Curvature-mediated rapid extravasation and penetration of nanoparticles against interstitial fluid pressure for improved drug delivery.

Elevated interstitial fluid pressure (IFP) within pathological tissues (e.g., tumors, obstructed kidneys, and cirrhotic livers) creates a significant hindrance to the transport of nanomedicine, ultimately impairing the therapeutic efficiency. Among these tissues, solid tumors present the most challenging scenario. While several strategies through reducing tumor IFP have been devised to enhance nanoparticle delivery, few approaches focus on modulating the intrinsic properties of nanoparticles to effectively counteract IFP during extravasation and penetration, which are precisely the stages obstructed by elevated IFP. Herein, we propose an innovative solution by engineering nanoparticles with a fusiform shape of high curvature, enabling efficient surmounting of IFP barriers during extravasation and penetration within tumor tissues. Through experimental and theoretical analyses, we demonstrate that the elongated nanoparticles with the highest mean curvature outperform spherical and rod-shaped counterparts against elevated IFP, leading to superior intratumoral accumulation and antitumor efficacy. Super-resolution microscopy and molecular dynamics simulations uncover the underlying mechanisms in which the high curvature contributes to diminished drag force in surmounting high-pressure differentials during extravasation. Simultaneously, the facilitated rotational movement augments the hopping frequency during penetration. This study effectively addresses the limitations posed by high-pressure impediments, uncovers the mutual interactions between the physical properties of NPs and their environment, and presents a promising avenue for advancing cancer treatment through nanomedicine.

Investigation of the Stability Mechanism of Stimulus-Responsive Wormlike Micelle-CO2 Foams in the Oil Phase.

Foam flooding is an important tool for reservoir development. This study aims to further investigate the interaction between stimulus-responsive wormlike micelle (WLM)-CO2 foams and crude oil. We performed micromorphology experiments as our major studies and used molecular dynamics simulations as an auxiliary tool for interfacial analysis. We utilized foam generation, liquid separation, and defoaming as the entry points of experimental research and energy as the quantitative assessment index to investigate the dynamic process of the action of different oil contents and oil phase types in a DOAPA@NaSal-H+ foam system. We also examined the role of NaSal in the generation and development of the foam system. Results indicated that the law of crude oil's effect on foam could be summarized as "low contents are beneficial and high contents are harmful." In addition, although the DOAPA@NaSal-H+ foam system has high compatibility for saturated and aromatic hydrocarbons, it is highly suitable for application in reservoir environments with relatively high asphaltene and resin contents. Through combined experimental and simulation approaches, we clarified the law governing the stability of the DOAPA@NaSal-H+ foam system in different oil-containing environments, identified the key role of NaSal, and provided a reference for the targeted application of the DOAPA@NaSal-H+ foam system in different oil reservoirs.

Emergent surgical retrieval of a left atrial appendage occluder migrated into the left ventricular outflow tract with secondary massive mitral regurgitation: A case report and literature review.

Thrombotic complications of atrial fibrillation continue to pose a significant challenge in clinical practice today. Left atrial appendage occlusion (LAAO) has emerged as a promising alternative to oral anticoagulation for high-risk patients with atrial fibrillation. However, despite the potential benefits, there is still the possibility of life-threatening complications such as device dislocation. In this case study, we present a patient who experienced severe hemodynamic disturbances due to the embolization of LAAO device into the left ventricular outflow tract, resulting in a torn mitral valve and secondary massive mitral regurgitation, just 3 hours after the procedure. As a result, emergent surgical intervention was required to remove the device and repair the mitral valve. We also conducted a review of previous studies on the retrieval of dislodged left atrial appendage occluders through surgical procedures. It is crucial to maintain vigilance, foster interdisciplinary collaboration, and respond promptly to ensure the safety and efficacy of LAAO procedures.

[Research progress in Astragali Radix and its active ingredients in treatment of lung cancer].

Lung cancer is the leading cause of cancer death, and its effective treatment is a difficult medical problem. Lung cancer belongs to the traditional Chinese medicine(TCM) disease categories of lung accumulation, lung amassment, and overstrain cough. Rich theoretical basis and practical experience have been accumulated in the TCM treatment of lung cancer. Astragali Radix is one of the representatives of Qi-tonifying drugs. It mainly treat the lung cancer with the syndrome of Qi deficiency and pathogen stagnation, following the principle of reinforcing healthy Qi and eliminating patgogenic Qi. Astragali Radix exerts a variety of pharmacological activities in the treatment of lung cancer, including inhibiting tumor cell proliferation and promoting tumor cell apoptosis, inhibiting tumor invasion and migration, regulating the tumor microenvironment, suppressing tumor angiogenesis, modulating autophagy, inducing macrophage polarization, enhancing immunity, inhibiting immune escape, and reversing cisplatin resistance. The active ingredients of Astragali Radix in treating lung cancer include polysaccharides, saponins, and flavonoids. This study reviewed the pharmacological activities and active ingredients of Astragali Radix in the treatment of lung cancer, providing a basis for the development and utilization of Astragali Radix resources and active ingredients and the research and development of anti-tumor drugs.

Oral Delivery of Gemcitabine-Loaded Glycocholic Acid-Modified Micelles for Cancer Therapy.

The clinical utility of gemcitabine, an antimetabolite antineoplastic agent applied in various chemotherapy treatments, is limited due to the required intravenous injection. Although chemical structure modifications of gemcitabine result in enhanced oral bioavailability, these modifications compromise complex synthetic routes and cause unexpected side effects. In this study, gemcitabine-loaded glycocholic acid-modified micelles (Gem-PPG) were prepared for enhanced oral chemotherapy. The in vitro transport pathway experiments revealed that intact Gem-PPG were transported across the intestinal epithelial monolayer via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway. In mice, the pharmacokinetic analyses demonstrated that the oral bioavailability of Gem-PPG approached 81%, compared to less than 20% for unmodified micelles. In addition, the antitumor activity of oral Gem-PPG (30 mg/kg, BIW) was superior to that of free drug injection (60 mg/kg, BIW) in the xenograft model. Moreover, the assessments of hematology, blood chemistry, and histology all indicated the hypotoxicity profile of the drug-loaded micelles.

Pupillary monitoring decreases remifentanil consumption during laparoscopic uterine surgery and improves postoperative recovery.

BACKGROUND: The aim of this paper was to explore pupillary monitoring for determining remifentanil consumption during general anesthesia and evaluating postoperative recovery quality. METHODS: Eighty patients undergoing elective laparoscopic uterine surgery were randomly divided into pupillary monitoring group (Group P) and control group (Group C). In Group P, remifentanil dosage during general anesthesia was determined according to pupil dilation reflex; in Group C, it was adjusted according to hemodynamic changes. Intraoperative remifentanil consumption and endotracheal tube extraction time were recorded. The Numerical Rating Scale (NRS) Score, hemodynamic changes, and opioid-related adverse reactions in the post-anesthesia care unit were also recorded. The parameters of pupil light reflex from extubation to 30 min after extubation were analyzed in Group P, and the responsiveness of these parameters and hemodynamic changes to NRS was determined by ROC curve analyses. RESULTS: Compared with Group C, in Group P, intraoperative remifentanil consumption, the NRS Score at 20 minutes after extubation, extubation time, and the incidence of nausea, vomiting, and respiratory amnesia were all significantly decreased (all, P<0.05). In Group P, ∆HR and ∆MAP had no value in judging the change of NRS. The ROC values and diagnostic cutoff values of ΔInit, ΔACV, and ΔMCV responding to NRS variation were 0.775 (95% CI: 0.582-0.968), 0.734(95% CI: 0.537-0.930), and 0.822 (95% CI: 0.648-0.997) and 0.21 (sensitivity, 92.3%; specificity, 23.1%), -1.3 (sensitivity, 92.3%; specificity, 18.3%), and -1.0 (sensitivity, 84.6%; specificity, 17.7%), respectively. CONCLUSIONS: Intraoperative pupil dilation reflex monitoring can reduce remifentanil consumption and improve postoperative recovery quality. Furthermore, postoperative pupil light reflex monitoring can help evaluate pain degree with high sensitivity.

Stellate ganglion block alleviates postoperative sleep disturbance in patients undergoing radical surgery for gastrointestinal malignancies.

STUDY OBJECTIVES: We explored the effects of stellate ganglion block on postoperative sleep disturbance in patients scheduled to undergo radical surgery for gastrointestinal malignancies. METHODS: Forty such patients were randomly assigned to the control group (Group C) or the preoperative stellate ganglion block treatment group (Group S). Using actigraphy, sleep quality was evaluated on the first night before the operation and first, second, and third postoperative nights. The Pittsburgh Sleep Quality Index scale was used for sleep state assessment on 1 day preoperatively and the first, second, third, fifth, and seventh days postoperatively. Plasma interleukin (IL)-1, IL-6, and IL-10 and melatonin levels were checked at 1 day preoperatively and the first and third days postoperatively. Mean arterial pressure, heart rate, and pulse oxygen saturation (SpO2) were recorded before general anesthesia induction, immediately after tracheal intubation, at the beginning of the operation, 1 and 2 hours after the beginning of the operation, at the end of the operation, immediately after extubation, and 30 minutes after transfer to the postanesthesia care unit. RESULTS: Compared with Group C, in Group S sleep efficiency, total sleep time, and sleep maintenance were increased and sleep period change index, number of awakenings, wake after sleep onset, and body movements were reduced on the first and second postoperative nights; Pittsburgh Sleep Quality Index scores and occurrence of postoperative sleep disturbance were lower on the first and second nights postoperatively; IL-6 was reduced on the first night postoperatively; IL-1 and IL-10 were reduced on the third night postoperatively; melatonin was increased on the first night postoperatively; and mean arterial pressure and heart rate were decreased before general anesthesia induction, immediately after tracheal intubation, and at the end of the operation (all P < .05). Conclusions: Stellate ganglion block alleviates postoperative sleep disturbance by reducing postoperative inflammatory response, increasing melatonin levels, and stabilizing perioperative hemodynamics in patients undergoing radical surgery for gastrointestinal malignancies. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: The Effect of Stellate Ganglion Block on Postoperative Sleep Disturbance and Cognitive Function in Elderly Surgical Patients; URL: https://clinicaltrials.gov/ct2/show/NCT04800653; Identifier: NCT04800653. CITATION: Yan S, Wang Y, Yu L, et al. Stellate ganglion block alleviates postoperative sleep disturbance in patients undergoing radical surgery for gastrointestinal malignancies. J Clin Sleep Med. 2023;19(9):1633-1642.

Advances in the treatment of invasive fungal disease.

With over 300 million severe cases and 1.5 million deaths annually, invasive fungal diseases (IFDs) are a major medical burden and source of global morbidity and mortality. The World Health Organization (WHO) recently released the first-ever fungal priority pathogens list including 19 fungal pathogens, considering the perceived public health importance. Most of the pathogenic fungi are opportunistic and cause diseases in patients under immunocompromised conditions such as HIV infection, cancer, chemotherapy, transplantation, and immune suppressive drug therapy. Worryingly, the morbidity and mortality caused by IFDs are continuously on the rise due to the limited available antifungal therapies, the emergence of drug resistance, and the increase of population that is vulnerable to IFDs. Moreover, the COVID-19 pandemic worsened IFDs as a globe health threat as it predisposes the patients to secondary life-threatening fungi. In this mini-review, we provide a perspective on the advances and strategies for combating IFDs with antifungal therapies.

Extraction, Composition, and Antioxidant Activity of Flavonoids from Xanthoceras sorbifolium Bunge Leaves.

BACKGROUND: Xanthoceras sorbifolium Bunge leaves (XLs) are valuable resources rich in phytochemicals, especially in flavonoids, but they are rarely exploited and utilized. OBJECTIVE: The purpose of this paper is to reduce the waste of XLs resources (usually used as agricultural waste) and extract the high added value of active ingredients from XLs. METHODS: The extraction of flavonoids from XLs using ultrasonic-assisted extraction (UAE) was reported. Response surface methodology (RSM) was used to adopt different ultrasonic conditions such as ethanol concentration, liquid:solid ratio, and ultrasonic power. In addition, the chemical structures were identified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and HPLC. RESULTS: Response surface analysis indicated the optimal level of ethanol concentration, liquid:solid ratio, and ultrasonic power as 71.49%, 13.87 mL/g, and 157.49 W respectively for the maximum response of total flavonoids (5.52 ± 0.23%), which fitted well with the predicted value (5.68 ± 0.17%). In addition, the extracts from XLs exhibited potent antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) ammonium salt (ABTS). CONCLUSION: The potent antioxidant activity of flavonoids from XLs is beneficial for their application in the food and drug industry, which will facilitate the rise of the added value of the flavonoids from XLs. HIGHLIGHTS: Myricetin, rutin, and epicatechin, which may be responsible for the antioxidant activity of the extracts from XLs, were confirmed by UPLC-MS/MS and HPLC analysis. The extracted flavonoids can be used as a natural antioxidant additive to food products.

Serum level of calpains product as a novel biomarker of acute lung injury following cardiopulmonary bypass.

Objective: The aim of this study was to test the hypothesis whether serum level of calpains could become a meaningful biomarker for diagnosis of acute lung injury (ALI) in clinical after cardiac surgery using cardiopulmonary bypass (CPB) technology. Methods and results: Seventy consecutive adults underwent cardiac surgery with CPB were included in this prospective study. Based on the American-European Consensus Criteria (AECC), these patients were divided into ALI (n = 20, 28.57%) and non-ALI (n = 50, 71.43%) groups. Serum level of calpains in terms of calpains' activity which was expressed as relative fluorescence unit (RFU) per microliter and measured at beginning of CPB (baseline), 1 h during CPB, end of CPB as well as 1, 12, and 24 h after CPB. Difference of serum level of calpains between two groups first appeared at the end of CPB and remained different at subsequent test points. Univariate and multivariate logistic regression analysis indicated that serum level of calpains 1 h after CPB was an independent predictor for postoperative ALI (OR 1.011, 95% CI 1.001, 1.021, p = 0.033) and correlated with a lower PaO2/FiO2 ratio in the first 2 days (The first day: r = -0.389, p < 0.001 and the second day: r = -0.320, p = 0.007) as well as longer mechanical ventilation time (r = 0.440, p < 0.001), intensive care unit (ICU) length of stay (LOS) (r = 0.419, p < 0.001) and hospital LOS (r = 0.297, p = 0.013). Conclusion: Elevated serum level of calpains correlate with impaired lung function and poor clinical outcomes, indicating serum level of calpains could act as a potential biomarker for postoperative ALI following CPB in adults. Clinical trial registration: [https://clinicaltrials.gov/show/NCT05610475], identifier [NCT05610475].

Improved Aluminum Adjuvants Eliciting Stronger Immune Response When Mixed with Hepatitis B Virus Surface Antigens.

Adjuvants can regulate the immune response triggered by vaccines. Traditional aluminum adjuvants can induce humoral immunity, but they lack the ability to effectively induce Th1 cellular immunity, which is not conducive to the development of vaccines with improved protective effects. Aluminum adjuvants from different sources may have different physicochemical properties, and therefore, completely different immune responses can be triggered. This suggests that adjuvant recognition by the immune system and its responses are closely associated with the physicochemical properties of the adjuvant itself. To test this hypothesis, in this study, we developed a new method for preparing an aluminum adjuvant. This aluminum adjuvant has a pseudoboehmite structure, strong protein adsorption capacity, and excellent suspension stability. The adjuvant was tested using the hepatitis B virus surface antigen (HBsAg) as a model antigen for immunization; the results showed that this aluminum adjuvant effectively induced not only humoral immunity but also an outstanding cellular immune response. These results provide a reference for improving the efficacy of adjuvants.

Effects of dexmedetomidine on cardiac electrophysiology in patients undergoing general anesthesia during perioperative period: a randomized controlled trial.

BACKGROUND: Dexmedetomidine has controversial influence on cardiac electrophysiology. The aim of this study was to explore the effects of dexmedetomidine on perioperative cardiac electrophysiology in patients undergoing general anesthesia. METHODS: Eighty-one patients were randomly divided into four groups: groups D1, D2, D3 receiving dexmedetomidine 1, 1, 0.5 µg/kg over 10 min and 1, 0.5, 0.5 µg/kg/h continuous infusion respectively, and control group (group C) receiving normal saline. Twelve-lead electrocardiograms were recorded at the time before dexmedetomidine/normal saline infusion (T1), loading dose finish (T2), surgery ending (T6), 1 h (T7) after entering PACU, 24 h (T8), 48 h (T9), 72 h (T10) and 1 month (T11) postoperatively. Cardiac circulation efficiency (CCE) were also recorded. RESULTS: Compared with group C, QTc were significantly increased at T2 in groups D1 and D2 while decreased at T7 and T8 in group D3 (P < 0.05), iCEB were decreased at T8 (P < 0.05). Compared with group D1, QTc at T2, T6, T7, T9 and T10 and iCEB at T8 were decreased, and CCE at T2-T4 were increased in group D3 significantly (P < 0.05). Compared with group D2, QTc at T2 and iCEB at T8 were decreased and CCE at T2 and T3 were increased in group D3 significantly (P < 0.05). CONCLUSIONS: Dexmedetomidine at a loading dose of 0.5 µg/kg and a maintenance dose of 0.5 µg/kg/h can maintain stability of cardiac electrophysiology during perioperative period and has no significant adverse effects on CCE. TRIAL REGISTRATION: ClinicalTrials.gov NCT04577430 (Date of registration: 06/10/2020).

Fast Lasso-type safe screening for Fine-Gray competing risks model with ultrahigh dimensional covariates.

The Fine-Gray proportional sub-distribution hazards (PSH) model is among the most popular regression model for competing risks time-to-event data. This article develops a fast safe feature elimination method, named PSH-SAFE, for fitting the penalized Fine-Gray PSH model with a Lasso (or adaptive Lasso) penalty. Our PSH-SAFE procedure is straightforward to implement, fast, and scales well to ultrahigh dimensional data. We also show that as a feature screening procedure, PSH-SAFE is safe in a sense that the eliminated features are guaranteed to be inactive features in the original Lasso (or adaptive Lasso) estimator for the penalized PSH model. We evaluate the performance of the PSH-SAFE procedure in terms of computational efficiency, screening efficiency and safety, run-time, and prediction accuracy on multiple simulated datasets and a real bladder cancer data. Our empirical results show that the PSH-SAFE procedure possesses desirable screening efficiency and safety properties and can offer substantially improved computational efficiency as well as similar or better prediction performance in comparison to their baseline competitors.

Effects of dexmedetomidine on glucose-related hormones and lactate in non-diabetic patients under general anesthesia: a randomized controlled trial.

BACKGROUND: The aim of this study was to explore the effects of dexmedetomidine on glucose-related hormones and lactate levels in non-diabetic patients undergoing malignant gastrointestinal tumor radical resection. METHODS: Groups D1 and D2 received dexmedetomidine loading dose 1 µg/kg and maintenance dose 0.25 and 0.5 µg/kg/h, respectively. Group C received saline solution. Glucose, lactate, insulin, glucagon, cortisol, epinephrine, norepinephrine and dopamine levels were measured before dexmedetomidine infusion (T1), 1 h after surgery beginning (T2), at surgery ending (T3), and 1 h after transfer to the postanesthesia care unit (T4). RESULTS: Compared with group C, glucose levels increased in group D2 at T2 and reduced in groups D1 and D2 at T4. Lactate levels reduced in groups D1 and D2 at T4. A positive correlation between glucose and lactate levels was found in all groups. Compared with group C, insulin level reduced in group D2 at T2; glucagon levels reduced in groups D1 and D2 at T4; cortisol levels reduced in group D1 at T4 and in group D2 at T3 and T4; epinephrine and norepinephrine levels reduced in group D1 at T4 and in group D2 at T2 and T4; and dopamine level reduced in group D2 at T4. CONCLUSIONS: Dexmedetomidine loading dose 1 µg/kg and maintenance dose 0.25 µg/kg/h produces a stable insulin level and significant postoperative decreases in glucagon, cortisol, epinephrine and norepinephrine secretion with stable maintenance of intraoperative and postoperative blood glucose levels and decreased postoperative lactate levels in non-diabetic patients under general anesthesia.

Optimal Dose of Dexmedetomidine for Perioperative Blood Glucose Regulation in Non-Diabetic Patients Undergoing Gastrointestinal Malignant Tumor Resection: A Randomized Double-Blinded Controlled Trial.

PURPOSE: To evaluate the optimal dose of dexmedetomidine for perioperative blood glucose regulation in non-diabetic patients with gastrointestinal malignant tumor. METHODS: One hundred patients were randomly divided into four groups: control group (group C), dexmedetomidine 1 µg/kg + 0.25 mcg/kg/h (group D1); + 0.5 mcg/kg/h (group D2); and + 1 mcg/kg/h (group D3). Blood glucose concentrations were measured before dexmedetomidine infusion (T1), 1 h after surgery beginning (T2), at the end of surgery (T3), and 1 h in PACU (T4). Duration of surgery, extubation time, anesthetics doses, adverse reactions, postoperative pulmonary infection, total peritoneal drainage 2 days after surgery and hospital stay were recorded. RESULTS: Compared with T1, blood glucose concentrations were higher at T4 in group C and at T2-4 in groups D1, D2, and D3 (p < 0.01). Compared with group C, blood glucose concentrations were higher at T2 and T3 in groups D2 and D3 (p < 0.05), but significantly lower at T4 in groups D1, D2, and D3 (p < 0.01). Propofol and remifentanil consumption in groups D1, D2, and D3 decreased significantly compared with group C (p < 0.01). In group D3, doses of ephedrine (p < 0.05) and atropine (p < 0.01) were higher, and extubation time was prolonged (p < 0.01) compared with the other groups. The incidence of bradycardia was higher in group D3 than that in group C (p < 0.05). CONCLUSIONS: Dexmedetomidine loading dose of 1 mcg/kg followed by maintenance with 0.25 mcg/kg/h can regulate perioperative blood glucose well in non-diabetic patients undergoing gastrointestinal malignant tumor resection and reduce doses of anesthetics without extending extubation time.

Effects of Peak Inspiratory Pressure-Guided Setting of Intracuff Pressure for Laryngeal Mask Airway Supreme™ Use during Laparoscopic Cholecystectomy: A Randomized Controlled Trial.

PURPOSE: To determine the effects of peak inspiratory pressure (PIP)-guided intracuff pressure (ICP) modulation of laryngeal mask airway (LMA) Supreme™ during laparoscopic cholecystectomy. METHODS: Totally 120 patients were randomly divided using computer-generated numbers into a control group (n = 60; ICP, 60 cmH2O) and a PIP group (n = 60), in which ICP was increased with 5 cmH2O each time from PIP level until no air leaks from the oropharynx. PIP, ICP, cuff volume (CV), oropharyngeal leak pressure (OLP) and leak fraction (LF) were recorded before and after pneumoperitoneum establishment. Postoperative pharyngolaryngeal complications (sore throat, dysphagia, pharyngeal hematoma, and dysphonia) were also recorded. RESULTS: Demographic data were similar in the two groups. The CV and ICP before and after pneumoperitoneum were significantly lower in the PIP group (CV: 15.6 ± 2.3 mL and 21.0 ± 2.6 mL; ICP: 14.3 ± 2.9 cmH2O and 20.5 ± 3.4 cmH2O) than in the control group (CV: 33.0 ± 2.8 mL and 32.8 ± 1.9 mL; ICP: 60.0 ± 0.1 cmH2O and 60.0 ± 0.1 cmH2O) (P < 0.05). Although OLP was lower in the PIP group (P < 0.05), the LF was similar in the two groups (P > 0.05). There were fewer postoperative pharyngolaryngeal complications in the PIP group (P < 0.05). CONCLUSIONS: Compared with a fixed ICP of 60 cmH2O, PIP-guided ICP modulation during LMA Supreme™ use provided effective airway sealing at a lower CV and ICP, and produced fewer postoperative pharyngolaryngeal complications in patients undergoing laparoscopic cholecystectomy.

Median Effective Dose of Lidocaine for the Prevention of Pain Caused by the Injection of Propofol Formulated with Medium- and Long-Chain Triglycerides Based on Lean Body Weight.

OBJECTIVE: To determine the median effective dose (ED50) of prophylactic intravenous lidocaine for the prevention of propofol medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion injection pain. DESIGN: Prospective trial, Dixon up-and-down sequential method. SETTING: Operating room of a single hospital. PATIENTS: Thirty patients aged 18-65 years with American Society of Anesthesiologists (ASA) status I or II who were scheduled for elective surgery under general anesthesia (GA) were included. INTERVENTIONS: The initial dose of prophylactic lidocaine before propofol MCT/LCT emulsion injection was set at 0.5 mg/kg lean body weight (LBW). The lidocaine dose was adjusted according to the degree of patients' injection pain using the Dixon up-and-down sequential method. MEASUREMENTS: The ED50 and 95% confidence intervals (CIs) of lidocaine were calculated using the Dixon-Massey formula. Vital signs and adverse effects were recorded. In the postanesthesia care unit (PACU), patients were asked if they recalled feeling any injection pain with visual analog scale (VAS) evaluation. RESULTS: The ED50 of lidocaine for the prevention of propofol MCT/LCT emulsion injection pain was 0.306 mg/kg LBW (95% CI, 0.262-0.357 mg/kg LBW). No adverse reactions to lidocaine occurred. In the PACU, 90.9% of patients who experienced injection pain recalled this pain (VAS score, 2.8±1.8). CONCLUSIONS: Prophylactic intravenous lidocaine (0.306 mg/kg LBW) effectively prevented propofol MCT/LCT emulsion injection pain in 50% of patients scheduled for elective surgery under GA with no adverse reaction occurring.

Directed Biosynthesis of Iso-aclacinomycins with Improved Anticancer Activity.

A four-enzyme catalyzed hydroxy regioisomerization of anthracycline was integrated into the biosynthetic pathway of aclacinomycin A (ALM-A), to generate a series of iso-ALMs via directed combinatorial biosynthesis combined with precursor-directed mutasynthesis. Most of the newly acquired iso-ALMs exhibit obviously (1-5-fold) improved antitumor activity. Therefore, we not only developed iso-ALMs with potential as clinical drugs but also demonstrated the utility of this tailoring tool for modification of anthracycline antibiotics in drug discovery and development.

Genome Mining of Alkaloidal Terpenoids from a Hybrid Terpene and Nonribosomal Peptide Biosynthetic Pathway.

Biosynthetic pathways containing multiple core enzymes have potential to produce structurally complex natural products. Here we mined a fungal gene cluster that contains two predicted terpene cyclases (TCs) and a nonribosomal peptide synthetase (NRPS). We showed the flv pathway produces flavunoidine 1, an alkaloidal terpenoid. The core of 1 is a tetracyclic, cage-like, and oxygenated sesquiterpene that is connected to dimethylcadaverine via a C-N bond and is acylated with 5,5-dimethyl-l-pipecolate. The roles of all flv enzymes are established on the basis of metabolite analysis from heterologous expression.

Optimal dose of pretreated-dexmedetomidine in fentanyl-induced cough suppression: a prospective randomized controlled trial.

BACKGROUND: To investigate the optimal dose of pretreated-dexmedetomidine in fentanyl-induced cough (FIC) suppression. METHODS: Patients of 180 undergoing elective surgery with general anesthesia, aged 18-65 years, BMI 18.5-30 kg/m2, ASA I or II, were equally randomized into four groups (n = 45) to receive intravenous pretreatment of dexmedetomidine with 0 (group 1), 0.3 (group 2), 0.6 (group 3) and 0.9 (group 4) mcg/kg over 10 mins, respectively. After the pretreatment, all patients were given a 5-s intravenous injection of fentanyl 4 mcg/kg. The symptoms of irritating cough including the severity and onset time were recorded for 1 min after fentanyl injection. General anesthesia induction was completed with midazolam, propofol and cisatracurium, then endotracheal tube or laryngeal mask was inserted and connected to an anesthesia machine. MAP, HR and SpO2 at the beginning of pretreatment (T0), 3 min (T1), 6 min (T2), 9 min (T3) and 12 min (T4) after the beginning of pretreatment were recorded. Side effects of dexmedetomidine, such as bradycardia, hypertension, hypotension, and respiratory depression were also recorded during the course. RESULTS: Totally 168 patients completed the study. The incidences of cough were 52.4, 42.9, 11.9, and 14.3% in groups 1, 2, 3, and 4, respectively, with no significant differences between groups 1 and 2 (P > 0.05) and between groups 3 and 4 (P > 0.05). The incidence and severity of cough in groups 3 and 4 were significantly lower than those in groups 1 and 2 (P < 0.05). Compared to T0, HR at T2 (P < 0.05), T3 (P < 0.01), and T4 (P < 0.01) decreased significantly and MAP at T4 decreased significantly (P < 0.05) in group 4. Bradycardia occurred in 1 case and respiratory depression occurred in 1 case in group 4. Compared to group 1, the onset time of cough in the other 3 groups were delayed significantly (P < 0.05). CONCLUSION: Pretreated dexmedetomidine 0.6 mcg/kg blous intravenous infusion over 10 mins could reduce FIC effectively without side effects. TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03126422), April 13, 2017.