Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia.Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation.Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3-11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients.Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1-2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced.Funding None. Articles 2www.thelancet.com/respiratory Published online February 21, 2020 https://doi.

Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which causes novel coronavirus disease 2019 (COVID‐19), is spreading rapidly around the world. Thrombocytopenia in patients with COVID‐19 has not been fully studied. Objective To describe thrombocytopenia in patients with COVID‐19. Methods For each of 1476 consecutive patients with COVID‐19 from Jinyintan Hospital, Wuhan, China, nadir platelet count during hospitalization was retrospectively collected and categorized into (0, 50], (50, 100], (100‐150], or (150‐) groups after taking the unit (×109/L) away from the report of nadir platelet count. Nadir platelet counts and in‐hospital mortality were analyzed. Results Among all patients, 238 (16.1%) patients were deceased and 306 (20.7%) had thrombocytopenia. Compared with survivors, non‐survivors were older, were more likely to have thrombocytopenia, and had lower nadir platelet counts. The in‐hospital mortality was 92.1%, 61.2%, 17.5%, and 4.7% for (0, 50], (50, 100], (100‐150], and (150‐) groups, respectively. With (150‐) as the reference, nadir platelet counts of (100‐150], (50, 100], and (0, 50] groups had a relative risk of 3.42 (95% confidence interval [CI] 2.36‐4.96), 9.99 (95% CI 7.16‐13.94), and 13.68 (95% CI 9.89‐18.92), respectively. Conclusions Thrombocytopenia is common in patients with COVID‐19, and it is associated with increased risk of in‐hospital mortality. The lower the platelet count, the higher the mortality becomes.

The pandemic of the coronavirus disease 2019 has become a global public health crisis. The symptoms of COVID-19 range from mild to severe conditions. However, the physiological changes associated with COVID-19 are barely understood. In this study, we performed targeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected whole-body metabolism of the patients. In particular, malic acid of the TCA cycle and carbamoyl phosphate of urea cycle reveal the altered energy metabolism and hepatic dysfunction, respectively. It should be noted that carbamoyl phosphate is profoundly down-regulated in fatal patients compared with mild patients. And more importantly, guanosine monophosphate (GMP), which is mediated by not only GMP synthase but also CD39 and CD73, is significantly changed between healthy subjects and COVID-19 patients, as well as between the mild and fatal groups. In addition, the dyslipidaemia was observed in COVID-19 patients. Overall, the disturbed metabolic patterns have been found to align with the progress and severity of COVID-19. This work provides valuable knowledge about plasma biomarkers associated with COVID-19 and potential therapeutic targets, as well as important resource for further studies of COVID-19 pathogenesis.

The COVID-19 pandemic is a global public health crisis. However, little is known about the pathogenesis and biomarkers of COVID-19. Herein, we profiled host responses to COVID-19 by performing plasma proteomics of a cohort of COVID-19 patients including non-survivors and survivors recovered from mild or severe symptoms, and uncovered numerous COVID-19-associated alterations of plasma proteins. We developed a machine learning-based pipeline to identify 11 proteins as biomarkers and a set of biomarker combinations, which were validated by an independent cohort and accurately distinguished and predicted COVID-19 outcomes. Some of the biomarkers were further validated by ELISA using a larger cohort. These markedly altered proteins, including the biomarkers mediate pathophysiological pathways such as immune or inflammatory responses, platelet degranulation and coagulation, and metabolism, that likely contribute to the pathogenesis. Our findings provide valuable knowledge about COVID-19 biomarkers, and shed light on the pathogenesis and potential therapeutic targets of COVID-19.

Background The global numbers of confirmed cases and deceased critically ill patients with COVID-19 are increasing. However, the clinical course, and the 60-day mortality and its predictors in critically ill patients have not been fully elucidated. The aim of this study is to identify the clinical course, and 60-day mortality and its predictors in critically ill patients with COVID-19. Methods Critically ill adult patients admitted to intensive care units (ICUs) from 3 hospitals in Wuhan, China, were included. Data on demographic information, preexisting comorbidities, laboratory findings at ICU admission, treatments, clinical outcomes, and results of SARS-CoV-2 RNA tests and of serum SARS-CoV-2 IgM were collected including the duration between symptom onset and negative conversion of SARS-CoV-2 RNA. Results Of 1748 patients with COVID-19, 239 (13.7%) critically ill patients were included. Complications included acute respiratory distress syndrome (ARDS) in 164 (68.6%) patients, coagulopathy in 150 (62.7%) patients, acute cardiac injury in 103 (43.1%) patients, and acute kidney injury (AKI) in 119 (49.8%) patients, which occurred 15.5 days, 17 days, 18.5 days, and 19 days after the symptom onset, respectively. The median duration of the negative conversion of SARS-CoV-2 RNA was 30 (range 6–81) days in 49 critically ill survivors that were identified. A total of 147 (61.5%) patients deceased by 60 days after ICU admission. The median duration between ICU admission and decease was 12 (range 3–36). Cox proportional-hazards regression analysis revealed that age older than 65 years, thrombocytopenia at ICU admission, ARDS, and AKI independently predicted the 60-day mortality. Conclusions Severe complications are common and the 60-day mortality of critically ill patients with COVID-19 is considerably high. The duration of the negative conversion of SARS-CoV-2 RNA and its association with the severity of critically ill patients with COVID-19 should be seriously considered and further studied.

Background: A COVID-19 outbreak started in Wuhan, China, last December and now has become a global pandemic. The clinical information in caring of critically ill patients with COVID-19 needs to be shared timely, especially under the situations that there is still a largely ongoing spread of COVID-19 in many countries. Methods: A multicenter prospective observational study investigated all the COVID-19 patients received in 19 ICUs of 16 hospitals in Wuhan, China, over 24 h between 8 AM February 2h and 8 AM February 27, 2020. The demographic information, clinical characteristics, vital signs, complications, laboratory values, and clinical managements of the patients were studied.Results: A total of 226 patients were included. Their median (interquartile range, IQR) age was 64 (57-70) years, and 139 (61.5%) patients were male. The duration from the date of ICU admission to the study date was 11 (5-17) days, and the duration from onset of symptoms to the study date was 31 (24-36) days. Among all the patients, 155 (68.6%) had at least one coexisting disease, and their sequential organ failure assessment score was 4 (2-8). Organ function damages were found in most of the patients: ARDS in 161 (71.2%) patients, septic shock in 34 (15.0%) patients, acute kidney injury occurred in 57 (25.2%) patients, cardiac injury in 61 (27.0%) patients, and lymphocytopenia in 160 (70.8%) patients. Of all the studied patients, 85 (37.6%) received invasive mechanical ventilation, including 14 (6.2%) treated with extracorporeal membrane oxygenation (ECMO) at the same time, 20 (8.8%) received noninvasive mechanical ventilation, and 24 (10.6%) received continuous renal replacement therapy. By April 9, 2020, 87 (38.5%) patients were deceased and 15 (6.7%) were still in the hospital.(Continued on next page)

The pandemic of the coronavirus disease 2019 has become a global public health crisis. The symptoms of COVID-19 range from mild to severe conditions. However, the physiological changes associated with COVID-19 are barely understood.In this study, we performed targeted metabolomic and lipidomic analyses of plasma from a cohort of COVID-19 patients who had experienced different symptoms. We found the metabolite and lipid alterations exhibit apparent correlation with the course of disease in these COVID-19 patients, indicating that the development of COVID-19 affected whole-body metabolism of the patients. In particular, malic acid of the TCA cycle and carbamoyl phosphate of urea cycle reveal the altered energy metabolism and hepatic dysfunction, respectively. It should be noted that carbamoyl phosphate is profoundly down-regulated in fatal patients compared with mild patients. And more importantly, guanosine monophosphate (GMP), which is mediated by not only GMP synthase but also CD39 and CD73, is significant changed between healthy subjects and

Keywords: dasatinib, doxorubicin, ERK pathway, multidrug resistance, P-glycoprotein Abbreviations: MDR, multidrug resistance; P-gp, P-glycoprotein; DOX, doxorubicin; ERKextracellular signal-regulated kinase; P-ERK, phosphorylated extracellular signal-regulated kinase.Multidrug resistance (MDR) is one of the major obstacles to the efficiency of cancer chemotherapy, which often results from the overexpression of drug efflux transporters such as P-glycoprotein (P-gp). In the present study, we determined the effect of dasatinib which was approved for imatinib resistant chronic myelogenous leukemia (CML) and (Ph C ) acute lymphoblastic leukemia (ALL) treatment on P-gp-mediated MDR. Our results showed that dasatinib significantly increased the sensitivity of P-gp-overexpressing MCF-7/Adr cells to doxorubicin in MTT assays; thus lead to an enhanced cytotoxicity of doxorubicin in MCF-7/Adr cells. Additionally, dasatinib increased the intracellular accumulation, inhibited the efflux of doxorubicin in MCF-7/Adr cells, and significantly enhanced doxorubicin-induced apoptosis in MCF-7/Adr cells. Further studies showed that dasatinib altered the expression levels of mRNA, protein levels of P-gp, and the phosphorylation of signal-regulated kinase (ERK) both in time-dependent (before 24 h) and dose-dependent manners at concentrations that produced MDR reversals. In conclusion, dasatinib reverses P-gpmediated MDR by downregulating P-gp expression, which may be partly attributed to the inhibition of ERK pathway. Dasatinib may play an important role in circumventing MDR when combined with other conventional antineoplastic drugs.