Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.

Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

A systematic analysis of the global and regional burden of colon and rectum cancer and the difference between early- and late-onset CRC from 1990 to 2019.

The burden of colorectal cancer (CRC) varies substantially across different geographical locations. However, there was no further quantitative analysis of regional social development and the disease burden of CRC. In addition, the incidence of early- and late-onset CRC has increased rapidly in developed and developing regions. The main purpose of this study was to investigate the trends in CRC burden across different regions, in addition to the epidemiological differences between early and late-onset CRC and their risk factors. In this study, estimated annual percentage change (EAPC) was employed to quantify trends in age-standardized incidence rate (ASIR), mortality rate, and disability-adjusted life-years. Restricted cubic spline models were fitted to quantitatively analyze the relationship between trends in ASIR and Human Development Index (HDI). In addition, the epidemiological characteristics of early- and late-onset CRC were investigated using analyses stratified by age groups and regions. Specifically, meat consumption and antibiotic use were included to explore the differences in the risk factors for early- and late-onset CRC. The quantitative analysis showed that the ASIR of CRC was exponentially and positively correlated with the 2019 HDI in different regions. In addition, the growing trend of ASIR in recent years varied substantially across HDI regions. Specifically, the ASIR of CRC showed a significant increase in developing countries, while it remained stable or decreased in developed countries. Moreover, a linear correlation was found between the ASIR of CRC and meat consumption in different regions, especially in developing countries. Furthermore, a similar correlation was found between the ASIR and antibiotic use in all age groups, with different correlation coefficients for early-onset and late-onset CRC. It is worth mentioning that the early onset of CRC could be attributable to the unrestrained use of antibiotics among young people in developed countries. In summary, for better prevention and control of CRC, governments should pay attention to advocate self-testing and hospital visits among all age groups, especially among young people at high risk of CRC, and strictly control meat consumption and the usage of antibiotics.

Suppression of innate and acquired immunity in severe hand foot and mouth disease caused by EV71 infections in children.

Hand, foot, and mouth disease (HFMD) is a common children infectious disease caused by human enteroviruses. Most of the cases have minimal symptoms, however, some patients may develop serious neurological, cardiac complications, or even death. The pathological mechanism leading to severe HFMD is not clearly understood, and the immunological status of the individual patient may play an important role. Transcriptomes of peripheral blood mononuclear cells from EV71-infected patients (n = 45) and healthy controls (n = 36) were examined. Immune pathways were up-regulated in patients with mild disease symptoms (n = 11, M) compared to the healthy controls (n = 36, H), demonstrating an effective anti-viral response upon EV71 infection. However, in patients with severe symptoms (n = 23, S) as well as severe patients following treatment (n = 11, A), their innate and acquired immune pathways were down-regulated, indicating a global immunity suppression. Such immune suppression characteristics could thus provide an opportunity for early EV-71 infection prognosis prediction. Based on our cohort, an SVM model using RNA-seq expression levels of five genes (MCL1, ZBTB37, PLEKHM1P, IFNAR2 and YEATS2) was developed and achieved a high ROC-AUC (91·3%) in predicting severe HFMD. Meanwhile, qPCR fold-changes method was performed based three genes (MCL1, IFNAR2 and YEATS2) on additional cohort. This qPCR method achieved a ROC-AUC of 78.6% in predicting severe HFMD, which the patients could be distinguished in 2-3 h. Therefore, our models demonstrate the possibility of HFMD severity prediction based on the selected biomarkers that predict severe HFMD effectively.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

The Relationship Between Hepcidin-Mediated Iron Dysmetabolism and COVID-19 Severity: A Meta-Analysis.

Backgrounds: Hepcidin has been identified as a systemic iron-regulatory hormone. Recent studies have suggested that iron metabolism disorders may be involved in the pathogenesis of acute respiratory distress syndrome and multiple organ dysfunction in coronavirus disease 2019 (COVID-19). Objectives: To re-evaluate the hepcidin-related iron metabolism parameters and explore the relationship between hepcidin-mediated iron dysmetabolism and COVID-19 severity. Methods: COVID-19 is classified as mild and moderate as non-severe, severe and critical as severe. A meta-analysis was conducted. Four bibliographic databases were comprehensively searched up to December 31st 2021. Results: Six unique studies with data from 477 COVID-19 patients were included. Compared to non-severe cases, severe cases had higher hepcidin (standardized mean difference (SMD), -0.39; 95% Confidence Interval (CI) [-0.76, -0.03]; P = 0.03) and ferritin (SMD, -0.84; 95% CI [-1.30, -0.38]; P = 0.0004). In five out of six studies, a total of 427 patients were tested for serum iron, and there were significant differences in their levels between severe and non-severe cases (SMD, 0.22; 95% CI [0.02, 0.41]; P = 0.03). A total of 320 patients from four out of six studies were tested for transferrin saturation, and the statistical difference was not significant (SMD, 0.06; 95% CI [-0.17, 0.28]; P = 0.64). Conclusion: Severe COVID-19 cases had higher serum levels of hepcidin and ferritin, and lower serum iron, without significant differences in transferrin saturation. Further studies are needed to verify whether targeting the hepcidin-mediated iron metabolism axis may influence the outcome and treatment of COVID-19.

New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation.

Successful engraftment of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs) may be considered as a basis for the repopulation of the blood cells after transplantation in adults. Therefore, in vivo and ex vivo expansion of HSCs holds great promise for clinical applications. In this review, the mechanisms of HSC expansion will be discussed, considering the previous studies and works of literature. This is aimed to identify the signaling pathways that regulate HSC expansion and improve the application of engraftment in disease management. The following aspects will be included: (i) Stimulation of HSCs growth in vivo through gene regulation and cytokines activation; (ii) direct or indirect induction of HSC expansion by regulating signaling pathways; (iii) addition to assisting cells to help in the proliferation of HSCs; (iv) changing of living environment in the HSCs cultures via adjusting components and forms of cultures; (v) enhancement of HSC expansion by incorporating substances, such as extracellular vesicles (EVs), UM171, among others. In this review, recent new findings that provide us with new insights into HSC expansion methods have been summarized. Furthermore, these findings will also provide more possibilities for the development of some novel strategies for expanding and engrafting HSCs applied for treatments of some hematopoietic disorders.

Sequence Requirements for miR-424-5p Regulating and Function in Cancers.

MiRNAs (microRNAs) are the most abundant family of small noncoding RNAs in mammalian cells. Increasing evidence shows that miRNAs are crucial regulators of individual development and cell homeostasis by controlling various biological processes. Therefore, miRNA dysfunction can lead to human diseases, especially in cancers with high morbidity and mortality worldwide. MiRNAs play different roles in these processes. In recent years, studies have found that miR-424-5p is closely related to the occurrence, development, prognosis and treatment of tumors. This review discusses how miR-424-5p plays a role in different kinds of cancers from different stages of tumors, including its roles in (i) promoting or inhibiting tumorigenesis, (ii) regulating tumor development in the tumor microenvironment and (iii) participating in cancer chemotherapy. This review provides a deep discussion of the latest findings on miR-424-5p and its importance in cancer, as well as a mechanistic analysis of the role of miR-424-5p in various tissues through target gene verification and pathway analysis.

Multi-scale information with attention integration for classification of liver fibrosis in B-mode US image.

BACKGROUND AND OBJECTIVE: Chronic hepatitis B (CHB) is one of the most common liver diseases in the world, which threats a lot to people's usual life. The increased deposition of fibrotic tissues in livers for patients with CHB may lead to the development of liver cirrhosis, hepatocellular carcinoma, or even liver failure. Accurate fibrosis staging is very important for the targeted treatment of liver fibrosis and its recovery. METHODS: In this paper, we propose a new deep convolutional neural network (DCNN) with functions of multi-scale information extraction and attention integration for more accurate liver fibrosis classification from ultrasound (US) images. The proposed network uses two pyramid-structured CNN elements to extract multi-scale features from US images. Such a design significantly enlarges the receptive field of the convolution layer, such that more useful information can be explored by the neural network to associate with the final classification. Based on this, a new feature distillation method is also proposed to enhance the ability of deep features derived from multi-scale information. The proposed distillation method employs attention maps to automatically extract class-related features from multi-scale information, which effectively suppress the influence of potential distractors. RESULTS: Experimental results on the US liver fibrosis dataset collected from 286 participants show that the proposed deep framework achieves promising classification performance. The proposed method achieves a classification accuracy of 95.66% on the test dataset. CONCLUSION: Our proposed framework could stage liver fibrosis highly accurately. It might provide effective suggestions for the clinical treatment of liver fibrosis that can facilitate its recovery.

The Effects of Increasing Aortic Occlusion Times at the Level of the Highest Renal Artery (Zone II) in the Normovolemic Rabbit Model.

PURPOSE: The purpose of this study was to evaluate the effects of increasing zone II resuscitative endovascular balloon occlusion of the aorta (REBOA) occlusion times on physiological, end-organ and inflammatory responses in rabbits to assess the safe aortic occlusion time in a normovolemic rabbit model. METHODS: The zone ll aorta was occluded with a balloon in 32 rabbits (8 animals each for 15, 30, 60, and 90 min). 8 rabbits served as a control. ELISAs were used to examine the serum levels of ALT, AST, Cr, BUN, MDA, SOD, IL-8, IL-6, and TNF-α; HE staining was used to identify the morphological changes in the kidney; RT-PCR was used to detect the mRNA levels of IL-6, IL-8, TNF-α and NF-κB in the kidney and uterus; and Western blotting was used to measure the protein expression levels of IL-6, IL-8, TNF-α and NF-κB in the kidney and uterus. RESULTS: Plasma concentrations of liver markers, kidney markers, inflammatory factors and oxidative stress indicators were significantly increased at the end of reperfusion in the 30 min, 60 min and 90 min groups. Damage to the kidney occurred in the 30 min, 60 min and 90 min groups. The mRNA and protein expression levels of IL-6, IL-8, TNF-α and NF-κB in the kidney and uterus were significantly increased at the end of reperfusion in the 30 min group, and as the time of occlusion extended, these levels continued to increase. CONCLUSION: Activation of systemic inflammation and ischaemia-reperfusion injury of end-organs occurred when the occlusion time reached 30 min. Therefore, 15 min should be regarded as a safe period of REBOA in zone II.

Protein tyrosine phosphatase, receptor type B is a potential biomarker and facilitates cervical cancer metastasis via epithelial-mesenchymal transition.

Cervical cancer (CC) is one of the most common malignant tumors. This study analyzed the impact of protein tyrosine phosphatase, receptor type B (PTPRB) on malignant behavior of CC and explored its possible molecular mechanism. RT-PCR, western blot and Immunohistochemistry were applied to examine the expression of PTPRB in CC specimens and cells. Aberrant PTPRB expression in CC and survival outcomes were constructed using The Cancer Genome Atlas (TCGA) database and tissue microarray cervical squamous cell carcinoma cohort. Cultured human CC cells were assayed for viability, apoptosis, migration, and invasion in vitro and in vivo. Kyoto Encyclopedia of Genes and Genomes (KEGG) assays and gene set enrichment analysis (GSEA) assays were used to delve into PTPRB-related pathways using TCGA datasets. The levels of proteins associated with the epithelial-mesenchymal transition (EMT) pathway and modulated by PTPRB were examined through Western blot. We found that the levels of PTPRB in CC tissues and cells were distinctly up-regulated. PTPRB was also an unfavorable prognostic factor for CC patients. Functionally, PTPRB knockdown exhibits tumor-suppressive function via reducing cell proliferation and metastasis and inducing cell apoptosis. KEGG assays and GSEA assays suggested PTPRB overexpression was associated with several tumor-related pathways. The results of Western blot assays suggested that N-cadherin was decreased in the PTPRB-knockdown CC cells, while E-cadherin was increased. Overall, PTPRB is highly expressed in CC and can effectively enhance the proliferation, metastasis and EMT process of tumor cells. PTPRB is expected to be a therapeutic target for CC.

Cytokine/Chemokine Expression Is Closely Associated Disease Severity of Human Adenovirus Infections in Immunocompetent Adults and Predicts Disease Progression.

Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1ß, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the "cytokine storm" occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1ß, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression.

S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling.

Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3ß signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 µmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3ß pathway.

Efficacy and safety of tenofovir alafenamide fumarate for preventing mother-to-child transmission of hepatitis B virus: a national cohort study.

BACKGROUND: Data on tenofovir alafenamide fumarate (TAF) for preventing mother-to-child transmission of hepatitis B virus (HBV) are lacking. AIMS: To investigate the efficacy and safety of TAF therapy for preventing hepatitis B mother-to-child transmission. METHODS: Mothers with chronic HBV infection, positive for hepatitis B e-antigen and with HBV DNA >200 000 IU/mL received TAF for preventing mother-to-child transmission were enrolled retrospectively from multiple centres with data collection on mother-infant dyads up to postpartum week 24-28. Primary measurements were the mother-to-child transmission rate and infants' malformation rate. Secondary assessments included maternal HBV DNA reduction at delivery, and maternal or infant adverse events during follow up. RESULTS: Among 71 mothers enrolled, the mean (±SD) age was 30.3 (±2.2) years. TAF was initiated during the second or third trimester and continued to delivery with a mean (±SD) duration of 12.8 (±4.0) weeks. At delivery, 85.9% (61/71) of the mothers achieved HBV DNA <200 000 IU/L. Seventy-three infants (two sets of twins) were born from mothers treated with TAF and none had congenital defects or malformations. All infants received HBV immunoglobulin and vaccine at birth with additional HBV vaccinations at one and six months. At age 24-28 weeks, all infants had negative hepatitis B surface antigen and undetectable levels of HBV DNA (<100 IU/mL). Body weight, height, and head circumferences were comparable to national standards for physical development. No severe adverse effects were reported in either mothers or infants. CONCLUSIONS: TAF for highly viraemic mothers effectively prevented mother-to-child transmission of hepatitis B. There were no safety concerns for either mothers or infants with 24-28 weeks of follow up.

Obesity and COVID-19 Severity in a Designated Hospital in Shenzhen, China.

OBJECTIVE: Patients with obesity are at increased risk of exacerbations from viral respiratory infections. However, the association of obesity with the severity of coronavirus disease 2019 (COVID-19) is unclear. We examined this association using data from the only referral hospital in Shenzhen, China. RESEARCH DESIGN AND METHODS: A total of 383 consecutively hospitalized patients with COVID-19 admitted from 11 January 2020 to 16 February 2020 and followed until 26 March 2020 at the Third People's Hospital of Shenzhen were included. Underweight was defined as a BMI <18.5 kg/m2, normal weight as 18.5-23.9 kg/m2, overweight as 24.0-27.9 kg/m2, and obesity as ≥28 kg/m2. RESULTS: Of the 383 patients, 53.1% were normal weight, 4.2% were underweight, 32.0% were overweight, and 10.7% were obese at admission. Obese patients tended to have symptoms of cough (P = 0.03) and fever (P = 0.06) compared with patients who were not obese. Compared with normal weight patients, those who were overweight had 1.84-fold odds of developing severe COVID-19 (odds ratio [OR] 1.84, 95% CI 0.99-3.43, P = 0.05), while those who were obese were at 3.40-fold odds of developing severe disease (OR 3.40, 95% CI 1.40-2.86, P = 0.007), after adjusting for age, sex, epidemiological characteristics, days from disease onset to hospitalization, presence of hypertension, diabetes, cardiovascular disease, chronic obstructive pulmonary disease, liver disease, and cancer, and drug used for treatment. Additionally, after similar adjustment, men who were obese versus those who were normal weight were at increased odds of developing severe COVID-19 (OR 5.66, 95% CI 1.80-17.75, P = 0.003). CONCLUSIONS: In this study, obese patients had increased odds of progressing to severe COVID-19. As the severe acute respiratory syndrome coronavirus 2 may continue to spread worldwide, clinicians should pay close attention to obese patients, who should be carefully managed with prompt and aggressive treatment.

First case of COVID-19 complicated with fulminant myocarditis: a case report and insights.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has been demonstrated to be the cause of pneumonia. Nevertheless, it has not been reported as the cause of acute myocarditis or fulminant myocarditis. CASE PRESENTATION: A 63-year-old male was admitted with pneumonia and cardiac symptoms. He was genetically confirmed as having COVID-19 according to sputum testing on the day of admission. He also had elevated troponin I (Trop I) level (up to 11.37 g/L) and diffuse myocardial dyskinesia along with a decreased left ventricular ejection fraction (LVEF) on echocardiography. The highest level of interleukin-6 was 272.40 pg/ml. Bedside chest radiographs showed typical ground-glass changes indicative of viral pneumonia. Laboratory test results for viruses that cause myocarditis were all negative. The patient conformed to the diagnostic criteria of the Chinese expert consensus statement for fulminant myocarditis. After receiving antiviral therapy and mechanical life support, Trop I was reduced to 0.10 g/L, and interleukin-6 was reduced to 7.63 pg/mL. Moreover, the LVEF of the patient gradually recovered to 68%. The patient died of aggravation of secondary infection on the 33rd day of hospitalization. CONCLUSION: COVID-19 patients may develop severe cardiac complications such as myocarditis and heart failure. This is the first report of COVID-19 complicated with fulminant myocarditis. The mechanism of cardiac pathology caused by COVID-19 needs further study.

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.

The outbreak of the 2019-nCoV infection began in December 2019 in Wuhan, Hubei province, and rapidly spread to many provinces in China as well as other countries. Here we report the epidemiological, clinical, laboratory, and radiological characteristics, as well as potential biomarkers for predicting disease severity in 2019-nCoV-infected patients in Shenzhen, China. All 12 cases of the 2019-nCoV-infected patients developed pneumonia and half of them developed acute respiratory distress syndrome (ARDS). The most common laboratory abnormalities were hypoalbuminemia, lymphopenia, decreased percentage of lymphocytes (LYM) and neutrophils (NEU), elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH), and decreased CD8 count. The viral load of 2019-nCoV detected from patient respiratory tracts was positively linked to lung disease severity. ALB, LYM, LYM (%), LDH, NEU (%), and CRP were highly correlated to the acute lung injury. Age, viral load, lung injury score, and blood biochemistry indexes, albumin (ALB), CRP, LDH, LYM (%), LYM, and NEU (%), may be predictors of disease severity. Moreover, the Angiotensin II level in the plasma sample from 2019-nCoV infected patients was markedly elevated and linearly associated to viral load and lung injury. Our results suggest a number of potential diagnosis biomarkers and angiotensin receptor blocker (ARB) drugs for potential repurposing treatment of 2019-nCoV infection.

Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation.

Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.

Unsatisfying antiviral therapeutic effect in patients with mother-to-child transmissed chronic hepatitis B virus infection: a prospective multi-center clinical study.

BACKGROUND: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. METHODS: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. RESULTS: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. CONCLUSION: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. TRIAL REGISTRATION: NCT01962155; https://clinicaltrials.gov.