Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

Biofouling control potential of quorum quenching anaerobes in lab-scale anaerobic membrane bioreactors: Foulants profile and microbial dynamics.

Indigenously isolated anaerobes encoding four quorum quenching (QQ) enzymes were applied in immobilized- and bioaugmented forms for their implications on membrane foulants, microbial taxa, and biofouling control. Two identical anaerobic membrane bioreactors (AnMBRs) with different immobilizing media, i.e. silica-alginate (AnMBR-Si) and hollow fiber-alginate (AnMBR-Hf), were sequentially operated for two conventional and three QQ based phases. The synergistic addition of QQ anaerobes in free cells and the immobilized form prolonged the membrane filtration operation by 172 ± 29% and 284 ± 12% in AnMBR-Si and AnMBR-Hf, respectively. Biocake with low surface coverage was prominent during QQ application compared to conventional phases. Despite the better control of AHLs (3OC6-, C6-, 3OC8, C8, and C10-HSL) and AI-2 at various points of QQ phases, the QQ consortium could not maintain a low concentration of signals for longer period. Therefrom, quenching of targeted signal molecules instigate the dominance of microbial species bearing non-targeted quorum sensing mechanism. The QQ significantly altered the biofilm-forming community in mixed liquor, while the members with robust signal transduction systems became dominant to counteract the QQ mechanism and were the ultimate cause of biofouling. The improved methane content in biogas and increased methanogens composition during QQ phases demonstrated the synergism of exogenous and immobilized QQ as the most viable option for long-term AnMBR operation.

Fabrication of versatile polyvinyl alcohol and carboxymethyl cellulose-based hydrogels for information hiding and flexible sensors: Heat-induced adjustable stiffness and transparency.

With the growing demand for wearable electronics, designing biocompatible hydrogels that combine self-repairability, wide operating temperature and precise sensing ability offers a promising scheme. Herein, by interpenetrating naturally derived carboxymethyl cellulose (CMC) into a polyvinyl alcohol (PVA) gel matrix, a novel hydrogel is successfully developed via simple coordination with calcium chloride (CaCl2). The chelation of CMC and Ca2+ is applied as a second crosslinking mechanism to stabilize the hydrogel at relatively high temperature (95 °C). In particular, it has unique heat-induced healing behavior and unexpected tunable stiffness & transparency. Like the sea cucumber, the gel can transform between a stiffened state and a relaxed state (nearly 23 times modulated stiffness from 453 to 20 kPa) which originates from the reconstruction of the crystallites. The adjustable transparency enables the hydrogel to become an excellent information hiding material. Due to the presence of Ca2+, the hydrogels show favorable conductivity, anti-freezing and long-term stability. Based on the advantages, a self-powered sensor, where chemical energy is converted to electrical energy, is assembled for human motion detection. The low-cost, environmentally friendly strategy, at the same time, complies to the "green" chemistry concept with the full employment of the biopolymers. Therefore, the proposed hydrogel is deemed to find potential use in wearable sensors.

Hyperbranched polyphthalocyanine micelles with dual PTT/PDT functions for bacteria eradication under an NIR window.

A Zinc phthalocyanine-based (ZnPc-PA) polymeric micelle around 70 nm and with dual-modal PTT/PDT functions for non-antibiotic bacteria eradication was developed. It showed an excellent bacterial killing efficiency of 95.2% and 96.7% in vitro against Methicillin-resistant Staphylococcus aureus (MRSA) and its biofilm, respectively. Furthermore, the in vivo experiments proved its great potential for implant-associated infection (IAI).

Dimeric artesunate phospholipid-conjugated liposomes as promising anti-inflammatory therapy for rheumatoid arthritis.

OBJECTIVE: The dimeric artesunate phospholipid conjugate (Di-ART-GPC) is a novel amphipathic artemisinin derivative, which can be assembled into liposomes. Di-ART-GPC liposomes were prepared and evaluated as potential anti-inflammatory agents for rheumatic arthritis (RA). METHODS: Di-ART-GPC was assembled into liposomes utilizing thin film dispersion-high pressure homogenization. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and electron cryo microscopy (cryo-EM) were employed to characterize the liposomal size and morphology. The in vitro cytotoxicity of the Di-ART-GPC liposomes was assessed using Cell Counting Kit-8 (CCK8). The anti-inflammatory effects were studied utilizing the inflammatory cell model. Finally, the in vivo efficacy of the Di-ART-GPC-conjugated liposomes was investigated using the arthritis rat model. RESULTS: The particle size of the Di-ART-GPC liposomes decreased to a narrow range of approximately 70 nm following high-pressure homogenization. The in vitro studies revealed low cytotoxicity and good anti-inflammatory effects of the Di-ART-GPC liposomes, which exhibited significantly higher inhibition of the cell secretion of pro-inflammatory cytokines than ART. The in vivo evaluation confirmed that treatment with Di-ART-GPC resulted in a decline in the ankle swelling rate and a low inflammatory response compared with the model control and ART. CONCLUSION: Di-ART-GPC liposomes demonstrate remarkable potential as novel ART-based anti-inflammatory agents for RA.

[Design and application of an oral health self-efficacy scale for patients with dental implants].

PURPOSE: To design an oral health self-efficacy scale for patients with dental implants and to evaluate their reliability and validity. METHODS: Based on literature review, we designed and developed a self-efficacy energy table that met the characteristics of implant patients. The scale consisted of 16 items which were divided into 3 dimensions, including self-efficacy of dental implant surgery, self-efficacy of postoperative supportive care, and self-efficacy of oral hygiene habits. The reliability and validity of the scale were evaluated by factor analysis in 102 outpatients with dental implants using SPSS 13.3 software package. RESULTS: A total of 4 common factors were extracted from the scale, and the cumulative contribution rate was 75.35%. The overall Cronbach's α coefficient of the scale was 0.910, and the retest correlation coefficient was 0.882, which belonged to high-signal scale. CONCLUSIONS: The oral health self-efficacy energy scale for implant patients with independent design has high reliability and validity. It can provide targeted guidance for oral health education for implant patients and improve the success rate of implant surgery.

2,2'-Dithiodisuccinic acid-stabilized polyion complex micelles for pH and reduction dual-responsive drug delivery.

In this work, a new kind of polyion complex (PIC) micelles with pH and reduction dual responsiveness was developed for effective intracellular drug delivery. The PIC micelles can be readily prepared by mixing a polycationic block polymer, methoxy poly(ethylene glycol)-b-poly(l-lysine) (mPEG-PLL), with a small molecule polyacid, 2, 2'-dithiodisuccinic acid (DTS) in aqueous media. The resultant PIC micelles are of uniform spherical shapes with hydrodynamic radii ranging from 65 to 75 nm based on different feeding ratios of mPEG-PLL and DTS. Interestingly, by using the small molecule polyacid DTS, the obtained PIC micelles show distinct pH-responsive disintegration in acid solution. Meanwhile, the PIC micelles were also assessed to be reduction-responsive due to the presence of disulfide bond in DTS. In view of these stimuli-responsive properties, the potential use of this PIC micelle as smart drug carrier was then investigated. Doxorubicin (DOX), a cationic anticancer drug, was loaded into the PIC micelles with high efficiency. In vitro drug release studies revealed that release of DOX from the PIC micelles was suppressed in neutral solutions due to the stable electrostatic interactions between PIC micelles and DOX, but could be accelerated in acidic solutions or under high GSH condition. Furthermore, flow cytometry and confocal laser scanning microscopy (CLSM) studies indicated that the DOX-loaded PIC micelles could be effectively internalized by MCF-7 human breast cancer cells and release the loaded DOX in intracellular environment. Consequently, the DOX-loaded PIC micelles were capable of inhibiting the proliferation of C26 murine colon cancer and MCF-7 human breast cancer cells in high efficiency, showing similar IC50 values as free DOX. Thus, this biocompatible PIC micelle may be promising for intracellular drug delivery.

Strengthened and Thermally Resistant Poly(lactic acid)-Based Composite Nanofibers Prepared via Easy Stereocomplexation with Antibacterial Effects.

Strengthened poly(lactic acid) (PLA)-based materials with improved mechanical performance and improved thermal resistance, notably, are prepared by introducing stereocomplex crystallite (SC), an ideal filler, into the materials. Owing to the intermolecular hydrogen bond among the stereoisomer chains, the melting point of the special crystallite is up to 200 °C, which is 50 °C higher than the isostatic crystallite. The modulus of the PLA-based materials can be enhanced to several 100 MPa because of the integrated polymer chain arrangement. In this study, we electrospun hybrid nanofibers consisted of PLA stereoisomers and induced the stereocomplex crystallization under a mild condition (65 °C for 1 h). The mild warming is favorable for the protection of chlorogenic acid (CA) that was selected as the antibacterial agent. Both of Gram-positive and Gram-negative bacteria were efficiently cleared away using the warmed nanofibers that released CA rapidly within just a few hours. Used as filters, the SC electrospinning membrane also presented a potent filtering effect, leaving no bacteria retained in the filtrates. Attributing to SC, the PLA-based nanofibers showed extremely increased melting temperature over 200 °C and improved Young's modulus up to 270.0 MPa. The durable nanofibers prepared in present study are meaningful for enlarging the application of PLA-based materials, for example, as filters, masks, and packages.

Potent Anti-adhesion Barrier Combined Biodegradable Hydrogel with Multifunctional Turkish Galls Extract.

Clinically, postoperative adhesions are common and serious complications, which almost always happen after abdominal or pelvic surgery. The adhesion development process is accompanied by increased inflammatory cell infiltration and oxygen-free radical production. In this study, the naturally occurring antioxidative and anti-inflammatory compounds extracted from Turkish galls by ethyl acetate (GEA) were encapsulated into an injectable and biodegradable thermosensitive hydrogel. Antiadhesion efficacy of the barrier system (GEA-NP/H) was tested on a rat peritoneum injury-cecum abrasion model. Upon injection, the mildly viscous liquid formed a potent physical barrier over the injured cecum and peritoneum without any additional cross-linkers or light sources. Once formed, GEA-NP/H acted as a durable wound dressing for more than 5 days, as well as a sustained drug depot of GEA. The polymer hydrogel can be degraded and absorbed gradually. After 14 days, severe adhesion occurred among rats treated with normal saline and GEA-loaded nanoparticles (GEA-NP). Whereas, frequency of score 1 adhesion among the blank hydrogel group is 30%, and 90% of the rats from GEA-NP/H group exhibited no adhesion. In addition, pathological sections and scanning electron microscopy assay demonstrated that operative defects treated with GEA-NP/H suffered from mild oxidative stress and inflammatory damages at early days after injury, as well as accelerated wound healing and more mature mesothelial cell deposition at the 14th day in contrast to the blank hydrogel treatment. Therefore, the study provided an available biodegradable hydrogel barrier to effectively prevent postsurgical adhesion.

Protein adsorption on polyurethane catheters modified with a novel antithrombin-heparin covalent complex.

Highly anticoagulant covalent antithrombin-heparin complex (ATH) was covalently grafted onto polyurethane catheters to suppress adsorption/activation of procoagulant proteins and enhance adsorption/activation of anticoagulant proteins for blood compatibility. Consistency of catheter coating was demonstrated using immunohistochemical visualization of ATH. The ability of the resulting immobilized ATH heparin chains to bind antithrombin (AT) from plasma, as measured by binding of (125)I-radiolabeled AT, was greater than that for commercially-available heparin-coated catheters, and much greater than for uncoated catheters. Complementary measurements of antifactor Xa (FXa) activity and plasma protein binding were also performed. Both ATH-coated and heparin-coated catheters demonstrated functional binding of exogenous AT. However, the ATH-coated catheters gave a trend towards elevated anti- FXa activities/AT binding ratios, consistent with the higher active pentasaccharide content in starting ATH. Western blot analysis of proteins adsorbed to catheters after incubation with rabbit plasma established protein binding profiles that showed AT and albumin as major plasma proteins adsorbed to ATH-coated catheters, while AT and altered forms of fibrinogen were major plasma protein species adsorbed to heparinized catheters.

A simple method to fabricate a chitosan-gold nanoparticles film and its application in glucose biosensor.

A novel film of chitosan-gold nanoparticles is fabricated by a direct and facile electrochemical deposition method and its application in glucose biosensor is investigated. HAuCl(4) solution is mixed with chitosan and electrochemically reduced to gold nanoparticles, which can be stabilized by chitosan and electrodeposited onto glassy carbon electrode surfaces along with the electrodeposition of chitosan. Then a model enzyme, glucose oxidase (GOD) is immobilized onto the resulting film to construct a glucose biosensor through self-assembly. The resulting modified electrode surfaces are characterized with both AFM and cyclic voltammetry. Effects of chitosan and HAuCl(4) concentration in the mixture together with the deposition time and the applied voltage on the amperometric response of the biosensor are also investigated. The linear range of the glucose biosensor is from 5.0 x 10(-5) approximately 1.30 x 10(-3) M with a Michaelis-Menten constant of 3.5 mM and a detection limit of about 13 microM.

Core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles for reduction and pH dual responsive intracellular drug delivery.

A kind of core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles (CPD NPs) was prepared by a simple chemical cross-linking method for reduction and pH dual response drug delivery. The resultant CPD NPs are of homogeneous spherical structure with sizes from 69±11 to 107±18nm. Doxorubicin (DOX) was then loaded into the CPD NPs in high efficiency, and showing typical reduction and pH dual responsive release profiles. The flow cytometric analysis and confocal laser scanning microscopy (CLSM) confirmed that the DOX-loaded CPD NPs could be internalized into cancer cell efficiently and release DOX in intracellular environment. Furthermore, cell cytotoxicity assays indicated that the CPD NPs had good biocompatibility toward both cancerous and normal cells, while the Dox-loaded CPD NPs exhibited significant inhibition of cell proliferation in various cancer cells. Therefore, this biocompatible CPD NP may have great potential for intracellular drug delivery in clinical cancer therapy.

Chronic performance of polyurethane catheters covalently coated with ATH complex: a rabbit jugular vein model.

Covalent complexes of antithrombin (AT) and heparin (ATH) have superb anticoagulant activity towards thrombin and factor Xa. Stability of polyurethane central venous catheters covalently modified with radiolabeled ATH was studied using a roller pump with saline or protease P-5147. Saline wash removed loosely bound ATH molecules to decrease graft density from 26 to 12 pmol/cm2. However, only slightly more ATH was removed by strong protease (from 12 to 7 pmol/cm2). To evaluate ATH-coated, heparin-coated, and uncoated catheters, a chronic rabbit jugular vein model was developed with catheters maintained for up to 30-106 days. Lumen occlusion was tested by drawing blood twice daily. Although unmodified or heparin-coated catheters occluded within 5-7 days after insertion, all ATH catheters remained patent throughout the experiment. Scanning electron microscopy (SEM) analysis of heparin and uncoated catheters revealed extensive thrombosis (lumen+mural) while ATH catheters were unaffected. Visual observation showed significant deposition of protein and cells on control and heparin-modified catheters and, to a lesser degree, on ATH-coated surfaces. SEM showed no fibrin inside or outside of ATH catheters, which remained patent in extended studies out to 106 days. Although atomic force microscopy showed ATH coatings to be rough, 6-fold higher anti-factor Xa activity likely contributed to increased patency. Our data confirm that ATH-modified catheters are stable and have superior potency compared to heparin or control catheters.

In vivo rabbit acute model tests of polyurethane catheters coated with a novel antithrombin-heparin covalent complex.

Catheter use has been associated with an increased risk of thrombotic complications. The objective was to make catheters less thrombogenic with the use of antithrombin-heparin covalent complex (ATH). The antithrombotic activity of ATH-coated catheters was compared to uncoated (control) and heparincoated catheters in an acute rabbit model of accelerated occluding clot formation. Anaesthetized rabbits were pre-injected with rabbit (125)I-fibrinogen, followed by insertion of test catheters into the jugular vein. Blood was drawn and held in a syringe, reinjected, then flushed with saline. The experiment was terminated when blood could no longer be withdrawn (occluding clot). Efficacy was defined as the ability of catheters to remain unoccluded. Clot formation, determined by measuring deposition of radiolabeled fibrin, was a secondary endpoint. ATH-coated catheters were resistant to clotting for the full 240-minute duration, while uncoated and heparin-coated catheters had an average clotting time of 78 and 56 minutes, respectively. The patency of ATH coating was dependant on intact heparin pentasaccharide sequences, rather than the chemistries of the basecoat, the PEO spacer arm, or the antithrombin (AT) protein. The ATH coating was stable to ethylene oxide sterilization, modest abrasion, protease attack, and the coating did not appear to leach off the catheter. Surface tension measurements showed that the ATH modified surface was more hydrophilic than uncoated control catheters or heparin-coated catheters. Thus, ATH-coated catheters are better at preventing clots than uncoated or heparin-coated catheters and show promise as an alternative to the currently available catheters in reducing thrombotic complications associated with its use.

Chemical-physical characterization of polyurethane catheters modified with a novel antithrombin-heparin covalent complex.

Detailed structural studies were made of polyurethane catheter surfaces modified with a covalent antithrombin-heparin (ATH) complex that has superior anticoagulant activity compared to unfractionated heparin. ATH was grafted onto polyurethane catheters by surface film preparation involving a three-step process: (1) activation of ATH through functionalized poly(ethylene glycol) (PEG), (2) base-coating treatment of the polyurethane surface and (3) final attachment of ATH onto the surface by free radical polymerization. With the application of base coating, composed of polyhydroxyethylmethacrylates and poly(ethylene oxide) (PEO), the coating process could easily be transferred to other biomaterials by adjusting the base-coating composition. Anti-factor Xa assays confirmed high anticoagulant activity of the ATH coatings. To determine structural aspects critical for biological function, the product was analyzed using differential scanning calorimetry and SDS-PAGE. Radiolabeled ATH was used to determine the graft density, homogeneity and stability of modified surfaces, as well as the competition of PEO-ATH migration to the surface with self-aggregation of the PEO-ATH molecules during the coating process. X-ray photoelectron spectroscopy was used to investigate the surface chemical composition before and after ATH application. Analysis showed that PEO-ATH was strongly surface-bound at a final density of 15-200 pmol/cm(2), depending on the incubation concentration.

[The preliminary study of incorporating tetrapod-like zinc oxide whisker on the antibacterial activity of soft denture liners].

OBJECTIVE: To research the effects of incorporating tetrapod-like zinc oxide whisker (T-ZnOw) of different proportions on the antibacterial activity of different kinds of soft denture liners. METHODS: The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of T-ZnOw against Saccharomyces albicans (S. albicans) were examined by the broth dilution test. Add T-ZnOw 0%, 1%, 2%, 3% to Silagum soft denture liners and soft denture liners respectively. The antimicrobial rate of S. albicans was determined by the membrane covering method. RESULTS: The MIC of T-ZnOw against S. albicans was 78 microg mL(-1) and the MBC was 156 microg mL(-1). Comparing 1%, 2%, 3% T-ZnOw group with control group, the results showed significant difference (P<0.05). And as the T-ZnOw antibacterial agent added ratio increased, antibacterial increased significantly. CONCLUSION: The soft denture liners incorporating with 1%, 2%, 3% of T-ZnOw can improve antibacterial activity. Following the increased proportions of T-ZnOw, antibacterial rate was significantly increasing.

[Retrospective analysis on three operative methods for curettage of adenoids in children].

OBJECTIVE: To compare the three different approaches in the curettage of adenoid hypertrophy: the traditional curettage of adenoids through mouth (group A), the adenoidectomy through nose under nasal endoscope (group B), the adenoidectomy through both mouth and nose under nasal endoscope (group C). METHOD: Clinical data of adenoid hypertrophy patients who had accepted the surgery therapy, were retrospectively analyzed; Symptoms of night snore, nasal obstruction, rhinorrhea, acouesthesia and the adenoid residue among the patients who had got three different surgery, were compared among them. RESULT: Adenoid residue were found in six cases of group A. No adenoid residue were found in group B and C . Recovery of nasal obstruction and night snore in group C were much better than that in group A and B (P<0.01, <0.05). CONCLUSION: The ideal way to cure adenoidal hypertrophy is the adenoidectomy done through mouth and nose under nasal endoscope.

Electrochemical determination of arsenite in neutral media on reusable gold nanostructured films.

We report a simple and novel method of stirring-only-driven accumulation and electrochemical determination of arsenite (As(III)) with both of the oxidation and reduction peaks associated with As(0)/As(III) using a gold nanofilm electrode in neutral solution. Under stirring, a large amount of As(III) was deposited on the modified electrode and the electrochemical response was greatly amplified. The accumulated As(III) on the electrode showed well-defined redox couple in 0.1M blank phosphate buffer solution (pH 7.0), which could be used for the measurement of As(III). Under optimal conditions, As(III) could be detected in the range from 0.20 to 375 ppb with a detection limit of 0.04 ppb. In particular, with the use of the reduction peak of As(III) the modified electrode exhibits excellent performance for As(III) determination even in the presence of abundant Cu(II). The regeneration of the electrodes is facile with good reproducibility. The electrochemical system was applied to analyze As(III) in lake water, As(III) spiked tap water and drinking water.

A glucose biosensor based on chitosan-glucose oxidase-gold nanoparticles biocomposite formed by one-step electrodeposition.

An amperometric biosensor for the quantitative measurement of glucose is reported. The biosensor is based on a biocomposite that is homogeneous and easily prepared. This biocomposite is made of chitosan hydrogel, glucose oxidase, and gold nanoparticles by a direct and facile electrochemical deposition method under enzyme-friendly conditions. The resulting biocomposite provided a shelter for the enzyme to retain its bioactivity at considerably extreme conditions, and the decorated gold nanoparticles in the biocomposite offer excellent affinity to enzyme. The biosensor exhibited a rapid response (within 7s) and a linear calibration range from 5.0 microM to 2.4 mM with a detection limit of 2.7 microM for the detection of glucose. The combination of gold nanoparticles affinity and the promising feature of the biocomposite with the onestep nonmanual technique favor the sensitive determination of glucose with improved analytical capabilities.