ObjectiveTo examine the protective effects of appropriate personal protective equipment for frontline healthcare professionals who provided care for patients with coronavirus disease 2019 (covid-19).DesignCross sectional study.SettingFour hospitals in Wuhan, China.Participants420 healthcare professionals (116 doctors and 304 nurses) who were deployed to Wuhan by two affiliated hospitals of Sun Yat-sen University and Nanfang Hospital of Southern Medical University for 6-8 weeks from 24 January to 7 April 2020. These study participants were provided with appropriate personal protective equipment to deliver healthcare to patients admitted to hospital with covid-19 and were involved in aerosol generating procedures. 77 healthcare professionals with no exposure history to covid-19 and 80 patients who had recovered from covid-19 were recruited to verify the accuracy of antibody testing.Main outcome measuresCovid-19 related symptoms (fever, cough, and dyspnoea) and evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, defined as a positive test for virus specific nucleic acids in nasopharyngeal swabs, or a positive test for IgM or IgG antibodies in the serum samples.ResultsThe average age of study participants was 35.8 years and 68.1% (286/420) were women. These study participants worked 4-6 hour shifts for an average of 5.4 days a week; they worked an average of 16.2 hours each week in intensive care units. All 420 study participants had direct contact with patients with covid-19 and performed at least one aerosol generating procedure. During the deployment period in Wuhan, none of the study participants reported covid-19 related symptoms. When the participants returned home, they all tested negative for SARS-CoV-2 specific nucleic acids and IgM or IgG antibodies (95% confidence interval 0.0 to 0.7%).ConclusionBefore a safe and effective vaccine becomes available, healthcare professionals remain susceptible to covid-19. Despite being at high risk of exposure, study participants were appropriately protected and did not contract infection or develop protective immunity against SARS-CoV-2. Healthcare systems must give priority to the procurement and distribution of personal protective equipment, and provide adequate training to healthcare professionals in its use.

Dear Editor, Accumulating clinical data suggest the main causes of death by COVID-19 include respiratory failure and the onset of sepsis. 1 Importantly, sepsis has been observed in nearly all deceased patients. 2-5 It remains elusive how SARS-CoV-2 infection results in viral sepsis in humans. Toll-like receptor 4 (TLR4) mediates antigram-negative bacterial immune responses by recognizing lipopolysaccharide (LPS) from bacteria. 6 We recently found that SARS-CoV-2 infection provoked an anti-bacterial like response at the very early stage of infection via TLR4. However, the identity of the original trigger initiating these abnormal immune responses during SARS-CoV-2 infection is unknown. Previous in silico studies predicted cell surface TLRs, especially TLR4, are most likely to be involved in recognizing molecular patterns, probably spike protein, from SARS-CoV-2 to induce inflammatory responses. 7,8 Consistently, we found that the induction of IL1B by SARS-CoV-2 was completely blocked by TLR4-specific inhibitor Resatorvid (Fig. 1a). Combined with our recent data that TLR4 signaling was activated by SARS-CoV-2, we hypothesized that spike protein could activate TLR4 pathway. A recent study has reported that trimeric SARS-CoV-2 spike proteins are high quality antigens. 9 To this end, we purified the trimeric spike protein (1-1208 aa) (Fig. 1b; Supplementary information, Fig. S1a), as this form of spike protein presents on the surface of viral particle, which most likely interacts with the proteins on the cell surface. Results of the surface plasmon resonance (SPR) assay showed that SARS-CoV-2 spike trimer directly bound to TLR4 with an affinity of~300 nM (Fig. 1b), comparable to many virus-receptor interactions. We then treated THP-1 cells, a cell line of human monocytes, with purified spike protein. IL1B was robustly induced by spike protein in a dose-dependent manner (Fig. 1c), which was comparable to LPS (Supplementary information, Fig. S1b). IL6 was also induced by spike protein (Supplementary information, Fig. S1c). As IL1B induction was much more robust than that of IL6, we chose IL1B production as a marker of immune activation. Moreover, the pseudovirus expressing spike protein can also induce IL1B production (Fig. 1d). Neutrophils also express TLR4 on their cell surface and play an important role in the development of sepsis. We utilized all-trans retinoic acid (ATRA) to treat HL-60 cell (a promyelocytic leukemia cell line), which directed those cells to differentiate into neutrophils. Spike proteins significantly induced IL1B production in HL-60 cells after ATRA treatment (Fig. 1e; Supplementary information, Fig. S1d). We treated THP-1 cells with the N-terminal domain (NTD) or the receptor-binding domain (RBD) of spike protein. Only the trimeric protein could induce IL1B and IL6 (Fig. 1f; Supplementary information, Fig. S1e). To examine if this activation was mediated by TLR4, we treated cells with Resatorvid. Resatorvid greatly blocked induction of IL1B by spike protein and LPS (Fig. 1g). Moreover, spike pro...

The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2 infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2 infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 were dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.

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BackgroundPancreatic fistula (PF) remains the most challenging complication after pancreaticoduodenectomy (PD). The purpose of this study was to identify the risk factors of PF and delineate its impact on patient outcomes.MethodsWe retrospectively reviewed clinical data of 532 patients who underwent PD and divided them into PF group and no PF group. Risk factors and outcomes of PF following PD were examined.ResultsPF was found in 65 (12.2%) cases, of whom 11 were classified into ISGPF grade A, 42 grade B, and 12 grade C. Clinically serious postoperative complications in the PF versus no PF group were mortality, abdominal bleeding, bile leak, intra-abdominal abscess and pneumonia. Univariate and multivariate analysis showed that blood loss ≥ 500 ml, pancreatic duct diameter ≤ 3 mm and pancreaticojejunostomy type were independent risk factors of PF after PD.ConclusionsBlood loss ≥ 500 ml, pancreatic duct diameter ≤ 3 mm and pancreatico-jejunostomy type were independent risk factors of PF after PD. PF was related with higher mortality rate, longer hospital stay, and other complications.