Taihe Hospital

BACKGROUND: The coronavirus disease 2019 (COVID-19) 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.

In December 2019, an outbreak of severe acute respiratory syndrome coronavirus 2 infection occurred in Wuhan, Hubei Province, China, and spread across China and beyond. On February 12, 2020, the World Health Organization officially named the disease caused by the novel coronavirus as coronavirus disease 2019 (COVID-19). Because most patients infected with COVID-19 had pneumonia and characteristic CT imaging patterns, radiologic examinations have become vital in early diagnosis and the assessment of disease course. To date, CT findings have been recommended as major evidence for clinical diagnosis of COVID-19 in Hubei, China. This review focuses on the etiology, epidemiology, and clinical symptoms of COVID-19 while highlighting the role of chest CT in prevention and disease control.

OBJECTIVE: To systematically review the methodological assessment tools for pre-clinical and clinical studies, systematic review and meta-analysis, and clinical practice guideline. METHODS: We searched PubMed, the Cochrane Handbook for Systematic Reviews of Interventions, Joanna Briggs Institute (JBI) Reviewers Manual, Centre for Reviews and Dissemination, Critical Appraisal Skills Programme (CASP), Scottish Intercollegiate Guidelines Network (SIGN), and the National Institute for Clinical Excellence (NICE) up to May 20th, 2014. Two authors selected studies and extracted data; quantitative analysis was performed to summarize the characteristics of included tools. RESULTS: We included a total of 21 assessment tools for analysis. A number of tools were developed by academic organizations, and some were developed by only a small group of researchers. The JBI developed the highest number of methodological assessment tools, with CASP coming second. Tools for assessing the methodological quality of randomized controlled studies were most abundant. The Cochrane Collaboration's tool for assessing risk of bias is the best available tool for assessing RCTs. For cohort and case-control studies, we recommend the use of the Newcastle-Ottawa Scale. The Methodological Index for Non-Randomized Studies (MINORS) is an excellent tool for assessing non-randomized interventional studies, and the Agency for Healthcare Research and Quality (ARHQ) methodology checklist is applicable for cross-sectional studies. For diagnostic accuracy test studies, the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool is recommended; the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool is available for assessing animal studies; Assessment of Multiple Systematic Reviews (AMSTAR) is a measurement tool for systematic reviews/meta-analyses; an 18-item tool has been developed for appraising case series studies, and the Appraisal of Guidelines, Research and Evaluation (AGREE)-II instrument is widely used to evaluate clinical practice guidelines. CONCLUSIONS: We have successfully identified a variety of methodological assessment tools for different types of study design. However, further efforts in the development of critical appraisal tools are warranted since there is currently a lack of such tools for other fields, e.g. genetic studies, and some existing tools (nested case-control studies and case reports, for example) are in need of updating to be in line with current research practice and rigor. In addition, it is very important that all critical appraisal tools remain subjective and performance bias is effectively avoided.

BACKGROUND: The 2019 novel coronavirus (2019-nCoV) causing an outbreak of pneumonia in Wuhan, Hubei province of China was isolated in January 2020. This study aims to investigate its epidemiologic history, and analyze the clinical characteristics, treatment regimens, and prognosis of patients infected with 2019-nCoV during this outbreak. METHODS: Clinical data from 137 2019-nCoV-infected patients admitted to the respiratory departments of nine tertiary hospitals in Hubei province from December 30, 2019 to January 24, 2020 were retrospectively collected, including general status, clinical manifestations, laboratory test results, imaging characteristics, and treatment regimens. RESULTS: None of the 137 patients (61 males, 76 females, aged 20-83 years, median age 57 years) had a definite history of exposure to Huanan Seafood Wholesale Market. Major initial symptoms included fever (112/137, 81.8%), coughing (66/137, 48.2%), and muscle pain or fatigue (44/137, 32.1%), with other, less typical initial symptoms observed at low frequency, including heart palpitations, diarrhea, and headache. Nearly 80% of the patients had normal or decreased white blood cell counts, and 72.3% (99/137) had lymphocytopenia. Lung involvement was present in all cases, with most chest computed tomography scans showing lesions in multiple lung lobes, some of which were dense; ground-glass opacity co-existed with consolidation shadows or cord-like shadows. Given the lack of effective drugs, treatment focused on symptomatic and respiratory support. Immunoglobulin G was delivered to some critically ill patients according to their conditions. Systemic corticosteroid treatment did not show significant benefits. Notably, early respiratory support facilitated disease recovery and improved prognosis. The risk of death was primarily associated with age, underlying chronic diseases, and median interval from the appearance of initial symptoms to dyspnea. CONCLUSIONS: The majority of patients with 2019-nCoV pneumonia present with fever as the first symptom, and most of them still showed typical manifestations of viral pneumonia on chest imaging. Middle-aged and elderly patients with underlying comorbidities are susceptible to respiratory failure and may have a poorer prognosis.

Abstract 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 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 Objective To evaluate the spectrum of comorbidities and its impact on the clinical outcome in patients with coronavirus disease 2019 (COVID-19). Design Retrospective case studies Setting 575 hospitals in 31 province/autonomous regions/provincial municipalities across China Participants 1,590 laboratory-confirmed hospitalized patients. Data were collected from November 21 st , 2019 to January 31 st , 2020. 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. 269 (16.9%), 59 (3.7%), 30 (1.9%), 130 (8.2%), 28 (1.8%), 24 (1.5%), 21 (1.3%), 18 (1.1%) and 3 (0.2%) patients reported having hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, 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. Highlights What is already known on this topic - Since November 2019, the rapid outbreak of coronavirus disease 2019 (COVID-19) has recently become a public health emergency of international concern. There have been 79,331 laboratory-confirmed cases and 2,595 deaths globally as of February 25 th , 2020 - Previous studies have demonstrated the association between comorbidities and other severe acute respiratory diseases including SARS and MERS. - No study with a nationwide representative cohort has demonstrated the spectrum of comorbidities and the impact of comorbidities on the clinical outcomes in patients with COVID-19. What this study adds - In this nationwide study with 1,590 patients with COVID-19, comorbidities were identified in 399 patients. Comorbidities of COVID-19 mainly included hypertension, cardiovascular diseases, cerebrovascular diseases, diabetes, hepatitis B infections, chronic obstructive pulmonary disease, chronic kidney diseases, malignancy and immunodeficiency. - The presence of as well as the number of comorbidities predicted the poor clinical outcomes (admission to intensive care unit, invasive ventilation, or death) of COVID-19. - Comorbidities should be taken into account when estimating the clinical outcomes of patients with COVID-19 on hospital admission.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

Typical Klebsiella pneumoniae is an opportunistic pathogen, which mostly affects those with weakened immune systems and tends to cause nosocomial infections. A subset of hypervirulent K. pneumoniae serotypes with elevated production of capsule polysaccharide can affect previously healthy persons and cause life-threatening community-acquired infections, such as pyogenic liver abscess, meningitis, necrotizing fasciitis, endophthalmitis and severe pneumonia. K. pneumoniae utilizes a variety of virulence factors, especially capsule polysaccharide, lipopolysaccharide, fimbriae, outer membrane proteins and determinants for iron acquisition and nitrogen source utilization, for survival and immune evasion during infection. This article aims to present the state-of-the-art understanding of the molecular pathogenesis of K. pneumoniae.

Importance: Several randomized clinical trials have recently established the safety and efficacy of endovascular treatment (EVT) of acute ischemic stroke in the anterior circulation. However, it remains uncertain whether patients with acute basilar artery occlusion (BAO) benefit from EVT. Objective: To evaluate the association between EVT and clinical outcomes of patients with acute BAO. Design, Setting, and Participants: This nonrandomized cohort study, the EVT for Acute Basilar Artery Occlusion Study (BASILAR) study, was a nationwide prospective registry of consecutive patients presenting with an acute, symptomatic, radiologically confirmed BAO to 47 comprehensive stroke centers across 15 provinces in China between January 2014 and May 2019. Patients with acute BAO within 24 hours of estimated occlusion time were divided into groups receiving standard medical treatment plus EVT or standard medical treatment alone. Main Outcomes and Measures: The primary outcome was the improvement in modified Rankin Scale scores (range, 0 to 6 points, with higher scores indicating greater disability) at 90 days across the 2 groups assessed as a common odds ratio using ordinal logistic regression shift analysis, adjusted for prespecified prognostic factors. The secondary efficacy outcome was the rate of favorable functional outcomes defined as modified Rankin Scale scores of 3 or less (indicating an ability to walk unassisted) at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage and 90-day mortality. Results: A total of 1254 patients were assessed, and 829 patients (of whom 612 were men [73.8%]; median [interquartile] age, 65 [57-74] years) were recruited into the study. Of these, 647 were treated with standard medical treatment plus EVT and 182 with standard medical treatment alone. Ninety-day functional outcomes were substantially improved by EVT (adjusted common odds ratio, 3.08 [95% CI, 2.09-4.55]; P < .001). Moreover, EVT was associated with a significantly higher rate of 90-day modified Rankin Scale scores of 3 or less (adjusted odds ratio, 4.70 [95% CI, 2.53-8.75]; P < .001) and a lower rate of 90-day mortality (adjusted odds ratio, 2.93 [95% CI, 1.95-4.40]; P < .001) despite an increase in symptomatic intracerebral hemorrhage (45 of 636 patients [7.1%] vs 1 of 182 patients [0.5%]; P < .001). Conclusions and Relevance: Among patients with acute BAO, EVT administered within 24 hours of estimated occlusion time is associated with better functional outcomes and reduced mortality.

BACKGROUND: Transmembrane 4 L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. METHODS: We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. RESULTS: TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-β1 (TGF-β1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/β-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. CONCLUSION: Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/β-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

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 have 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 hospitalised 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 within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined. Results At the data cut-off (31 January 2020), 1590 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 (92.3%) out of 647) were older (mean age 49.7 versus 44.9 years), had more cases with comorbidity (32.9% versus 19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7 versus 4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0% versus 11.1%, death rate 7.3% versus 0.3%, HR (95% CI) for critical illness 1.59 (1.05–2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4 versus 4.7 days) and prognosis (HR (95%) 0.84 (0.40–1.80)) 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 (95%) 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 hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.

Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc's involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc's cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.

UNLABELLED: We have previously shown that Toll-like receptor (TLR)-activated murine nonparenchymal liver cells [(NPC); Kupffer cells (KC), liver sinusoidal endothelial cells (LSEC)] can suppress hepatitis B virus (HBV) replication. Therefore, the aim of this study was to investigate whether HBV has the ability to counteract the TLR-mediated control of its replication. Freshly purified murine hepatocytes and NPCs obtained from C57BL6 mice were stimulated by TLR 1-9 ligands in the presence or absence of hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), HBV virions, or supernatants from HBV-producing HBV-Met cells, and HBV replication was suppressed by anti- hepatitis B virus X protein (HBx) small interfering RNA (siRNA) in HBV-Met cells. Supernatants were collected and tested for antiviral cytokines by viral protection assay. HBV gene expression and replication was analyzed by southern blot. RNA and proteins were analyzed by quantitative reverse transcription polymerase chain reaction (RT-PCR) or western blot and enzyme-linked immunosorbent assay, respectively. Pretreatment of hepatocytes and NPCs with HBV-Met cells supernatants, HBsAg, HBeAg, or HBV virions almost completely abrogated TLR-induced antiviral activity, which correlated with suppression of interferon beta (IFN-beta) production and subsequent interferon-stimulated gene induction as well as suppressed activation of interferon regulatory factor 3 (IRF-3), nuclear factor kappa B (NF-kappaB), and extracellular signal-regulated kinase (ERK) 1/2. In HBV-infected HBV-Met cells, TLR stimulation did not induce antiviral cytokines in contrast to primary hepatocytes. TLR-stimulated expression of proinflammatory cytokines [tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6)], and activation of IRF-3 was suppressed after up-regulation of HBV replication in HBV-Met cells. Accordingly, suppression of HBV replication by siRNA led to activation or expression of proinflammatory transcription factors and cytokines. CONCLUSION: Our data indicate that HBV can suppress the TLR-induced antiviral activity of liver cells. This has major implications for the interaction between HBV and the immune system.

Early diagnosis has been proved to improve survival rate of lung cancer patients. The availability of blood-based screening could increase early lung cancer patient uptake. Our present study attempted to discover Chinese patients' plasma metabolites as diagnostic biomarkers for lung cancer. In this work, we use a pioneering interdisciplinary mechanism, which is firstly applied to lung cancer, to detect early lung cancer diagnostic biomarkers by combining metabolomics and machine learning methods. We collected total 110 lung cancer patients and 43 healthy individuals in our study. Levels of 61 plasma metabolites were from targeted metabolomic study using LC-MS/MS. A specific combination of six metabolic biomarkers note-worthily enabling the discrimination between stage I lung cancer patients and healthy individuals (AUC = 0.989, Sensitivity = 98.1%, Specificity = 100.0%). And the top 5 relative importance metabolic biomarkers developed by FCBF algorithm also could be potential screening biomarkers for early detection of lung cancer. Naïve Bayes is recommended as an exploitable tool for early lung tumor prediction. This research will provide strong support for the feasibility of blood-based screening, and bring a more accurate, quick and integrated application tool for early lung cancer diagnostic. The proposed interdisciplinary method could be adapted to other cancer beyond lung cancer.

UNLABELLED: Hepatitis B virus (HBV) infection is one of the most frequent causes of chronic liver disease worldwide. Because recent studies have suggested that Toll-like receptor (TLR)-based therapies may be a promising approach in the treatment of HBV infection, we studied the role of the local innate immune system of the liver as a possible mediator of this effect. Murine nonparenchymal cells, including Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs), were isolated from C57/BL6 wild-type or MyD88(-/-) mice and stimulated by agonists of TLR1 to TLR9. Supernatants were harvested and assayed for their antiviral activity against HBV in HBV-Met cells. No direct antiviral effect of TLR agonists could be observed. In controls (myeloid dendritic cells), TLR1, TLR3, TLR4, TLR7, and TLR9 activation lead to production of antiviral cytokines. By contrast, only supernatants from TLR3-stimulated and TLR4-stimulated KCs and TLR3-stimulated LSECs from wild-type mice were able to potently suppress HBV replication as assessed via Southern blotting. Similar results were found with cells from MyD88(-/-) mice, indicating that the effect was independent of this signaling pathway. Cellular HBV RNA and hepatitis B surface antigen or hepatitis B e antigen levels in supernatants remained unchanged. Using neutralizing antibodies, we demonstrated that the TLR3-mediated effect but not the TLR4-mediated effect is mediated exclusively through interferon-beta. CONCLUSION: Our data indicate that the innate immune system of the liver can control HBV replication after activation by TLR agonists. This has implications for the development of TLR-based therapeutic approaches against HBV.

Tumor‐associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells‐1 (TREM‐1) in TAMs, resulting in immunosuppression. Specifically, TREM‐1‐positive (TREM‐1 + ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8 + T cells and induced CD8 + T‐cells apoptosis. Biological and functional assays showed that TREM‐1 + TAMs had higher expression of programmed cell death ligand 1 (PD‐L1) under hypoxic environment. However, TREM‐1 + TAMs could abrogate spontaneous and PD‐L1‐blockade‐mediated antitumor effects in vivo , suggesting that TREM‐1 + TAM‐induced immunosuppression was dependent on a pathway separate from PD‐L1/programmed cell death 1 axis. Moreover, TREM‐1 + TAM‐associated regulatory T cells (Tregs) were crucial for HCC resistance to anti‐PD‐L1 therapy. Mechanistically, TREM‐1 + TAMs elevated chemokine (C‐C motif) ligand 20 expression through the extracellular signal‐regulated kinase/NF‐κβ pathway in response to hypoxia and tumor metabolites leading to CCR6 + Foxp3 + Treg accumulation. Blocking the TREM‐1 pathway could significantly inhibit tumor progression, reduce CCR6 + Foxp3 + Treg recruitment, and improve the therapeutic efficacy of PD‐L1 blockade. Thus, these data demonstrated that CCR6 + Foxp3 + Treg recruitment was crucial for TREM‐1 + TAM‐mediated anti‐PD‐L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion : This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM‐1 + TAMs attracting CCR6 + Foxp3 + Tregs, and TREM‐1 + TAMs endowed HCC with anti‐PD‐L1 therapy resistance.

Objective There is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need. Design and results A total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI −12.59 to −2.50; p=0.0018), respectively. Conclusions This is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group. Trial registration NCT01770431 ; Post-results.

OBJECTIVE: The effect of transplanted mesenchymal stem cells (MSCs) on the left ventricular (LV) function and morphology in a rat myocardial infarct heart with reperfusion model were analyzed. METHODS: One week after 60 min of myocardial ischemia and reperfusion by left anterior descending artery (LAD) occlusion, 1.0x10(7) 6-diamidino-2-phenylindole (DAPI)-labeled MSCs were injected into the infarcted myocardium and compared with controls, and sham-operated rats, in which a cell-free serum medium was injected into the infarcted region or the myocardial wall, respectively. Measurement of vascular endothelial growth factor (VEGF) expression 1 week after MSC injection using Western blot analysis (n=5), and immunohistochemical staining using HE staining and fluorescent microscopy of the DAPI-positive regions from MSC implantation, cTnT immunostaining of potential myocardial-like cells, and SM-actin and CD31 immunostaining demonstrating neovascular transformation of implanted MSCs 1 week, 2 weeks and 4 weeks after transplantation (n=5). Hemodynamic measurements were performed after 4 weeks in vivo. Subsequently, hearts were quickly removed and cut for histological analysis using HE staining with measurement of the infarcted LV-area, the LV-wall thickness within the scar segment compared to non-infarcted scar segments, and the capillary density counting capillary vessels with 400x light microscopy (n=10). RESULTS: Measurement of hemodynamics 4 weeks after transplantation in vivo showed LV function to be significantly greater in MSCs than in the control group. Semi-quantitative histomorphometric examinations showed a significantly lower infract size, a greater LV-wall thickness, and a lower Hochman-Choo expansion index in the MSC-treated group compared to the control group. Immunofluorescence demonstrated that transplanted MSCs were positive for cTnT, suggesting that a small number of transplanted MSCs can differentiate into cardiomyocytes. Other MSCs were positive for CD31 and SM-actin. The transplanted MSCs in MI area had significantly higher expression rates of cTnT, CD31 and SM-actin 2 weeks after transplantation. HE staining showed marked augmentation of neovascularization in the MSC group. Semi-quantitative analysis demonstrated that capillary density was significantly higher in the MSC group than in the control group. CONCLUSION: Implanted MSCs could improve cardiac structure and function through the combined effect of myogenesis and angiogenesis.

OBJECTIVE: To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. ELIGIBILITY CRITERIA: Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. DATA COLLECTION AND ANALYSIS: Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. RESULTS: 60 studies (n=353,639), consisting of 55 randomised controlled trials (n=33,350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320,289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). CONCLUSIONS: The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk.

Abstract Background Few specific medications have been proven effective for the treatment of patients with severe coronavirus disease 2019 (COVID-19). Here, we tested whether high-dose vitamin C infusion was effective for severe COVID-19. Methods This randomized, controlled, clinical trial was performed at 3 hospitals in Hubei, China. Patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the ICU were randomly assigned in as 1:1 ratio to either the high-dose intravenous vitamin C (HDIVC) or the placebo. HDIVC group received 12 g of vitamin C/50 ml every 12 h for 7 days at a rate of 12 ml/hour, and the placebo group received bacteriostatic water for injection in the same way within 48 h of arrival to ICU. The primary outcome was invasive mechanical ventilation-free days in 28 days (IMVFD28). Secondary outcomes were 28-day mortality, organ failure (Sequential Organ Failure Assessment (SOFA) score), and inflammation progression (interleukin-6). Results Only 56 critical COVID-19 patients were ultimately recruited due to the early control of the outbreak. There was no difference in IMVFD28 between two groups (26.0 [9.0–28.0] in HDIVC vs 22.0 [8.50–28.0] in control, p = 0.57). HDIVC failed to reduce 28-day mortality ( P = 0.27). During the 7-day treatment period, patients in the HDIVC group had a steady rise in the PaO 2 /FiO 2 (day 7: 229 vs. 151 mmHg, 95% CI 33 to 122, P = 0.01), which was not observed in the control group. IL-6 in the HDIVC group was lower than that in the control group (19.42 vs. 158.00; 95% CI -301.72 to -29.79; P = 0.04) on day 7. Conclusion This pilot trial showed that HDIVC failed to improve IMVFD28, but might show a potential signal of benefit in oxygenation for critically ill patients with COVID-19 improving PaO2/FiO2 even though.