Intermediate aminophenol enables hectogram-scale synthesis of highly bright red carbon quantum dots under ambient conditions.

Carbon quantum dots (C-dots) have developed into potential nanomaterials for lighting, catalysis and bioimaging because of their excellent optical properties and good biocompatibility. However, it is still a challenge to produce efficient red emitting carbon quantum dots (R-C-dots) due to their obscure formation mechanism. This work offered a method to reveal the formation process from the precursor o-phenylenediamine (o-PDA) to R-C-dots. Different from traditional hydrothermal reactions, R-C-dots were synthesized at relatively low temperature and ambient pressure. The pre-oxidation intermediate aminophenol played an important role in the synthesis of R-C-dots, which further cross-linked and polymerized with o-PDA in an acid environment to form R-C-dots. The obtained R-C-dots had a photoluminescence quantum yield of up to 33.26% and excellent two-photon fluorescence properties. A white light-emitting diode (WLED) based on R-C-dots as the red phosphor exhibited standard white light CIE color coordinates of (0.33, 0.33) with a correlated color temperature of 5342 K and a high color rendering index (CRI) of 94.5. The obtained rendering index is the highest value among WLEDs with color coordinates of (0.33, 0.33) based on C-dots. This work provides a new perspective for the controllable large-scale synthesis of red C-dots.

Vacuum-Boosting Precise Synthetic Control of Highly Bright Solid-State Carbon Quantum Dots Enables Efficient Light Emitting Diodes.

Carbon quantum dots (C-dots) have emerged as efficient fluorescent materials for solid-state lighting devices. However, it is still a challenge to obtain highly bright solid-state C-dots because of the aggregation caused quenching. Compared to the encapsulation of as-prepared C-dots in matrices, one-step preparation of C-dots/matrix complex is a good method to obtain highly bright solid-state C-dots, which is still quite limited. Here, an efficient and controllable vacuum-boosting gradient heating approach is demonstrated for in situ synthesis of a stable and efficient C-dots/matrix complex. The addition of boric acid strongly bonded with urea, promoting the selectivity of the reaction between citric acid and urea. Benefiting from the high reaction selectivity and spatial-confinement growth of C-dots in porous matrices, in situ synthesize C-dots bonded can synthesized dominantly with a crosslinked octa-cyclic compound, biuret and cyanuric acid (triuret). The obtained C-dots/matrix complex exhibited bright green emission with a quantum yield as high as 90% and excellent thermal and photo stability. As a proof-of-concept, the as-prepared C-dots are used for the fabrication of white light-emitting diodes (LEDs) with a color rendering index of 84 and luminous efficiency of 88.14 lm W-1, showing great potential for applications in LEDs.

Retraction: Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites.

[This retracts the article DOI: 10.1039/C9RA10593J.].

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

Impact of nonalcoholic fatty liver disease status change on antiviral efficacy of nucleos(t)ide analogues in HBeAg-positive chronic hepatitis B.

Data on the dynamic changes in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD) during antiviral therapy are scarce. We aimed to investigate the evolution of NAFLD status change in CHB patients treated with nucleos(t)ide analogues (NAs) and its influence on therapeutic outcomes. This retrospective study included 164 HBeAg-positive CHB patients from a randomized controlled trial who were treated with NAs for 104 weeks and underwent paired liver biopsies. Histological evaluation was performed at baseline and Week 104. The patients were divided into four groups according to NAFLD status changes. From baseline to Week 104, the overall percentage of CHB patients with concurrent NAFLD increased from 17.1% to 26.2% (p = 0.044). Among them, 7 of 28 patients (25.0%) with NAFLD at baseline showed NAFLD remission at week 104, while 22 of 136 patients (16.2%) without NAFLD at baseline developed new-onset NAFLD. In subgroup analyses, the new-onset and sustained NAFLD groups showed significantly lower rates of biochemical response at week 104 as compared to the sustained non-NAFLD group (77.3% and 57.1% vs. 93.9%, respectively; all p < 0.05), as well as fibrosis improvement (31.8% and 42.9% vs. 69.3%, respectively; all p < 0.05). NAFLD status changes did not influence the virological response, HBeAg seroconversion, and necroinflammation improvement (all p > 0.05). In HBeAg-positive CHB patients receiving NAs therapy, new-onset and sustained NAFLD may counteract the benefits of antiviral therapy, reducing the rate of biochemical response and fibrosis improvement.

Anti-TLR4 IgG2 Prevents Acetaminophen-induced Acute Liver Injury through the Toll-like Receptor 4/MAPKs Signaling Pathway in Mice.

BACKGROUND AND OBJECTIVE: Acetaminophen (APAP) is a widely used antipyretic and analgesic. If taken in excess, it can cause severe drug-induced acute liver injury. The purpose of this study was to investigate the effects of anti-TLR4 IgG2 on APAP-induced liver injury and its underlying mechanisms. METHODS: We injected APAP into the abdominal cavity of mice to establish a liver injury model. Mice were divided into the control group, APAP group, and APAP + anti-TLR4 IgG2 group. In order to verify the implication of the toll-like receptor4 and mitogen-activated protein kinases activation (TLR4/MAPKs) signaling pathway, mice were intraperitoneally injected with a TLR4 / MAPKs inhibitor anti-TLR4 IgG2. We evaluated the effects of TLR4 IgG2 on the antioxidant, anti-apoptotic, anti-inflammatory, and liver histopathology of APAP mice. In addition, the expression of the TLR4 / MAPKs signaling pathway was detected by Western blot. RESULTS: Our study showed that APAP mouse models were successfully established; however, pretreatment with anti-TLR4 IgG2 alleviated APAP-induced hepatic injury, as evidenced by the 24-h survival rate. Meanwhile, anti-TLR4 IgG2 prevented the elevation of serum biochemical parameters and lipid profile. Furthermore, compared with the APAP group, hepatic antioxidants, including 3- Nitrotyrosine, high mobility group protein B1, superoxide dismutase, catalase, and glutathione, were increased in APAP + anti-TLR4 IgG2 group. In contrast, a significant decrease was observed in the levels of the malondialdehyde, which is a lipid peroxidation product. Moreover, the western blotting analysis showed that anti-TLR4 IgG2 treatment inhibited the activation of the apoptotic pathway by increasing Bcl-2 and decreasing Bax, P53, and cleaving caspase-3 / caspase-3 protein expression. These results were further validated by TUNEL staining and immunohistochemical. Histopathological observation also revealed that pretreat-ment with anti-TLR4 IgG2 could significantly reverse hepatocyte inflammatory infiltration, congestion, and necrosis in liver tissues by APAP. Importantly, anti-TLR4 IgG2 effectively alleviated APAP-induced liver injury by inhibiting tolllike receptor4 and mitogen-activated protein kinases activation signaling pathways (TLR4/MAPKs). CONCLUSION: The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of anti-TLR4 IgG2 in APAP-induced hepatotoxicity may be due to its antioxidation, anti-apoptosis, and anti-inflammation effects through inhibition of the TLR4/MAPKs signaling axis.

Icariin Treatment Rescues Diabetes Induced Bone Loss via Scavenging ROS and Activating Primary Cilia/Gli2/Osteocalcin Signaling Pathway.

Diabetes-associated bone complications lead to fragile bone mechanical strength and osteoporosis, aggravating the disease burden of patients. Advanced evidence shows that chronic hyperglycemia and metabolic intermediates, such as inflammatory factor, reactive oxygen species (ROS), and advanced glycation end products (AGEs), are regarded as dominant hazardous factors of bone complications, whereas the pathophysiological mechanisms are complex and controversial. By establishing a diabetic Sprague-Dawley (SD) rat model and diabetic bone loss cell model in vitro, we confirmed that diabetes impaired primary cilia and led to bone loss, while adding Icariin (ICA) could relieve the inhibitions. Mechanistically, ICA could scavenge ROS to maintain the mitochondrial and primary cilia homeostasis of osteoblasts. Intact primary cilia acted as anchoring and modifying sites of Gli2, thereby activating the primary cilia/Gli2/osteocalcin signaling pathway to promote osteoblast differentiation. All results suggest that ICA has potential as a therapeutic drug targeting bone loss induced by diabetes.

Expression of Concern: Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites.

Expression of Concern for 'Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites' by Maorong Wang et al., RSC Adv., 2020, 10, 8044-8053, https://doi.org/10.1039/C9RA10593J.

Efficacy and safety of a nanoparticle therapeutic vaccine in patients with chronic hepatitis B: A randomized clinical trial.

BACKGROUND AND AIM: HBV DNA can be reduced using antiviral drugs in patients with chronic hepatitis B (CHB); however, the rate of HBeAg seroconversion remains low. A clinical trial was conducted to assess the efficacy and safety of a de novo designed liposome-based nanoparticle lipopeptide vaccine, εPA-44, for CHB. APPROACH AND RESULTS: A two-stage phase 2 trial, which included a 76-week, randomized, double-blind, placebo-controlled trial (stage 1) and a 68-week open-label extension (stage 2), was conducted in 15 centers across China (Clinicaltrials.gov No. NCT00869778). In stage 1, 360 human leukocyte antigen A2 (HLA-A2)-positive and HBeAg-positive patients were randomly and equally distributed to receive six subcutaneous injections of 600 µg or 900 µg εPA-44 or placebo at week 0, 4, 8, 12, 20, and 28. In stage 2, 183 patients received extended 900 µg εPA-44, and 26 patients were observed for relapse without further treatment. The primary endpoint was the percentage of patients with HBeAg seroconversion at week 76. At week 76, patients receiving 900 µg εPA-44 achieved significantly higher HBeAg seroconversion rate (38.8%) versus placebo (20.2%) (95% CI, 6.9-29.6%; p = 0.002). With a combined endpoint of HBeAg seroconversion, alanine aminotransferase normalization and HBV DNA < 2,000 IU/mL, both 900 µg (18.1%) and 600 µg (14.3%), resulted in significantly higher rate versus placebo (5.0%) (p = 0.002 and p = 0.02, respectively) at week 76. In stage 2, none (0 of 20) of 900 µg εPA-44-treated patients experienced serologic relapse. The safety profile of εPA-44 was comparable to that of placebo. CONCLUSIONS: Among HLA-A2-positive patients with progressive CHB, a finite duration of 900 µg εPA-44 monotherapy resulted in significantly higher HBeAg seroconversion rate than placebo and sustained off-treatment effect. A phase 3 trial is ongoing (ChiCTR2100043708).

Nickel-vanadium layered double hydroxide nanosheets as the saturable absorber for a passively Q-switched 2 µm solid-state laser.

Nickel-vanadium (NiV)-layered double hydroxide (LDH) was fabricated into a novel saturable absorber (SA) by the liquid phase exfoliation method and utilized as the laser modulator for the first time, to our best knowledge. We investigated a passive Q-switched Tm:YAG ceramic laser at 2 µm with the NiV-LDH SA. Under an absorbed pump power of 7.2 W, the shortest pulse width of 398 ns was obtained with an average output power of 263 mW and a pulse repetition frequency of 101.8 kHz, corresponding to a single pulse energy at 2.30 µJ. The results indicate that the NiV-LDH SA has great research potential in the field of laser modulation.

New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection: Increase of entecavir dosage.

Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 106 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.

Near-infrared heavy-metal-free SnSe/ZnSe quantum dots for efficient photoelectrochemical hydrogen generation.

Solar-driven photoelectrochemical (PEC) hydrogen production is one of the most effective strategies for solar-to-hydrogen energy conversion. Among various types of semiconductors used for PEC anodes, colloidal quantum dots (QDs) have been widely used as new and promising absorbers for PEC and other optoelectronic devices. However, currently, most efficient optoelectronic devices contain toxic Pb/Cd elements or non-earth-abundant elements (In/Ag). It is still a challenge to produce Pb/Cd-free QDs without using any toxic and non-earth-abundant elements. Here, we synthesized SnSe QDs via a diffusion-controlled hot injection approach and further stabilized the as-prepared SnSe QDs via a cation exchange reaction. The as-synthesized Zn-stabilized SnSe QDs (SnSe/ZnSe) have an orthorhombic crystal structure with indirect bandgaps ranging from 1 to 1.37 eV. Zn stabilization can significantly decrease the number of QD surface metallic Sn bonds, thereby decreasing the number of recombination centers of defects/traps. As a proof-of-concept, SnSe/ZnSe QDs are used as light absorbers for PEC hydrogen production, leading to a saturated photocurrent density of 7 mA cm-2, which is comparable to best values reported for PEC devices based on toxic-metal-free QDs. Our results indicate that Zn-stabilized SnSe QDs have great potential for use in emerging optoelectronic devices.

Bioactive hyaluronic acid fragments inhibit lipopolysaccharide-induced inflammatory responses via the Toll-like receptor 4 signaling pathway.

The high- and the low-molecular weight hyaluronic acids (HMW-HA and LMW-HA, respectively) showed different biological activities in inflammation. However, the role of LMW-HA in inflammatory response is controversial. In this study, we aimed to investigate the effect of bioactive hyaluronan (B-HA) on lipopolysaccharide (LPS)-induced inflammatory responses in human macrophages and mice. B-HA was produced from HA treated with glycosylated recombinant human hyaluronidase PH20. Human THP-1 cells were induced to differentiate into macrophages. THP-1-derived macrophages were treated with B-HA, LPS, or B-HA + LPS. The mRNA expression and the production of inflammatory cytokines were determined using quantitative real-time PCR and enzyme-linked immunosorbent assay. The phosphorylation levels of proteins in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and IRF-3 signaling pathways were measured using Western blot. The in vivo efficacy of B-HA was assessed in a mouse model of LPS-induced inflammation. Results showed that B-HA inhibited the expression of TNF-α, IL-6, IL-1, and IFN-ß, and enhanced the expression of the antiinflammatory cytokine IL-10 in LPS-induced inflammatory responses in THP-1-derived macrophages and in vivo. B-HA significantly suppressed the phosphorylation of the TLR4 signaling pathway proteins p65, IKKα/ß, IκBα, JNK1/2, ERK1/2, p38, and IRF-3. In conclusion, our results demonstrated that the B-HA attenuated the LPS-stimulated inflammatory response by inhibiting the activation of the TLR4 signaling pathway. B-HA could be a potential anti-inflammatory drug in the treatment of inflammatory disease.

ABO blood group influence COVID-19 infection: a meta-analysis.

INTRODUCTION: Previous studies have linked the relationship between ABO blood group and COVID-19 infection. However, existing evidence is preliminary and controversial. This meta-analysis sought to identify studies that describe COVID-19 and ABO blood group. METHODOLOGY: A literature search was conducted from PubMed, Web of Science, MedRxiv, BioRxiv and Google Scholar databases. Members of cases and controls were extracted from collected studies. Pooled Odds ratio (OR) and 95% confidence interval (95%CI) were calculated and interpreted from extracted data. Publication bias and sensitivity analysis were also applied to confirm our discovery. RESULTS: Total 13,600 patients and 3,445,047 controls were included in the study. Compared to other ABO blood group, blood group O was associated with a lower risk of COVID-19 infection (OR = 0.76, 95%CI 0.66-0.84), while blood group A and AB was associated with a higher risk (OR = 1.25, 95%CI 1.10-1.41; OR = 1.13, 95%CI 1.04-1.23, respectively). In the subgroup analysis, the relationship between blood group A, O and COVID-19 infection remained stable among Chinese, European and Eastern Mediterranean populations. In American population, blood groups B was linked with increased risk of COVID-19 infection (OR = 1.21, 95%CI 1.09-1.35). CONCLUSIONS: Our data suggested that individuals with blood types A and AB are more susceptible to COVID-19, while people with blood type O are less susceptible to infection. More research is needed to clarify the precise role of the ABO blood group in COVID-19 infection to address the global question.

Synergistic Effect of Plasmonic Gold Nanoparticles Decorated Carbon Nanotubes in Quantum Dots/TiO2 for Optoelectronic Devices.

Here, a facile approach to enhance the performance of solar-driven photoelectrochemical (PEC) water splitting is described by means of the synergistic effects of a hybrid network of plasmonic Au nanoparticles (NPs) decorated on multiwalled carbon nanotubes (CNTs). The device based on TiO2-Au:CNTs hybrid network sensitized with colloidal CdSe/(CdSe x S1- x )5/(CdS)1 core/alloyed shell quantum dots (QDs) yields a saturated photocurrent density of 16.10 ± 0.10 mA cm-2 [at 1.0 V vs reversible hydrogen electrode (RHE)] under 1 sun illumination (AM 1.5G, 100 mW cm-2), which is ≈26% higher than the control device. The in-depth mechanism behind this significant improvement is revealed through a combined experimental and theoretical analysis for QDs/TiO2-Au:CNTs hybrid network and demonstrates the multifaceted impact of plasmonic Au NPs and CNTs: i) hot-electron injection from Au NPs into CNTs and TiO2; ii) near-field enhancement of the QDs absorption and carrier generation/separation processes by the plasmonic Au NPs; iii) enhanced photoinjected electron transport due to the highly directional pathways offered by CNTs. These results provide fundamental insights on the properties of QDs/TiO2-Au:CNTs hybrid network, and highlights the possibility to improve the performance of other solar technologies.

A practical base mediated synthesis of 1,2,4-triazoles enabled by a deamination annulation strategy.

A rapid and efficient base mediated synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed using the annulation of nitriles with hydrazines, which can be expanded to a wide range of triazoles in good to excellent yields. Ammonia gas is liberated during the reaction, and halo and hetero functional groups as well as free hydroxyl and amino groups are tolerated in this transformation. A variety of alkyl and aryl-substituted nitriles can be functionalized with aromatic and aliphatic hydrazines employing this procedure. This finding provides a practical and useful strategy for the synthesis of various 15N-labeled 1,2,4-triazole derivatives, and two types of mGlu5 receptor pharmaceuticals can be easily assembled in a one-pot manner.

Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis.

Background and Aims: Emitasvir is a new type of hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor, and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance. We conducted this phase 3 trial to further verify the efficacy and safety. Methods: We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate (100 mg) combined with sofosbuvir (400 mg) once daily in non-cirrhotic patients with genotype 1 HCV infection. The primary endpoint was a sustained virological response at 12 weeks (SVR12) after the end of treatment. Results: Of the 362 patients enrolled in the trial, 39.8% were male, 99.2% had HCV genotype 1b, 0.8% had genotype 1a and 79.8% were treatment-naïve. The average age was 47.2 years. All patients completed the treatment and follow-up. All 3 patients with genotype 1a achieved SVR. Two genotype 1b treatment-naïve patients experienced virologic relapse. The rate of SVR12 was 99.7% (358/359), and SVR24 was 99.4% (357/359) in genotype 1b. Overall, 36.2% had resistance-associated substitutions (RASs) in NS5A and 98.3% had RASs in NS5B at baseline. The RASs at baseline had no effect on the rates of response. Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir. Most adverse events did not require therapy. Conclusions: The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis, who had not been treated or who had been treated with interferon-based regimen previously.

Human monoclonal anti­TLR4 antibody negatively regulates lipopolysaccharide­induced inflammatory responses in mouse macrophages.

Previous studies have revealed that activation of the Toll­like receptor 4 (TLR4)­mediated proinflammatory signaling pathway plays an important role in acute inflammation, sepsis and chronic inflammatory disorders. Moreover, TLR4 significantly contributes to lipopolysaccharide (LPS)­induced immune response. Thus, modulation of the TLR4 pathway is an important strategy to specifically target these pathologies. The aim of the present study was to develop a complete human anti­TLR4 IgG2 antibody by screening human TLR4 Fab from a phage­display library and integrating it with constant regions of the heavy chain of human IgG2 via antibody engineering. ELISA, a BLItz system and fluorescence­activated cell sorting were used to assess its affinity. Furthermore, mouse­derived peritoneal macrophages were treated with human anti­TLR4 IgG2 and induced with LPS in vitro. Reverse transcription­quantitative PCR and western blotting were used to determine mRNA expression levels of cytokines and phosphorylation levels of signaling pathways, respectively. It was found that human anti­TLR4 IgG2 bound to TLR4 with a high affinity of 8.713x10­10 M, and that preincubation with anti­TLR4 IgG2 inhibited the LPS­induced production of tumor necrosis factor­α, interferon­ß and interleukin­6 mRNA expression levels in mouse peritoneal macrophages. It was also demonstrated that human anti­TLR4 IgG2 inhibited LPS­induced TLR4 signaling by reducing the phosphorylation of the NF­κB, mitogen­activated protein kinase and interferon regulatory factor 3 signaling pathways. In addition, human anti­TLR4 IgG2 protected mice from LPS challenge with a survival rate of 40% and also significantly increased the survival time in the cecal ligation and puncture model. Therefore, it was speculated that human anti­TLR4 IgG2 plays a protective role against sepsis­associated injury and is potentially applicable for the treatment of infection­associated immune dysfunction.

THERAPEUTIC EFFECTS OF COMBINATION REGIMENS INCLUDING METHIMAZOLE ON GRAVES HYPERTHYROIDISM: A NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS.

Objective: To analyze the effects of methimazole (MMI)-containing combination regimens on the thyroid status and relapse rates in patients with Graves hyperthyroidism (GH) using a network meta-analysis to provide guidance for clinical application. Methods: We conducted a literature review, which identified 21 trials for inclusion. The major outcomes were serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. The secondary outcome was relapse rate. A network meta-analysis was used to compare multiple regimens to identify the most advantageous regimen. Results: The types of combined drugs included anti-oxidant complexes, selenium, vitamin D3, cholestyramine, risedronate, iodine, potassium bromide, immunosuppressants, and ß-adrenergic antagonists. Regarding the FT3 results, the rank probability of the best result showed that potassium bromide (0.897) and vitamin D3 (0.833) had relative advantages in reducing FT3 at the 1-month time point. According to the time trend analysis, compared with the control treatment, cholestyramine and iodine showed advantages in reducing FT3 during the early stage (0 to 3 months). The immunosuppressants showed advantages in reducing FT3 during the late stage (>9 months) but not the early stage. Regarding the FT4 results, potassium bromide had the highest P-score (.965) at the 1-month time point. Iodine and cholestyramine had advantages in reducing FT4 during the early stage. The immunosuppressants had advantages during both the early and late stages. Conclusion: MMI combined with cholestyramine or iodine was shown to regulate serum FT3 and FT4 during the early stage of GH. MMI combined with immunosuppressants had a long-term advantage in FT3/FT4 regulation and reduced the relapse rate. Abbreviations: ATD = antithyroid drug; CI = confidence interval; FT3 = free triiodothyronine; FT4 = free thyroxine; GH = Graves hyperthyroidism; MMI = methimazole; OR = odds ratio; RCT = randomized controlled trial; SMD = standard mean difference; TCM = traditional Chinese medicine.

Combining Hepatitis B Virus RNA and Hepatitis B Core-Related Antigen: Guidance for Safely Stopping Nucleos(t)ide Analogues in Hepatitis B e Antigen-Positive Patients With Chronic Hepatitis B.

BACKGROUND: Safe nucleos(t)ide analogue discontinuation in chronic hepatitis B (CHB) is an unmet need. We aimed to investigate whether combining hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) could perform satisfactorily in predicting off-treatment outcomes. METHODS: The evaluation cohort included 127 hepatitis B e antigen (HBeAg)-positive patients from a multicenter prospective trial who stopped telbivudine-based therapy after achieving HBeAg seroconversion and HBV DNA < 50 IU/mL for > 48 weeks. As validation, 59 patients treated with entecavir or tenofovir before discontinuation were analyzed. RESULTS: At the end of treatment (EOT), HBV RNA and HBcrAg were significant independent predictors of the clinical relapse risk. In the evaluation cohort, no clinical relapse occurred among patients with negative HBV RNA and HBcrAg < 4 log10 U/mL at EOT (low-risk group), whereas 46.8% patients with positive HBV RNA and HBcrAg ≥ 4 log10 U/mL (high-risk group) experienced clinical relapse during 4-year posttreatment follow-up (P < .001); the corresponding incidences in the validation cohort were 0% and 69.4% (P < .001), respectively. More patients in the low-risk group achieved HBsAg loss than the other patients after treatment cessation (16.1% vs 1.3%, P = .002). CONCLUSIONS: Combining HBV RNA and HBcrAg performed satisfactorily in predicting clinical relapse and HBsAg loss after treatment cessation in HBeAg-positive patients with CHB.The combination of hepatitis B virus RNA and hepatitis B core-related antigen performed satisfactorily in predicting clinical relapse and hepatitis B surface antigen loss after stopping nucleos(t)ide analogue treatment among noncirrhotic hepatitis B e antigen-positive patients with chronic hepatitis B and could be used to guide safe discontinuation.