PLCγ1 deficiency in chondrocytes accelerates the age-related changes in articular cartilage and subchondral bone.

Ageing is the most prominent risk for osteoarthritis (OA) development. This study aimed to investigate the role of phosphoinositide-specific phospholipase Cγ (PLCγ) 1, previously linked to OA progression, in regulating age-related changes in articular cartilage and subchondral bone. d-galactose (d-Gal) was employed to treat chondrocytes from rats and mice or injected intraperitoneally into C57BL/6 mice. RTCA, qPCR, Western blot and immunohistochemistry assays were used to evaluate cell proliferation, matrix synthesis, senescence genes and senescence-associated secretory phenotype, along with PLCγ1 expression. Subchondral bone morphology was assessed through micro-CT. In mice with chondrocyte-specific Plcg1 deficiency (Plcg1flox/flox; Col2a1-CreERT), articular cartilage and subchondral bone were examined over different survival periods. Our results showed that d-Gal induced chondrocyte senescence, expedited articular cartilage ageing and caused subchondral bone abnormalities. In d-Gal-induced chondrocytes, diminished PLCγ1 expression was observed, and its further inhibition by U73122 exacerbated chondrocyte senescence. Plcg1flox/flox; Col2a1-CreERT mice exhibited more pronounced age-related changes in articular cartilage and subchondral bone compared to Plcg1flox/flox mice. Therefore, not only does d-Gal induce senescence in chondrocytes and age-related changes in articular cartilage and subchondral bone, as well as diminished PLCγ1 expression, but PLCγ1 deficiency in chondrocytes may also accelerate age-related changes in articular cartilage and subchondral bone. PLCγ1 may be a promising therapeutic target for mitigating age-related changes in joint tissue.

New Amphiphilic Terpolymers of N-Vinylpyrrolidone with Acrylic Acid and Triethylene Glycol Dimethacrylate as Promising Drug Delivery: Design, Synthesis and Biological Properties In Vitro.

The terpolymers of N-vinylpyrrolidone (VP) with acrylic acid and triethylene glycol methacrylate were synthesized with more than 90% yield by radical copolymerization in ethanol from monomeric mixtures of different molar composition (98:2:2, 95:5: 2 and 98:2:5) and their monomer composition, absolute molecular masses and hydrodynamic radii in aqueous media were determined. Using the MTT test, these terpolymers were established to be low toxic for non-tumor Vero cells and HeLa tumor cells. Polymer compositions of hydrophobic dye methyl pheophorbide a (MPP) based on studied terpolymers and linear polyvinylpyrrolidone (PVP) were obtained and characterized in water solution. Quantum-chemical modeling of the MPP-copolymer structures was conducted, and the possibility of hydrogen bond formation between terpolymer units and the MPP molecule was shown. Using fluorescence microscopy, the accumulation and distribution of polymer particles in non-tumor (FetMSC) and tumor (HeLa) cells was studied, and an increase in the accumulation of MPP with both types of particles was found.

Development of Peptide-Based Probes for Molecular Imaging of the Postsynaptic Density in the Brain.

The postsynaptic density (PSD) comprises numerous scaffolding proteins, receptors, and signaling molecules that coordinate synaptic transmission in the brain. Postsynaptic density protein 95 (PSD-95) is a master scaffold protein within the PSD and one of its most abundant proteins and therefore constitutes a very attractive biomarker of PSD function and its pathological changes. Here, we exploit a high-affinity inhibitor of PSD-95, AVLX-144, as a template for developing probes for molecular imaging of the PSD. AVLX-144-based probes were labeled with the radioisotopes fluorine-18 and tritium, as well as a fluorescent tag. Tracer binding showed saturable, displaceable, and uneven distribution in rat brain slices, proving effective in quantitative autoradiography and cell imaging studies. Notably, we observed diminished tracer binding in human post-mortem Parkinson's disease (PD) brain slices, suggesting postsynaptic impairment in PD. We thus offer a suite of translational probes for visualizing and understanding PSD-related pathologies.

Structure-Guided Design of Potent Coronavirus Inhibitors with a 2-Pyrrolidone Scaffold: Biochemical, Crystallographic, and Virological Studies.

Zoonotic coronaviruses are known to produce severe infections in humans and have been the cause of significant morbidity and mortality worldwide. SARS-CoV-2 was the largest and latest contributor of fatal cases, even though MERS-CoV has the highest case-fatality ratio among zoonotic coronaviruses. These infections pose a high risk to public health worldwide warranting efforts for the expeditious discovery of antivirals. Hence, we hereby describe a novel series of inhibitors of coronavirus 3CLpro embodying an N-substituted 2-pyrrolidone scaffold envisaged to exploit favorable interactions with the S3-S4 subsites and connected to an invariant Leu-Gln P2-P1 recognition element. Several inhibitors showed nanomolar antiviral activity in enzyme and cell-based assays, with no significant cytotoxicity. High-resolution crystal structures of inhibitors bound to the 3CLpro were determined to probe and identify the molecular determinants associated with binding, to inform the structure-guided optimization of the inhibitors, and to confirm the mechanism of action of the inhibitors.

[18F]Flotaza for Aß Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.

Highly efficient and sensitive detection of tetracycline in environmental water: Insights into the synergistic mechanism of biomass-derived carbon dots and N-methyl pyrrolidone solvent.

The tetracycline (TC) residue in water environment has caused serious public safety issue. Thus, efficient sensing of TC is highly desirable for environmental protection. Herein, biomass-derived nitrogen-doped carbon dots (N-CDs) synthesized from natural Ophiopogon japonicus f. nanus (O. japonicus) were used for TC detection. The unique solvent synergism efficiently enhanced detection sensitivity, and the detailed sensing mechanism was deeply investigated. The blue fluorescence of N-CDs was quenched by TC via static quenching and inner filter effect. Moreover, the enhancement of green fluorescence from deprotonated TC was firstly proposed and sufficiently verified. The solvent effect of N-methyl pyrrolidone (NMP) and the fluorescence resonance energy transfer (FRET) with N-CDs achieved an instantaneous enhancement of the green emission by 64-fold. Accordingly, a ratiometric fluorescence method was constructed for rapid and sensitive sensing of TC with a low detection limit of 6.3 nM within 60 s. The synergistic effect of N-CDs and solvent assistance significantly improved the sensitivity by 7-fold compared to that in water. Remarkably, the biomass-derived N-CDs displayed low cost, good solubility, and desired stability. The deep insights into the synergism with solvent can provide prospects for the utilization of biomass-based materials and broaden the development of advanced sensors with promising applications.

Investigating clinical pharmacokinetics of brivaracetam by using a pharmacokinetic modeling approach.

The development of technology and the processing speed of computing machines have facilitated the evaluation of advanced pharmacokinetic (PK) models, making modeling processes simple and faster. The present model aims to analyze the PK of brivaracetam (BRV) in healthy and diseased populations. A comprehensive literature review was conducted to incorporate the BRV plasma concentration data and its input parameters into PK-Sim software, leading to the creation of intravenous (IV) and oral models for both populations. The developed physiologically based pharmacokinetic (PBPK) model of BRV was then assessed using the visual predictive checks, mean observed/predicted ratios (Robs/pre), and average fold error for PK parameters including the maximum systemic concentration (Cmax), the area under the curve at time 0 to t (AUC0-∞), and drug clearance (CL). The PBPK model of BRV demonstrated that mean Robs/pre ratios of the PK parameters remained within the acceptable limits when assessed against a twofold error margin. Furthermore, model predictions were carried out to assess how AUC0-∞ is affected following the administration of BRV in individuals with varying degrees of liver cirrhosis, ranging from different child-pugh (CP) scores like A, B, and C. Moreover, dose adjustments were recommended by considering the variations in Cmax and CL in various kidney disease stages (mild to severe).

Development of heterocyclic-based frameworks as potential scaffold of 5-HT1A receptor agonist and future perspectives: A review.

As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.

Biological treatment of N-methylpyrrolidone, cyclopentanone, and diethylene glycol monobutyl ether distilled residues and their effects on nitrogen removal in a full-scale wastewater treatment plant.

Manufacturing processes in semiconductor and photonics industries involve the use of a significant amount of organic solvents. Recycle and reuse of these solvents produce distillate residues and require treatment before being discharged. This study aimed to evaluate the performance of the biological treatment system in a full-scale wastewater treatment plant that treats wastewater containing distillate residues from the recycling of electronic chemicals. Batch experiments were conducted to investigate the optimal operational conditions for the full-scale wastewater treatment plant. To achieve good nitrogen removal efficiency with effluent ammonia and nitrate concentrations below 20 mg N/L and 50 mg N/L, respectively, it was suggested to control the ammonia concentration and pH of the influent below 500 mg N/L and 8.0, respectively. In addition, the biodegradability of N-methylpyrrolidone, diethylene glycol monobutyl ether, and cyclopentanone distillate residues from the electronic chemicals manufacturing process were evaluated under aerobic, anoxic, and anaerobic conditions. N-methylpyrrolidone and cyclopentanone distillate residues were suggested to be treated under anoxic condition. However, substrate inhibition occurred when using cyclopentanone distillate residue as a carbon source with chemical oxygen demand (COD) levels higher than 866 mg/L and nitrate levels higher than 415 mg N/L. Under aerobic condition, the COD from both N-methylpyrrolidone and cyclopentanone distillate residues could be easily degraded. Nevertheless, a negative effect on nitrification was observed, with a prolonged lag time for ammonia oxidation as the initial COD concentration increased. The specific ammonia oxidation rate and nitrate production rate decreased under high COD concentration contributed by N-methylpyrrolidone and cyclopentanone distillate residues. Furthermore, the biodegradability of diethylene glycol monobutyl ether distillate residue was found to be low under aerobic, anoxic, and anaerobic conditions. With respect to the abundance of nitrogen removal microorganisms in the wastewater treatment plant, results showed that Comammox may have an advantage over ammonia oxidizing bacteria under high pH conditions. In addition, Comammox may have higher resistance to environmental changes. Dominance of Comammox over ammonia oxidizing bacteria under high ammonia condition was first reported in this study.

Characterization of structure of peptidyl-tRNA hydrolase from Enterococcus faecium and its inhibition by a pyrrolinone compound.

In bacteria, peptidyl-tRNA hydrolase (Pth, E.C. 3.1.1.29) is a ubiquitous and essential enzyme for preventing the accumulation of peptidyl-tRNA and sequestration of tRNA. Pth is an esterase that cleaves the ester bond between peptide and tRNA. Here, we present the crystal structure of Pth from Enterococcus faecium (EfPth) at a resolution of 1.92 Å. The two molecules in the asymmetric unit differ in the orientation of sidechain of N66, a conserved residue of the catalytic site. Enzymatic hydrolysis of substrate α-N-BODIPY-lysyl-tRNALys (BLT) by EfPth was characterized by Michaelis-Menten parameters KM 163.5 nM and Vmax 1.9 nM/s. Compounds having pyrrolinone scaffold were tested for inhibition of Pth and one compound, 1040-C, was found to have IC50 of 180 nM. Antimicrobial activity profiling was done for 1040-C. It exhibited equipotent activity against drug-susceptible and resistant S. aureus (MRSA and VRSA) and Enterococcus (VSE and VRE) with MICs 2-8 µg/mL. 1040-C synergized with gentamicin and the combination was effective against the gentamicin resistant S. aureus strain NRS-119. 1040-C was found to reduce biofilm mass of S. aureus to an extent similar to Vancomycin. In a murine model of infection, 1040-C was able to reduce bacterial load to an extent comparable to Vancomycin.

Polymer Nanoparticles for Preferential Delivery of Drugs Only by Exploiting the Slightly Elevated Temperature of Cancer Cells and Real-Time Monitoring of Drug Release.

Rapid proliferation and a faster rate of glycolysis in cancer cells often result in an elevated local temperature (40-43 °C) at the tumor site. Nanoparticles prepared from polymers with two lower critical solution temperatures (LCSTs) can be utilized to take advantage of this subtle temperature elevation to deliver anticancer drugs preferably to the cancer cells, thereby enhancing the overall therapeutic efficacy and reducing side effects. In this direction, we synthesized N-vinyl-2-pyrrolidone (NVP) and substituted NVP (sub-NVP: C2-NVP, C4-NVP)-based polymers with precisely controlled LCSTs by varying the ratio of NVP and sub-NVP. The first LCST (LCST1) was kept below 37 °C to promote self-assembly, drug loading, and structural stability in physiological conditions and the second LCST (LCST2) was in the range of 40-43 °C to ensure mild hyperthermia-induced drug release. Additionally, covalent attachment of tetraphenylethylene (TPE, AIEgen) resulted in aggregation-induced emission in thermoresponsive micellar nanoparticles in which TPE acted as a Förster Resonance Energy Transfer (FRET) pair with the loaded anticancer drug doxorubicin (DOX). Tracking of FRET-induced fluorescence recovery of TPE molecules was utilized to confirm the real-time thermoresponsive release of DOX from nanoparticles and eventual localization of TPE in the cytoplasm and DOX in the nucleus. In vitro cellular studies such as cytotoxicity, cellular uptake, and thermoresponsive drug release showed that the DOX-loaded polymeric nanoparticles were nontoxic to normal cells (HEK-293) but significantly more effective in cancer cells (MCF-7) at 40 °C. To our knowledge, this is the first report of preferential delivery of anticancer drugs only by exploiting the slightly elevated temperature of cancer cells.

Biosynthesis, biological activities, and structure-activity relationships of decalin-containing tetramic acid derivatives isolated from fungi.

Covering: up to December 2023Decalin-containing tetramic acid derivatives, especially 3-decalinoyltetramic acids (3-DTAs), are commonly found as fungal secondary metabolites. Numerous biological activities of this class of compounds, such as antibiotic, antiviral, antifungal, antiplasmodial, and antiprotozoal properties, have been the subject of ongoing research. For this reason, these molecules have attracted a lot of interest from the scientific community and various efforts including semi-synthesis, co-culturing with bacteria and biosynthetic gene sequencing have been made to obtain more derivatives. In this review, 3-DTAs are classified into four major groups based on the absolute configuration of the bicyclic decalin ring. Their biosynthetic pathways, various biological activities, and structure-activity relationship are then introduced.

Preparation of amphiphilic poly(divinylbenzene-co-N-vinylpyrrolidone)-functionalized polydopamine magnetic nanoadsorbents for enrichment of synthetic cannabinoids in wastewater.

Concerns have been raised about synthetic cannabinoids (SCs), which are among the most often trafficked and used illegal substances. An analytical method that holds promise for determining illicit drug use in the general population is wastewater-based epidemiology (WBE). Unfortunately, the concentration of SCs in wastewater is often extremely low on account of their hydrophobic nature, thus presenting a significant obstacle to the accurate detection and quantification of SCs using WBE. In this study, we present novel magnetic nanomaterials as amphiphilic adsorbents for pretreatment of wastewater using magnetic solid phase extraction (MSPE). Polydopamine-modified Fe3O4 nanoparticles were used as the magnetic core and further functionalized with poly(divinylbenzene-N-vinylpyrrolidone). Coupled with UHPLC-MS/MS analysis, an analytical method to simultaneously detect nine SCs at trace-levels in wastewater was developed and validated, enriching 50 mL wastewater to 100 µL with limits of detection (LOD) being 0.005-0.5 ng L-1, limits of quantification (LOQ) being 0.01-1.0 ng L-1, recoveries ranging from 73.99 to 110.72%, and the intra- and inter-day precision's relative standard deviations less than 15%. In comparison to the time-consuming conventional column-based solid phase extraction, the entire MSPE procedure from sample pre-treatment to data acquisition could be finished in one hour, thus largely facilitating the WBE method for drug surveillance and control.

The cenobamate KORK study-A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add-on lacosamide, perampanel, and brivaracetam.

OBJECTIVE: In Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal-onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real-world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult-to-treat epilepsies. Our aim was to investigate the efficacy of add-on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add-on lacosamide, perampanel, and brivaracetam therapy. METHODS: Patients were enrolled from the CENKORK study, which is a prospective, non-interventional, open-label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure-free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center. RESULTS: Between June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow-up, leaving 150 cases for the 1-year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6-month and 1-year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6-month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001). SIGNIFICANCE: Add-on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs. PLAIN LANGUAGE SUMMARY: This observational study was carried out in 172 adult patients with difficult-to-treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Total Syntheses of the Structures Assigned to Denigrins A, B, C, F, and G, 3,4-Diaryl-Pyrrole and -Pyrrolidinone Alkaloids, and the Conversion of Congener B into the Co-metabolite Spirodactylone.

The title marine natural products have been prepared by total synthesis and in the case of congeners 3, 6, and 7 for the first time. Each of these was obtained by manipulation of readily prepared denigrin B (2). The structure, 3, assigned to denigrin C is shown to be incorrect. Reaction of compound 2 with DDQ has led, in high yield, to the related natural product spirodactylone (16), while treating the corresponding permethyl ether 15 with PIFA/BF3·Et2O provides compound 20, embodying an isomeric framework.

Bioactivity-Based Molecular Networking-Guided Isolation of Epicolidines A-C from the Endophytic Fungus Epicoccum sp. 1-042.

Bioactivity-based molecular networking-guided fractionation enabled the isolation of three new polycyclic tetramic acids bearing cis-decalin, epicolidines A-C (1-3), along with one known compound, PF 1052 (4), from the endophytic fungus Epicoccum sp. 1-042 collected in Tibet, China. Their structures were assigned on the basis of extensive spectroscopic data, partial hydrolysis, advanced Marfey's method, quantum chemistry calculations, and X-ray diffraction analysis. Compounds 2-4 displayed promising activities against Gram-positive bacteria in vitro. Particularly, compound 4 displayed remarkable potential against vancomycin-resistant Enterococcus faecium (VRE) with an MIC value of 0.25 µg/mL, lower than the MIC (0.5 µg/mL) of the antibiotic combination quinupristin/dalfopristin (Q/D). In a further in vivo study, compound 4 increased the survival rate to 100% in the VRE-G. mellonella infection model at a concentration of 10 mg/kg.

An injectable, nanostructured implant for the delivery of adenosine triphosphate: towards long-acting formulations of small, hydrophilic drugs.

While long-acting injectable treatments are gaining increasing interest in managing chronic diseases, the available drug delivery systems almost exclusively rely on hydrophobic matrixes, limiting their application to either hydrophobic drugs or large and hydrophilic molecules such as peptides. To address the technological lock for long-acting delivery systems tailored to small, hydrophilic drugs such as anticancer and antiviral nucleoside/nucleotide analogues, we have synthesized and characterized an original approach with a multi-scale structure: (i) a nucleotide (adenosine triphosphate, ATP) is first incorporated in hydrophilic chitosan-Fe(III) nanogels; (ii) these nanogels are then transferred by freeze-drying and resuspension into a water-free, hydrophobic medium containing PLGA and an organic solvent, N-methyl-2-pyrrolidone. We show that this specific association allows an injectable and homogeneous dispersion, able to form in situ implants upon injection in physiological or aqueous environments. This system releases ATP in vitro without any burst effect in a two-step mechanism, first as nanogels acting as an intermediate reservoir over a week, then as free drug over several weeks. In vivo studies confirmed the potential of such nanostructured implants for sustained drug release following subcutaneous injection to mice hock, opening perspectives for sustained and targeted delivery through the lymphatic system.

New insights into algal-bacterial sludge granulation based on the tightly-bound extracellular polymeric substances regulation in response to N-Methylpyrrolidone.

Algal-bacterial granular sludge (ABGS) system is promising in wastewater treatment for its potential in energy-neutrality and carbon-neutrality. However, traditional cultivation of ABGS poses significant challenges attributable to its long start-up period and high energy consumption. Extracellular polymeric substances (EPS), which could be stimulated as a self-defense strategy in cells under toxic contaminants stress, has been considered to contribute to the ABGS granulation process. In this study, photogranulation of ABGS by EPS regulation in response to varying loading rates of N-Methylpyrrolidone (NMP) was investigated for the first time. The results indicated the formation of ABGS with a maximum average diameter of ∼3.3 mm and an exceptionally low SVI5 value of 67 ± 2 mL g-1 under an NMP loading rate of 125 mg L-1 d-1, thereby demonstrating outstanding settleability. Besides, almost complete removal of 300 mg L-1 NMP could be achieved at hydraulic retention time of 48 h, accompanied by chemical oxygen demand (COD) and total nitrogen (TN) removal efficiencies higher than 90 % and 70 %, respectively. Moreover, possible degradation pathway and metabolism mechanism in the ABGS system for enhanced removal of NMP and nitrogen were proposed. In this ABGS system, the mycelium with network structure constituted by filamentous microorganisms was a prerequisite for photogranulation, instead of necessarily leading to granulation. Stress of 100-150 mg L-1 d-1 NMP loading rate stimulated tightly-bound EPS (TB-EPS) variation, resulting in rapid photogranulation. The crucial role of TB-EPS was revealed with the involved mechanisms being clarified. This study provides a novel insight into ABGS development based on the TB-EPS regulation by NMP, which is significant for achieving the manipulation of photogranules.

Development of iodine based sustained release antimicrobial coatings for polyurethane voice prostheses.

Voice prostheses are known to fail in few weeks to several months of implantation due to the clogging mainly caused by microbial biofilm formation, which is a cause of concern. Iodine is a known broad-spectrum biocide and is reported to easily form complexes with various polymers. For long term device disinfection, strong iodine complexation that offers sustained iodine release for a prolonged period is essential. The present research work deals with the synthesis of a poly(methyl methacrylate-n-butyl acrylate-N-vinyl-2-pyrrolidone) (poly[MMA-BA-NVP]) tercopolymer through free radical polymerization for surface coating thermoplastic polyurethane (TPU) based voice prostheses. The NVP content in the tercopolymer was varied from 20% to 50% to optimise iodine loading and subsequent release. Base TPU coated with the tercopolymer was treated with 4% aqueous iodine solution at room temperature (28 ± 3 °C) for two hours. It was observed that the tercopolymer containing 35% N-vinyl-2-pyrrolidone (NVP), 32.5% methyl methacrylate (MMA) and 32.5% butyl acrylate (nBA) gave a stable coating on TPUs together with sustained iodine release for a prolonged period. Furthermore, the tercopolymer coated and iodine loaded TPUs exhibited excellent antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli.

Time-course of drug-related psychiatric and behavioral treatment-emergent adverse events during brivaracetam treatment in adults with focal-onset seizures.

OBJECTIVE: We previously analyzed data from three phase lll trials of adjunctive brivaracetam (BRV) in adults showing that the incidence and prevalence of drug-related central nervous system treatment-emergent adverse events (TEAEs) quickly peaked and decreased over several weeks following BRV treatment initiation. However, that analysis did not assess psychiatric and behavioral side effects which can occur with antiseizure medication (ASM) treatment. Here, we investigate the time-course of psychiatric and behavioral TEAEs by week of BRV treatment and how these TEAEs were managed. METHODS: Data were pooled from three trials (N01252 [NCT00490035]; N01253 [NCT00464269]; N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal-onset seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the incidence and prevalence of drug-related psychiatric or behavioral TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) or placebo (PBO) during the 12-week treatment period. A logistic regression model was used to determine if psychiatric or behavioral comorbid conditions were predictors for drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. RESULTS: A total of 803 patients received BRV 50-200 mg/day, and 459 patients received PBO. Drug-related psychiatric or behavioral TEAEs were reported by 11.0 % of patients during adjunctive BRV treatment (PBO: 4.8 %) with onset early after BRV initiation (median time to onset of first drug-related psychiatric or behavioral TEAE: 15 days). Incidence peaked at week 1 and decreased over the first 4 weeks following BRV initiation. Prevalence peaked at week 4 and then remained stable between weeks 5-12. In an analysis excluding patients on concomitant levetiracetam (BRV: n = 744; PBO: n = 422), the incidence of drug-related psychiatric or behavioral TEAEs was similar to the incidence in the overall population. The most common drug-related psychiatric or behavioral TEAEs were irritability, insomnia, depression, and anxiety. Only 2 % of patients discontinued BRV due to psychiatric or behavioral TEAEs (PBO: 1.3 %), while most patients on BRV who reported drug-related psychiatric or behavioral TEAEs did not require a change in dose (84.1 %; PBO: 63.6 %). A history of psychiatric or behavioral comorbid conditions (not ongoing at BRV initiation) was not associated with an increased likelihood of drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. Ongoing psychiatric or behavioral comorbid conditions at BRV initiation increased the likelihood of drug-related psychiatric or behavioral TEAEs, but not the likelihood of BRV discontinuation due to psychiatric or behavioral TEAEs. CONCLUSIONS: Drug-related psychiatric and behavioral TEAEs occurred early during BRV treatment, and most patients did not require a change in BRV dose. These data can help guide clinician monitoring and patient expectations after starting BRV.