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Background & aims Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation. Methods We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival. Results Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects. Conclusions The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC. Clinical trials registration This study was registered at ClinicalTrials.gov (NCT03899415).

The traditional research method of fault diagnosis mechanism has poor stability, which leads to the difference of fault diagnosis and location results. Therefore, under the complex geological environment, a new research method of fault diagnosis mechanism of gear and bearing for coal mining equipment is proposed. This method calculates gears and bearings’ yield strength by analyzing coal mining equipment’s bearing capacity elasticity. According to the fitting degree, the equipment sample’s projection space is confirmed, the fault features of gear and bearing are extracted by segmentation algorithm, the optimal fitness is set by positioning algorithm, the location of fault center is obtained, and the fault mechanism diagnosis is studied. Experimental results show that compared with the traditional method, the proposed method is more stable, and the difference in fault diagnosis results is minimal. It can be seen that this method is more suitable for fault diagnosis of coal mining equipment.

Background: The development of severe coronavirus disease 2019 (COVID-19) is associated with systemic hyperinflammation, which drives multi-organ failure and death. Disease deterioration tends to occur when the virus is receding; however, whether other factors besides viral products are involved in the inflammatory cascade remains unclear. Methods: Twenty-eight COVID-19 patients with laboratory-confirmed SARS-CoV-2 infection hospitalized at the Fifth Medical Center of Chinese PLA General Hospital from January 23 to February 20, 2020 and nine healthy donors during the same period were recruited in the study. COVID-19 patients were grouped as mild, moderate, severe based on disease severity. Plasma damage-associated molecular patterns (DAMPs), including high mobility group box 1 (HMGB1), calprotectin (S100A8/A9), surfactant protein A (SP-A), cold-inducible RNA-binding protein (CIRBP), and Histone H4 were detected by ELISA assay, and analyzed in combination with clinical data. Plasma cytokines, chemokines and lymphocytes were determined by flow cytometry. Results: Plasma levels of HMGB1 (38292.3 ± 4564.4 vs. 32686.3 ± 3678.1, P = 0.002), S100A8/A9 (1490.8 ± 819.3 vs. 742.2 ± 300.8, P = 0.015), and SP-A (6713.6 ± 1708.7 vs. 5296.3 ± 1240.4, P = 0.048) were increased in COVID-19 patients compared to healthy donors, while CIRBP (57.4 ± 30.7 vs. 111.9 ± 55.2, P = 0.004) levels decreased. Five DAMPs did not vary among mild, moderate, and severe patients. Moreover, SP-A levels correlated positively with inflammatory cytokines and negatively with time elapsed after symptom onset, whereas CIRBP showed an opposite pattern. Conclusions: These findings suggest SP-A may involve in the inflammation of COVID-19, while CIRBP likely plays a protective role. Therefore, DAMPs represent a potential target in the prevention or treatment of COVID-19.

Perovskite solar cell (PSC) is a promising candidate of tandem solar cells (TSCs), especially as the top cell in perovskite/Si TSCs due to the easily tunable energy bandgap. However, the deposition...

Background: Terlipressin can effectively control acute gastrointestinal bleeding (GIB) in cirrhotic patients by acting on the V1 receptors, but may lead to the development of dilutional hyponatremi...

Objective: At present, the association of body mass index (BMI) with the prognosis of liver cirrhosis is controversial. Our retrospective study aimed to evaluate the impact of BMI on the outcome of liver cirrhosis.Methods: In the first part, long-term death was evaluated in 436 patients with cirrhosis and without malignancy from our prospectively established single-center database. In the second part, in-hospital death was evaluated in 379 patients with cirrhosis and with acute gastrointestinal bleeding (AGIB) from our retrospective multicenter study. BMI was calculated and categorized as underweight (BMI 2), normal weight (18.5 ≤ BMI < 23.0 kg/m2), and overweight/obese (BMI ≥ 23.0 kg/m2).Results: In the first part, Kaplan–Meier curve analyses demonstrated a significantly higher cumulative survival rate in the overweight/obese group than the normal weight group (p = 0.047). Cox regression analyses demonstrated that overweight/obesity was significantly associated with decreased long-term mortality compared with the normal weight group [hazard ratio (HR) = 0.635; 95% CI: 0.405–0.998; p = 0.049] but not an independent predictor after adjusting for age, gender, and Child–Pugh score (HR = 0.758; 95%CI: 0.479–1.199; p = 0.236). In the second part, Kaplan–Meier curve analyses demonstrated no significant difference in the cumulative survival rate between the overweight/obese and the normal weight groups (p = 0.094). Cox regression analyses also demonstrated that overweight/obesity was not significantly associated with in-hospital mortality compared with normal weight group (HR = 0.349; 95%CI: 0.096-1.269; p = 0.110). In both of the two parts, the Kaplan–Meier curve analyses demonstrated no significant difference in the cumulative survival rate between underweight and normal weight groups.Conclusion: Overweight/obesity is modestly associated with long-term survival in patients with cirrhosis but not an independent prognostic predictor. There is little effect of overweight/obesity on the short-term survival of patients with cirrhosis and with AGIB.

Introduction Acute gastrointestinal bleeding (GIB) is a major cause of death in liver cirrhosis. This multicenter study aims to develop and validate a novel and easy-to-access model for predicting the prognosis of patients with cirrhosis and acute GIB. Methods Patients with cirrhosis and acute GIB were enrolled and randomly divided into the training (n = 865) and validation (n = 817) cohorts. In the training cohort, the independent predictors for in-hospital death were identified by logistic regression analyses, and then a new prognostic model (i.e., CAGIB score) was established. Area under curve (AUC) of CAGIB score was calculated by receiver operating characteristic curve analysis and compared with Child–Pugh, model for end-stage liver disease (MELD), MELD-Na, and neutrophil–lymphocyte ratio (NLR) scores. Results In the training cohort, hepatocellular carcinoma (HCC), diabetes, total bilirubin (TBIL), albumin (ALB), alanine aminotransferase (ALT), and serum creatinine (Scr) were independent predictors of in-hospital death. CAGIB score = diabetes (yes = 1, no = 0) × 1.040 + HCC (yes = 1, no = 0) × 0.974 + TBIL (μmol/L) × 0.005 − ALB (g/L) × 0.091 + ALT (U/L) × 0.001 + Scr (μmol/L) × 0.012 − 3.964. In the training cohort, the AUC of CAGIB score for predicting in-hospital death was 0.829 (95% CI 0.801–0.854, P

Background Mesenchymal stem cell (MSC) infusion was reported to improve liver function in patients with decompensated liver cirrhosis (DLC); however, whether the medication can improve outcome of these patients is poorly understood. Methods This prospective, open-labeled, randomized controlled study enrolled 219 patients with HBV-related DLC who were divided into control group (n = 111) and umbilical cord-derived MSC (UC-MSC)-treated group (n = 108), then all of them received a follow-up check from October 2010 to October 2017. The treated patients received three times of UC-MSC infusions at 4-week intervals plus conventional treatment that was only used for control group. The overall survival rate and HCC-free survival rate were calculated as primary endpoints and the liver function and adverse events associated with the medication were also evaluated. Results During the follow-up check period from 13 to 75th months, there was a significantly higher overall survival rate in the treated group than the control group, while the difference of the hepatocellular carcinoma event-free survival rate between the treated and control groups was not observed during the 75-month follow-up. UC-MSC treatment markedly improved liver function, as indicated by the levels of serum albumin, prothrombin activity, cholinesterase, and total bilirubin during 48 weeks of follow-up. No significant side effects or treatment-related complications were observed in the UC-MSC group. Conclusions Therapy of UC-MSC is not only well tolerated, but also significantly improves long-term survival rate, as well as the liver function in patients with HBV-related DLC. UC-MSC medication, therefore, might present a novel therapeutic approach for the disease. Graphic abstract

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was −13.31%, 95% CI −29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: −15.45%; 95% CI −30.82%, −0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

Background Coronavirus disease 2019 (COVID-19) is pandemic. It is critical to identify COVID-19 patients who are most likely to develop a severe disease. This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression. Methods Seventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing, China from December 27, 2019 to March 12, 2020 were enrolled in this study and followed-up to March 16, 2020. Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by the χ2 test or the Fisher exact test (categorical variables) and independent group t test or Mann–Whitney U test (continuous variables). The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19. Results The mean incubation was 8.67 (95% confidence interval, 6.78–10.56) days. Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38 (9.86–12.90) days. Compared to pneumonia-free patients, pneumonia patients were 16.5 years older and had higher frequencies of having hypertension, fever, and cough and higher circulating levels of neutrophil proportion, interleukin-6, low count (+ T cells, and neutrophil/lymphocyte ratio. Thirteen patients deteriorated during hospitalization. Cox regression analysis indicated that older age and higher serum levels of interleukin-6, C-reactive protein, procalcitonin, and lactate at admission significantly predicted the progression of COVID-19. During hospitalization, circulating counts of T lymphocytes, CD4+ T cells, and CD8+ T cells were lower, whereas neutrophil proportion, neutrophil/lymphocyte ratio, and the circulating levels of interleukin-6, C-reactive protein, and procalcitonin were higher, in pneumonia patients than in pneumonia-free patients. CD8+ lymphocyte count in pneumonia patients did not recover when discharged. Conclusions Older age and higher levels of C-reactive protein, procalcitionin, interleukin-6, and lactate might predict COVID-19 progression. T lymphocyte, especially CD8+ cell-mediated immunity is critical in recovery of COVID-19. This study may help in predicting disease progression and designing immunotherapy for COVID-19.

Background We have demonstrated the ability of Hepatitis-B-virus (HBV)-specific T cell receptor (TCR) bioengineered T cells to recognize and lyse Hepatocellular carcinoma (HCC) cells expressing HBV antigens derived from HBV-DNA integration in patients with liver transplant.1 LioCyx-M is an immunotherapeutic product composing of autologous T cells transiently modified with in-vitro transcribed mRNA encoding HBV-specific TCR. The transient TCR expression makes LioCyx -M amenable to a dose escalating posology. Methods The primary endpoint of this phase 1 trial is to assess the safety and tolerability of LioCyx-M in patients with advanced HBV-HCC without curative treatment options. Eligible patients were diagnosed with Barcelona clinic liver cancer stage B or C HCC (Child-Pugh 1 year antiviral treatment prior to enrollment. These patients had matching HLA class I genotypes which present HBV encoded antigen. Peripheral blood was collected from each patient prior to each dose for LioCyx-M manufacturing. Patients received 4 escalating doses of 1×104 cells/kg, 1×105 cells/kg, 1×106 cells/kg, 5×106 cells/kg bodyweight (BW) in the first treatment cycle, each intravenously administered weekly. Patients underwent 1-month safety assessment post the 4th infusion, according to Common Terminology NCI CTCAE Version 4.0.3. If there were no dose associated toxicities, patients were eligible to continue administration of LioCyx-M at dose of 5 × 106 cells/kg BW weekly. Tumor response per RECIST 1.1 criteria and survival time were assessed. Results At data cutoff (30 April 2020), eight patients were enrolled, with a median age of 53 (range: 49 - 67). These patients received a median number of 6 (range: 4 - 12) infusions of LioCyx-M. 1 patient developed Grade 3 elevations in alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST) and bilirubin after receiving LioCyx-M at dose level of 1×105 cells/kg BW. Another patient had Grade 1 transient fever after receiving LioCyx-M at dose level 5×106 cells/kg BW in the 4th, 5th and 6th infusions. No treatment-related adverse events (trAEs) such as cytokine release syndrome or neurotoxicity were observed. No fatal trAEs were observed. The median time to progression was 1.9 months (range: 0.2 - 9.5 months). The median overall survival was 34 months (range: 3 - 38.2 months). Conclusions The encouraging clinical outcome and tolerable safety highlight the good benefit-risk profile of LioCyx-M. Therefore, further exploration of efficacy of LioCyx-M treatment for advanced HBV-HCC is warranted in a Phase 2 proof-of-concept clinical study. Acknowledgements Funding: Lion TCR. Trial Registration NCT03899415 Ethics Approval The study was approved by Fifth Medical Center of Chinese PLA General Hospital’s Ethics Board, approval number R2016185DI010. Reference Tan AT, Yang N, Lee Krishnamoorthy T, et al. Use of Expression Profiles of HBV-DNA Integrated Into Genomes of Hepatocellular Carcinoma Cells to Select T Cells for Immunotherapy. Gastroenterology 2019;156(6):1862–1876.e9.

BACKGROUNDTreatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data.METHODSIn this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test, maximum vital capacity, diffusing capacity, and adverse events were recorded and analysed.RESULTS100 COVID-19 patients were finally recruited to receive either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95%CI -29.14%, 2.13%, P=0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P=0.043). The 6-minute walk test showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P=0.057). The incidence of adverse events was similar in the two groups.CONCLUSIONSUC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.)

No effective drug treatments are available for coronavirus disease 2019 (COVID-19). Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage, death, or long-term functional disability in survivors require clinical evaluation. We performed a parallel assigned controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease. The study enrolled 18 hospitalized patients with COVID-19 (n = 9 for each group). The treatment group received three cycles of intravenous infusion of UC-MSCs (3 × 107 cells per infusion) on days 0, 3, and 6. Both groups received standard COVID-treatment regimens. Adverse events, duration of clinical symptoms, laboratory parameters, length of hospitalization, serial chest computed tomography (CT) images, the PaO2/FiO2 ratio, dynamics of cytokines, and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed. No serious UC-MSCs infusion-associated adverse events were observed. Two patients receiving UC-MSCs developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion. Mechanical ventilation was required in one patient in the treatment group compared with four in the control group. All patients recovered and were discharged. Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated. Phase 2/3 randomized, controlled, double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.

Acute gastrointestinal bleeding (GIB) rapidly reduces effective blood volume, thereby precipitating acute kidney injury (AKI). Terlipressin, which can induce splanchnic vasoconstriction and increase renal perfusion, has been recommended for acute GIB and hepatorenal syndrome in liver cirrhosis. Thus, we hypothesized that terlipressin might be beneficial for cirrhotic patients with acute GIB and renal impairment. In this Chinese multi-center study, 1644 cirrhotic patients with acute GIB were retrospectively enrolled. AKI was defined according to the International Club of Ascites (ICA) criteria. Renal dysfunction was defined as serum creatinine (sCr) > 133 μmol/L at admission and/or any time point during hospitalization. Incidence of renal impairment and in-hospital mortality were the primary end-points. The incidence of any stage ICA-AKI, ICA-AKI stages 1B, 2, and 3, and renal dysfunction in cirrhotic patients with acute GIB was 7.1%, 1.8%, and 5.0%, respectively. The in-hospital mortality was significantly increased by renal dysfunction (14.5% vs. 2.2%, P

Diagnosis is the key point for confirmation and treatment of COVID-19. we focused on comparative analysis of virus dynamics between the upper respiratory and feces specimens in the COVID-19 patients. A total of 66 upper respiratory swabs, 51 feces, 56 urine and 56 plasma samples were sequentially collected from 23 patients in a designated hospital. The plasma and urine samples were all negative, except for urine samples from two severe cases at the latest available detection point. Conversely, virus was shed in respiratory swabs and feces samples during the diseased period. Ten of 12 (83.3%) cases were positive for feces samples, while 14 of 21 (66.7%) were positive for respiratory samples. In addition, the median duration of virus shedding was 10.0 days (IQR 8.0 to 17.0) in the upper respiratory swabs, but was 22.0 days (IQR 15.5 to 23.5) for the feces. Notably, at 26 days after discharge, case 3 (a 45-year-old) was detected positive again in the feces samples, but appears to be healthy and negative for respiratory swabs. These results indicated that beside respiratory samples, intestinal samples (e.g. feces) should be recommended for diagnosis of COVID-19, especially before a patient discharge and for monitoring the relapse of discharged patients.

BackgroundSARS-CoV-2-caused coronavirus disease (COVID-19) is posing a large casualty. The features of COVID-19 patients with and without pneumonia, SARS-CoV-2 transmissibility in asymptomatic carriers, and factors predicting disease progression remain unknown.MethodsWe collected information on clinical characteristics, exposure history, and laboratory examinations of all laboratory-confirmed COVID-19 patients admitted to PLA General Hospital. Cox regression analysis was applied to identify prognostic factors. The last follow-up was February 18, 2020.ResultsWe characterized 55 consecutive COVID-19 patients. The mean incubation was 8.42 (95% confidence interval [CI], 6.55-10.29) days. The mean SARS-CoV-2-positive duration from first positive test to conversion was 9.71 (95%CI, 8.21-11.22) days. COVID-19 course was approximately 2 weeks. Asymptomatic carriers might transmit SARS-CoV-2. Compared to patients without pneumonia, those with pneumonia were 15 years older and had a higher rate of hypertension, higher frequencies of having a fever and cough, and higher levels of interleukin-6 (14.61 vs. 8.06pg/mL, P=0.040), B lymphocyte proportion (13.0% vs.10.0%, P=0.024), low account (+ T cells (33.3% vs. 0, P=0.019). Multivariate Cox regression analysis indicated that circulating interleukin-6 and lactate independently predicted COVID-19 progression, with a hazard ratio (95%CI) of 1.052 (1.000-1.107) and 1.082 (1.013-1.155), respectively. During disease course, T lymphocytes were generally lower, neutrophils higher, in pneumonia patients than in pneumonia-free patients. CD8+ lymphocytes did not increase at the 20th days after illness onset.ConclusionThe epidemiological features are important for COVID-19 prophylaxis. Circulating interleukin-6 and lactate are independent prognostic factors. CD8+ T cell exhaustion might be critical in the development of COVID-19.

Background: Treatment of severe Corona Virus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC‑MSCs) to treat patients with severe COVID-19 with lung damage, based on our phase 1 data. Methods: In this randomised, double-blind, and placebo-controlled trial, we recruited 101 eligible patients with severe COVID-19 with lung damage aged between 18–74 years from two hospitals. Enrolled patients were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. We excluded patients with malignant tumours, shock, or other organ failure. The primary endpoint was an altered proportion of whole lung lesion areas from baseline to day 28, measured by chest computed tomography. Other imaging outcomes, 6-minute walk test, maximum vital capacity, diffusing capacity, plasma biomarkers, and adverse events were recorded and analysed. Primary analysis was done in the modified intention-to-treat (mITT) population and safety analysis was done in all patients who started their assigned treatment. Findings: From March 5, 2020, to March 28, 2020, 100 patients were finally enrolled and received either UC-MSCs (n = 65) or placebo (n = 35). During follow-up, the patients receiving UC-MSCs exhibited a trend of numerical improvement in whole lung lesions from baseline to day 28 compared with the placebo cases. UC-MSCs administration significantly reduced the proportions of consolidation lesions from baseline to day 28 in the treated patients compared with the placebo subjects. The 6-minute walk test showed an increased distance in patients treated with UC-MSCs. Notably, UC-MSCs delivery was well tolerated, with no serious adverse events. Interpretation: UC-MSCs treatment is a safe and potentially effective therapeutic approach for patients with severe COVID‑19. The trial suggests that UC-MSCs administration might benefit patients with COVID-19 with lung damage at the convalescent stage as well as the progression stage. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT04288102. Funding Statement: This trial was supported by The National Key RD The Innovation Groups of the National Natural Science Foundation of China (81721002); The National Science and Technology Major Project (2017YFA0105703). Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Ethical approval was obtained from the institutional review boards of each participating hospital. Written informed consent was obtained from all the enrolled patients or their legal representatives if they were unable to provide consent.

AlN thin films were deposited on c-, a- and r-plane sapphire substrates by the magnetron sputtering technique. The influence of high-temperature thermal annealing (HTTA) on the structural, optical properties as well as surface stoichiometry were comprehensively investigated. The significant narrowing of the (0002) diffraction peak to as low as 68 arcsec of AlN after HTTA implies a reduction of tilt component inside the AlN thin films, and consequently much-reduced dislocation densities. This is also supported by the appearance of E 2(high) Raman peak and better Al–N stoichiometry after HTTA. Furthermore, the increased absorption edge after HTTA suggests a reduction of point defects acting as the absorption centers. It is concluded that HTTA is a universal post-treatment technique in improving the crystalline quality of sputtered AlN regardless of sapphire orientation.

Transparent conducting electrodes have been systematically developed for optoelectronic devices and applications in industry through materials exploration and manufacturing process optimization. The nanostructural, optical and electrical properties were correlated with the embedded Ag interlayer thickness for the first time, for α-IGZO/Ag/α-IGZO trilayer electrodes fabricated using DC magnetron sputter deposition. Optimizing the Ag interlayer thickness at 14 nm achieves a maximum Haacke figure of merit (FOM) of 7.3 × 10−3 Ω−1, at least two orders of magnitude greater than that of the single IGZO film, with X-ray diffraction patterns indicating a crystalline phase that is also retained for thicker layers. Electrical and surface topography measurements confirm a uniform, continuous Ag interlayer film with bulk metallic behavior and resistivity as low as 6 × 10−5 Ω cm. Experimentally-calibrated finite-element modeling and ray tracing simulations unravel in the multilayer films, backscattering and transmission effects from random surface roughness, as well as phonon- or ionized impurity-scattering mediated free carrier absorption plus surface/interface scattering and interference effects. Moreover, film thickness-sensitive tuning of the optical bandgap between 2.98 and 3.14 eV was demonstrated, yielding a maximum bandgap and Haacke FOM at the optimized Ag interlayer thickness, and with many-body interactions outcompeting the Burstein-Moss effect above this thickness.

In magnetron sputtered oxide thin films, both the structure and physical properties are affected by bombardment-induced defects and their annihilation. Ga-doped zinc oxide (GZO) films with low Ga content (~1.7 at.%) were magnetron sputtered at various discharge voltages (70–220 V) and the growth temperatures (130 °C and 380 °C). The microstructure was characterized by X-ray Diffractometry, Raman Spectroscopy, and Transmission Electron Microscopy. Meanwhile, the electrical and optical properties were measured by Hall-effect measurement and Spectroscopic Ellipsometry, respectively. We found that reducing the discharge voltage led to higher structural quality and better electrical properties, independent of the growth temperature. The benefit, from using a high temperature (i.e., 380 °C), of the structural improvement, can only be achieved when the discharge voltage has been decreased to ultralow (i.e., 70 V). Our results suggest that for high quality GZO films deposition, controlling the defect generation should be preferable to simply increasing the growth temperature.

Background & Aims Production of neutralizing antibodies against hepatitis B surface antigen (HBsAg) is dysregulated in patients with persistent hepatitis B virus (HBV) infection. We investigated mechanisms by which this immune response to the virus is disrupted and whether it can be restored to promote clearance of HBV. Methods Immune-competent C57BL/6N and C57BL/6J, as well as mice deficient in follicular helper T cells (Tfh-cell-deficient), B cells, or Foxp3+ T-regulatory cells (Treg cell deficient), were given hydrodynamic injections of pAAV/HBV1.2 plasmids. Some mice were given injections of sorted Tfh cells, pan-B cells, Treg cells, or a blocking antibody against CTLA4. Production of antibodies against HBsAg and clearance of HBV were assessed by flow cytometry, enzyme-linked immunosorbent assay, polymerase chain reaction, and immunohistochemical analyses. We obtained blood samples from patients with HBV infection and isolated Treg cells. We measured the ability of Treg cells to suppress production of interleukin 21 (IL21) in CD4+ T cells. Results Immune-competent C57BL/6N and C57BL/6J mice transfected with the plasmid encoding HBV had features of viral clearance and viral persistence observed in humans. A Tfh-cell response to HBsAg was required for clearance of HBV and was suppressed by Treg cells in mice with persistent HBV infection. Depletion of Treg cells or inhibition of Treg-cell function (with blocking antibody against CTLA4) restored the Tfh-cell response against HBsAg and clearance of HBV in mice. Impaired Tfh-cell response to HBsAg was observed in blood from patients with chronic HBV infection, responsiveness was restored by depletion of Treg cells or blocking antibody against CTLA4. Conclusions In studies of HBV-infected mice and blood from patients with chronic HBV infection, we found a Tfh-cell response to HBsAg of to be required for HBV clearance, and that this response was blocked by Treg cells. Inhibiting Treg-cell activity using neutralizing antibody against CTLA4 restored the ability of Tfh cells to clear HBV infection; this approach might be developed for treatment of patients with chronic HBV infection.

This paper reports investigation on a polarity control scheme of GaN thin films and realization of Schottky barrier diode (SBD) fabricated on a lateral-polarity-structure (LPS) GaN without intentionally doping. Specifically, Ga-polar and N-polar GaN were grown simultaneously side by side on sapphire substrate with patterned AlN buffer. Due to the surface energy difference between two polarities, N-polar regions are n-type conductive with rough surface morphology, while Ga-polar regions are semi-insulating with atomic flat surface morphology. Annealing conditions of both ohmic contact and Schottky contact were investigated. Current–voltage (I–V) characteristic revealed that the SBD fabricated on LPS GaN has higher forward current, barrier height closer to 0.7 eV, and ideality factor closer to unity compared to SBD fabricated on conventional undoped GaN. The specific on-state resistance ( ${R}_{{ \mathrm{\scriptscriptstyle ON}}})$ for the SBD based on LPS GaN is 77 $\text{m}\Omega \cdot \text {cm}^{{{{2}}}}$ lower than the SBD fabricated on conventional GaN. With oxide passivation on SBD surface, forward current exceeds 0.2 A at 10 V, while reverse current is less than 10−5 A at −10 V, respectively. The utilization of LPS in SBD demonstrates a promising approach for the development of lateral n+/n− SBD with a simple fabrication scheme.

Introduction: Preliminary data suggested that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in liver cirrhosis. The primary objectives were to investigate non-invasive markers for diagnosing and grading OV in patients with primary biliary cirrhosis. Material and methods: This study included a total of 106 consecutive treatment-naive patients with primary biliary cirrhosis (PBC). Results of physical examination, blood tests, and abdominal ultrasound scan (USS) were measured. Performance of non-invasive markers for OV was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC). Results: Oesophageal varices were found in 54 (50.9%) and large OV in 28 of the 106 patients. Variables found to differ significantly between patients with any grade or large and without OV included increased spleen length, increased portal vein diameter, low platelet count, and low levels of albumin or low -glutamyltranspeptidase (-GGT) values. Area under the receiver operating characteristic curve showed that spleen length (cutoff = 156.0) had AUC 0.753 (95% CI: 0.657–0.849), and high NPV (82.1%) to exclude any grade OV. Large OV could be excluded with NPV 70.6% by spleen length. Conclusions : Predictive risk factors that use readily available laboratory results and ultrasound scan results may reliably identify esophageal varices in patients with PBC.

Chemotherapy drug resistance frequently happens in more than 50% of bladder cancer patients and is the major obstacle for the bladder cancer therapy. Recent studies have shown that long noncoding RNA (lncRNA) is involved in the development of chemoresistance. In this study, we reported hypoxia inducible factor 1α-antisense RNA 2 (HIF1A-AS2), as a subtype-specific hypoxia inducible lncRNA, is upregulated in bladder cancer cells and tissue after cisplatin (Cis) treatment. The induction of HIF1A-AS2 in bladder cancer cells rendered resistance to Cis-induced apoptosis. Silencing HIF1A-AS2 in Cis-resistant bladder cancer cells was re-sensitized to Cis-induced apoptosis. Mechanically, we found that HIF1A-AS2 suppressed the transcription activity of p53 family proteins by promoting the expression of high-mobility group A1 (HMGA1). The induction of HMGA1 physically interacts with p53, p63, and p73, and therefore constrains their transcriptional activity on Bax. Knockdown of HIF1A-AS2 or HMGA1 rescued the expression of Bax, which therefore enhanced the killing effect of Cis. Furthermore, we also found that the expression of HIF1A-AS2 was higher in the human bladder tumor tissues after Cis treatment, and was positive correlated to the expression of HIF1α and HMGA1. This study suggests that upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer. Our data suggested that HIF1A-AS2 plays oncogenic roles and can be used as a therapeutic target for treating human bladder cancer.

Lymph node (LN) metastasis of gastric cancer (GC) is the strongest prognostic indicator for this disease; however, the majority of the LN metastasis profiles of GC remain unknown, which notably hinders the therapeutic efficacy in clinic. In the present study, an orthotopic model of human GC was established for investigation of time-dependent LN metastasis patterns in mice. Luciferase-expressing NCI-N87 human GC cells were injected into the subserosa of the gastric body, resulting in a tumor formation rate of 100%. LN metastasis at four different anatomical positions in the abdomen were characterized until week 10 after tumor cell injection using sensitive bioluminescence imaging and histopathological analyses. Skip LN metastases were observed at later stages (weeks 8-10) of the experiment. Metastases in other major organs, including liver, spleen and lung, were also examined. Characterization of this orthotopic GC model and metastasis patterns in LNs and major organs should aid in the preclinical GC research regarding the metastatic mechanism and drug development.

Herein we report an investigation of a CH3NH3PbI3 planar solar cell, showing significant power conversion efficiency (PCE) improvement from 4.88% to 6.13% by introducing a homogeneous and uniform NiO blocking interlayer fabricated with the reactive magnetron sputtering method. The sputtered NiO layer exhibits enhanced crystallization, high transmittance, and uniform surface morphology as well as a preferred in-plane orientation of the (200) plane. The PCE of the sputtered-NiO-based perovskite p-i-n planar solar cell can be further promoted to 9.83% when a homogeneous and dense perovskite layer is formed with solvent-engineering technology, showing an impressive open circuit voltage of 1.10 V. This is about 33% higher than that of devices using the conventional spray pyrolysis of NiO onto a transparent conducting glass. These results highlight the importance of a morphology- and crystallization-compatible interlayer toward a high-performance inverted perovskite planar solar cell.

Single-chain variable domain fragment (scFv) 637 is an antigen-specific scFv of myasthenia gravis. In this study, scFv and human serum albumin genes were conjugated and the fusion protein was expressed in Pichia pastoris. The affinity of scFv-human serum albumin fusion protein to bind to acetylcholine receptor at the neuromuscular junction of human intercostal muscles was detected by immunofluorescence staining. The ability of the fusion protein to block myasthenia gravis patient sera binding to acetylcholine receptors and its stability in healthy serum were measured by competitive ELISA. The results showed that the inhibition rate was 2.0-77.4%, and the stability of fusion protein in static healthy sera was about 3 days. This approach suggests the scFv-human serum albumin is a potential candidate for specific immunosuppressive therapy of myasthenia gravis.

Background: Our previous study developed Liaoning score as a non-invasive approach for predicting esophageal varices (EVs) in liver cirrhosis. This nationwide multicenter cross-sectional study aimed to externally validate the diagnostic accuracy of Liaoning score and further evaluate its performance for predicting high-risk EVs. Methods: Cirrhotic patients with acute gastrointestinal bleeding (GIB) without history of endoscopic variceal therapy who underwent endoscopic examinations at their admissions were included. Liaoning score and several non-invasive liver fibrosis scores, including aspartate aminotransferase (AST) to platelet ratio index (APRI), AST to alanine aminotransferase ratio (AAR), fibrosis 4 index (FIB-4), King, and Lok scores, were evaluated. Area under curves (AUCs), cut-off value, sensitivity, and specificity were calculated. Results: Overall, 612 patients were included. The prevalence of EVs and high-risk EVs was 96.2% and 95.6%, respectively. In overall patients, the AUCs of Liaoning score for predicting EVs and high-risk EVs were higher than non-invasive liver fibrosis scores (0.737 versus 0.626–0.721; 0.734 versus 0.611–0.719). The cut-off value of Liaoning score for high-risk EVs was 0.477 with a sensitivity of 81.96% and a specificity of 65.22%. In patients with hematemesis, Liaoning score could significantly predict EVs and high-risk EVs (AUCs =0.708 and 0.702, respectively), but not non-invasive liver fibrosis scores. The cut-off value of Liaoning score for high-risk EVs was 0.437 with a sensitivity of 83.16% and a specificity of 60%. Conclusions: Liaoning score should be a non-invasive alternative for predicting EVs and high-risk EVs in cirrhotic patients with acute GIB.

Surfactant protein B (SP-B) deficiency has become increasingly recognized as a cause of severe prolonged respiratory distress. However, little has been reported with regard to the genetic variability of SP-B in Chinese infants with neonatal respiratory distress syndrome (RDS). One case of a Chinese male infant with neonatal RDS was analyzed for clinical manifestation and genetic variability of SP-B. The clinical manifestations, including grunting, intercostal retractions, nasal flaring, cyanosis and tachypnea were discovered in the physical examination. The initial chest X-ray indicated hyper-inflation, diffuse opacification and air bronchogram of the lungs. Pathological tests of lung tissue revealed RDS and SP-B deficiency. Atelectasis and pneumonedema were observed in the lobes of the lung. Molecular analysis of genomic DNA revealed a mutation of 121del2 in intron 4 of the SP-B gene. In conclusion, the variant in intron 4 of the SP-B gene was associated with neonatal RDS in a Chinese male infant.

Objective: To explore the safety and efficacy of percutaneous nephrolithotomy (PCNL) for the treatment of renal calculi in elderly patients. Methods: Totally 57 elderly patients (mean age 69 years, ranged from 61 to 87 years) with renal calculi were treated by PCNL in our hospital from January 2013 to December 2015. Working tunnels F16-F24 were established under B-ultrasound guidance. EMS or holmium laser lithotripsy was used to fragment and remove stones by nephroscopy. Results: The procedure was completed in a mean of 65 min (ranged from 30 to 140 rain), and one-session stone-free rate was 78.9% (45/57). After the procedure, one patient developed fever(>38.5 o C)and then was cured by antibiotics; two patients received blood transfusion(1800 and 2500 ml, respectively)because of massive hemorrhage, and one of them was diagnosed with pseudoaneurysm, and then was cured by selective renal artery embolization. No patient had severe complications. Residual stones were detected in 12 patients, 4 of them received a second PCNL and 5 of them underwent postoperative ESML; one who received second PCNL and one who received ESML still showed a few residual stones in the lower renal calyces, the other 7 showed no residual stones after the second operation. Five of the 12 cases of residual stones were followed up for 6 to 24 months, 4 of them showed no significant change, and the other showed mildly enlarged renal stone. In the 46 patients who had the stones removed completely, follow-up was achieved for 3 to 34 months with a mean of 14.3 months, only 2 of them had recurrence and thus received conservative therapy. Conclusions: PCNL is safe and effective for elderly patients with renal stones. The keys of the therapy include adequate preoperative preparation, skilled operation, and perioperative management. Elderly patients with heart and lung function compensatory ability are poor, and accompanied by chronic disease of other system. So the surgery is risking. Our hospital from January 2013 to December 2015, using percutaneous nephrolithotomy (PCNL) in treatment of 57 elderly kidney stones, the operation risk control and satisfactory effect is good, reports are as follows.

Objective: To summarize the clinic experience of flexible ureteroscope in diagnosis and treatment of upper urinary tract disease. Method: From Nov 2013 to Dec 2015, 60 hematuresis cases underwent flexible ureteroscope for diagnosis and treatment of upper urinary tract. Clinical data was analyzed retrospectively. Results: All the cases were diagnosed and cured successfully in a one-time success .19 cases were diagnosed epithelium cancer, 6 cases were diagnosed non-specificity pyeloureteritis, 18 cases were diagnosed as calculus of ureter, and 8 cases were renal pelvis venous hemorrhage, no abnormality seen in 9 cases. No serious complication happened. And the time of the surgeries was 10~70 min and the average time was 40 min. Hospitalization time was 3~9 days, and the average time was 4 days. Conclusion: Flexible ureteroscope can be used to diagnose and cure tumor, calculus, inflammation and other diseases of upper urinary tract, especially, to upper urinary minimal lesion. Flexible ureteroscope has an obvious advantage. From Nov 2013 to Dec 2015, 58 hematuria patients underwent flexible ureteroscope for diagnosis and treatment of upper urinary tract diseases. Now we report as followed.

Background/Objective: It has been reported that Krüppel like factor 6 intervening sequence (KLF6 IVS) 1-27 G > A might be associated with cancer susceptibility. Here, we conducted a meta-analysis to summarize and clarify this association. Materials and Methods/Main Results: A systematic search of studies on the association between KLF6 IVS 1-27 G > A, and cancer susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. Seven articles were included in our meta-analysis. Overall and in prostate cancer, population-based subgroup overall and Caucasian subgroup overall, no evidence was found for the association between KLF6 IVS 1-27 G > A polymorphism and cancer susceptibility in any genetic model and the results showed stability in sensitivity analyses. Conclusions: KLF6 IVS 1-27 G > A may not be associated with cancer susceptibility, especially the susceptibility of unselected prostate cancer. However, there was insufficient data to fully confirm the association between KLF6 IVS 1-27 G > A and familial prostate cancer, sporadic prostate cancer, gastric cancer, and cancers from different ethnicity, and the results should be interpreted with caution.

Intracerebroventricular (i.c.v.) injection of streptozotocin has been introduced as a means to inhibit glucose utilization in the rat brain, and to induce changes in neurotransmitter systems and behavior which resemble those seen in Alzheimer's disease. In this study, enzyme activities previously investigated in Alzheimer's disease (peptidases, dehydrogenases and acetyltransferases) were measured in the septum and hippocampus of control and streptozotocin-treated rats. Streptozotocin-treated rats receiving acetyl-l-carnitine were also included in the experiments, to assess possible neuroprotective effects of this substance. All enzyme activities in the septum were affected by streptozotocin, with the exception of choline acetyltransferase activity. By contrast, choline acetyltransferase activity was the only enzyme activity affected in the hippocampus. The weight of the septum was reduced in streptozotocin-treated animals. These findings indicate that i.c.v. injection of streptozotocin causes septal damage and enzymatic changes that do not closely resemble those seen in Alzheimer's disease, which are more specific. Acetyl-l-carnitine partly prevented this damage, as reflected by an attenuation of the streptozotocin-induced decrease in hippocampal choline acetyltransferase activity. This finding indicates that streptozotocin-treated rats may be valuable to test possible neuroprotective effects of drugs.