Porous Poly(ionic Liquid) Membrane with Metal Nanoparticle Gradient: A Smart Actuator for Visualizing Chemical Reactions.

Poly(ionic liquid) (PIL)-based porous membranes are extensively investigated as soft polymer actuators. While PILs have shown significant advancements in membrane fabrication and stabilization of metal nanoparticles (MNPs), research on integrating MNPs into porous membranes to achieve actuation behavior under multiple stimuli is limited. Herein, this work presents a new paradigm for designing a porous PIL-polyacrylic acid (PAA) membrane with a distinct MNP gradient via a top-bottom diffusion approach involving a metal salt precursor solution and NaBH4 as a reducing agent. The strong binding sites provided by PILs, combined with the gradient distribution of -COO- groups across the membrane cross-section, play a significant role in controlling the MNPs' gradient distribution. Interestingly, the MNPs within the membrane display excellent catalytic activity in exothermic reactions such as H2O2 decomposition, dissipating uneven heat that quickly permeates the membrane network. This induces asymmetrical swelling of polymer chains, resulting in rapid membrane bending. Furthermore, such MNP-loaded membrane could serve as a portable test paper for visually monitoring H2O2. This advancement paves the way for the development of intricate smart actuation materials and expands their practical applications in various real-life scenarios.

Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study.

BACKGROUND: While several traditional observational studies have suggested associations between gut microbiota and asthma, these studies are limited by factors such as participant selection bias, confounders, and reverse causality. Therefore, the causal relationship between gut microbiota and asthma remains uncertain. METHODS: We performed two-sample bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota and asthma as well as its phenotypes. We also conducted MR analysis to evaluate the causal effect of gut metabolites on asthma. Genetic variants for gut microbiota were obtained from the MiBioGen consortium, GWAS summary statistics for metabolites from the TwinsUK study and KORA study, and GWAS summary statistics for asthma from the FinnGen consortium. The causal associations between gut microbiota, gut metabolites and asthma were examined using inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted model and further validated by MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis. RESULTS: We identified nine gut microbes whose genetically predicted relative abundance causally impacted asthma risk. After FDR correction, significant causal relationships were observed for two of these microbes, namely the class Bacilli (OR = 0.84, 95%CI = 0.76-0.94, p = 1.98 × 10-3) and the order Lactobacillales (OR = 0.83, 95%CI = 0.74-0.94, p = 1.92 × 10-3). Additionally, in a reverse MR analysis, we observed a causal effect of genetically predicted asthma risk on the abundance of nine gut microbes, but these associations were no longer significant after FDR correction. No significant causal effect of gut metabolites was found on asthma. CONCLUSIONS: Our study provides insights into the development mechanism of microbiota-mediated asthma, as well as into the prevention and treatment of asthma through targeting specific gut microbiota.

The involvement of Neuregulin-1 in the process of facial nerve injury repair through the utilization of dental pulp stem cells.

BACKGROUND: Facial nerve injury often results in poor prognosis due to the challenging process of nerve regeneration. Neuregulin-1, a human calmodulin, is under investigation in this study for its impact on the reparative capabilities of Dental Pulp Stem Cells (DPSCs) in facial nerve injury. METHODS: Lentivirus was used to transfect and construct Neuregulin-1 overexpressed DPSCs. Various techniques assessed the effects of Neuregulin-1: osteogenic induction, lipid induction, Reverse Transcription Polymerase Chain Reaction, Western Blot, Cell Counting Kit-8 assay, wound healing, immunofluorescence, Phalloidin staining, nerve stem action potential, Hematoxylin-eosin staining, transmission electron microscopy, and immunohistochemistry. RESULTS: Neuregulin-1 effectively enhanced the proliferation, migration, and cytoskeletal rearrangement of DPSCs, while simultaneously suppressing the expression of Ras homolog gene family member A (RhoA) and Microfilament actin (F-actin). These changes facilitated the neural differentiation of DPSCs. Additionally, in vivo experiments showed that Neuregulin-1 expedited the restoration of action potential in the facial nerve trunk, increased the thickness of the myelin sheath, and stimulated axon regeneration. CONCLUSION: Neuregulin-1 has the capability to facilitate the repair of facial nerve injuries by promoting the regenerative capacity of DPSCs. Thus, Neuregulin-1 is a significant potential gene in the reparative processes of nerve damage.

Conjugated Poly(ionic liquid)-Based Nanoporous Membrane for Rapid Moisture Response.

Stimuli-responsive nanoporous materials represent a newly emerging category of functional materials, for which instant and significant response behavior is strongly demanded but still challenging. Herein, a new kind of conjugated poly(ionic liquid)s (PILs) synthesized via a simple one-pot spontaneous nucleophilic substitution and polymerization between 4,4'-vinylenedipyridine and propargyl bromide is reported. A nanoporous membrane actuator is further developed via ionic complexation between the current PIL and trimesic acid. The actuator carries a gradient density in the hydrophobicity content along the membrane cross-section, which results in a fast response to moisture.

Polystyrene Microplastics Induce Oxidative Stress in Mouse Hepatocytes in Relation to Their Size.

Microplastics have become a new type of environmental pollutant that can accumulate in various tissues and organs of the body and cause chronic damage. In this study, two different size polystyrene microplastics (PS-MPs, 5 µm and 0.5 µm) exposure models were established in mice to investigate the effects of PS-MPs with different particle sizes on oxidative stress in the liver. The results showed that PS-MPs exposure caused a decrease in body weight and liver-to-body weight. The hematoxylin and eosin staining and transmission electron microscopy results showed that exposure to PS-MPs led to the disorganized cellular structure of liver tissue, nuclear crinkling, and mitochondrial vacuolation. The extent of damage in the 5 µm PS-MP exposure group was more extensive when compared with the other group. The evaluation of oxidative-stress-related indicators showed that PS-MPs exposure exacerbated oxidative stress in hepatocytes, especially in the 5 µm PS-MPs group. The expression of oxidative-stress-related proteins sirtuin 3(SIRT3) and superoxide dismutase (SOD2) was significantly reduced, and the reduction was more pronounced in the 5 µm PS-MPs group. In conclusion, PS-MPs exposure led to oxidative stress in mouse hepatocytes and caused more severe damage in the 5 µm PS-MPs group when compared with the 0.5 µm PS-MPs group.

Research on the low-temperature degradation of dental zirconia ceramics fabricated by stereolithography.

STATEMENT OF PROBLEM: Stereolithography is a promising method of fabricating zirconia ceramics with high strength and accuracy. However, studies of the aging effects on zirconia ceramics fabricated by this technique are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the aging effects on the crystalline content, microstructure, and mechanical properties of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) printed by stereolithography apparatus (SLA) and digital light processing (DLP) compared with those of zirconia milled by computer numerical control (CNC). MATERIAL AND METHODS: Bar-shaped specimens were fabricated after layer-by-layer printing, debinding, and sintering by SLA and DLP. Specimens milled and sintered by CNC were used as controls (n=24/material). The specimens were divided into 12 groups (n=6) and aged (0/5/10/15 hours, 134 °C, 0.2 MPa), after which the crystalline content, microstructure, and mechanical properties were evaluated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and 3-point bend tests. The flexural strength and monoclinic (m) phase content were statistically evaluated (α=.05). RESULTS: The XRD results showed that an m peak was not detected for any of the tested materials before aging. The m-phase content was the highest for SLA (5/10/15 hours: 19.64%/34.76%/41.88%), followed by DLP (5/10/15 hours: 9.62%/21.76%/28.43%) and CNC (5/10/15 hours: 2.29%/7.77%/7.66%). The SEM images showed zirconia grain fragments for DLP and grain pullout for SLA, while surface defects were not obvious for CNC. Within the materials, the flexural strength was the highest for SLA after aging for 5 hours (1010.3 MPa), followed by 10 hours (913.06 MPa) and 15 hours and 0 hours, which exhibited no difference (0/15 hours: 776.71/814.28 MPa) (P<.001). The flexural strength for CNC and DLP did not significantly change after aging for 5 hours, 10 hours, and 15 hours (P>.05). The flexural strength for CNC was always more than 1200 MPa, and that for DLP was approximately 800 MPa before and after aging. CONCLUSIONS: Although the m-phase content for SLA and DLP increased with the aging time, the mechanical properties did not significantly decrease, indicating the stability of both materials.

Rehabilitation of long-term mandibular defects by whole-process digital fibula flap combining with implants: A case report.

Currently, the gold standard and workhorse in mandibular reconstruction is the free vascularized fibula flap. Particularly for patients who have had mandibulectomy for a long time, it is still difficult to precisely reconstruct the mandibular contour and successfully restore the patient's chewing function and esthetics. For the restoration and rehabilitation of long-term mandibular abnormalities, three-dimensional (3D) virtual surgical planning (VSP) and 3D-printed surgical guides are essential. Digital design and manufacturing were used to improve the accuracy of prostheses and facilitate occlusal reconstruction. Therefore, equipped with the methods of 3D VSP, 3D-printed surgical guides, free vascularized fibular flap, and immediate dental implants, this clinical report provides a feasible solution for mandibular reconstruction.

Dual Biosignal-Functional Injectable Microspheres for Remodeling Osteogenic Microenvironment.

Bone defect regeneration depends on the population and lifespan of M2 macrophages, which are regulated by dual signals generated by the "physical" spatial configuration of biological tissues and "molecular" chemokines. Herein, inspired by the reprogramming of macrophages, immunoengineered porous microspheres are constructed to accelerate bone repair through the regulation of both "physical" and "molecular" signals. The porous structure of injectable poly (l-lactic acid) (PLLA) microspheres prepared by the microfluidic technique provides a "physical signal" for osteogenic differentiation. Additionally, interleukin (IL)-4-loaded liposomes (Ls) are modified on PLLA microspheres through amide bonds to produce IL-4/Ls/PLLA microspheres, providing a "molecular signal" in stimulating the differentiation of macrophages to M2 type. It is confirmed that IL-4/Ls/PLLA microspheres could induce M2-macrophages polarization and potentiate osteoblast proliferation and differentiation while coculturing with macrophages and osteoblasts in vitro. Besides, IL-4/Ls/PLLA microspheres are proved to promote bone defect regeneration by inducing the conversion of M1 macrophages to M2 through dual biosignal-functional regulation in both the calvaria defect and maxillary sinus defect models. Overall, the immuno-reprogrammed IL-4/Ls/PLLA microspheres achieve the precise immuno-reprogramming of macrophages by dual biosignal-functional regulation. This immune reengineering strategy paves a way for clinical bone defect treatment.

Periodontitis aggravates renal inflammatory response in a mouse model of renal fibrosis.

OBJECTIVES: To assess the effects of periodontitis on renal interstitial fibrosis in a mouse model. MATERIALS AND METHODS: Thirty C57BL/6 male mice were divided into control, periodontitis (PD), unilateral ureteral ligation (UUO) and PD+UUO groups. Unilateral ureteral ligation was performed 6 days after periodontitis. After 2 weeks, all mice were sacrificed, and samples were collected for the assessment of gene expression, immune cells, biochemical indicators and renal pathology. RESULTS: Expression of tumour necrosis factor-α, interleukin-1ß, and Ly6G in the kidneys in the PD+UUO group was significantly greater than in the UUO group. The percentage of CD11b+ Ly6G+ cells was significantly higher in the PD+UUO than in the UUO group. Fibrotic areas in the kidneys in the PD+UUO group were slightly, but not significantly, greater than those in the UUO group. Kidneys from the PD+UUO group showed markedly higher gene expression of matrix metalloproteinase-9, but not α-smooth muscle actin or collagen I, than those in the UUO group. There were no significant differences in blood urea nitrogen, serum creatinine and uric acid between the PD+UUO and UUO groups. CONCLUSIONS: Periodontitis increases the renal inflammatory response without showing a significant influence on renal interstitial fibrosis or renal function in the UUO mouse model.

Expanded Transoral Microvascular Mandibular Reconstruction: A Scar-Free Approach.

PURPOSE: We present our experience with transoral segmental mandibulectomy, in conjunction with vascularized osseous mandibular reconstruction, utilizing an intraoral anastomosis and free of extraoral incisions. Virtual surgical planning and intraoperative navigation were used to help achieve this minimally invasive and scar-free approach. METHODS: A retrospective study was performed on 9 patients who underwent transoral segmental mandibulectomy followed by vascularized osseous reconstruction using an intraoral anastomosis between January 2018 and October 2018. The anastomotic recipient vessels were the facial artery and vein. The outcome variable was defined as the flap survival. Postoperative panoramic radiographs and computed tomography images were obtained for assessment of the neo-mandible. In addition, we performed a cadaver dissection to highlight relevant anatomic details of the facial artery and vein. RESULTS: Successful transoral segmental mandibulectomy was achieved in 9 patients, with an intraoral anastomosis successfully achieved in 8 patients. In one patient, an extraoral anastomosis was required because of challenging facial vein anatomy. Both recipient and donor sites healed uneventfully with a 100% successful rate of flap survival. In all cases, a well-positioned neo-mandible with good occlusion was demonstrated on postoperative imaging and examination. A symmetric facial appearance with no restrictions in mouth opening was also achieved in each case. In our cadaver dissection, we describe the anatomical course of the facial artery and vein. An average angle of 30° between these vessels is identified. CONCLUSIONS: Transoral segmental mandibulectomy combined with intraoral microvascular mandibular reconstruction is a surgically achievable technique with the benefit of being scar free.

Microplastics Exacerbate Cadmium-Induced Kidney Injury by Enhancing Oxidative Stress, Autophagy, Apoptosis, and Fibrosis.

Cadmium (Cd) is a potential pathogenic factor in the urinary system that is associated with various kidney diseases. Microplastics (MPs), comprising of plastic particles less than 5 mm in diameter, are a major carrier of contaminants. We applied 10 mg/L particle 5 µm MPs and 50 mg/L CdCl2 in water for three months in vivo assay to assess the damaging effects of MPs and Cd exposure on the kidney. In vivo tests showed that MPs exacerbated Cd-induced kidney injury. In addition, the involvement of oxidative stress, autophagy, apoptosis, and fibrosis in the damaging effects of MPs and Cd on mouse kidneys were investigated. The results showed that MPs aggravated Cd-induced kidney injury by enhancing oxidative stress, autophagy, apoptosis, and fibrosis. These findings provide new insights into the toxic effects of MPs on the mouse kidney.

The effect of anatomy on osteogenesis after maxillary sinus floor augmentation: a radiographic and histological analysis.

OBJECTIVES: To assess how anatomy and osteogenesis correlated with results of maxillary sinus floor augmentation (MSFA). MATERIALS AND METHODS: Patients with partial edentulism and advanced atrophy of the posterior maxillae (≤ 4 mm residual bone height, RBH) underwent MSFA with sole deproteinized bovine bone matrix (DBBM) through a lateral approach. After a 6 to 9-month healing period, bone core biopsies were obtained from the sites of implant insertion for histological evaluation. The correlations between anatomical and histomorphometric variables were analyzed in a multiple regression model. RESULTS: Forty-nine patients were recruited. One biopsy per patient was obtained from the augmented sinus. Thirty-seven bone core biopsies were intact and met the requirement for histomorphometry analysis. The mean (± standard deviation) percentages of vital bone (VB), remaining DBBM, and non-mineralized tissue were 18.25 ± 4.76%, 27.74 ± 6.68%, and 54.08 ± 6.07%, respectively. No statistically significant correlations were found between RBH and VB% (p = 0.44) or between sinus contour and VB% (p = 0.33). However, there was an inverse correlation between the sinus width (SW) and VB % (SW1: R2 = 0.13, p = 0.03; SW2: R2 = 0.15, p = 0.02). CONCLUSIONS: After a healing period of 6-9 months, wider sinuses augmented with DBBM alone tended to have a lower proportion of new bone formation, while RBH and sinus contour did not appear to affect osteogenesis after MSFA. CLINICAL RELEVANCE: This study emphasized the effect of anatomy on osteogenesis after MSFA. The result of the study may have an indication to the clinician that SW is a consideration when selecting the bone grafting material and deciding the healing period of MSFA.

Randomized Controlled Clinical Trial to Assess the Utility of Computer-Aided Intraoperative Navigation in Bimaxillary Orthognathic Surgery.

ABSTRACT: Accurate application of the preoperative surgical plan in actual surgical settings is of paramount importance in orthognathic surgery. This randomized controlled clinical trial aimed to evaluate the accuracy of computer-aided intraoperative navigation (Ci-Navi) compared with that of conventional navigation methods in bimaxillary orthognathic surgery. Fifty-two patients were randomly divided into 2 groups. Group A (n = 26) patients underwent surgery assisted with Ci-Navi and group B (n = 26) patients underwent surgery assisted with conventional intraoperative navigation methods. During the operation, after LeFort I osteotomy, the mobile maxilla was repositioned to the designated position either using assistance from real-time Ci-Navi (group A) or using an intermediate splint (group B). Intra- and intergroup linear and angular differences between preoperative planning and postoperative outcomes were calculated. In group A, the overall mean linear difference was 0.79 mm (0.62 mm for the maxilla and 0.88 mm for the mandible) and the overall mean angular difference was 1.20°. In 23 cases, the difference from the upper incisor point to the Frankfort horizontal plane, midfacial sagittal plane, and coronal plane was less than 1 mm. In group B, the overall mean linear difference was 1.98 mm (1.76 mm for the maxilla and 2.02 mm for the mandible) and the overall mean angular difference was 2.08°. The difference from the upper incisor point to the Frankfort horizontal plane, midfacial sagittal plane, and coronal plane was less than 1 mm in 15 cases. This study demonstrates the utility of Ci-Navi is superior to the conventional methods in aiding the accurate repositioning of bony segments in bimaxillary orthognathic surgery.

Dimensional accuracy and clinical adaptation of ceramic crowns fabricated with the stereolithography technique.

STATEMENT OF PROBLEM: The stereolithography technique has been a promising method of fabricating fracture-resistant ceramic restorations efficiently. However, studies on the dimensional accuracy and clinical adaptation of ceramic crowns fabricated with the technique are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the dimensional accuracy and clinical adaptation of ceramic crowns fabricated with the stereolithography technique. MATERIAL AND METHODS: A typodont maxillary right first molar abutment tooth was scanned by using an extraoral scanner, and a crown was designed by using 3Shape Dental System CAD software. Ten ceramic crowns were fabricated with 2 different stereolithography systems, CeraFab7500 (CF) alumina and CSL150 (CL) zirconia, and a conventional computer-aided design and computer-aided manufacturing system, X-MILL500 (XM) zirconia. The crowns were scanned, and the digital casts were exported. Dimensional accuracy was measured by superimposing the digital casts with the reference model by using Geomagic Qualify software. The silicone replica method was applied to measure clinical adaptation. Results were statistically analyzed by using a 1-way analysis of variance (α=.05). RESULTS: CeraFab7500 reported better dimensional accuracy (41 ±11 µm) than CSL150 (65 ±6 µm) or X-MILL500 (72 ±13 µm) (P<.001). No significant difference was found between the CSL150 and X-MILL500 groups (P>.05). X-MILL500 reported significantly better adaptation in the marginal, corner, and occlusal areas but inferior adaptation in the axial area compared with CeraFab7500 and CSL150 (P<.05). Significant differences were only apparent in the axial and occlusal areas between CeraFab7500 and CSL150 (P<.05). No significant difference was found in the marginal or corner area between CeraFab7500 and CSL150 (P>.05). CONCLUSIONS: Both CeraFab7500 and CSL150 can fabricate ceramic crowns with high dimensional accuracy and marginal adaptation within clinically acceptable limits. The results indicate that the fabrication of ceramic crowns by using the stereolithography technique seems to be promising.

[The Roles of RUNX1 in the Proliferation and Osteogenic and Adipogenic Differentiation of Dental Pulp Stem Cells].

OBJECTIVE: To investigate the influence of Runt-related transcription factor 1 (RUNX1) on the proliferation, osteogenic differentiation and adipogenic differentiation of dental pulp stem cells (DPSC) in vitro. METHODS: DPSCs were transfected through lentiviral vector carrying the target gene RUNX1 and green fluorescent protein (GFP). After 48 h, transfection efficiency was determined with the fluorescent marking of GFP and Western blot. The effect of the overexpression of RUNX1 on DPSC proliferation and colony formation was determined with CCK-8 and colony formation assay; cell cycle of DPSC was detected by flow cytometry. RUNX1 siRNA was transfected into the DPSCs. After mineralized induction, the effect of RUNX1 overexpression/silencing on the osteogenetic differentiation of DPSC was tested by alkaline phosphatase (ALP) staining and alizarin red staining. After adipogenic induction, oil red O staining was done in order to observe the effect of overexpression/silencing of RUNX1 on the adipogenic differentiation of DPSC. RESULTS: RUNX1 protein was overexpressed in DPSC after lentiviral transfection. Fluorescent test showed successful transfection of lentiviral transfection and over 70% of the cells showed stable expression of GFP protein. The proliferation and colony-formation efficiency of DPSC was enhanced significantly and the proportion of DPSCs in the S phase was significantly increased in the RUNX1-overexpessed group ( P<0.05). ALP activity and mineralized nodule formation ability increased, while lipid droplets decreased in the RUNX1-overexpessed group ( P<0.05). ALP activity and mineralized nodule formation ability decreased, while lipid droplets increased in the RUNX1 knockdown group ( P<0.05) . CONCLUSION: RUNX1 promotes DPSC proliferation and osteogenic differentiation while it inhibits DPSC adipogenic differentiation.

Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha.

BACKGROUND & AIMS: Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS: We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS: We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS: In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.

Boosting the Theranostic Effect of Liposomal Probes toward Prominin-1 through Optimized Dual-Site Targeting.

Ligand-targeting specific liposomal probes are increasingly used as imaging and delivery vehicles for in vivo diagnosis. Thereinto, the ligand variety and density profoundly affect the binding behaviors toward the target. The synergetic effect of different ligands could be achieved only when the optimized molecular-recognition configuration occurred. In this study, we construct a dual-peptides-targeting liposomal probe named BTLS that could synergistically bind two different sites of prominin-1, a cancer stem cell marker. At the distance of 11 Å between the two new peptides, ligands could insert into the hollow pocket of prominin-1 and BTLS could achieve the appropriate spatial structure, showing the strong binding affinity in both cellular and in vivo levels. It is indicated that the design of density-optimized peptide-targeted liposomes could be promising to maximize the multifunctional targeting effects on the cancer theranostics.

Polyethylene glycol loxenatide (PEX168) in subjects with renal impairment: A pharmacokinetic study.

AIMS: Type 2 diabetes mellitus (T2DM) is commonly complicated by renal impairment. Polyethylene glycol loxenatide (PEX168) is a novel long-acting glucagon-like peptide-1 receptor agonist for T2DM. PEX168 pharmacokinetics was studied to identify requirements for dose-modification in T2DM complicated by renal impairment. METHODS: This was a single-centre, open-labelled, parallel-group, single-dose, phase I clinical trial of patients with mild and moderate renal impairment, and with or without T2DM. Age-, sex- and body mass index-matched subjects with normal renal function, and with or without T2DM were recruited as controls. Subjects received a single abdominal subcutaneous injection of PEX168 200 µg. Pharmacokinetic samples were taken at 0, 24, 48, 72, 96, 120, 144, 216, 312, 480, 648 and 720 hours. RESULTS: Twenty-three patients were included in the pharmacokinetics analysis. Vz/F and CL/F were lower in the moderate impairment group than in the other groups. The mean t1/2 (163 hours) in the moderate impairment group was prolonged compared to the mild impairment (117 hours) and normal (121 hours) groups. AUC0-inf increased by 13 and 100.7% in patients with mild and moderate renal impairment, respectively. Most adverse events were mild gastrointestinal disorders, with only 1 serious adverse event observed. CONCLUSION: A single dose of 200 µg of PEX168 was in general well tolerated in patients with renal impairment. The in vivo clearance rate of PEX168 in patients with moderate renal impairment is slower than in patients with mild renal impairment and normal renal function and dose adjustment might be required (ClinicalTrials.org #NCT02467790).

Sustained serological and complete responses in HBeAg-positive patients treated with Peginterferon alfa-2b: a 6-year long-term follow-up of a multicenter, randomized, controlled trial in China.

BACKGROUND: Pegylated interferon (PEG-IFN) alfa-2b is recommended for chronic hepatitis B (CHB). We aimed to investigate the sustainability of off-treatment responses among Chinese HBeAg-positive CHB patients treated with PEG-IFN alfa-2b from a randomized trial. METHODS: Eligible Chinese patients (n = 322) were followed up by one visit after a median of 6 years (LTFU) following their participation in a randomized trial evaluating the efficacy of three PEG-IFN alfa-2b dosing regimens (1.0 or 1.5 µg/kg/wk. 24 weeks or 1.5 µg/kg/wk. 48 weeks). Primary endpoints at the LTFU were sustained SR and CR (SR/CR at the end of original study [EOS] and at the LTFU). SR was defined as HBeAg loss and seroconversion to anti-HBe and CR as HBeAg loss and seroconversion to anti-HBe and HBV-DNA < 2000 IU/mL. RESULTS: The proportions of patients achieving sustained SR among patients who had SR at EOS were high in three treatment groups (61.9, 65.5, 76.5%, respectively, p = 0.46); treatment with PEG-IFN alfa-2b 1.5 µg/kg/wk. 48 weeks had the highest proportion of a sustained CR among patients who had CR at EOS (75.0%, p = 0.05). A considerable number of patients achieved sustained SR (18.2-29.9%) and sustained CR (14.8-18.3%) after EOS despite no further NA treatment. At the LTFU, rates of SR and CR were less than 70.0 and 50.0%, respectively, among all enrolled patients regardless of additional nucleos(t)ide analogs before the LTFU. CONCLUSIONS: PEG IFN alfa-2b therapy had considerable off-treatment sustainability in Chinese HBeAg positive chronic hepatitis B patients with serological and complete responses.

WITHDRAWN: Expanded Transoral Microvascular Mandibular Reconstruction: A Scar-Free Approach.

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