Association of procalcitonin levels with the progression and prognosis of hospitalized patients with COVID-19.

Rationale: Coronavirus disease 2019 (COVID-19) was first announced in Wuhan, and has rapidly evolved into a pandemic. However, the risk factors associated with the severity and mortality of COVID-19 are yet to be described in detail. Methods: We retrospectively reviewed the information of 1525 cases from the Leishenshan Hospital in Wuhan. Univariate and multivariate Cox regression analyses were generated to explore the relationship between procalcitonin (PCT) level and the progression and prognosis of COVID-19. Univariate and multivariate logistic regression analyses were performed to explore the relationship between disease severity in hospitalized patients and their PCT levels. Survival curves and the cumulative hazard function for COVID-19 progression were conducted in the two groups. To further detect the relationship between the computed tomography score and survival days, curve-fitting analyses were performed. Results: Patients in the elevated PCT group had a higher incidence of severe and critical severity conditions (P < 0.001), death, and higher computed tomography (CT) scores. There was an association between elevated PCT levels and mortality in the univariate ((hazard ratio [1], 3.377; 95% confidence interval [2], 1.012-10.344; P = 0.033) and multivariate Cox regression analysis (HR, 4.933; 95% CI, 1.170-20.788; P = 0.030). Similarly, patients with elevated PCT were more likely to have critically severe disease conditions in the univariate (odds ratio [2], 7.247; 95% CI, 3.559-14.757; P < 0.001) and multivariate logistic regression analysis (OR, 10.679; 95% CI, 4.562-25.000; P < 0.001). Kaplan-Meier curves showed poorer prognosis for patients with elevated PCT (P = 0.024). The CT score 1 for patients with elevated PCT peaked at day 40 following the onset of symptoms then decreased gradually, while their total CT score was relatively stable. Conclusion: PCT level was shown as an independent risk factor of in-hospital mortality among COVID-19 patients. Compared with inpatients with normal PCT levels, inpatients with elevated PCT levels had a higher risk for overall mortality and critically severe disease. These findings may provide guidance for improving the prognosis of patients with critically severe COVID-19.

Transcription factor EB­mediated autophagy promotes dermal fibroblast differentiation and collagen production by regulating endoplasmic reticulum stress and autophagy­dependent secretion.

Autophagy is reported to be involved in the formation of skin hypertrophic scar (HTS). However, the role of autophagy in the process of fibrosis remains unclear, therefore an improved understanding of the molecular mechanisms associated with autophagy may accelerate the development of effective therapeutic strategies against HTS. The present study evaluated the roles of autophagy mediated by transcription factor EB (TFEB), a pivotal regulator of lysosome biogenesis and autophagy, in transforming growth factor­ß1 (TGF­ß1)­induced fibroblast differentiation and collagen production. Fibroblasts were treated with TGF­ß1, TGF­ß1 + tauroursodeoxycholic acid (TUDCA) or TGF­ß1 + TFEB­small interfering RNA (siRNA). TGF­ß1 induced phenotypic transformation of fibroblasts, as well as collagen synthesis and secretion in fibroblasts in a dose­dependent manner. Western blotting and immunofluorescence analyses demonstrated that TGF­ß1 upregulated the expression of autophagy­related proteins through the endoplasmic reticulum (ER) stress pathway, whereas TUDCA reversed TGF­ß1­induced changes. Reverse transcription­quantitative PCR (RT­qPCR), western blotting and RFP­GFP­LC3 double fluorescence analyses demonstrated that knockdown of TFEB by TFEB­siRNA decreased autophagic flux, upregulated the expression of proteins involved in the apoptotic pathway, such as phosphorylated­α subunit of eukaryotic initiation factor 2, C/EBP homologous protein and cysteinyl aspartate specific proteinase 3, and also downregulated the expression of α­smooth muscle actin and collagen I (COL I) in fibroblasts. Immunofluorescence confocal analyses and enzyme­linked immunosorbent assay indicated that TGF­ß1 increased the colocalization of COL I with lysosomal­associated membrane protein 1 and Ras­related protein Rab­8A, a marker of secretory vesicles, in fibroblasts, as well as the secretion of pro­COL Iα1 in culture supernatants. Meanwhile, these effects were abolished by TFEB knockdown. The present results suggested that autophagy reduced ER stress, decreased cell apoptosis and maintained fibroblast activation not only through degradation of misfolded or unfolded proteins, but also through promotion of COL I release from the autolysosome to the extracellular environment.

Refusal of cancer-directed surgery in male breast cancer.

ABSTRACT: It has been reported that some male breast cancer patients may refuse the recommended surgery, but the incidence rate in the United States is not clear. The purpose of this study was to identify the incidence, trends, risk factors, and eventual survival outcomes associated with the rejection of such cancer-directed surgery.We collected data on 5860 patients with male breast cancer (MBC) from the Surveillance, Epidemiology, and End Results database, including 50 patients refusing surgery as recommended. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to identify the effects of refusing surgery on cancer-specific survival (CSS) and overall survival (OS). The association between acceptance or rejection of surgery and mortality were estimated by nested Cox proportional hazards regression models with adjustment for age, race, clinical characteristics, and radiation.Of the 5860 patients identified, 50 (0.9%) refused surgery. Old age (≥65: hazard ratio [HR]: 3.056, 95% confidence interval [CI]: 1.738-5.374, P < .0001), higher AJCC stage (III: HR: 3.283, 95% CI: 2.134-5.050, P < .0001, IV: HR: 14.237, 95% CI: 8.367-24.226, P < .0001), progesterone receptor status (negative: HR: 1.633, 95% CI: 1.007-2.648, P = .047) were considered risk factors. Compared with the surgery group, the refusal group was associated with a poorer prognosis in both OS and CSS (χ2 = 94.81, P < .001, χ2 = 140.4, P < .001). Moreover, significant differences were also observed in OS and CSS among 1:3 matched groups (P = .0002, P < .001).Compared with the patients undergoing surgery, the patients who refused the cancer-directed surgery had poor prognosis in the total survival period, particularly in stage II and III. The survival benefit for undergoing surgery remained even after adjustment, which indicates the importance of surgical treatment before an advanced stage for male breast cancer patients.

Comparing the Value of Cystatin C and Serum Creatinine for Evaluating the Renal Function and Predicting the Prognosis of COVID-19 Patients.

Background: Coronavirus disease- (COVID-19-) related renal function abnormality is associated with poor prognosis. However, the clinical significance of dynamic changes in renal function indicators has not been studied, and no studies have evaluated the renal function in COVID-19 patients by cystatin C. Objective: This study aimed to evaluate the effect of abnormal renal function on admission on prognosis of COVID-19 patients and the prognostic value of various renal function indicators. Methods: A total of 1,764 COVID-19 patients without a history of chronic kidney disease were categorized into two groups, an elevated cystatin C group and a normal cystatin C group, based on the results of renal function tests on admission. The clinical characteristics were compared between the two groups, and logistic or Cox regression analyses were performed to explore the associations between elevated cystatin C/serum creatinine levels and disease severity and survival. We also performed receiver operating characteristic (ROC) curve, Kaplan-Meier survival, and curve fitting analyses. Results: When adjusted for several significant clinical variables, elevated cystatin C levels on admission were independent predictors of disease severity (p < 0.001), and elevated creatinine levels were independent predictors of death (p = 0.020). Additionally, the ROC curve analysis shows that elevated cystatin C levels [area under the curve (AUC): 0.656] have a better predictive value for disease severity than elevated creatinine levels (AUC: 0.540). The survival curves of patients with elevated cystatin C/creatinine levels show a sharper decline than those of patients with normal cystatin C/creatinine levels (p < 0.001). The curve fitting analysis revealed that, compared to the flat curves of cystatin C and creatinine levels for patients who survived, the curves for patients who died kept rising, and cystatin C levels rose above the normal range earlier than creatinine. Conclusions: Elevated cystatin C, which occurs earlier than serum creatinine, is useful for the early detection of renal function abnormality and might have better predictive value for disease severity in COVID-19 patients, while elevated serum creatinine may have a better predictive value for risks of death.

Abnormal Fibrinogen Level as a Prognostic Indicator in Coronavirus Disease Patients: A Retrospective Cohort Study.

Purpose: The coronavirus disease (COVID-19) pandemic poses a global threat, and identification of its prognostic biomarkers could prove invaluable. Fibrinogen (FIB) could be one such indicator as coagulation and fibrinolysis abnormalities are common among COVID-19 patients. We examined the role of FIB levels in the prognosis of COVID-19. Methods: This retrospective cohort study enrolled 1,643 COVID-19 patients from the Leishenshan Hospital in Wuhan, China. The follow-up was conducted from February 8, 2020 to April 15, 2020. The cohort was divided into three groups according to the FIB level on admission, and associations with mortality and disease severity were determined using Cox and logistic regression analyses, respectively. Further, Kaplan-Meier (K-M) analyses by log-rank tests were used to assess the survival of patients with varying FIB levels. Results: Patients with FIB < 2.2 g/L [hazard ratio (HR): 9.02, 95% confidence interval (CI): 1.91-42.59, P = 0.006] and >4.2 g/L (HR: 4.79, 95% CI: 1.14-20.20, P = 0.033) showed higher mortality risks compared to those with FIB between 2.2 and 4.2 g/L. The survival curves showed similar results in K-M analyses (P < 0.001). Additionally, an elevated FIB level was associated with a greater risk of developing critical disease (odds ratio: 2.16, 95% CI: 1.04-4.46, P = 0.038) than a FIB level within the normal range. Conclusion: Abnormal FIB levels may be associated with mortality risk among COVID-19 patients and could predict critical disease development. Thus, assessment of FIB levels may assist in determining the prognosis of COVID-19 patients.

Elevated α-hydroxybutyrate dehydrogenase as an independent prognostic factor for mortality in hospitalized patients with COVID-19.

AIMS: Many studies have explored the clinical characteristics of patients with coronavirus disease (COVID-19), especially patients with cardiovascular disease. However, associated mechanisms and markers remain to be further investigated. This study aimed to investigate the effect of α-hydroxybutyrate dehydrogenase (α-HBDH) levels on disease progression and prognosis of patients with COVID-19. METHODS AND RESULTS: One thousand seven hundred and fifty-one patients from the Leishenshan hospital in Wuhan were divided into elevated and normal groups by α-HBDH level, and the clinical information between the two groups was compared retrospectively. The main outcome evaluation criteria included in-hospital death and disease severity. Univariate and multivariate regression analyses, survival curves, logistic regression, and receiver operating characteristic curve models were performed to explore the relationship between elevated α-HBDH and the two outcomes. Besides, curve fitting analyses were conducted to analyse the relationship between computed tomography score and survival. Among 1751 patients with confirmed COVID-19, 15 patients (0.87%) died. The mean (SD) age of patients was 58 years in normal α-HBDH group and 66 years in elevated α-HBDH group (P < 0.001). The mortality during hospitalization was 0.26% (4 of 1559) for patients with normal α-HBDH levels and 5.73% (11 of 192) for those with elevated α-HBDH levels (P < 0.001). Multivariate Cox analysis confirmed an association between elevated α-HBDH levels and higher risk of in-hospital mortality [hazard ratio: 4.411, 95% confidence interval (95% CI), 1.127-17.260; P = 0.033]. Multivariate logistic regression for disease severity and α-HBDH levels showed significant difference between both groups (odds ratio = 3.759; 95% CI, 1.895-7.455; P < 0.001). Kaplan-Meier curves also illustrated the survival difference between normal and elevated α-HBDH patients (P < 0.001). CONCLUSIONS: Our study found that serum α-HBDH is an independent risk factor for in-hospital mortality and disease severity among COVID-19 patients. α-HBDH assessment may aid clinicians in identifying high-risk individuals among COVID-19 patients.

Synergistic removal of cadmium and organic matter by a microalgae-endophyte symbiotic system (MESS): An approach to improve the application potential of plant-derived biosorbents.

Plant-derived materials as environmentally friendly biosorbents to remove heavy metals from wastewater have been extensively studied. However, the chemical oxygen demand (COD) increase caused by the plant-derived biosorbent has not been considered previously. In this study, water hyacinth was used as biosorbent to remove Cd(II) from wastewater. About 66% of Cd(II) was removed by the biosorbent with a maximum biosorption capacity (qmax) of 21.6 mg g-1. However, the COD of the filtrate increased from 0 to 292 mg L-1 during this process. Subsequently, endophytes, microalgae and the microalgae-endophyte symbiotic system (MESS) were assessed for the simultaneous Cd(II) and COD removal. Among these three systems, the MESS achieved the best performance. After 3 d of inoculation, the extent of total Cd(II) removal increased to 99.2% while COD decreased to 77 mg L-1. This study provides a new insight into the application of a plant-derived biosorbent in combination with microalgae and endophytes for the effective treatment of heavy metal-bearing wastewater.

Decreased CO2 Levels as Indicators of Possible Mechanical Ventilation-Induced Hyperventilation in COVID-19 Patients: A Retrospective Analysis.

Background: Six months since the outbreak of coronavirus disease (COVID-19), the pandemic continues to grow worldwide, although the outbreak in Wuhan, the worst-hit area, has been controlled. Thus, based on the clinical experience in Wuhan, we hypothesized that there is a relationship between the patient's CO2 levels and prognosis. Methods: COVID-19 patients' information was retrospectively collected from medical records at the Leishenshan Hospital, Wuhan. Logistic and Cox regression analyses were conducted to determine the correlation between decreased CO2 levels and disease severity or mortality risk. The Kaplan-Meier curve analysis was coupled with the log-rank test to understand COVID-19 progression in patients with decreased CO2 levels. Curve fitting was used to confirm the correlation between computed tomography scores and CO2 levels. Results: Cox regression analysis showed that the mortality risk of COVID-19 patients correlated with decreased CO2 levels. The adjusted hazard ratios for decreased CO2 levels in COVID-19 patients were 8.710 [95% confidence interval (CI): 2.773-27.365, P < 0.001], and 4.754 (95% CI: 1.380-16.370, P = 0.013). The adjusted odds ratio was 0.950 (95% CI: 0.431-2.094, P = 0.900). The Kaplan-Meier survival curves demonstrated that patients with decreased CO2 levels had a higher risk of mortality. Conclusions: Decreased CO2 levels increased the mortality risk of COVID-19 patients, which might be caused by hyperventilation during mechanical ventilation. This finding provides important insights for clinical treatment recommendations.

Bilirubin Levels as Potential Indicators of Disease Severity in Coronavirus Disease Patients: A Retrospective Cohort Study.

Objectives: The coronavirus disease (COVID-19) pandemic has caused a large number of deaths. Some patients with severe or critical COVID-19 have been observed to have elevated bilirubin levels. Studies on the association of bilirubin level and mortality in patients with COVID-19 are limited. This study aimed to examine the role of bilirubin levels in COVID-19 severity and mortality. Methods: A retrospective cohort study was conducted in patients hospitalized with COVID-19 in Leishenshan Hospital in Wuhan, China. Cox regression analyses and logistic regression analyses were conducted to investigate the risks for mortality and disease severity, respectively. Kaplan-Meier analyses with log-rank tests were performed to assess the association between bilirubin level and survival. Results: In total, 1,788 patients with COVID-19 were included in the analysis. 5.8% (4/69) of patients in the elevated serum total bilirubin (STB) group died, compared to 0.6% (11/1,719) of patients in the non-elevated STB group. The median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in the elevated STB group were 29 U/L [interquartile range (IQR): 16-45 U/L] and 22 U/L (IQR: 13-37 U /L), respectively, which were significantly higher than the median ALT (median: 23, IQR: 15-37) and AST (median: 20, IQR: 16-26) activities in the non-elevated STB group (both p < 0.05). Patients with an elevated STB level showed increased mortality [hazard ratio (HR): 9.45, P = 0.002], elevated conjugated bilirubin (CB) levels (HR: 4.38, P = 0.03), and an elevated ratio of CB to unconjugated bilirubin (UCB, CB/UCB) (HR: 2.49, P = 0.01). CB/UCB was positively correlated with disease severity (odds ratio: 2.21, P = 0.01). Conclusions: COVID-19 patients with elevated STB and CB levels had a higher mortality, and CB/UCB was predictive of disease severity and mortality. Thus, it is necessary to pay special attention to COVID-19 patients with elevated bilirubin levels in clinical management.

The effect of metastasis patterns on survival in male patients with different breast cancer subtypes: results from the Surveillance, Epidemiology, and End Results (SEER) database.

BACKGROUND: Metastasis sites and breast cancer subtypes are important for breast cancer patients. This study aimed to assess possible relationships between them and their influence on prognosis in male breast cancer (MBC) patients. METHODS: We collected data on 2,983 patients with MBC from the Surveillance, Epidemiology, and End Results database, including 250 patients with M1 stage disease. Information on metastatic patterns was provided for bone, brain, liver, and lung metastases. MBC was classified into four subtypes: Her2-/HR+, Her2+/HR+, Her2+/HR-, and triple negative (TN). Univariate and multivariate logistic regression analysis were used to analyze the association, and Cox regression analyses were used to analyze prognosis. RESULTS: The bone was the most common metastatic site and the brain was the least common metastatic site. Patients with the Her2-/HR+ subtype had the highest proportion of metastatic disease, and Her2+/HR- patients had the lowest proportion. Univariate and multivariate logistic regression analyses showed that there were significant differences in distant metastasis patterns in patients with different subtypes. Men with the Her2+/HR+ or Her2-/HR+ subtypes with bone metastasis had better cancer specific survival (CSS), and those with the TN subtype had the worst CSS in all metastatic patterns. CONCLUSIONS: MBC subtypes are associated with different metastasis patterns and can have different effects on prognosis. This study might provide insights into a better understanding of MBC.

Synergistic effects of histologic subtype, T-stage, and M-stage in the prognosis of differentiated thyroid cancer: a retrospective observational study.

BACKGROUND: The incidence of differentiated thyroid cancer has increased in many countries during the past few decades. This study aimed to investigate the synergistic effect of clinicopathological factors, including histologic subtype, T stage, and M stage, on the prognosis of differentiated thyroid cancer (DTC). METHODS: We collected data on 86,302 patients with DTC from 2004 to 2013 from the SEER database. We extracted multiple variables from the selected object of study. Demographic characteristics consisted of age at diagnosis, sex, year of diagnosis, and race. Pathological characteristics included T stage, N stage, M stage, multifocality, histologic subtype and extrathyroidal extension. Treatment characteristics included radiation therapy and surgery. Univariate and multivariate analyses were conducted to evaluate the correlation between clinicopathological factors and prognosis. The relative excess risk of synergistic effect (RERI), attributable proportion (AP) of synergistic effect, and synergy index (SI) were used to explore the synergistic effect of these factors on prognosis. RESULTS: Histologic subtype, T-stage, and M-stage were found to be risk factors for cancer-specific survival and all-cause survival in multivariate analysis. The cancer-specific mortality (CSM) rates per 1,000 person-years for patients were found to be higher in follicular thyroid carcinoma (FTC) patients and patients with T3-T4, M1 status disease. In addition, CSM and all-cause mortality (ACM) were also associated with age, sex, race, N- stage, extension, radiation treatment, and surgical approach (all, P<0.001). We also found that histologic subtype had a synergistic effect with both T and M status stage on the prognosis (RERI =7.431, AP =0.278, SI =1.407; RERI =37.889, AP =0.430, SI =1.771, respectively). Synergy was also noted between T- stage and M- stage (RERI =134.125, AP =0.537, SI =2.168). CONCLUSIONS: Histologic subtype, T-stage, and M-stage in different combinations were risk factors for poor prognosis in DTC, and had synergistic effects.

Analysis of the Risk Factors for Mortality in Adult COVID-19 Patients in Wuhan: A Multicenter Study.

Objectives: An outbreak of coronavirus disease (COVID-19) in 2019 in Wuhan, China, has spread quickly worldwide. However, the risk factors associated with COVID-19-related mortality remain controversial. Methods: A total of 245 adult patients with laboratory-confirmed COVID-19 from two centers were analyzed. Chi-square, Fisher's exact, and the Mann-Whitney U-tests were used to compare the clinical characteristics between the survivors and non-survivors. To explore the risk factors associated with in-hospital death, univariable and multivariable cox regression analyses were used. Results: Of the 245 patients included in this study, 23 (9.4%) died in the hospital. The multivariate regression analysis showed increased odds of in-hospital deaths associated with age, D-dimer levels >1,000 ng/L, platelet count <125, and higher serum creatinine levels. Conclusions: We identified risk factors that show significant association with mortality in adult COVID-19 patients, and our findings provide valuable references for clinicians to identify high-risk patients with COVID-19 at an early stage.

Research on the Rheological Characteristics and Aging Resistance of Asphalt Modified with Tourmaline.

Tourmaline modified asphalt (TMA) binders were prepared with different modifier types and contents in this research. The routine properties, rheological properties, and aging resistance were evaluated to research the function of tourmaline on the performances of asphalt binders. Test results show that the storage stability can be improved significantly by the smaller particle size and negative-ion treated surface of tourmaline modifier. It indicates that the stiffness and rutting-resistance of TMA binder can be enhanced significantly, and the elastic component of the viscoelastic characteristic can also be increased. Moreover, the complex viscosity and the Zero Shear Viscosity (ZSV) values of tourmaline modified asphalt are increased within the test frequency range, which results in the improvement of deformation resistance of tourmaline modified asphalt. When mixed with asphalt, the tourmaline modifier maintains a two-phase structure, which results in the good rheological property for tourmaline modified asphalt.

Knockdown of GRHL3 inhibits activities and induces cell cycle arrest and apoptosis of human colorectal cancer cells.

The Grainyhead-like 3 (GRHL3) is involved in epidermal barrier formation, neural tube closure and wound repair. Previous studies have suggested that GRHL3 has been linked to many different types of cancers. However, to date, its effects on human colorectal cancer (CRC) has not been clarified yet. Our microarray analysis has indicated predominant GRHL3 expression in CRC. The purpose of this study was to investigate the expression and significance of GRHL3 in CRC tumorigenesis using CRC tissues and paired paracancerous tissues, as well as using distinct CRC cell lines (HT29 and DLD1). We observed increased GRHL3 expression at both mRNA and protein levels in CRC tissues and CRC cell lines using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Moreover, silencing GRHL3 with siRNA could suppress CRC cell proliferation, viability and migration in vitro. We also found that knockdown of GRHL3 could promote cell cycle arrest at G0/G1 phase in HT29 cells and DLD1 cells, and induce cell apoptosis in HT29 cells. Together, our study revealed the down-regulation of GRHL3 in vitro could inhibit CRC cell activity and trigger cell cycle arrest at G0/G1 phase and apoptosis.

Inhibition of adhesion and metastasis of HepG2 hepatocellular carcinoma cells in vitro by DNA aptamer against sialyl Lewis X.

The sialyl Lewis X (SLex) antigen encoded by the FUT7 gene is the ligand of endotheliam-selectin (E-selectin). The combination of SLex antigen and E-selectin represents an important way for malignant tumor metastasis. In the present study, the effect of the SLex-binding DNA aptamer on the adhesion and metastasis of hepatocellular carcinoma HepG2 cells in vitro was investigated. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence staining were conducted to detect the expression of FUT7 at both transcriptional and translational levels. The SLex expression in HepG2 cells treated with different concentrations of SLex-binding DNA aptamer was detected by flow cytometry. Besides, the adhesion, migration, and invasion of HepG2 cells were measured by cell adhesion assay, and the Transwell migration and invasion assay. The results showed that the FUT7 expression was up-regulated at both mRNA and protein levels in HepG2 cells. SLex-binding DNA aptamer could significantly decrease the expression of SLex in HepG2 cells. The cell adhesion assay revealed that the SLex-binding DNA aptamer could effectively inhibit the interactions between E-selectin and SLex in the HepG2 cells. Additionally, SLex-binding DNA aptamers at 20 nmol/L were found to have the similar effect to the monoclonal antibody CSLEX-1. The Transwell migration and invasion assay revealed that the number of penetrating cells on the down-side of Transwell membrane was significantly less in cells treated with 5, 10, 20 nmol/L SLex-binding DNA aptamer than those in the negative control group (P<0.01). Our study demonstrated that the SLex-binding DNA aptamer could significantly inhibit the in vitro adhesion, migration, and invasion of HepG2 cells, suggesting that the SLex-binding DNA aptamer may be used as a potential molecular targeted drug against metastatic hepatocellular carcinoma.