollowing an outbreak of the plaguein October 2017.

In June 2009, the spread ofswine flu promptedChurch leaders to change MTC drop-off protocols. In addition, a suspectedstomach flu/norovirusimpacted 250 Latter-day Saint missionaries in the Provo Missionary Training Center in January 2013.

The Church slowed the expansion of Latter-day Saint missions during World War II. Missionary work continued, however, despite many men being drafted into military service.

Missionaries smile as they meet together outside in Mexico.

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Church Announces Adjustments to Missionary Work, Will ...

White House adviser Peter Navarro claimed Donald Trump was being tongue-in-cheek when he claimed to have asked public health officials to slow down coronavirus testing.

Trump made the remark at a campaign rally in Tulsa, Oklahoma, on Saturday evening.

On Sunday, Navarro also told CNNs Jake Tapper he did not hear me wrong when he claimed without foundation that the virus was a product of the Chinese Communist party.

China created this pandemic, the trade adviser said. They hid the virus. They created that virus. And they sent over hundreds of thousands of Chinese citizens here to spread that around and around the world.

Whether they did that on purpose, thats an open question. But thats a fact.

Experts agree Covid-19 originated in Wuhan province, most likely in a market where live animals are sold. Trump and allies have sought to blame China for the spread of the virus, some advancing the conspiracy theory that it was created in a military lab.

Navarro told CNN: In 2006, in a book I wrote called The Coming China Wars. On page 150, I predicted that China would create a viral pandemic that could possibly kill millions.

Why did I do that at the time? Because the whole structure of that authoritarian, repressive, non-transparent society is geared towards giving us exactly what they given us, which is a pandemic.

As the Guardian reported in April, Navarro was first recruited by Trump because he wrote a string of books about the Chinese strategic threat one called Death by China despite having spent almost no time in the country and having no grasp of the language.

Five of Navarros books cited a China hand with a particularly pithy turn of phrase called Ron Vara, who turned out not to exist. The name is an anagram of Navarro and the imaginary expert operated as an alter ego, confirming the authors views.

Navarros latest comments about China were as incendiary as Trumps remarks about testing were, to many, alarming. Experts have sought to dampen fears that the US may face a second wave of infections, but only because the first isnt over.

When you have 20,000-plus infections per day, how can you talk about a second wave? Dr Anthony Fauci of the National Institutes of Health told the Associated Press. Were in the first wave. Lets get out of the first wave before you have a second wave.

According to Johns Hopkins University, the US has confirmed more than 2.2m cases and nearly 120,000 Covid-19 deaths. The real numbers are believed to be higher.

New cases have shown sudden rises in several states, but not just due to testing many states, most Republican-led are seeking to reopen from lockdown. The wearing of masks and other public health guidelines has become a political fault line, with many Americans refusing to follow such advice.

Saturdays rally in Tulsa took place amid climbing case numbers in Oklahoma and against pleas from local health officials not to stage the event at all. Six campaign staffers tested positive, but in his speech Trump said the bad part of widespread testing is that it leads to logging more cases.

The president had already used racist language aimed at China, referring to Covid-19 as kung flu. He then described testing as a double-edged sword. The US had now tested 25 million people, far more than other countries, Trump said, adding: When you do testing to that extent, youre gonna find more people, youre gonna find more cases. So I said to my people slow the testing down.

Navarro insisted Trumps comment was tongue in cheek and made in a light moment. To Tappers contention that a deadly pandemic, where almost 120,000 Americans have died might not be really a good subject for a light moment, Navarro said: He takes that absolutely seriously.

On Sunday, Oklahoma reported a record number of new cases, at 478. The states previous record of 450 new cases in a day, was set on Thursday.

Democratic presidential candidate Joe Biden criticized Trump for putting politics ahead of the safety and health of Americans. House speaker Nancy Pelosi said the president was ethically unfit and intellectually unprepared to lead.

Also on CNN, Atlanta mayor Keisha Lance Bottoms, a potential Biden running mate, said: This is no time to joke. Even if it were a joke, which it was not, it was an inappropriate joke. Do you think the people, the 120,000 families out there who are missing their loved ones thought it was funny?

Acting homeland security secretary Chad Wolf told NBCs Meet the Press the White House coronavirus taskforce is working with governors to make sure the US can open up this economy in a safe and reasonable way.

I think thats what were seeing, he said.

Wolf told CBSs Face the Nation the task force was on top of all of these outbreaks, including in Arizona, Texas, Florida and other states having hot spots. The administration, he said, had sent medical equipment, staff and personnel to assist with reopening efforts.

Bottoms also condemned Trump for staging his rally in Tulsa, the site of a historic race massacre, after a month of protests and civil unrest over racism and police brutality, subjects he skipped entirely during his speech.

That rally was an embarrassment, she said. It was absolutely what the nation does not need right now. He did not speak about healing. He did not recognize any of the racial tensions that are happening across our country.

Instead, he does what he always does. He continues to try and divide us and really inflames the worst in people. And so I just hope that this is a good sign that the country is moving on from him.

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Peter Navarro: Trump call to slow Covid-19 testing was 'tongue-in-cheek' - The Guardian

As her father lay dying in a hospital bed in Arizona, after testing positive for Covid-19, Lina Washington pleaded with him to keep fighting.

When they hung up, Washington scrolled through Instagram. She saw stories of friends and former classmates drinking and socializing at crowded bars and clubs, even as coronavirus infections rose exponentially across the state. Yet there they were, smiling, maskless, as if the threat had disappeared and life returned to normal.

Would they be so reckless, she wondered, if they knew that just a few miles away doctors and nurses were toiling around the clock to save her fathers life?

People dont think that it can happen to them, Washington, a high school friend and classmate, told me during a phone interview this week. And that carelessness, that hubris, that arrogance may have cost my dad his life.

Robert Edward Washington Jr died on 11 June from complications related to the virus, less than a month after returning to work as a security guard at a tribal casino in Chandler.

In the days since his death, Washington, a television sports reporter in Sacramento, California who grew up in the Phoenix area, said she has been on a warpath, demanding accountability and leadership from public officials and business leaders in the state. She has directly challenged Arizona governor Doug Ducey over his response to the pandemic, and implored him to do more to protect vulnerable residents.

His death was preventable, she said. Im speaking out to ensure nobody else has to feel this pain.

In the last few days, as new coronavirus cases in Arizona have climbed to their highest levels of the pandemic, Washington amplified her calls for stricter safety precautions. She has given interviews to every local TV news station and has spoken to the Arizona Republic. Nationally, she has been featured on ABC and MSNBC.

Some of her sharpest criticism has been expressed on Twitter.

I know my AZ friends arent taking this seriously, Washington tweeted on Thursday. I see what Old Town & Mill Ave look like every weekend on IG & its obscene. Youre putting people like my dad at risk by not wearing a mask at the very least. A Covid-19 death happened to me & could happen to you. Wake up.

On Friday, Washington filmed herself walking inside a Walmart in Tempe, after she saw multiple customers shopping without masks.

If you get sick, you get sick, she said an employee told her. She proceeded to call out Ducey in the tweet, writing: WHERE IS THE ACCOUNTABILITY?!

Two days earlier, Ducey had said he would no longer prohibit local governments from requiring face masks to slow the spread the virus, a reversal that came amid mounting pressure from mayors and public health officials. Wearing a mask for the first time at a news briefing, he conceded that coronavirus was widespread in the state and urged Arizonans to act responsibly to protect one another.

Gila River Hotels & Casinos, which operates Lone Butte, where Washingtons father worked, announced on Thursday that it would temporarily close for two weeks to protect the health and safety of our team members and guests, as the Gila River Indian Community moved to make protective face coverings mandatory on community lands.

This move comes after the death of one of your employees, my dad, who returned to work on 15 May, Washington responded.

It was the same day Arizona lifted its stay-at-home order.

Were open, Phoenix! the casino tweeted that morning, encouraging guests to come and reclaim your fun.

Washington said she begged her father to stay home. But he was stubborn, a trait she says she inherited. He told her he needed to work, to ensure he had health and life insurance.

That night, he worked at the security desk, Washington said, exposing him to nearly every customer. Employees were required to wear protective gear. Guests of the casino were encouraged to wear masks but not required to do so.

Washington said her father called her the next day and expressed his concern. He told her 80% of the people waiting to get into the casino at 4.30 in the morning werent wearing masks.

Within 10 days of him returning back to work he had tested positive for Covid and two weeks after that he was dead, she said.

I really wonder how many people were in that line that I knew, that we probably went to school with, she said, adding: I know so many people who would do that. Because its Arizona, and we dont really care about one another in ways like other communities do. Especially people who look like me and my dad.

Washingtons fathers death came amid a national reckoning over racism in America that has affected her professionally and personally. Inspired by the Black Lives Matter demonstrations, she helped start a community art project to benefit black youth organizations in Sacramento. It was just getting off the ground when she learned her father was ill.

It was a perfect storm, a black woman, in news, with a dad in the hospital with coronavirus, she said. It just all came down at once and then my worst fears were realized.

Washington said she was initially hesitant about speaking out. As a sports reporter, she would rather be talking about the Sacramento Kings NBA season than her own tragedy. But she said she felt a responsibility to use her platform to seek accountability and raise awareness.

Im just grateful that me expressing my pain is making a difference and putting a face to Covid in Arizona, she said.

Robert Washington was 68. He was a diabetic and had overcome prostate cancer. His daughter said they were acutely aware of the virus unequal toll on Black Americans, who are 2.3 times more likely to die from the disease than white Americans.

The last time Washington saw her father in person was in March. During a visit to Arizona, she asked him to sit for an interview.

Filmed in his backyard, Robert Washington recalled his adolescence in Ohio. A talented athlete, he excelled in nearly every sport he played. Football earned him a full scholarship to the University of Notre Dame in the early 1970s.

He was a devoted father who took her to dance, taught her to drive and prepared her for the challenges she would face as a black woman in an industry dominated by white men.

She also credits him with kindling her love of sports. When she was young, he who would take her to work at his shoeshine stand at what was then America West Arena, so she could watch the Phoenix Suns play.

He was my best friend, she said, her voice breaking. I wish I could call him right now.

Washington will lay her father to rest in Arizona on Sunday, Fathers Day.

Originally posted here:

Daughter speaks out after her father dies of Covid-19: 'It was preventable' - The Guardian

The First Presidency of The Church of Jesus Christ of Latter-day Saints sent the following letter April 16, 2020, to Church leaders around the globe. Also see the latest updates on how COVID-19 is impacting Latter-day Saints..

We are grateful for the efforts many of you are making to follow the directions carefully from national, state, and local leaders in many countries in response to the COVID-19 pandemic. The Church of Jesus Christ of Latter-day Saints is also taking appropriate precautions and is providing assistance to those in need.

Under the present circumstances and under conditions that may exist in the future, the Church and its members will faithfully exhibit our commitment to being good citizens and good neighbors.

Attached to this letter are documents that explain administrative principles for the Church during challenging times. Directions are enclosed for essential ordinances, blessings, and other Church functions to guide leaders through the current crisis and the challenging days that are ahead.

These documents are issued in response to the disruptions in Church procedures and member activities caused by the worldwide COVID-19 pandemic. They should provide guidance as long as this pandemic exists in a particular country or region. Other directions may be issued later.

Sincerely,

The First Presidency

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First Presidency Letter on Administrative Principles in ...