Sustainable Implementation of Physician-Pharmacist Collaborative Clinics for Diabetes Management in Primary Healthcare Centers: A Qualitative Study.

BACKGROUND: Although physician-pharmacist collaborative clinics for diabetes management have been shown to be effective and cost-effective worldwide, there is limited understanding of the factors that influence their sustainable implementation. This study aims to identify the associated factors and provide sustainability strategy to better implement physician-pharmacist collaborative clinics for diabetes management in primary healthcare centers in China. METHODS: A sample of 43 participants were participated in face-to-face, in-depth, semi-structured interviews. Consolidated Framework for Implementation Research was used to identify facilitators and barriers to implementing physician-pharmacist collaborative clinics for diabetes management in primary healthcare centers, and to explore discriminating factors between low and high implementation units. A sustainable strategy repository based on dynamic sustainability framework was established to inform further implementation. RESULTS: This study demonstrated that clear recognition of intervention benefits, urgent needs of patients, adaptive and tailored plan, highly collaborative teamwork and leadership support were the major facilitators, while the major barriers included process complexity, large number and poor health literacy of patients in primary areas, inappropriate staffing arrangements, weak financial incentives and inadequate staff competencies. Six constructs were identified to distinguish between high and low implementation units. Sixteen strategies were developed to foster the implementation of physician-pharmacist collaborative clinics, targeting Intervention, Practice setting, and Ecological system. CONCLUSION: This qualitative study demonstrated facilitators and barriers to implementing physician-pharmacist collaborative clinics for diabetes management in primary healthcare centers and developed theory-based strategies for further promotion, which has the potential to improve the management of diabetes and other chronic diseases in under-resourced areas.

Naodesheng Pills Ameliorate Cerebral Ischemia Reperfusion-Induced Ferroptosis via Inhibition of the ERK1/2 Signaling Pathway.

Background: Ferroptosis plays a crucial role in the occurrence and development of cerebral ischemia-reperfusion (I/R) injury and is regulated by mitogen-activated protein kinase 1/2 (ERK1/2). In China, Naodesheng Pills (NDSP) are prescribed to prevent and treat cerebrosclerosis and stroke. However, the protective effects and mechanism of action of NDSP against cerebral I/R-induced ferroptosis remain unclear. We investigated whether NDSP exerts its protective effects against I/R injury by regulating ferroptosis and aimed to elucidate the underlying mechanisms. Methods: The efficacy of NDSP was evaluated using a Sprague-Dawley rat model of middle cerebral artery occlusion and an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) model. Brain injury was assessed using 2,3,5-triphenyltetrazolium chloride (TTC), hematoxylin and eosin staining, Nissl staining, and neurological scoring. Western blotting was performed to determine the expression levels of glutathione peroxidase 4 (GPX4), divalent metal-ion transporter-1 (DMT1), solute carrier family 7 member 11 (SLC7A11), and transferrin receptor 1 (TFR1). Iron levels, oxidative stress, and mitochondrial morphology were also evaluated. Network pharmacology was used to assess the associated mechanisms. Results: NDSP (1.08 g/kg) significantly improved cerebral infarct area, cerebral water content, neurological scores, and cerebral tissue damage. Furthermore, NDSP inhibited I/R- and OGD/R-induced ferroptosis, as evidenced by the increased protein expression of GPX4 and SLC7A11, suppression of TFR1 and DMT1, and an overall reduction in oxidative stress and Fe2+ levels. The protective effects of NDSP in vitro were abolished by the GPX4 inhibitor RSL3. Network pharmacology analysis revealed that ERK1/2 was the core target gene and that NDSP reduced the amount of phosphorylated ERK1/2. Conclusion: NDSP exerts its protective effects against I/R by inhibiting cerebral I/R-induced ferroptosis, and this mechanism is associated with the regulation of ferroptosis via the ERK1/2 signaling pathway.

Safe Induction of Acute Inflammation with Enhanced Antitumor Immunity by Hydrogel-Mediated Outer Membrane Vesicle Delivery.

Acute inflammation has the potential for the recruitment of immune cells, inhibiting tumor angiogenesis, metastasis, and drug resistance thereby overcoming the tumor immunosuppressive microenvironment caused by chronic inflammation. Here, an acute inflammation inducer using bacteria outer membrane vesicles (OMVs) loaded in thermal-sensitive hydrogel (named OMVs-gel) for localized and controlled release of OMVs in tumor sites is proposed. OMVs trigger neutrophil recruitment and amplify acute inflammation inside tumor tissues. The hydrogel ensures drastic inflammation is confined within the tumor, addressing biosafety concerns that the direct administration of free OMVs may cause fatal effects. This strategy eradicated solid tumors safely and rapidly. The study further elucidates one of the possible immune mechanisms of OMVs-gel therapy, which involves the assembly of antitumor neutrophils and elastase release for selective tumor killing. Additionally, tumor vascular destruction induced by OMVs-gel results in tumor darkening, allowing for combinational photothermal therapy. The findings suggest that the use of OMVs-gel can safely induce acute inflammation and enhance antitumor immunity, representing a promising strategy to promote acute inflammation application in tumor immunotherapy.

Biomimetic nanodecoys deliver cholesterol-modified heteroduplex oligonucleotide to target dopaminergic neurons for the treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of α-synuclein (α-syn) aggregates called Lewy bodies leading to the gradual loss of dopaminergic (DA) neurons in the substantia nigra. Although α-syn expression can be attenuated by antisense oligonucleotides (ASOs) and heteroduplex oligonucleotide (HDO) by intracerebroventricular (ICV) injection, the challenge to peripheral targeted delivery of oligonucleotide safely and effectively into DA neurons remains unresolved. Here, we designed a new DNA/DNA double-stranded (complementary DNA, coDNA) molecule with cholesterol conjugation (Chol-HDO (coDNA)) based on an α-syn-ASO sequence and evaluated its silence efficiency. Further, Chol-HDO@LMNPs, Chol-HDO-loaded, cerebrovascular endothelial cell membrane with DSPE-PEG2000-levodopa modification (L-DOPA-CECm)-coated nanoparticles (NPs), were developed for the targeted treatment of PD by tail intravenous injection. CECm facilitated the blood-brain barrier (BBB) penetration of NPs, together with cholesterol escaped from reticuloendothelial system uptake, as well as L-DOPA was decarboxylated into dopamine which promoted the NPs toward the PD site for DA neuron regeneration. The behavioral tests demonstrated that the nanodecoys improved the efficacy of HDO on PD mice. These findings provide insights into the development of biomimetic nanodecoys loading HDO for precise therapy of PD. STATEMENT OF SIGNIFICANCE: The accumulation of α-synuclein (α-syn) aggregates is a hallmark of PD. Our previous study designed a specific antisense oligonucleotide (ASO) targeting human SNCA, but the traumatic intracerebroventricular (ICV) is not conducive to clinical application. Here, we further optimize the ASO by creating a DNA/DNA double-stranded molecule with cholesterol-conjugated, named Chol-HDO (coDNA), and develop a DA-targeted biomimetic nanodecoy Chol-HDO@LMNPs by engineering cerebrovascular endothelial cells membranes (CECm) with DSPE-PEG2000 and L-DOPA. The in vivo results demonstrated that tail vein injection of Chol-HDO@LMNPs could target DA neurons in the brain and ameliorate motor deficits in a PD mouse model. This investigation provides a promising peripheral delivery platform of L-DOPA-CECm nanodecoy loaded with a new Chol-HDO (coDNA) targeting DA neurons in PD therapy.

Bacteria-based immunotherapy for cancer: a systematic review of preclinical studies.

Immunotherapy has been emerging as a powerful strategy for cancer management. Recently, accumulating evidence has demonstrated that bacteria-based immunotherapy including naive bacteria, bacterial components, and bacterial derivatives, can modulate immune response via various cellular and molecular pathways. The key mechanisms of bacterial antitumor immunity include inducing immune cells to kill tumor cells directly or reverse the immunosuppressive microenvironment. Currently, bacterial antigens synthesized as vaccine candidates by bioengineering technology are novel antitumor immunotherapy. Especially the combination therapy of bacterial vaccine with conventional therapies may further achieve enhanced therapeutic benefits against cancers. However, the clinical translation of bacteria-based immunotherapy is limited for biosafety concerns and non-uniform production standards. In this review, we aim to summarize immunotherapy strategies based on advanced bacterial therapeutics and discuss their potential for cancer management, we will also propose approaches for optimizing bacteria-based immunotherapy for facilitating clinical translation.

Coaxial electrostatic spray-based preparation of localization missile liposomes on a microfluidic chip for targeted treatment of triple-negative breast cancer.

Due to triple-negative breast cancer (TNBC) lacking specific targets for efficient therapies, nanoparticles have been widely developed to enhance efficacy and reduce the toxicity of chemotherapeutics. We prepared unique liposomes containing PTX and DOX by microfluidics-based coaxial electrostatic spray method, which have a uniform particle size, high drug loading capacity, and good stability. Meanwhile, the cRGD peptide was fused with the lipid membrane to form PTX/DOX@cRGD-Lipo, which played a GPS role in locating tumor neovascularization and further targeting TNBC cells where both overexpress αvß3. The PTX/DOX@cRGD-Lipo showed synergistic anti-tumor activity of double drugs and enhanced tumor cell apoptosis. Fluorescence microscopy and flow cytometry showed that the co-loaded targeted liposomes could be effectively absorbed by MDA-MB-231 and 4T1 cells and then released the content. In addition, the PTX/DOX@cRGD-Lipo presented excellent targeting biodistribution in vivo and a higher tumor growth inhibition rate in the orthotopic tumor mouse model. All results suggested that the double drug-loaded targeted liposome could be a promising treatment modality for TNBC.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Bacterial outer membrane vesicles-based therapeutic platform eradicates triple-negative breast tumor by combinational photodynamic/chemo-/immunotherapy.

Bacterial outer membrane vesicles (OMVs) are potent immuno-stimulating agents and have the potentials to be bioengineered as platforms for antitumor nanomedicine. In this study, OMVs are demonstrated as promising antitumor therapeutics. OMVs can lead to beneficial M2-to-M1 polarization of macrophages and induce pyroptosis to enhance antitumor immunity, but the therapeutic window of OMVs is narrow for its toxicity. We propose a bioengineering strategy to enhance the tumor-targeting ability of OMVs by macrophage-mediated delivery and improve the antitumor efficacy by co-loading of photosensitizer chlorin e6 (Ce6) and chemotherapeutic drug doxorubicin (DOX) into OMVs as a therapeutic platform. We demonstrate that systemic injection of the DOX/Ce6-OMVs@M therapeutic platform, providing combinational photodynamic/chemo-/immunotherapy, eradicates triple-negative breast tumors in mice without side effects. Importantly, this strategy also effectively prevents tumor metastasis to the lung. This OMVs-based strategy with bioengineering may serve as a powerful therapeutic platform for a synergic antitumor therapy.

Functional insights from targeted imaging BACE1: the first near-infrared fluorescent probe for Alzheimer's disease diagnosis.

BACKGROUND: ß-Secretase (BACE1) is the vital enzyme in the pathogenic processes of Alzheimer's disease (AD). However, the development of a powerful tool with sensitivity for BACE1 determination in vivo is a challenge. METHODS: A novel NIR fluorescent probe HBAE was synthetized from 2-hydroxy-3-methylbenzaldehyde and 2-amino-benzenethiol by 5 steps. The fluorescence mechanism in the ESIPT systems of HBAE probe was insighted with time-dependent density functional theory (TD-DFT) at the TDPBE0 level with the def2-TZVP approach. The corresponding docking between HBAE and BACE1 (PDB: 5I3Y) was performed through the ducking method by DOCK6.8. Then the BBB permeability of HBAE is verified by transwell orifice plate. 22-month-old male AD-model (5XFAD) mice and age-matched wild-type mice were employed to observe the brain kinetics by intravenous injection. Finally, Immunohistochemistry was performed on the AD brain section to reveal the levels of BACE1 in hippocampus and cortex areas and other regions in AD mice through the brain tissue slices by HBAE. RESULTS: The NIR fluorescent probe HBAE was successfully applied in imaging BACE1 in AD model mice. The capability of HBAE in reflecting different level of BACE1 was performed by the specific imaging of the hippocampus region. CONCLUSIONS: We reported the first ESIPT near-infrared fluorescence probe HBAE for monitoring endogenous BACE1 in the AD live model mice, thus offering a versatile chemical tool for visualizing in the pathological processes of AD live brains. Remarkably, high resolution images showed the localization of red fluorescence stains in hippocampus of the AD brain. This study provides a promising way for functional insights from protein BACE1 in vivo.

Nonviral delivery systems for antisense oligonucleotide therapeutics.

Antisense oligonucleotides (ASOs) are an important tool for the treatment of many genetic disorders. However, similar to other gene drugs, vectors are often required to protect them from degradation and clearance, and to accomplish their transport in vivo. Compared with viral vectors, artificial nonviral nanoparticles have a variety of design, synthesis, and formulation possibilities that can be selected to accomplish protection and delivery for specific applications, and they have served critical therapeutic purposes in animal model research and clinical applications, allowing safe and efficient gene delivery processes into the target cells. We believe that as new ASO drugs develop, the exploration for corresponding nonviral vectors is inevitable. Intensive development of nonviral vectors with improved delivery strategies based on specific targets can continue to expand the value of ASO therapeutic approaches. Here, we provide an overview of current nonviral delivery strategies, including ASOs modifications, action mechanisms, and multi-carrier methods, which aim to address the irreplaceable role of nonviral vectors in the progressive development of ASOs delivery.

Apoptotic bodies for advanced drug delivery and therapy.

Extracellular vesicles (EVs) have emerged as promising candidates for multiple biomedical applications. Major types of EVs include exosomes, microvesicles, and apoptotic bodies (ABs). ABs are conferred most properties from parent cells in the final stages of apoptosis. A wide variety of sources and stable morphological features are endowed to ABs by the rigorous apoptotic program. ABs accommodate more functional biomolecules by relying on the larger volume and maintaining their naturalness in circulation. The predominant body surface ratio of ABs facilitates their recognition by recipient cells and is advantageous for interactions with microenvironments. ABs can modulate and alleviate symptoms of numerous diseases for their origins, circulation, and high biocompatibility. In addition, ABs have been emerging in disease diagnosis, immunotherapy, regenerative therapy, and drug delivery. Here, we aim to present a thorough discussion on current knowledge about ABs. Of particular interest, we will summarize the application of AB-based strategies for diagnosis and disease therapy. Perspectives for the development of ABs in biomedical applications are highlighted.

Ferroptosis in inflammatory arthritis: A promising future.

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which is characterized by mitochondrial morphological changes and has a complex regulatory network. Ferroptosis has been gradually emphasized in the pathogenesis of inflammatory arthritis. In this review, we summarized the relevant research on ferroptosis in various inflammatory arthritis including rheumatoid arthritis (RA), osteoarthritis, gout arthritis, and ankylosing spondylitis, and focused on the relationship between RA and ferroptosis. In patients with RA and animal models of RA, there was evidence of iron overload and lipid peroxidation, as well as mitochondrial dysfunction that may be associated with ferroptosis. Ferroptosis inducers have shown good application prospects in tumor therapy, and some anti-rheumatic drugs such as methotrexate and sulfasalazine have been shown to have ferroptosis modulating effects. These phenomena suggest that the role of ferroptosis in the pathogenesis of inflammatory arthritis will be worth further study. The development of therapeutic strategies targeting ferroptosis for patients with inflammatory arthritis may be a promising future.

Tizoxanide Promotes Apoptosis in Glioblastoma by Inhibiting CDK1 Activity.

The antiparasitic drug nitazoxanide (NTZ) has received considerable attention for its potential in cancer therapy. In this study, we demonstrate that tizoxanide (TIZ), an active metabolite of NTZ, exhibits antiglioma activity in vitro and in vivo by inducing G2/M cell cycle arrest and apoptosis. In vitro, TIZ dose-dependently inhibited the proliferation of U87, U118, and A172 human glioblastoma (GBM) cells at 48 h with IC50 values of 1.10, 2.31, and 0.73 µM, respectively. Treatment with TIZ (1 and 10 µM) also dose-dependently inhibited the colony formation of these GBM cells and accumulated ROS damage in the nucleus. In silico target fishing combined with network pharmacological disease spectrum analyses of GBM revealed that cycle-dependent kinase 1 (CDK1) is the most compatible target for TIZ and molecular docking by Molecule Operating Environment (MOE) software confirmed it. Mechanistically, TIZ inhibited the phosphorylation of CDK1 at Thr161 and decreased the activity of the CDK1/cyclin B1 complex, arresting the cell cycle at the G2/M phase. TIZ may induce apoptosis via the ROS-mediated apoptotic pathway. In vivo, TIZ suppressed the growth of established subcutaneous and intracranial orthotopic xenograft models of GBM without causing obvious side effects and prolonged the survival of nude mice bearing glioma. Taken together, our results demonstrated that TIZ might be a promising chemotherapy drug in the treatment of GBM.

A monomeric polysaccharide from Polygonatum sibiricum improves cognitive functions in a model of Alzheimer's disease by reshaping the gut microbiota.

Polygonatum sibiricum polysaccharides (PSPs) have the function of nourishing the nerves and beneficial intelligence, but the underlying mechanisms remain unclear. Here we initially isolated and purified a monomeric polysaccharide named PSP-1 from PSPs. UV and IR were utilized for characterizing PSP-1. The molecular weight of PSP-1 was 18.796 kDa. Utilizing 5xFAD mice as a research model, we identified that the initial time of PSP-1 oral administration was 3 months of age for mice by determining the 16S rRNA of fecal samples from wild type (WT) and 5xFAD mice at 3 months or 6 months of age. A 3-month course of PSP-1 improved the pathological behaviors related to memory and cognition, prevented synaptic loss, enhanced microglial phagocytosis of Aß plaques, and decreased the concentrations of Aß1-40 and Aß1-42 in the brains of 5xFAD mice. Moreover, PSP-1 reconstructed the gut microbiota composition, including reducing the relative abundance of Helicobacter, and increasing Akkermansia muciniphila. The gut barrier integrity damage, the inflammatory responses, and the intestinal Aß deposition were prevented by the PSP-1 treatment. The present study identified a monomeric polysaccharide purified from PSPs that significantly attenuates the cognitive deficits in 5xFAD mice, which could be partly explained by the reshaped gut microbiome.

Establishing and evaluating physician-pharmacist collaborative clinics to manage patients with type 2 diabetes in primary hospitals in Hunan province: study protocol of a multi-site randomized controlled trial in the era of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has exerted an unprecedented and universal impact on global health system, resulting in noticeable challenges in traditional chronic disease care, of which diabetes was reported to be most influenced by the reduction in healthcare resources in the pandemic. China has the world's largest diabetes population, and current diabetes management in China is unsatisfactory, particularly in rural areas. Studies in developed countries have demonstrated that physician-pharmacist collaborative clinics are efficient and cost-effective for diabetes management, but little is known if this mode could be adapted in primary hospitals in China. The aim of this proposed study is to develop and evaluate physician-pharmacist collaborative clinics to manage type 2 diabetes mellitus (T2DM) in primary hospitals in Hunan province. METHODS: A multi-site randomized controlled trial will be conducted to evaluate the effectiveness and cost-effectiveness of the physician-pharmacist collaborative clinics compared with usual care for Chinese patients with T2DM. Six primary hospitals will participate in the study, which will recruit 600 eligible patients. Patients in the intervention group will receive services from both physicians and pharmacists in the collaborative clinics, while the control group will receive usual care from physicians. Patients will be followed up at the 3rd, 6th, 9th and 12th month. Comparison between the two groups will be conducted by assessing the clinical parameters, process indicators and costs on diabetes. A satisfaction survey will also be carried out at the end of the study. DISCUSSION: If effective, the physician-pharmacist collaborative clinics can be adapted and used in primary hospitals of China to improve glycemic control, enhance medication adherence, decrease incidence of complications and reduce patients' dependence on physicians. Findings from the present study are meaningful for developing evidence-based diabetes care policy in rural China, especially in the COVID-19 pandemic era. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000031839 , Registered 12 April 2020.

Hybrid Cell Membrane-Functionalized Biomimetic Nanoparticles for Targeted Therapy of Osteosarcoma.

PURPOSE: In order to prepare a biomimetic nano-carrier which has inflammatory chemotaxis, homologous targeting and reduce immune clearance, for targeted chemotherapy of osteosarcoma, we fabricated the paclitaxel-loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles coated with 143B-RAW hybrid membrane (PTX-PLGA@[143B-RAW] NPs) and evaluate its anti-cancer efficacy in vitro and vivo. METHODS: PTX-PLGA@[143B-RAW] NPs were prepared by the ultrasonic method and were characterized by size, zeta potential, polymer dispersion index (PDI), Coomassie bright blue staining, transmission electron microscopy (TEM) and high performance liquid chromatography (HPLC). Cellular uptake, cell viability assay, flow cytometry and chemotactic effect of PTX-PLGA@[143B-RAW] NPs were evaluated in vitro. Biodistribution, anti-cancer therapeutic efficacy and safety of PTX-PLGA@[143B-RAW] NPs were evaluated in 143B osteosarcoma xenograft mice. RESULTS: The hybrid membrane successfully coated onto the surface of PLGA nanoparticles. PTX-PLGA@[143B-RAW] NPs had a drug loading capacity of 4.24 ± 0.02% and showed targeting ability to osteosarcoma. PTX-PLGA@[143B-RAW] NPs showed high cellular uptake and improved anti-cancer efficacy against 143B cells. More importantly, PTX-PLGA@[143B-RAW] NPs treatment suppressed tumor growth in tumor-bearing mice with minimal damage to normal tissues. CONCLUSION: PTX-PLGA@[143B-RAW] NPs could be used for targeted drug delivery and osteosarcoma therapy.

Recent Advance of Nanomaterial-Mediated Tumor Therapies in the Past Five Years.

Cancer has posed a major threat to human life and health with a rapidly increasing number of patients. The complexity and refractory of tumors have brought great challenges to tumor treatment. In recent years, nanomaterials and nanotechnology have attracted more attention and greatly improved the efficiency of tumor therapies and significantly prolonged the survival period, whether for traditional tumor treatment methods such as radiotherapy, or emerging methods, such as phototherapy and immunotherapy, sonodynamic therapy, chemodynamic therapy and RNA interference therapeutics. Various monotherapies have obtained positive results, while combination therapies are further proposed to prevent incomplete eradication and recurrence of tumors, strengthen tumor killing efficacy with minimal side effects. In view of the complementary promotion effects between different therapies, it is vital to utilize nanomaterials as the link between monotherapies to achieve synergistic performance. Further development of nanomaterials with efficient tumor-killing effect and better biosafety is more in line with the needs of clinical treatment. In a word, the development of nanomaterials provides a promising way for tumor treatment, and here we will review the emerging nanomaterials towards radiotherapy, phototherapy and immunotherapy, and summarized the developed nanocarriers applied for the tumor combination therapies in the past 5 years, besides, the advances of some other novel therapies such as sonodynamic therapy, chemodynamic therapy, and RNA interference therapeutics have also been mentioned.

The Microglial membrane receptor TREM2 mediates exosome secretion to promote phagocytosis of amyloid-ß by microglia.

Considerable evidence links the microglial transmembrane receptor TREM2 to the progression of Alzheimer's disease through its involvement in Aß phagocytosis by microglia. While previous studies have mainly focused on the phagocytic regulation of microglia itself, the antigen presentation of microglial exosomes in the process of immunity has been less investigated. Here, we identified TREM2 expressed on the membrane of microglial exosomes and found that it controlled exosome secretion without affecting exosome size. Microglial exosomes bind to Aß in a TREM2-dependent manner, which changes the inflammatory environment around Aß and promotes microglia to phagocytose Aß. These findings delineate a novel exosome-mediated mechanism of microglial cell-Aß crosstalk that facilitates Aß clearance under either physiological or pathological conditions in the central nervous system.

Recent progress of macrophage vesicle-based drug delivery systems.

Nanoparticle drug delivery systems (NDDSs) are promising platforms for efficient delivery of drugs. In the past decades, many nanomedicines have received clinical approval and completed translation. With the rapid advance of nanobiotechnology, natural vectors are emerging as novel strategies to carry and delivery nanoparticles and drugs for biomedical applications. Among diverse types of cells, macrophage is of great interest for their essential roles in inflammatory and immune responses. Macrophage-derived vesicles (MVs), including exosomes, microvesicles, and those from reconstructed membranes, may inherit the chemotactic migration ability and high biocompatibility. The unique properties of MVs make them competing candidates as novel drug delivery systems for precision nanomedicine. In this review, the advantages and disadvantages of existing NDDSs and MV-based drug delivery systems (MVDDSs) were compared. Then, we summarized the potential applications of MVDDSs and discuss future perspectives. The development of MVDDS may provide avenues for the treatment of diseases involving an inflammatory process.

Does Prolonged Infusion Time Really Improve the Efficacy of Meropenem Therapy? A Prospective Study in Critically Ill Patients.

INTRODUCTION: Meropenem is a carbapenem antibiotic, which has demonstrated excellent antimicrobial activity against gram-negative clinical isolates. It is also commonly used in critically ill patients. This study aimed to determine the pharmacokinetics/pharmacodynamics of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. METHODS: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix. RESULTS: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), and volume of peripheral compartment (V2) were 6.15 l/h, 2.83 l/h, 17.40 l, and 17.48 l, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance ≤ 60 ml/min and uric acid > 400 µmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/l, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC < 4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4 MIC, no significant statistical difference was observed in critically ill patients. CONCLUSIONS: Critically ill patients with lower creatinine clearance and higher uric acid levels tended to need a lower dosage of meropenem. Prolonged infusion time was not always beneficial for those who needed a higher therapeutic target (100% fT > MIC, 100% fT > 4 MIC) or with MIC > 4 mg/l. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients. TRIAL REGISTRATION: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Meropenem is commonly used empirically or targeted in critically ill patients for bacterial infection. Many studies have reported that prolonged infusion time can improve the efficacy of meropenem therapy. However, we are skeptical about that. Meanwhile, prolonged injections can sometimes cause mobility problems for patients. A quantitative method is used to evaluate meropenem use. It is called the population pharmacokinetic model or pharmacodynamic study. Using this method, we found two significant influencing factors of meropenem metabolism: creatinine clearance and uric acid level. It is likely that patients with a lower level of creatinine clearance and a high uric acid level tend to require lower dosages of meropenem. As for the effect of infusion time, Monte Carlo simulation was used, which can do 3000 simulations on an individual. The result was complex. We found infusion time was beneficial only when bacteria were sensitive to meropenem. The evidence suggests that prolonged injection duration sometimes does not significantly improve the outcome of antimicrobial therapy.