Background: The coronavirus disease 2019 outbreak is evolving rapidly worldwide. Objective: To evaluate the risk of serious adverse outcomes in patients with COVID-19 by stratifying the comorbidity status. Methods: We analysed data from 1590 laboratory confirmed hospitalised patients from 575 hospitals in 31 provinces/autonomous regions/provincial municipalities across mainland China between 11 December 2019 and 31 January 2020. We analysed the composite end-points, which consisted of admission to an intensive care unit, invasive ventilation or death. The risk of reaching the composite end-points was compared according to the presence and number of comorbidities. Results: The mean age was 48.9 years and 686 (42.7%) patients were female. Severe cases accounted for 16.0% of the study population. 131 (8.2%) patients reached the composite end-points. 399 (25.1%) reported having at least one comorbidity. The most prevalent comorbidity was hypertension (16.9%), followed by diabetes (8.2%). 130 (8.2%) patients reported having two or more comorbidities. After adjusting for age and smoking status, COPD (HR (95% CI) 2.681 (1.424-5.048)), diabetes (1.59 (1.03-2.45)), hypertension (1.58 (1.07-2.32)) and malignancy (3.50 (1.60-7.64)) were risk factors of reaching the composite end-points. The hazard ratio (95% CI) was 1.79 (1.16-2.77) among patients with at least one comorbidity and 2.59 (1.61-4.17) among patients with two or more comorbidities. Conclusion: Among laboratory confirmed cases of COVID-19, patients with any comorbidity yielded poorer clinical outcomes than those without. A greater number of comorbidities also correlated with poorer clinical outcomes. This article has supplementary material available from

Health professions preventing and controlling Coronavirus Disease 2019 are prone to skin and mucous membrane injury, which may cause acute and chronic dermatitis, secondary infection and aggravation of underlying skin diseases. This is a consensus of Chinese experts on protective measures and advice on handcleaning-and medical-glove-related hand protection, mask-and goggles-related face protection, UV-related protection, eye protection, nasal and oral mucosa protection, outer ear, and hair protection. It is necessary to strictly follow standards of wearing protective equipment and specification of sterilizing and cleaning. Insufficient and excessive protection will have adverse effects on the skin and mucous membrane barrier. At the same time, using moisturizing products is highly recommended to achieve better protection. K E Y W O R D SCOVID-19, healthcare workers, protect, SARS-CoV-2, skin and mucous membrane barrier

Please cite this article as: Liang W-hua, Guan W-jie, Li C-chen, et al. Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicenter) and outside Hubei (non-epicenter): A Nationwide Analysis of China. Eur Respir J 2020; in press (https://doi.Abstract BACKGROUND: During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in other parts of China has been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences. METHODS:Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalized COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients in and outside of Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicenter as well the administrative center of Hubei province) and the duration between symptom onset and admission on prognosis were also determined. RESULTS:Upon data cut-off (Jan 31st, 2020), 1,590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597/647, 92.3%) were older (mean: 49.7 vs. 44.9 years), had more cases with comorbidity (32.9% vs. 19.7%), higher symptomatic burden, abnormal radiologic manifestations, and, especially, a longer waiting time between symptom onset and admission (5.7 vs. 4.5 days) compared with patients outside Hubei. Patients in Hubei [severe event rate 23.0% vs. 11.1%, death rate 7.3% vs. 0.3%, hazards ratio (HR) for critical illness 1.59, 95%CI 1.05-2.41] have a poorer prognosis compared with patients outside of Hubei after adjusting for age and comorbidity. However, among patients outside of Hubei, the duration from symptom onset to hospitalization (mean: 4.4 vs. 4.7 days) and prognosis (HR 0.84, were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR 1.05, 1.01-1.08).CONCLUSION: There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalization in the epicenter. Future studies to determine the reason for delaying hospitalization are warranted.

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 The responses of cancer patients to immune checkpoint inhibitors (ICIs) vary in success. CD8+ tumor infiltrating lymphocytes (TILs) play a key role in killing tumor cells. This study aims to evaluate the prognostic role of CD8+ TILs in cancer patients treated with ICIs. Methods We systematically searched all publications from PubMed, EMBASE, and Cochrane Library until 12 Jul 2021 without any restriction of language or article types. Studies assessing high versus low CD8+ TILs in predicting efficacy and survival of various cancer patients were included. The outcomes included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). The study protocol is prospectively registered on PROSPERO (registration number CRD42021233654). Findings Findings: A total of 33 studies consisting of 2559 cancer patients were included. The result showed that high CD8+ TILs were significantly associated with better OS (HR, 0.52; 95% confidence interval: 0.41–0.67; p < 0.001), PFS (HR, 0.52; 95% confidence interval: 0.40–0.67; p < 0.001) and ORR (OR, 4.08; 95% confidence interval: 2.73–6.10; p < 0.001) in patients treated with ICIs. Subgroup analyses suggested that patients with high CD8+ TILs had a better clinical benefit, regardless of different treatments (ICI mono therapy, or combination therapy), cancer types (NSCLC, melanoma and others), and CD8+ T cells locations (intra-tumor, stroma, and invasive margin). The higher baseline circulating CD8+ T cells from peripheral blood did not contribute to the improved OS (HR, 0.93; 95% confidence interval: 0.67–1.29; p = 0.67) and PFS (HR, 0.89; 95% confidence interval: 0.60–1.32; p = 0.56) compared with the low baseline. Interpretation Interpretation: Our results suggested that high intra-tumoral, stromal, or invasive marginal, but not circulating CD8+ T cells, can predict treatment outcomes in patients with ICIs therapy across different cancers, in either single-agent ICIs or combination with other therapies. Funding Funding: China National Science Foundation (Grant No. 82,022,048, 81,871,893), Key Project of Guangzhou Scientific Research Project (Grant No. 201,804,020,030), High-level university construction project of Guangzhou medical university (Grant No. 20,182,737, 201,721,007, 201,715,907, 2,017,160,107); National key R & D Program (Grant No. 2017YFC0907903 & 2017YFC0112704) and the Guangdong high level hospital construction "reaching peak" plan.

Circadian clock genes regulate cancer development and chemotherapy susceptibility. Accordingly, chronotherapy based on circadian phenotypes might be applied to improve therapeutic efficacy. In this study, we investigated whether the circadian clock gene Bmal1 inhibited tumor development and increased paclitaxel sensitivity in tongue squamous cell carcinoma (TSCC). Bmal1 expression was downregulated and its rhythmic pattern of expression was affected in TSCC samples and cell lines. Ectopic Bmal1 inhibited cell proliferation, migration and invasion in vitro, and tumor growth in mouse xenograft models of TSCC. After exposure to paclitaxel, Bmal1-overexpressing cells displayed a relative increase in apoptosis and were more susceptible to paclitaxel treatment in vivo Mechanistic investigations suggested a regulatory connection between Bmal1, TERT, and the oncogenic transcriptional repressor EZH2 (enhancer of zeste homolog 2), the recruitment of which to the TERT promoter increased paclitaxel-induced apoptosis and cell growth inhibition. Clinically, paclitaxel efficacy correlated positively with Bmal1 expression levels in TSCC. Overall, our results identified Bmal1 as a novel tumor suppressor gene that elevates the sensitivity of cancer cells to paclitaxel, with potential implications as a chronotherapy timing biomarker in TSCC. Cancer Res; 77(2); 532-44. ©2016 AACR.

Rationale Disruption of the circadian clock in mice produces vascular dysfunction as evidenced by impairments in endothelium-dependent signaling, vasomotion, and blood vessel remodeling. Although the altered function of endothelial NO synthase and the overproduction of reactive oxygen species are central to dysfunction of the endothelium, to date, the impact of the circadian clock on endothelial NO synthase coupling and vascular reactive oxygen species production is not known. Objective The goals of the present study were to determine whether deletion of a critical component of the circadian clock, Bmal1, can influence endothelial NO synthase coupling and reactive oxygen species levels in arteries from Bmal1-knockout (KO) mice. Methods and Results Endothelial function was reduced in aortae from Bmal1-KO mice and improved by scavenging reactive oxygen species with polyethylene glycol-superoxide dismutase and nonselectively inhibiting cyclooxygenase isoforms with indomethacin. Aortae from Bmal1-KO mice exhibited enhanced superoxide levels as determined by electron paramagnetic resonance spectroscopy and dihydroethidium fluorescence, an elevation that was abrogated by administration of nitro-L -arginine methyl ester. High-performance liquid chromatography analysis revealed a reduction in tetrahydrobiopterin and an increase in dihydrobiopterin levels in the lung and aorta of Bmal1-KO mice, whereas supplementation with tetrahydrobiopterin improved endothelial function in the circadian clock KO mice. Furthermore, levels of tetrahydrobiopterin, dihydrobiopterin, and the key enzymes that regulate biopterin bioavailability, GTP cyclohydrolase and dihydrofolate reductase exhibited a circadian expression pattern. Conclusions Having an established influence in the metabolic control of glucose and lipids, herein, we describe a novel role for the circadian clock in metabolism of biopterins, with a significant impact in the vasculature, to regulate coupling of endothelial NO synthase, production of superoxide, and maintenance of endothelial function. (Circ Res. 2012; 111:1157–1165.)

The physical confinement of cell microenvironment could enhance the invasive capability and drug resistance of cancer cells. However, due to the lack of in vitro experimental platform to mimic both stiffness and confinement of the tumor microenvironment, the underlying mechanism remains elusive. Here, we developed a hydrogel-based microchannel platform with independently tunable channel stiffness and width in a physiological range. We found that the migration speed of the cancer cell is influenced by the synergistic effect of channel stiffness and width. In addition, the mesenchymal-amoeboid transition has a strong correlation with the channel stiffness. Besides, with a developed computational model, the role of nuclear stiffness on cancer migration speed and thus the mesenchymal-amoeboid transition in microchannels was also revealed. This platform is capable of mimicking the native physical microenvironment during metastasis, providing a powerful tool for high-throughput screening applications and investigating the interaction between cancer migration and biophysical microenvironment.