Macrophage membrane (MMs) camouflaged near-infrared (NIR) responsive bone defect area targeting nanocarrier delivery system (BTNDS) for rapid repair: promoting osteogenesis via phototherapy and modulating immunity.

Bone defects remain a significant challenge in clinical orthopedics, but no targeted medication can solve these problems. Inspired by inflammatory targeting properties of macrophages, inflammatory microenvironment of bone defects was exploited to develop a multifunctional nanocarrier capable of targeting bone defects and promoting bone regeneration. The avidin-modified black phosphorus nanosheets (BP-Avidin, BPAvi) were combined with biotin-modified Icaritin (ICT-Biotin, ICTBio) to synthesize Icaritin (ICT)-loaded black phosphorus nanosheets (BPICT). BPICT was then coated with macrophage membranes (MMs) to obtain MMs-camouflaged BPICT (M@BPICT). Herein, MMs allowed BPICT to target bone defects area, and BPICT accelerated the release of phosphate ions (PO43-) and ICT when exposed to NIR irradiation. PO43- recruited calcium ions (Ca2+) from the microenvironment to produce Ca3(PO4)2, and ICT increased the expression of osteogenesis-related proteins. Additionally, M@BPICT can decrease M1 polarization of macrophage and expression of pro-inflammatory factors to promote osteogenesis. According to the results, M@BPICT provided bone growth factor and bone repair material, modulated inflammatory microenvironment, and activated osteogenesis-related signaling pathways to promote bone regeneration. PTT could significantly enhance these effects. This strategy not only offers a solution to the challenging problem of drug-targeted delivery in bone defects but also expands the biomedical applications of MMs-camouflaged nanocarriers.

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner.

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.

Dual-targeted nanoparticles with removing ROS inside and outside mitochondria for acute kidney injury treatment.

Mitochondrial oxidative stress and inflammation are the main pathological features of acute kidney injury (AKI). However, systemic toxicity of anti-inflammatory drugs and low bioavailability of antioxidants limit the treatment of AKI. Here, the lipid micelle nanosystem modified with l-serine was designed to improve treatment of AKI. The micelle kernels coating the antioxidant drug 4-carboxybutyl triphenylph-osphine bromide-modified curcumin (Cur-TPP) and quercetin (Que). In the cisplatin (CDDP)-induced AKI model, the nanosystem protected mitochondrial structure and improved renal function. Compared to mono-targeted group, the mitochondrial ROS content of renal tubular epithelial cells acting in the dual-target group decreased about 1.66-fold in vitro, serum creatinine (Scr) and urea nitrogen (BUN) levels were reduced by 1.5 and 1.2 mmol/L in vivo, respectively. Mechanistic studies indicated that the nanosystem inhibited the inflammatory response by interfering with the NF-κB and Nrf2 pathways. This study provides an efficient and low-toxicity strategy for AKI therapy.

Current Sample Preparation Methods and Determination Techniques for the Determination of Phthalic Acid Ester Plasticizers in Edible Oils.

In the process of production, processing, transportation, and storage of edible oils, the oils inevitably come into contact with plastic products. As a result, plasticizers migrate into edible oils, are harmful to human health, and can exhibit reproductive toxicity. Therefore, the determination of plasticizers in edible oils is very important, and a series of sample preparation methods and determination techniques have been developed for the determination of plasticizers in edible oils. Phthalic acid ester (PAE) plasticizers are the most widely used among all plasticizers. This review aims to provide a comprehensive overview of the sample preparation methods and detection techniques reported for the determination of PAEs in edible oils since 2010, focusing on sample preparation methods of edible oils combined with various separation-based analytical techniques, such as gas chromatography (GC) and liquid chromatography (LC) with different detectors. Furthermore, the advantages, disadvantages, and limitations of these techniques as well as the prospective future developments are also discussed.

Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

A Study of the Detection of SARS-CoV-2 by the Use of Electrochemiluminescent Biosensor Based on Asymmetric Polymerase Chain Reaction Amplification Strategy.

A new and reliable method has been constructed for detecting severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) open reading frames 1ab (ORF1ab) gene via highly sensitive electrochemiluminescence (ECL) biosensor technology based on highly efficient asymmetric polymerase chain reaction (asymmetric PCR) amplification strategy. This method uses magnetic particles coupled with biotin-labeled one complementary nucleic acid sequence of the SARS-CoV-2 ORF1ab gene as the magnetic capture probes, and [Formula: see text]-labeled amino-modified another complementary nucleic acid sequence as the luminescent probes, and then a detection model of magnetic capture probes-asymmetric PCR amplification nucleic acid products-[Formula: see text]-labeled luminescent probes is formed, which combines the advantages of highly efficient asymmetric PCR amplification strategy and highly sensitive ECL biosensor technology, enhancing the method sensitivity of detecting the SARS-CoV-2 ORF1ab gene. The method enables the rapid and sensitive detection of the ORF1ab gene and has a linear range of 1-[Formula: see text] copies/[Formula: see text], a regression equation of [Formula: see text] = [Formula: see text] + 2919.301 ([Formula: see text] = 0.9983, [Formula: see text] = 7), and a limit of detection (LOD) of 1 copy/[Formula: see text]. In summary, it can meet the analytical requirements for simulated saliva and urine samples and has the benefits of easy operation, reasonable reproducibility, high sensitivity, and anti-interference abilities, which can provide a reference for developing efficient field detection methods for SARS-CoV-2.

Inhibitory effect and mechanism of hirsuteine on NCI­H1299 lung cancer cell lines.

Traditionally, the bark of Uncaria rhynchophylla (UR) has been employed for the treatment of hypertension, cancer, convulsions, haemorrhage, autoimmune disorders and other ailments. The primary aim of the present study was to explore the antiproliferative activity of hirsuteine (HTE) isolated from UR over a range of concentrations in human NSCLC NCI-H1299 cells and to explore the mechanisms underlying its therapeutic efficacy. The effects of HTE on cell viability were examined using Cell Counting Kit-8 (CCK-8) and colony formation assays, while apoptosis was assessed by flow cytometry. Cell cycle progression was additionally evaluated via propidium iodide staining, while reverse transcription-quantitative PCR and western blotting methods were employed to assess the protein levels and genes related to apoptosis and progression of the cell cycle, respectively. NCI-H1299 cell proliferation was markedly suppressed by HTE in a time- and dose-dependent manner. However, clear changes in cell morphology were also induced, resulting in G0-G1 phase cell cycle arrest, which was associated with cyclin E and CDK2 downregulation. HTE additionally induced robust NSCLC NCI-H1299 cell apoptosis, downregulation of Bcl-2 and upregulation of cytoplasmic cytochrome C, Bax, Apaf1, cleaved caspase-3 and cleaved caspase-9, which together drove the observed apoptotic cell death. HTE could effectively suppress human NSCLC NCI-H1299 cell growth by inducing apoptotic death in a dose-dependent fashion in vitro, therefore elucidating the mechanism by which this phytomedicine acts as a potent anticancer compound that warrants study as a treatment for human NSCLC patients.

Enhancement of Potential Health Benefits of Insoluble Dietary Fiber from the Fruiting Body of Medicinal Mushroom Schizophyllum commune (Agaricomycetes) through Superfine Pulverization.

The objective of the current study is to reveal the influence of particle size of ground Schizophyllum commune and its extracted dietary fiber (DF) on physicochemical and antioxidant properties. Sch. commune powder and the extracted DF was ground by regular and superfine grinding, and their particle sizes were determined using laser diffraction particle size analyzer. The results indicated that superfine grinding could significantly pulverize DF particles to micro-scale; the particle size distribution presented a Gaussian distribution. The soluble DF in Sch. commune was increased effectively with superfine grinding. Sub-micronized insoluble DF showed increased total phenolic content (TPC) and ferric reducing antioxidant power (FRAP). Moreover, with particle size reduction, the oil binding capacity (OBC), nitrite ion absorption capacity (NIAC), cation-exchange capacity (CEC), cholesterol absorption capacity (CAC), and Pb ion adsorption capacity were significantly (p < 0.05) increased and the water retention capacity (WRC), swelling capacity (SC) and Cu, Zn ions adsorption capacity had no significant changes. A kind of health beneficial DF with higher soluble DF content, OBC, NIAC, CEC, CAC, Pb ion adsorption capacity and antioxidant activity (TPC and FRAP) was obtained through superfine grinding. Sch. commune DF could be potentially used as an ingredient for functional food and nutraceuticals.

Cascade nanozymes based on the "butterfly effect" for enhanced starvation therapy through the regulation of autophagy.

Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency may be weakened by autophagy, a self-protection mechanism exerted by tumors under starvation stress. Interestingly, over-activated autophagy not only improves the efficacy of starvation therapy, but also induces autophagic death. Herein, we report cascade nanozymes for enhanced starvation therapy by inducing over-activated autophagy. First, glucose oxidase (GOx) modified metal-organic frameworks (NH2-MIL88, MOF) were constructed (MOF-GOx). After loading with curcumin (Cur), Cur@MOF-GOx was further decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozymes. GOx can catalyze glucose into H2O2 and gluconic acid, which not only leads to tumor starvation, but also provides reactants for the Fenton reaction mediated by the MOF to generate hydroxyl radicals (˙OH) for chemo-dynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be over-activated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemo-dynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a "butterfly effect", which induces enhanced starvation therapy through subsequent autophagic cell death to completely break the self-protective mechanism of cancer cells, and generate ˙OH for chemo-dynamic therapy. Precise design allows for the use of cascade nanozymes to realize efficient cancer treatment and restrain metastasis.

Efficacy and Safety of Ceftazidime-Avibactam for the Treatment of Carbapenem-Resistant Enterobacterales Bloodstream Infection: a Systematic Review and Meta-Analysis.

Several clinicians use ceftazidime-avibactam (CAZ-AVI) to treat bloodstream infections (BSIs) due to carbapenem-resistant Enterobacterales (CRE), although no conclusive data support this practice. We aimed to assess the efficacy and safety of CAZ-AVI in the treatment of CRE bacteremia. PubMed, Embase, and Cochrane Library were systematically searched until 5 November 2021. Studies comparing the clinical outcome of CAZ-AVI with other regimens in CRE BSI were included if they reported data on mortality. Results were expressed as risk ratios (RRs) or mean differences with accompanying 95% confidence intervals (95% CIs). Eleven articles with 1,205 patients were included. CAZ-AVI groups showed a significantly lower 30-day mortality than control groups of other regimens (RR = 0.55, 95% CI of 0.45 to 0.68, P < 0.00001). The result is robust when a colistin-based regimen serves as the control group (RR = 0.48, 95% CI 0.33 of 0.69, P < 0.0001). In subgroup meta-analyses, the 30-day mortality was significantly lower in patients infected with CRE producing Klebsiella pneumoniae carbapenemase (RR = 0.59, 95% CI of 0.46 to 0.75, P < 0.0001). Additionally, patients in CAZ-AVI groups had a significantly higher clinical cure rate (RR = 1.75, 95% CI of 1.57 to 2.18, P < 0.00001) and lower nephrotoxicity rate (RR = 0.41, 95% CI of 0.20 to 0.84, P = 0.02). No significant differences of relapse rates were demonstrated in 2 groups (RR = 0.69, 95% CI of 0.29 to 1.66, P = 0.41). Although the current study is based on observational studies with a small sample of participants, the findings suggest that CAZ-AVI treatment is effective and safe compared with other antibiotics, including colistin, in CRE BSI. IMPORTANCE Ceftazidime-avibactam (CAZ-AVI) has been used as a frontline agent in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. However, the efficacy and safety of CAZ-AVI on carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs) remain unclear. Patients with CRE BSIs were often enrolled in small-sized clinical studies, together with other sites of infections, which reported pooled results. In this meta-analysis, the efficacy and safety were compared between CAZ-AVI and any other regimens used against CRE infections. The findings suggest that patients in the CAZ-AVI group had a significantly lower 30-day mortality than any other regimens and than colistin-based regimens. This paper provides a rationale for the use of CAZ-AVI in one of the most urgent antimicrobial-resistant infections of CRE bloodstream infections.

A Study of the Detection of SARS-CoV-2 ORF1ab Gene by the Use of Electrochemiluminescent Biosensor Based on Dual-Probe Hybridization.

To satisfy the need to develop highly sensitive methods for detecting the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and further enhance detection efficiency and capability, a new method was created for detecting SARS-CoV-2 of the open reading frames 1ab (ORF1ab) target gene by a electrochemiluminescence (ECL) biosensor based on dual-probe hybridization through the use of a detection model of "magnetic capture probes-targeted nucleic acids-Ru(bpy)32+ labeled signal probes". The detection model used magnetic particles coupled with a biotin-labeled complementary nucleic acid sequence of the SARS-CoV-2 ORF1ab target gene as the magnetic capture probes and Ru(bpy)32+ labeled amino modified another complementary nucleic acid sequence as the signal probes, which combined the advantages of the highly specific dual-probe hybridization and highly sensitive ECL biosensor technology. In the range of 0.1 fM~10 µM, the method made possible rapid and sensitive detection of the ORF1ab gene of the SARS-CoV-2 within 30 min, and the limit of detection (LOD) was 0.1 fM. The method can also meet the analytical requirements for simulated samples such as saliva and urine with the definite advantages of a simple operation without nucleic acid amplification, high sensitivity, reasonable reproducibility, and anti-interference solid abilities, expounding a new way for efficient and sensitive detection of SARS-CoV-2.

Anti-inflammatory effect of flavonoids from chestnut flowers in lipopolysaccharide-stimulated RAW 264.7 macrophages and acute lung injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Chestnut flowers were one of the by-products during chestnut industrial processing. Chestnut (Castanea mollissima Blume) flower is rich in flavonoids and has been used as a traditional medicine to treat a variety of diseases including respiratory disorders for a long history. AIM OF THE STUDY: The present study aims to investigate the potential anti-inflammatory effect of flavonoids from chestnut flower (FCF) in lipopolysaccharide (LPS)-treated RAW 264.7 cells and stimulated acute lung injury (ALI) in mice. MATERIALS AND METHODS: HPLC-ESI-MS/MS was applied to identify flavonoids from Chestnut flower. The ROS content in cells and lung tissue was measured by flow cytometry. The malondialdehyde (MDA) content, superoxide dismutase (SOD) activity and glutathione (GSH) content in cells and bronchoalveolar lavage fluid (BALF) was analyzed by photometry. Furthermore, the level of pro-inflammatory factors was analyzed by ELISA, and the expression of inflammatory gene mRNA by fluorescence quantitative PCR. H&E staining was used to evaluate the degree of lung tissue injury in mice. MPO activity was used to measure the degree of neutrophil infiltration. Total protein content was detected by BCA method. RESULTS: A total of forty-nine flavonoids compounds were tentatively identified in FCF by mass spectrometry analysis. The results of cell experiment suggested that FCF could alleviate oxidative injury via increasing SOD activity and GSH content, as well as inhibiting the production of intracellular ROS and MDA. FCF exerted its protective effect by suppressing the expression of both inducible nitric oxide synthase (iNOS) and cycooxygenase 2 (COX-2) to inhibit the synthesis of pro-inflammatory factors and cytokines, including NO, PGE2, TNF-α, IL-6 and IL-1ß. Besides, FCF treatment could alleviate the thickening of alveolar wall and pulmonary congestion in LPS-treated ALI mice, and significantly inhibit the activity of myeloperoxidas (MPO) and the expression of cytokines in BALF. CONCLUSIONS: FCF could ameliorate inflammation and oxidative stress in LPS-treated inflammation, resulting in an overall improvement in both macroscopic and histological parameters.

Eliminating protein interference when quantifying potato reducing sugars with the miniaturized Somogyi-Nelson assay.

Reducing sugar (RS) quantification is essential in the potato industry because RS content plays a vital role in potato quality, acrylamide formation, post-harvest management, and new variety development. A miniaturized Somogyi-Nelson (SN) analysis can effectively and accurately quantify RS. However, soluble proteins in potatoes interfere with SN analysis. Our research goal was to develop an applicable deprotinization procedure without influencing the precision of the SN analysis. Results showed ethanol effectively removed potato proteins and, unlike other chemicals (salts, acids), ethanol did not affect SN accuracy. Protein removal also can be achieved by heating and pH adjustment, but the ethanol-based procedure provides a simpler alternative. RS content measured by the miniaturized SN assay after deproteinization by ethanol was precise and validated by HPAEC-PAD. Data from 118 potao juicies showed that a commonly used biochemical analyzer obtained a lower reducing sugar content than the deprotinization-SN assay because fructose was not identified by the biochemical analyzer. Results demonstrate the reliability of quantifying potato RS with the SN assay following the ethanol-based deproteinization.

[A multicenter prospective cohort study of Xuebijing injection in the treatment of severe coronavirus disease 2019].

OBJECTIVE: To evaluate the effect of Xuebijing injection on the improvement of pneumonia severity index (PSI) and prognosis in patients with severe coronavirus disease 2019 (COVID-19). METHODS: A multicenter prospective cohort study was designed. Adult patients with COVID-19 admitted to the intensive care unit (ICU) of 28 designated COVID-19 hospitals in 15 provinces and cities of China from January to March 2020 were enrolled. All patients were treated according to the standard treatment plan of COVID-19 issued by the National Health Commission of the People's Republic of China. They were divided into Xuebijing group and standard treatment group according to whether they received Xuebijing injection or not. In the standard treatment group, routine medical care measures such as antiviral, respiratory support, circulatory support and symptomatic treatment were taken. In the Xuebijing group, on the basis of standard treatment, Xuebijing was used within 12 hours of admission to the ICU, 100 mL each time, twice daily. The minimum duration of Xuebijing administration was 1 day. The improvement rate of PSI risk rating on the 8th day and clinical outcome on the 28th day were recorded. RESULTS: A total of 276 COVID-19 patients were screened continuously, and the data of 144 severe patients who met PSI risk rating III-V were analyzed. Seventy-two cases were involved each in standard treatment group and Xuebijing group. The average age of the standard treatment group and Xuebijing group were (65.7±7.9) years old and (63.5±10.9) years old, and male accounted for 75.0% (54/72) and 70.8% (51/72), respectively. There were no significant differences in general conditions, comorbidities, PSI risk rating and score, sequential organ failure assessment (SOFA) score, oxygenation index (PaO2/FiO2), respiratory support mode and other baseline indicators between the two groups. Compared with the standard treatment group, the improvement rate of PSI risk rating in Xuebijing group on the 8th day after admission was significantly improved [56.9% (41/72) vs. 20.8% (15/72), between-group difference and 95% confidence interval (95%CI) was 36.1% (21.3% to 50.9%), P < 0.01], PSI score, SOFA score and PaO2/FiO2 were significantly improved [PSI score: 83.7±34.8 vs. 108.2±25.6, between-group difference (95%CI) was -24.5 (-34.9 to -14.1); SOFA score: 2.0 (1.0, 4.0) vs. 7.0 (4.0, 10.0), between-group difference (95%CI) was -3.5 (-5.0 to -2.0); PaO2/FiO2 (mmHg, 1 mmHg = 0.133 kPa): 289.4±111.6 vs. 188.5±98.1, between-group difference (95%CI) was 100.9 (65.3 to 136.5); all P < 0.01]. The 28-day discharge rate of Xuebijing group was 44.5% higher than that of standard treatment group [66.7% (48/72) vs. 22.2% (16/72), P < 0.01], and the 28-day survival rate was 9.8% [91.7% (66/72) vs. 81.9% (59/72), P < 0.01]. There was no significant difference in the combination of antiviral drugs, antibiotics, anticoagulants and vasopressor drugs between the two groups. There was no significant difference in the incidence of adverse events between the Xuebijing group and standard treatment group [41.7% (30/72) vs. 43.1% (31/72), P > 0.05], and no serious adverse events and adverse reactions of Xuebijing were reported. CONCLUSIONS: Standard treatment combined with Xuebijing injection can significantly improve the PSI risk score and clinical prognosis of patients with severe COVID-19 without increasing drug safety risk.

Feasibility and efficacy of modified fixed citrate concentration protocol using only commercial preparations in critically ill patients: a prospective cohort study with a historical control group.

BACKGROUND: The cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients. METHODS: A prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement. RESULTS: The filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank, p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol, p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3-4.5] vs. 5.7 [IQR 3.3-6.9], p = 0.001 and 1.9 [IQR 0.5-2.7] vs. 6.3 [IQR 4.2-7.9], p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%, p = 0.024). CONCLUSIONS: Our modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA. TRIAL REGISTRATION: Clinicaltrials.gov. NCT02663960 . Registered 26 January 2016.

Mid- to long-term results of modified avascular fibular grafting for ONFH.

Free vascularized fibular grafting was reported a favorable method to prevent the collapse of the femoral head. This study analyzed the mid- to long-term outcomes of avascular fibular grafting (AVFG) for osteonecrosis of the femoral head (ONFH) with 6- to 8-year follow-up. From March 2009 to March 2012, 34 patients (48 hips) were diagnosed with ONFH operated with AVFG in Jiangsu Province Hospital of traditional Chinese Medicine. We retrospectively reviewed the clinic outcomes of these patients and evaluated the differences in outcomes by diverse stages [Association Research Circulation Osseous (ARCO)] and types [China-Japan Friendship Hospital (CJFH) classification] annually. The hip survival rate, Harris hip score (HHS), activity level and imaging stability were calculated. The average follow-up time was 6.7 years. At the last follow-up, 34 of 48 hips survived totally. According to the ARCO stage, the overall clinical success rate for hip preserving were 76.0% (19/25) in II stage, 85.7% (12/14) in IIIA stage and 33.3% (3/9) in IIIB stage. Referring to the CJFH classification system, the hip survival rate were 100% (2/2) in M type, 90.9% (10/11) in C type, 77.8% (14/18) in L1 type, 57.1% (8/14) in L2 type and 0% (0/3) in L3 type. The mean visual analog scale (VAS) score, HHS and Western Ontario McMaster Osteoarthritis index (WOMAC) were significantly improved at the final follow-up compared with pre-operative values (P < 0.001). The AVFG operation can increase the hip function and improve patients' lives quality. The mid- to long-term efficacy can satisfy fundamental life requirements, especially for those early-stage and small-scale patients who suffer ONFH to avoid or put off the time of total hip arthroplasty surgery.

Chemotherapy based on "Domino-effect" combined with immunotherapy amplifying the efficacy of an anti-metastatic treatment.

In tumor immunotherapy, Treg cells are immunosuppressive cells. In general, the main strategy of chemo immune-therapy for Treg cells is to eliminate them using chemotherapy drugs combined with immune checkpoint inhibitors. However, the dead Treg cells still exert immunosuppressive effects via the nucleoside adenosine pathway. To improve immunosuppression, we designed a nanosystem to deliver synthetic chemotherapeutics and immune activators. The homemade curcumin analog (CA) was encapsulated by α-lactalbumin (α-LA), and the Treg cell specific antibody (mAb), as a therapeutic agent, was linked to the drug-loaded protein via matrix metalloproteinase-responded peptide (P). After the cleavage peptide responded to matrix metalloproteinase (MMP-2), the CA@α-LA-P-mAb nanoparticles were separated into CA@α-LA and antibody, which can specifically enter cancer cells and Treg cells via membrane fusion and Nrp-1 receptors, respectively. Finally, we found that CA can not only lead to cell death by the chondriosome apoptosis approach but also reduce the production of Treg cells by inhibiting the expression of foxp3 (a key transcription factor of Treg cells). In addition, specific antibodies can improve the immunosuppression of existing Treg cells. The combined effect of CA and antibodies amplifies the role of chemotherapy in metastatic breast cancer.

Assessment of Chinese medicine for coronavirus-related pneumonia: A protocol for systematic review and meta-analysis.

BACKGROUND: The 2019 novel coronavirus disease has caused a global pandemic with substantial morbidity and mortality. Chinese medicine has been extensively employed in the coronavirus-related pandemic in China. We aim to assess the efficacy and safety of Chinese medicine in treatment of coronavirus-related pneumonia with the updated results of relevant clinical trials. METHODS: Six electronic databases including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Chongqing VIP, and SinoMed will be searched to identify randomized controlled trials up to May 2020. Patients diagnosed with coronavirus-related pneumonia including severe acute respiratory syndrome, Middle East respiratory syndrome, and 2019 novel coronavirus disease and administrated with Chinese medicine will be included. The primary outcome is the all cause mortality at the longest follow up available. The second outcomes include the length of stay in hospital and intensive care units, the duration of mechanical ventilation, and adverse events. The pooled effects will be analyzed and reported as risk ratios for dichotomous data using the Mantel-Haenszel method or mean differences for continuous data using the inverse-variance method. Sensitivity and subgroup analyses will be performed to test the robustness of the results and to explore the potential sources of heterogeneities. The Egger test and/or funnel plots will be used for the examination of publication bias. The grades of recommendation assessment, development, and evaluation methodology will be used to summarize the quality of evidence. The trial sequential analysis will be conducted to test whether the meta-analysis has a sufficient sample size after adjustment of the increased type I and II error risks. RESULTS: The evidence to date of Chinese medicine in treatment of coronavirus-related pneumonia will be systematically reviewed and meta-analyzed. CONCLUSION: The relevant studies will be summarized and further evidence will be provided.PROSPERO registration number: CRD42020178879.

Mild Acid-Responsive "Nanoenzyme Capsule" Remodeling of the Tumor Microenvironment to Increase Tumor Penetration.

Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a "nanoenzyme capsule" was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.