Hypercytokinemia is a critically fatal factor in COVID-19. However, underlying pathogenic mechanisms are unknown. Here we show that brinogen and leukotriene-A4 hydrolase (LTA4H), two of the most potent in ammatory contributors, are elevated by 67.7 and astonishing 227.7% in the plasma of patients infected by SARS-CoV-2 and admitted to intensive care unit in comparison with healthy control, respectively. Conversely, transferrin identi ed as a brinogen immobilizer in our recent work and Spink6 are down-regulated by 40.3 and 25.9%, respectively. Furthermore, we identify Spink6 as the rst endogenous inhibitor of LTA4H, a pro-in ammatory enzyme catalyzing nal and rating limited step in biosynthesis of leukotriene-B4 that is an extremely in ammatory mediator and a target to design superior anti-in ammatory drugs. Additionally, virus Spike protein is found to evoke LTA4H and brinogen expression in vivo. Collectively, these ndings identify the imbalance between in ammatory drivers and antagonists, which likely contributes to hypercytokinemia in COVID-19. Spink6 may have superior antiin ammatory function because it speci cally targets epoxide hydrolase of LTA4H to inhibit leukotriene-B4 biosynthesis without effecting LTA4H's aminopeptidase activity.

Background: Since December 2019, acute respiratory disease (ARD) due to 2019 novel coronavirus (2019-nCoV) emerged in Wuhan city and rapidly spread throughout China. We sought to delineate the clinical characteristics of these cases. Methods:We extracted the data on 1,099 patients with laboratory-confirmed 2019-nCoV ARD from 552 hospitals in 31 provinces/provincial municipalities through January 29 th , 2020. Results:The median age was 47.0 years, and 41.90% were females. Only 1.18% of patients had a direct contact with wildlife, whereas 31.30% had been to Wuhan and 71.80% had contacted with people from Wuhan. Fever (87.9%) and cough (67.7%) were the most common symptoms. Diarrhea is uncommon. The median incubation period was 3.0 days (range, 0 to 24.0 days). On admission, ground-glass opacity was the typical radiological finding on chest computed tomography (50.00%).Significantly more severe cases were diagnosed by symptoms plus reverse-transcriptase polymerase-chain-reaction without abnormal radiological findings than non-severe cases (23.87% vs. 5.20%, P<0.001). Lymphopenia was observed in 82.1% of patients. 55 patients (5.00%) were . CC-BY-NC-ND 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.is the (which was not peer-reviewed) The copyright holder for this preprint . https://doi.org/10. 1101 /2020 admitted to intensive care unit and 15 (1.36%) succumbed. Severe pneumonia was independently associated with either the admission to intensive care unit, mechanical ventilation, or death in multivariate competing-risk model (sub-distribution hazards ratio, 9.80; 95% confidence interval, 4.06 to 23.67). Conclusions:The 2019-nCoV epidemic spreads rapidly by human-to-human transmission. Normal radiologic findings are present among some patients with 2019-nCoV infection. The disease severity (including oxygen saturation, respiratory rate, blood leukocyte/lymphocyte count and chest X-ray/CT manifestations) predict poor clinical outcomes. Abstract: 249 words; main text: 2677 words : medRxiv preprint Clinical outcomesThe percentages of patients being admitted to the ICU, requiring invasive ventilation and death were 5.00%, 2.18% and 1.36%, respectively. This corresponded to 67 (6.10%) of patients having reached to the composite endpoint ( Table 3).Results of the univariate competing risk model are shown in Table E1 in Supplementary Appendix. Severe pneumonia cases (SDHR, 9.803; 95%CI, 4.06 to 23.67), leukocyte count greater than 4,000/mm 3 (SDHR, 4.01; 95%CI, 1.53 to 10.55) and interstitial abnormality on chest X-ray (SDHR, 4.31; 95%CI, 1.73 to 10.75) were associated with the composite endpoint (Fig. 2, see Table E2 in Supplementary Appendix). Sensitivity analyses are shown in Figure E2 in Supplementary Appendix. DiscussionThis study has shown that fever occurred in only 43.8% of patients with 2019-nCoV ARD on presentation but developed in 87.9% following hospitalization. Severe pneumonia occurred in 15.7% of cases. No radiolo...

Experienced surgeons can safely perform LG with D2 lymphadenectomy for AGC.

IMPORTANCE Laparoscopic distal gastrectomy is accepted as a more effective approach to conventional open distal gastrectomy for early-stage gastric cancer. However, efficacy for locally advanced gastric cancer remains uncertain. OBJECTIVE To compare 3-year disease-free survival for patients with locally advanced gastric cancer after laparoscopic distal gastrectomy or open distal gastrectomy. DESIGN, SETTING, AND PATIENTS The study was a noninferiority, open-label, randomized clinical trial at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3, or T4a gastric cancer without bulky nodes or distant metastases were enrolled from September 2012 to December 2014. Final follow-up was on December 31, 2017. INTERVENTIONS Participants were randomized in a 1:1 ratio after stratification by site, age, cancer stage, and histology to undergo either laparoscopic distal gastrectomy (n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy. MAIN OUTCOMES AND MEASURESThe primary end point was 3-year disease-free survival with a noninferiority margin of −10% to compare laparoscopic distal gastrectomy with open distal gastrectomy. Secondary end points of 3-year overall survival and recurrence patterns were tested for superiority. RESULTS Among 1056 patients, 1039 (98.4%; mean age, 56.2 years; 313 [30.1%] women) had surgery (laparoscopic distal gastrectomy [n=519] vs open distal gastrectomy [n=520]), and 999 (94.6%) completed the study. Three-year disease-free survival rate was 76.5% in the laparoscopic distal gastrectomy group and 77.8% in the open distal gastrectomy group, absolute difference of −1.3% and a 1-sided 97.5% CI of −6.5% to ϱ, not crossing the prespecified noninferiority margin. Three-year overall survival rate (laparoscopic distal gastrectomy vs open distal gastrectomy: 83.1% vs 85.2%; adjusted hazard ratio, 1.19; 95% CI, 0.87 to 1.64; P = .28) and cumulative incidence of recurrence over the 3-year period (laparoscopic distal gastrectomy vs open distal gastrectomy: 18.8% vs 16.5%; subhazard ratio, 1.15; 95% CI, 0.86 to 1.54; P = .35) did not significantly differ between laparoscopic distal gastrectomy and open distal gastrectomy groups.CONCLUSIONS AND RELEVANCE Among patients with a preoperative clinical stage indicating locally advanced gastric cancer, laparoscopic distal gastrectomy, compared with open distal gastrectomy, did not result in inferior disease-free survival at 3 years.

BackgroundAlthough many studies have documented health effects of ambient temperature, little evidence is available in subtropical or tropical regions, and effect modifiers remain uncertain. We examined the effects of daily mean temperature on mortality and effect modification in the subtropical city of Guangzhou, China.MethodsA Poisson regression model combined with distributed lag non-linear model was applied to assess the non-linear and lag patterns of the association between daily mean temperature and mortality from 2003 to 2007 in Guangzhou. The case-only approach was used to determine whether the effect of temperature was modified by individual characteristics, including sex, age, educational attainment and occupation class.ResultsHot effect was immediate and limited to the first 5 days, with an overall increase of 15.46% (95% confidence interval: 10.05% to 20.87%) in mortality risk comparing the 99th and the 90th percentile temperature. Cold effect persisted for approximately 12 days, with a 20.39% (11.78% to 29.01%) increase in risk comparing the first and the 10th percentile temperature. The effects were especially remarkable for cardiovascular and respiratory mortality. The effects of both hot and cold temperatures were greater among the elderly. Females suffered more from hot-associated mortality than males. We also found significant effect modification by educational attainment and occupation class.ConclusionsThere are significant mortality effects of hot and cold temperatures in Guangzhou. The elderly, females and subjects with low socioeconomic status have been identified as especially vulnerable to the effect of ambient temperatures.

Objective: To evaluate the spectrum of comorbidities and its impact on the clinical outcome in patients with coronavirus disease 2019 . Design: Retrospective case studiesSetting: 575 hospitals in 31 province/autonomous regions/provincial municipalities across China Participants: 1,590 laboratory-confirmed hospitalized patients. Main outcomes and measures: Epidemiological and clinical variables (in particular, comorbidities)were extracted from medical charts. The disease severity was categorized based on the American Thoracic Society guidelines for community-acquired pneumonia. The primary endpoint was the composite endpoints, which consisted of the admission to intensive care unit (ICU), or invasive ventilation, or death. The risk of reaching to the composite endpoints was compared among patients with COVID-19 according to the presence and number of comorbidities.Results: Of the 1,590 cases, the mean age was 48.9 years. 686 patients (42.7%) were females. 647 (40.7%) patients were managed inside Hubei province, and 1,334 (83.9%) patients had a contact history of Wuhan city. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached to the composite endpoints. 399 (25.1%) reported having at least one comorbidity. : medRxiv preprint 5 malignancy and immunodeficiency, respectively. 130 (8.2%) patients reported having two or more comorbidities. Patients with two or more comorbidities had significantly escalated risks of reaching to the composite endpoint compared with those who had a single comorbidity, and even more so as compared with those without (all P<0.05). After adjusting for age and smoking status, patients with COPD (HR 2.681, 95%CI 1.424-5.048), diabetes (HR 1.59, 95%CI 1.03-2.45), hypertension (HR 1.58, 95%CI 1.07-2.32) and malignancy (HR 3.50, 95%CI 1.60-7.64) were more likely to reach to the composite endpoints than those without. As compared with patients without comorbidity, the HR (95%CI) was 1.79 (95%CI 1.16-2.77) among patients with at least one comorbidity and 2.59 (95%CI 1.61-4.17) among patients with two or more comorbidities. Conclusion:Comorbidities are present in around one fourth of patients with COVID-19 in China, and predispose to poorer clinical outcomes. FUNDING: Supported by National Health Commission, Department of Science and Technology of Guangdong Province. The funder had no role in the conduct of the study.

Background and objectives A major challenge in early treatment of acute cardiorenal syndrome (CRS) is the lack of predictors for progression of AKI. We aim to investigate the utility of urinary angiotensinogen and other renal injury biomarkers in predicting AKI progression in CRS.Design, settings, participants, & measurements In this prospective, multicenter study, we screened 732 adults who admitted for acute decompensated heart failure from September 2011 to December 2014, and evaluated whether renal injury biomarkers measured at time of AKI diagnosis can predict worsening of AKI. In 213 patients who developed Kidney Disease Improving Global Outcomes stage 1 or 2 AKI, six renal injury biomarkers, including urinary angiotensinogen (uAGT), urinary neutrophil gelatinase-associated lipocalin (uNGAL), plasma neutrophil gelatinase-associated lipocalin, urinary IL-18 (uIL-18), urinary kidney injury molecule-1, and urinary albumin-to-creatinine ratio, were measured at time of AKI diagnosis. The primary outcome was AKI progression defined by worsening of AKI stage (50 patients). The secondary outcome was AKI progression with subsequent death (18 patients).Results After multivariable adjustment, the highest tertile of three urinary biomarkers remained associated with AKI progression compared with the lowest tertile: uAGT (odds ratio [OR], 10.8; 95% confidence interval [95% CI], 3.4 to 34.7), uNGAL (OR, 4.7; 95% CI, 1.7 to 13.4), and uIL-18 (OR, 3.6; 95% CI, 1.4 to 9.5). uAGT was the best predictor for both primary and secondary outcomes with area under the receiver operating curve of 0.78 and 0.85. These three biomarkers improved risk reclassification compared with the clinical model alone, with uAGT performing the best (category-free net reclassification improvement for primary and secondary outcomes of 0.76 [95% CI, 0.46 to 1.06] and 0.93 [95% CI, 0.50 to 1.36]; P,0.001). Excellent performance of uAGT was further confirmed with bootstrap internal validation.Conclusions uAGT, uNGAL, and uIL-18 measured at time of AKI diagnosis improved risk stratification and identified CRS patients at highest risk of adverse outcomes.

Transplantation of endothelial progenitor cells (EPCs) is a proven safe and effective method for treatment of cerebral ischemia in animal experiments. However, safety and efficacy need to be determined in clinical trials. We performed a two-center, randomized, placebo-controlled phase I/IIa trial with blinded outcome assessment on 18 patients with acute cerebral infarct within the middle cerebral artery territory, and followed for up to 4 years. Autologous ex vivo expanded EPCs were injected intravenously in the EPC group, and patients who received saline or autologous bone marrow stromal cells served as control groups. Mortality of any cause, adverse events, and new-onset comorbidities were monitored. Changes in neurological deficits were assessed at different time points. We found no toxicity events or infusional or allergic reactions in any treated group. Three patients in the placebo group died during the 4-year follow-up. We found that the EPC group had fewer serious adverse events compared with the placebo-controlled group, although there were no statistical differences in mortality among the three groups. Furthermore, there was no significant difference in neurological or functional improvement observed among the three groups, except for the Scandinavia Stroke Scale score at 3 months between the EPC group and placebo-controlled group. Autologous transplantation of EPCs appears to improve long-term safety in acute cerebral infarct patients, supporting the feasibility of this novel method for treatment of ischemic stroke. Stem Cells Translational Medicine 2018.