Poly(ADP-ribose) polymerase 1 (PARP1) is a multifunctional protein involved in diverse cellular functions, notably DNA damage repair. Pharmacological inhibition of PARP1 has therapeutic benefits for various pathologies. Despite the increased use of PARP inhibitors, challenges persist in achieving PARP1 selectivity and effective blood-brain barrier (BBB) penetration. The development of a PARP1-specific positron emission tomography (PET) radioligand is crucial for understanding disease biology and performing target occupancy studies, which may aid in the development of PARP1-specific inhibitors. In this study, we leverage the recently identified PARP1 inhibitor, AZD9574, to introduce the design and development of its ¹⁸F-isotopologue ([¹⁸F]AZD9574). Our comprehensive approach, encompassing pharmacological, cellular, autoradiographic, and in vivo PET imaging evaluations in non-human primates, demonstrates the capacity of [¹⁸F]AZD9574 to specifically bind to PARP1 and to successfully penetrate the BBB. These findings position [¹⁸F]AZD9574 as a viable molecular imaging tool, poised to facilitate the exploration of pathophysiological changes in PARP1 tissue abundance across various diseases.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

Apical microsurgery is accurate and minimally invasive, produces few complications, and has a success rate of more than 90%. However, due to the lack of awareness and understanding of apical microsurgery by dental general practitioners and even endodontists, many clinical problems remain to be overcome. The consensus has gathered well-known domestic experts to hold a series of special discussions and reached the consensus. This document specifies the indications, contraindications, preoperative preparations, operational procedures, complication prevention measures, and efficacy evaluation of apical microsurgery and is applicable to dentists who perform apical microsurgery after systematic training.
Microsurgery/standards* ; Humans ; Apicoectomy ; Contraindications, Procedure ; Tooth Apex/diagnostic imaging* ; Postoperative Complications/prevention & control* ; Consensus ; Treatment Outcome

OBJECTIVE To investigate the mechanism of action of Quzhuo Tongbi Granules(QZTB)in reducing uric acid and anti-inflammation in mice with hyperuricemia(HUA).METHODS The components of QZTB were identified by ultra-performance liquid chromatography-mass spectrometry(UPLC-MS).Sixty-four C57BL/6 mice were randomly divided into control group,model group,benzbromarone group,QZTB low-dose group,QZTB medium-dose group,QZTB high-dose group,MCC950 group,and MCC950+QZTB medium-dose group,with 8 mice in each group.Adenine(100 mg·kg-1)and potassium oxonate(500 mg·kg-1)were used to establish the HUA mouse model.Except for the control group,all other groups underwent 2 weeks of modeling followed by 4 weeks of treatment.After 2 weeks of modeling,blood was collected from the orbital venous plexus to measure serum uric acid(SUA)levels as the criterion for successful model induction.Mice were sacrificed after 4 weeks of continuous treatment for sample collection.An automatic biochemical analyzer was used to measure serum levels of SUA,urea nitrogen(BUN),and creatinine(Cr).Enzyme-linked immunosorbent assay(ELISA)was employed to detect serum levels of interleukin-1β(IL-1β),interleukin-6(IL-6),interleukin-18(IL-18),and tumor necrosis factor-α(TNF-α).The qPCR was used to assess mRNA expression of urate transporter 1(URAT1),ATP-binding cassette transporter G2(ABCG2),glucose transporter 9(GLUT9),and PDZ domain-contai-ning protein kinase 1(PDZK1)in kidney tissue.Western blot was performed to measure protein expression of urate transporters(URAT1,ABCG2,GLUT9,PDZK1),nuclear transcription factor κB(NF-κB)total protein,phosphorylated NF-κB(p-NF-κB),Nod-like receptor protein 3(NLRP3),Cleaved Caspase-1 and Pro-Caspase-1 proteins in kidney tissue.Immunohistochemistry was used to determine the expression levels of urate transporters(URAT1,ABCG2,PDZK1,GLUT9)in kidney tissue.RESULTS A to-tal of 9 representative active ingredients were identified in QZTB.Two weeks after modeling,SUA in the model group was significantly increased compared with that in the control group(P<0.000 1).Four weeks after administration,serum SUA,BUN and Cr in the model group were significantly increased(P<0.000 1),IL-1β,IL-6,IL-18 and TNF-α levels were increased(P<0.01,P<0.001),the expression of ABCG2 and PDZK1 proteins in renal tissue was decreased(P<0.01,P<0.001,P<0.000 1),and the ex-pression of URAT1,GLUT9,NLRP3,p-NF-κB p65/NF-κB p65 and Cleaved Caspase-1/Pro-Caspase-1 proteins was significantly increased(P<0.01,P<0.001,P<0.000 1).Compared with the model group,SUA,BUN and Cr in the benzbromarone group and the low-,medium-and high-dose QZTB intervention groups were reduced to varying degrees(P<0.001,P<0.000 1).QZTB could ef-fectively reduce the levels of serum inflammatory factors IL-1β,IL-6,IL-18 and TNF-α(P<0.05,P<0.01),increase the expres-sion of ABCG2 and PDZK1 proteins in renal tissue(P<0.05,P<0.01,P<0.000 1),and downregulate the expression of URAT1,GLUT9,NLRP3,p-NF-κB p65/NF-κB p65 and Cleaved Caspase-1/Pro-Caspase-1 proteins(P<0.05,P<0.01,P<0.001,P<0.000 1).Compared with the model group,the MCC950 group downregulated the protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and Cleaved Caspase-1/Pro-Caspase-1(P<0.01).Compared with the MCC950 group or the QZTB group,the MCC950+QZTB group downregulated the protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and Cleaved Caspase-1/Pro-Caspase-1(P<0.05,P<0.01,P<0.000 1).CONCLUSION QZTB can promote uric acid excretion by inhibiting the NF-κB/NLRP3 signaling pathway,thereby improving the symptoms of HUA.

OBJECTIVE To investigate the mechanism of action of Quzhuo Tongbi Granules(QZTB)in reducing uric acid and anti-inflammation in mice with hyperuricemia(HUA).METHODS The components of QZTB were identified by ultra-performance liquid chromatography-mass spectrometry(UPLC-MS).Sixty-four C57BL/6 mice were randomly divided into control group,model group,benzbromarone group,QZTB low-dose group,QZTB medium-dose group,QZTB high-dose group,MCC950 group,and MCC950+QZTB medium-dose group,with 8 mice in each group.Adenine(100 mg·kg-1)and potassium oxonate(500 mg·kg-1)were used to establish the HUA mouse model.Except for the control group,all other groups underwent 2 weeks of modeling followed by 4 weeks of treatment.After 2 weeks of modeling,blood was collected from the orbital venous plexus to measure serum uric acid(SUA)levels as the criterion for successful model induction.Mice were sacrificed after 4 weeks of continuous treatment for sample collection.An automatic biochemical analyzer was used to measure serum levels of SUA,urea nitrogen(BUN),and creatinine(Cr).Enzyme-linked immunosorbent assay(ELISA)was employed to detect serum levels of interleukin-1β(IL-1β),interleukin-6(IL-6),interleukin-18(IL-18),and tumor necrosis factor-α(TNF-α).The qPCR was used to assess mRNA expression of urate transporter 1(URAT1),ATP-binding cassette transporter G2(ABCG2),glucose transporter 9(GLUT9),and PDZ domain-contai-ning protein kinase 1(PDZK1)in kidney tissue.Western blot was performed to measure protein expression of urate transporters(URAT1,ABCG2,GLUT9,PDZK1),nuclear transcription factor κB(NF-κB)total protein,phosphorylated NF-κB(p-NF-κB),Nod-like receptor protein 3(NLRP3),Cleaved Caspase-1 and Pro-Caspase-1 proteins in kidney tissue.Immunohistochemistry was used to determine the expression levels of urate transporters(URAT1,ABCG2,PDZK1,GLUT9)in kidney tissue.RESULTS A to-tal of 9 representative active ingredients were identified in QZTB.Two weeks after modeling,SUA in the model group was significantly increased compared with that in the control group(P<0.000 1).Four weeks after administration,serum SUA,BUN and Cr in the model group were significantly increased(P<0.000 1),IL-1β,IL-6,IL-18 and TNF-α levels were increased(P<0.01,P<0.001),the expression of ABCG2 and PDZK1 proteins in renal tissue was decreased(P<0.01,P<0.001,P<0.000 1),and the ex-pression of URAT1,GLUT9,NLRP3,p-NF-κB p65/NF-κB p65 and Cleaved Caspase-1/Pro-Caspase-1 proteins was significantly increased(P<0.01,P<0.001,P<0.000 1).Compared with the model group,SUA,BUN and Cr in the benzbromarone group and the low-,medium-and high-dose QZTB intervention groups were reduced to varying degrees(P<0.001,P<0.000 1).QZTB could ef-fectively reduce the levels of serum inflammatory factors IL-1β,IL-6,IL-18 and TNF-α(P<0.05,P<0.01),increase the expres-sion of ABCG2 and PDZK1 proteins in renal tissue(P<0.05,P<0.01,P<0.000 1),and downregulate the expression of URAT1,GLUT9,NLRP3,p-NF-κB p65/NF-κB p65 and Cleaved Caspase-1/Pro-Caspase-1 proteins(P<0.05,P<0.01,P<0.001,P<0.000 1).Compared with the model group,the MCC950 group downregulated the protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and Cleaved Caspase-1/Pro-Caspase-1(P<0.01).Compared with the MCC950 group or the QZTB group,the MCC950+QZTB group downregulated the protein expressions of NLRP3,p-NF-κB p65/NF-κB p65,and Cleaved Caspase-1/Pro-Caspase-1(P<0.05,P<0.01,P<0.000 1).CONCLUSION QZTB can promote uric acid excretion by inhibiting the NF-κB/NLRP3 signaling pathway,thereby improving the symptoms of HUA.

Objective To explore the application value of telmisartan combined with calcium dobesilate in patients with non-dipper hypertension complicated with type 2 diabetes mellitus(T2DM).Methods A total of 260 patients with non-dipper hypertension complicated with T2DM in the endocrinology department of our hospital were selected in this study from January 2021 to December 2022.All the patients were randomly divided into telmisartan group(Tel,n=110)and telmisartan+calcium dobesilate group(Tel+Cal-dob,n=150).The blood pressure level,blood pressure rhythm changes,brachial flow mediated dilatation(FMD),carotid radial pulse wave velocity(crPWV),vasomotor factors[nitric oxide(NO),endothelin-1(ET-1),vascular endothelial growth factor(VEGF)]and the incidence of adverse reactions were compared between the two groups.Results There was no significant difference in general data and biochemical indexes between the two groups(P>0.05).After 3,6 and 12 months of treatment,the FMD and NO were higher,while the dSBP,dDBP,24 hSBP,24 hDBP,nSBP,nDBP,crPWV,ET-1 and VEGF were lower than before treatment in both groups(P<0.05).After 3,6 and 12 months of treatment,the FMD and NO were higher,while dSBP,dDBP,24 hSBP,24 hDBP,nSBP,nDBP,crPWV,ET-1 and VEGF were lower in Tel+Cal-dob group than in Tel group(P<0.05).After 3,6 and 12 months of treatment,the conversion rates of dipper blood pressure were higher in Tel+Cal-dob groupthan in Tel group(P<0.05).There was no significant difference in the incidence of adverse effects between the two groups(P>0.05).Conclusion Telmisartan combined with calcium dobesilate is effective in the treatment of patients with non-dipper hypertension complicated with T2DM.

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).