Risk factors for underlying comorbidities and complications in patients with hepatitis B virus-related acute-on-chronic liver failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a severe and life-threatening complication, characterised by multi-organ failure and high short-term mortality. However, there is limited information on the impact of various comorbidities on HBV-ACLF in a large population. This study aimed to investigate the relationship between comorbidities, complications and mortality. In this retrospective observational study, we identified 2166 cases of HBV-ACLF hospitalised from January 2010 to March 2018. Demographic data from the patients, medical history, treatment, laboratory indices, comorbidities and complications were collected. The mortality rate in our study group was 47.37%. Type 2 diabetes mellitus was the most common comorbidity, followed by alcoholic liver disease. Spontaneous bacterial peritonitis, pneumonia and hepatic encephalopathy (HE) were common in these patients. Diabetes mellitus and hyperthyroidism are risk factors for death within 90 days, together with gastrointestinal bleeding and HE at admission, HE and hepatorenal syndrome during hospitalisation. Knowledge of risk factors can help identify HBV-ACLF patients with a poor prognosis for HBV-ACLF with comorbidities and complications.

The impact of serum thyroid-stimulation hormone levels on the outcome of hepatitis B virus related acute-on-chronic liver failure: an observational study.

BACKGROUND: Thyroid dysfunction has been reported in severe liver diseases. The aim of this study was to analyze the impact of serum thyroid-stimulation hormone (TSH) levels on the prognosis of patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: This retrospective cohort study included 1,862 patients with HBV-related ACLF. Risk factors associated with 30-day and 90-day survival, hazard ratios (HRs), and 95% confidence intervals (CIs) for TSH were estimated using Cox proportional hazards regression. The Area Under the ROC curve (AUROC) analysis was carried out, and the cut-off values were calculated. After grouping by the cut-off value, survival was compared between the groups using the log-rank test. This study data is from the "Survival Cohort Study (SCS)", which has been registered at ClinicalTrials.gov (NCT03992898). RESULTS: Multivariate analysis indicated that an elevated TSH level was a highly significant predictor for 30-day survival (HR = 0.743, 95% CI: 0.629-0.878, P < 0.001) and 90-day survival (HR = 0.807, 95% CI: 0.717-0.909, P < 0.001). The AUROC of TSH level for 30-day and 90-day mortality were 0.655 and 0.620, respectively, with the same best cut-off values of 0.261 µIU/mL. Log-rank test showed that the group with higher TSH level had higher 30-day (78.5%, 95% CI: 76.1%-80.9% vs. 56.9%, 95% CI: 53.4%-60.4%; P < 0.001) and 90-day survival rate (61.5%, 95% CI: 58.6%-64.4% vs. 42.8%, 95% CI: 39.3%-46.3%; P < 0.001). Similar findings were observed in subgroups analysis. After adjusting for age and other risk factors, the higher level of TSH remained associated with 30-day survival (HR = 0.602, 95% CI: 0.502-0.721, P < 0.001) and 90-day survival (HR = 0.704, 95% CI, 0.609-0.814, P < 0.001). CONCLUSIONS: Serum TSH level significantly correlate with HBV-related ACLF patients' survival and may be of value for predicting 30-day and 90-day survival of patients with HBV-related ACLF.

Derivation and Validation of a Nomogram for Predicting 90-Day Survival in Patients With HBV-Related Acute-on-Chronic Liver Failure.

Background: Conventional prognostic models do not fully reflect the severity of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). This study aimed to establish an effective and convenient nomogram for patients with HBV-related ACLF. Methods: A nomogram was developed based on a retrospective cohort of 1,353 patients treated at the Third Affiliated Hospital of Sun Yat-sen University from January 2010 to June 2016. The predictive accuracy and discriminatory ability of the nomogram were determined by a concordance index (C-index) and calibration curve, and were compared with current scoring systems. The results were validated using an independent retrospective cohort of 669 patients consecutively treated at the same institution from July 2016 to March 2018. This study is registered at ClinicalTrials.gov (NCT03992898). Results: Multivariable analysis of the derivation cohort found that independent predictors of 90-day survival were age, white blood cell (WBC) count, hemoglobin (Hb), aspartate aminotransferase (AST), total bilirubin (TBil), international normalized ratio, serum creatinine (Cr), alpha fetoprotein (AFP), serum sodium (Na), hepatic encephalopathy (HE), pre-existing chronic liver disease(PreLD), and HBV DNA load. All factors were included in the nomogram. The nomogram calibration curve for the probability of 90-day survival indicated that nomogram-based predictions were in good agreement with actual observations. The C-index of the nomogram was 0.790, which was statistically significantly greater than those for the current scoring systems in the derivation cohort (P < 0.001). The results were confirmed in the validation cohort. Conclusions: The proposed nomogram is more accurate in predicting the 90-day survival of patients with HBV-related ACLF than current commonly used methods.

Persistent Viral Presence Determines the Clinical Course of the Disease in COVID-19.

BACKGROUND: The clinical management of coronavirus disease 2019 (COVID-19) is dependent on understanding the underlying factors that contribute to the disease severity. In the absence of effective antiviral therapies, other host immunomodulatory therapies such as targeting inflammatory response are currently being used without clear evidence of their effectiveness. Because inflammation is an essential component of host antiviral mechanisms, therapies targeting inflammation may adversely affect viral clearance and disease outcome. OBJECTIVE: To understand whether the persistent presence of the virus is a key determinant in the disease severity during COVID-19 and to determine whether the viral reactivation in some patients is associated with infectious viral particles. METHODS: The data for patients were available including the onset of the disease, duration of viral persistence, measurements of inflammatory markers such as IL-6 and C-reactive protein, chest imaging, disease symptoms, and their durations among others. Follow-up tests were performed to determine whether the viral negative status persists after their recovery. RESULTS: Our data show that patients with persistent viral presence (>16 days) have more severe disease outcomes including extensive lung involvement and requirement of respiratory support. Two patients who died of COVID-19 were virus-positive at the time of their death. Four patients demonstrated virus-positive status on the follow-up tests, and these patient samples were sent to viral culture facility where virus culture could not be established. CONCLUSIONS: These data suggest that viral persistence is the key determining factor of the disease severity. Therapies that may impair the viral clearance may impair the host recovery from COVID-19.

[Effects of Acupuncture Intervention on Levels of T Lymphocyte Subsets in Plasma and Thymus in Stress-induced Anxiety Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on the levels of CD 4+ and CD 8+ lymphocytes in the plasma and thymus in anxiety disorder rats, so as to explore its mechanism underlying favorable regulation of immune function. METHODS: Thirty-four SD rats were randomly divided into control (n = 10) , model (n = 12) and EA (n = 12) groups. The anxiety model was established by using chronic unpredictable emotional stress stimulation (fasting, water-deprivation, shaking, tail-clamping, forced warm- and cool-water swimming, electrical shock stimulation, etc.) for 15 days. EA (15 Hz/ 25 Hz) was applied to "Neiguan" (PC 6) and "Shenmen" (HT 7) for 15 min, once every other day for 15 days. The anxiety-like behavior was measured by elevated plus maze test. Anxiety reduction in the plus-maze is indicated by an increase in the proportion of time spent in the open arms (time in open arms/total time in open or closed arms) , and an increase in the proportion of entries into the open arms (entries into open arms/total entries into open or closed arms). While the contents and expression of CD 4+ and CD 8+ in the plasma and thymus tissues were measured by ELISA and immunohistochemistry, respectively. RESULTS: The values of proportions of open-arm entries (OE%) and the content of plasma CD 4+ lymphocytes were obviously lower in the model group than in the control group (P < 0.05), and were significantly higher in the EA group than in the model group (P < 0.05). Whereas, the content of plasma CD 8+ lymphocytes was obviously higher in the model group than in the control group (P < 0.05) and markedly down-regulated in the EA group after the treatment (P < 0.05). The ratio of CD 4+/CD 8+ was decreased in the model group in comparison with the control group (P = 0.054), and was significantly up-regulated in the EA group after EA stimulation (P < 0.01). Compared with the control group, the expression levels (optical density, OD values) of CD 4+ and CD 8+ lymphocytes in the thymus tissue were obviously decreased in the model group (P < 0.01). After EA, the expression levels of thymus CD 4+ and CD 8+ were remarkably up-regulated in the EA group (P < 0.05). No significant changes were found in proportion of open-arm time (OT%, P > 0.05). CONCLUSION: EA can effectively relieve anxiety disorder in anxiety rats, which may be related to its effects in up-regulating plasma CD 4+ , thymus CD 4+ and CD 8' levels as well as CD 4+/CD 8+ ratio, and down-regulating plasma CD 8+ content.

Acetylation of lysine 9 on histone H3 is associated with increased pro-inflammatory cytokine release in a cigarette smoke-induced rat model through HDAC1 depression.

OBJECTIVE AND DESIGN: Cigarette smoke (CS)-induced inflammation is critical in chronic obstructive pulmonary disease (COPD). However, the role of acetylation at histone 3 lysine 9 (H3K9) in COPD inflammation remains unclear. The present study assessed the effect of acetylation of H3K9 on transcription both in rat lungs and in macrophages. METHODS: Sprague-Dawley rats were exposed to CS for either 6 or 12 weeks and rat lungs were collected. Rat macrophages were subjected to 20 % cigarette smoke extract (CSE) for 48 h. RESULTS: CS increased MCP-1 and IL-8 expressions at both mRNA and protein levels in rat lungs after 6 and 12 weeks; increased TNF-α and MMP9 expressions at both levels were noted only after 12 weeks. CSE increased these genes expression in macrophages after 48 h exposure. Increased abundance of acetylated H3K9 protein in rat lungs and in macrophages were associated with decreased expression of histone deacetylase-1(HDAC1). Chromatin immunoprecipitation demonstrated increased level of acetylated H3K9 on promoter regions of these genes both in vivo and in vitro. Knockdown of HDAC1 increased these genes mRNA expression. CONCLUSIONS: CS increased H3K9 acetylation and subsequently altered the expression of pro-inflammatory mediators and protease genes through HDAC1 depression in CS-induced rat lungs and in macrophages.

[Effect of electro-acupuncture on metabolites in the cerebral cortex of ulcerative colitis rats based on Pi/Wei-brain related theory].

OBJECTIVE: To study the effect of electro-acupuncture (EA) at points along Foot Yangming Channel on metabolite of ulcerative colitis (UC) rats' cerebral cortex and to identify key metabolites by referring to Pi/Wei-brain related theory in Chinese medicine (CM). METHODS: The UC rat model was set up by dextran sulfate sodium (DSS) method. Male SD rats were randomly divided into the model group and the EA group, 13 in each group. Another 13 rats were recruited as the blank control group. Rats in the blank control group and the model group received no EA. EA was performed at Zusanli (ST36), Shangjuxu (ST37), and Tianshu (ST25) for 5 days by using disperse-dense wave. Then all rats were sacrificed. Their recto-colon and the ileocecal junction were pathomorphologically observed by light microscope and transmission electron microscope (TEM). Cerebral cortexes were extracted. Water-soluble and lipid-soluble brain tissue metabolites were respectively extracted for metabolic research using 1H nuclear magnetic resonance (1H-NMR). RESULTS: EA could obviously improve the general condition of UC model rats, decrease the value of DAI, reduce the infiltration of inflammatory cells in the intestinal tract, stabilize structures such as mitochondria, endoplasmic reticulum and so on (P <0.05). 1HNMR analysis showed that in the model group, contents of glutamic acid, cholesterol, very low density lipoproein (VLDL) in the pallium obviously decreased, while alanine and low density lipoprotein (LDL) significantly increased. After EA, levels of lactic acid, glutamic acid, total cholesterol (TC), and VLDL all increased, and levels of alanine and LDL decreased. All indices were approximate to those of the blank control group. CONCLUSION: EA at Foot Yangming channel was found to have some effect on metabolites in the brain tissue of UC model rats, which had specific metabonomic material basis and mechanism based on the Pi/Wei-brain related theory.

[Effect of electroacupuncture on ultrastructural changes of facial nerve in rabbits with facial nerve injury].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on ultrastructure of facial nerve and Schwann cells in facial nerve injury rabbits so as to explore its mechanism underlying improving facial palsy. METHODS: A total of 60 Japanese white rabbits were randomly assigned to normal control (normal, n = 6), sham-operation (sham, n = 18), model (n = 18) and EA (n = 18) groups. The facial nerve injury model was established by clamping the right facial nerve for 5 min by using a pair of forceps. EA (1.5 V, 3 Hz/60 Hz) was applied to "Yifeng" (TE 17)-"Hegu" (LI 4), and "Dicang" (ST4)-"Jiache" (ST6) on the affected side for 30 min, respectively, once daily for 3 weeks. Morphologic changes of the myelin sheath and Schwann cells of the facial nerve were observed by using electron microscope after 1, 2 and 3 weeks' treatment. RESULTS: Compared with the normal control group, the number of the myelin sheaths and the thickness values of the facial nerve after treatment of 1, 2 and 3 weeks in the model group were decreased significantly (P < 0.01, P < 0.05). While in comparison with the model group, the thickness value of the facial nerve 2 weeks after modeling in EA group was increased considerably (P < 0.01). In the model group, there were many vacuoles in the cytoplasm of Schwann cells instead of organells in the facial nerve. In the sham group, the demyelination was milder than that of the model group, and majority of myelin sheaths showed integral structure after 2 and 3 weeks, being similar to the normal group. Compared with the model group, the extent of demyelination was less distinct, with relatively more abundant organells in the facial nerve of the EA group, especially after 1 week of treatment. Among the three time points in the EA group, demyelination was milder in the 1st week not in the other time points. In contrast, along with the continuous EA treatment, the situation became worse after 3 weeks of treatment in the EA group. CONCLUSION: In the acute stage of facial nerve injury, EA intervention can play a positive effect on the repair of the nerve and Schwann cells. However, continuous 3- weeks' EA intervention may worsen the facial nerve injury.

[Effect of electroacupuncture on the expression of corticotropin releasing hormone (CRH) and CRHR 1 mRNA in paraventricular nucleus of hypothalamus in stress-induced anxiety rats].

OBJECTIVE: To investigate the effects of electroacupuncture (EA) on the expression of corticotropin releasing hormone (CRH) and CRHR 1 mRNA in paraventricular nucleus (PVN) of hypothalamus, to explore its mechanism in anti-anxiety. METHODS: Thirty-three male SD rats were randomly divided into control, model and EA groups. Chronic emotional stress anxiety model was established by using chronic unpredictable emotional stress stimulation for 21 days. EA (15/25 Hz, 1-2 mA) was applied to "Baihui" (GV 20) and "Sanyinjiao" (SP 6) for 15 min/d and 21 days. The expression of CRH and CRHR 1 mRNA in hypothalamic PVN was measured by immunohistochemistry and in situ hybridization techniques separately. RESULTS: Compared with control group, the values of open-arms entries (OE%) and open-arms time (OT%) in model group were decreased significantly (P<0.01). In comparison with model group, OE% and OT% in EA group were increased obviously (P<0.05, P<0.01). Compared with control group, the optical density values of CRH immuno-reaction positive products and CRHR 1 mRNA expressed neurons of hypothalamic PVN in model group were increased obviously (P<0.05, P<0.01); while in comparison with model group, those of CRH and CRHR 1 mRNA in EA group were significantly decreased (P<0.05, P<0.01). CONCLUSION: EA can effectively relieve chronic stress stimulation induced anxiety in the rat, which is closely related to its effect in down regulating both CRH and CRHR 1 mRNA expression in PVN of hypothalamus.