A Mechanically Resilient Soft Hydrogel Improves Drug Delivery for Treating Post-Traumatic Osteoarthritis in Physically Active Joints.

Intra-articular delivery of disease-modifying osteoarthritis drugs (DMOADs) is likely to be most effective in early post-traumatic osteoarthritis (PTOA) when symptoms are minimal and patients are physically active. DMOAD delivery systems therefore must withstand repeated mechanical loading without affecting the drug release kinetics. Although soft materials are preferred for DMOAD delivery, mechanical loading can compromise their structural integrity and disrupt drug release. Here, we report a mechanically resilient soft hydrogel that rapidly self-heals under conditions resembling human running while maintaining sustained release of the cathepsin-K inhibitor L-006235 used as a proof-of-concept DMOAD. Notably, this hydrogel outperformed a previously reported hydrogel designed for intra-articular drug delivery, used as a control in our study, which neither recovered nor maintained drug release under mechanical loading. Upon injection into mouse knee joints, the hydrogel showed consistent release kinetics of the encapsulated agent in both treadmill-running and non-running mice. In a mouse model of aggressive PTOA exacerbated by treadmill running, L-006235 hydrogel markedly reduced cartilage degeneration. To our knowledge, this is the first hydrogel proven to withstand human running conditions and enable sustained DMOAD delivery in physically active joints, and the first study demonstrating reduced disease progression in a severe PTOA model under rigorous physical activity, highlighting the hydrogel's potential for PTOA treatment in active patients.

SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction.

Members of the serine-arginine protein kinase (SRPK) family, SRPK1 and SRPK2, phosphorylate the hepatitis B core protein (Cp) and are crucial for pregenomic RNA encapsidation during viral nucleocapsid assembly. Among them, SRPK2 exhibits higher kinase activity toward Cp. In this study, we identified Cp sites that are phosphorylated by SRPK2 and demonstrated that the kinase utilizes an SRPK-specific docking groove to interact with and regulate the phosphorylation of the C-terminal arginine rich domain of Cp. We determined that direct interaction between the docking groove of SRPK2 and unphosphorylated Cp inhibited premature viral capsid assembly in vitro, whereas the phosphorylation of the viral protein reactivated the process. Pull-down assays together with the new cryo-electron microscopy structure of the HBV capsid in complex with SRPK2 revealed that the kinases decorate the surface of the viral capsid by interacting with the C-terminal domain of Cp, underscoring the importance of the docking interaction in regulating capsid assembly and pregenome packaging. Moreover, SRPK2-knockout in HepG2 cells suppressed Cp phosphorylation, indicating that SRPK2 is an important cellular kinase for HBV life cycle.

Current application and modification strategy of marine polysaccharides in tissue regeneration: A review.

Marine polysaccharides (MPs) are exceptional bioactive materials that possess unique biochemical mechanisms and pharmacological stability, making them ideal for various tissue engineering applications. Certain MPs, including agarose, alginate, carrageenan, chitosan, and glucan have been successfully employed as biological scaffolds in animal studies. As carriers of signaling molecules, scaffolds can enhance the adhesion, growth, and differentiation of somatic cells, thereby significantly improving the tissue regeneration process. However, the biological benefits of pure MPs composite scaffold are limited. Therefore, physical, chemical, enzyme modification and other methods are employed to expand its efficacy. Chemically, the structural properties of MPs scaffolds can be altered through modifications to functional groups or molecular weight reduction, thereby enhancing their biological activities. Physically, MPs hydrogels and sponges emulate the natural extracellular matrix, creating a more conducive environment for tissue repair. The porosity and high permeability of MPs membranes and nanomaterials expedite wound healing. This review explores the distinctive properties and applications of select MPs in tissue regeneration, highlighting their structural versatility and biological applicability. Additionally, we provide a brief overview of common modification strategies employed for MP scaffolds. In conclusion, MPs have significant potential and are expected to be a novel regenerative material for tissue engineering.

Biopharmaceutical applications of microbial polysaccharides as materials: A Review.

Biological characteristics of natural polymers make microbial polysaccharides an excellent choice for biopharmaceuticals. Due to its easy purifying procedure and high production efficiency, it is capable of resolving the existing application issues associated with some plant and animal polysaccharides. Furthermore, microbial polysaccharides are recognized as prospective substitutes for these polysaccharides based on the search for eco-friendly chemicals. In this review, the microstructure and properties of microbial polysaccharides are utilized to highlight their characteristics and potential medical applications. From the standpoint of pathogenic processes, in-depth explanations are provided on the effects of microbial polysaccharides as active ingredients in the treatment of human diseases, anti-aging, and drug delivery. In addition, the scholarly developments and commercial applications of microbial polysaccharides as medical raw materials are also discussed. The conclusion is that understanding the use of microbial polysaccharides in biopharmaceuticals is essential for the future development of pharmacology and therapeutic medicine.

Intravenous ketamine for depression: A clinical discussion reconsidering best practices in acute hypertension management.

Ketamine is a versatile medication with an emerging role for the treatment of numerous psychiatric conditions, including treatment resistant depression. Current psychiatry guidelines for its intravenous administration to treat depression recommend regular blood pressure monitoring and an aggressive approach to potential transient hypertensive episodes induced by ketamine infusions. While this approach is aimed at ensuring patient safety, it should be updated to align with best practice guidelines in the management of hypertension. This review defines and summarizes the currently recommended approach to the hypertensive emergency, the asymptomatic hypertensive urgency, and discusses their relevance to intravenous ketamine therapy. With an updated protocol informed by these best practice guidelines, ketamine treatment for depression may be more accessible to facilitate psychiatric treatment.

The impact of an outpatient parenteral antibiotic therapy (OPAT) clinic for adults with cellulitis: an interrupted time series study.

Emergency department (ED) patients with cellulitis requiring intravenous antibiotics may be eligible for outpatient parenteral antibiotic therapy (OPAT). The primary objective was to determine whether implementation of an OPAT clinic results in decreased hospitalizations and return ED visits for patients receiving OPAT. We conducted an interrupted time series study involving adults with cellulitis presenting to two EDs and treated with intravenous antibiotics. The intervention was the OPAT clinic, which involved follow up at 48-96 h with an infectious disease physician to determine the need for ongoing intravenous antibiotics (implemented January 1, 2014). The primary outcomes were hospital admission and return ED visits within 14 days. Secondary outcomes were treatment failure (admission after initiating OPAT) and adverse peripheral line or antibiotic events. We used an interrupted time series design with segmented regression analysis over one-year pre-intervention and one-year post-intervention. 1666 patients were included. At the end of the study period, there was a non-significant 12% absolute increase in hospital admissions (95% CI - 1.6 to 25.5%; p = 0.084) relative to what would have been expected in the absence of the intervention, but a significant 40.7% absolute reduction in return ED visits (95% CI 25.6-55.9%; p < 0.001). Treatment failure rates were < 2% and adverse events were < 6% in both groups. Implementation of an OPAT clinic significantly reduced return ED visits for cellulitis, but did not reduce hospital admission rates. An ED-to-OPAT clinic model is safe, and has a low rate of treatment failures.

Solid organ donation from the emergency department - missed donor opportunities.

OBJECTIVE: A significant gap exists between people awaiting solid organ transplantation and solid organ donors. The purpose of this study was to determine whether there were missed donors in the emergency department (ED). METHODS: We performed a health records and organ donation database review of all patients dying in a large tertiary ED from November 1, 2014 to October 31, 2017 at two campuses with 160,000 visits per year. Demographic and donor suitability data were collected. The primary outcome was missed potential solid organ donors. Missed potential donors were intubated, had a pulse, and had no donation contraindications. The secondary outcome was cases where no notification was made to the organ donation organization at all. RESULTS: There were 605 deaths in the ED. Patients had a mean age of 71.1 years, 58.3% were male, and 12.4% died of a traumatic cause. There were 10 missed potential donors. Missed potential donors had a mean age of 67.4 years, 70.0% were male, and 20.0% died from trauma. In all 10 cases, patients had withdrawal of life-sustaining therapy for medical futility, and referral for donation occurred after death. Missed ED donors could have increased hospital-wide donation up to 10.6%. No notification was made in 12 (2.0%) cases; however, none of these would have been successful solid organ donors. CONCLUSION: The ED is a source of missed organ donors. All potential donors were missed due to referral after withdrawal of life-sustaining therapy. ED physicians should consider the possibility of solid organ donation prior to the withdrawal of life-sustaining therapy.