Abstract This study aimed to explore biotinylated liposomes (BLPs) as novel carriers to enhance the oral delivery of insulin. Biotinylation was achieved by incorporating biotin-conjugated ...phospholipids into the liposome membranes. A significant hypoglycemic effect and enhanced absorption were observed after treating diabetic rats with the BLPs with a relative bioavailability of 12.09% and 8.23%, based on the measurement of the pharmacologic effect and the blood insulin level, respectively; this achieved bioavailability was approximately double that of conventional liposomes. The significance of the biotinylation was confirmed by the facilitated absorption of the BLPs through receptor-mediated endocytosis, as well as by the improved physical stability of the liposomes. Increased cellular uptake and quick gastrointestinal transport further verified the ability of the BLPs to enhance absorption. These results provide a proof of concept that BLPs can be used as potential carriers for the oral delivery of insulin. From the Clinical Editor Diabetes remains a major source of mortality in the Western world, and advances in its management are expected to have substantial socioeconomic impact. In this paper, biotinylated liposomes were utilized as carriers of insulin for local delivery, demonstrating the feasibility of this approach in a rat model.
Objective: To generate synthetic CT (sCT) images with high quality from CBCT and planning CT (pCT) for dose calculation by using deep learning methods. Methods: 169 NPC patients with a total of 20926 ...slices of CBCT and pCT images were included. In this study the CycleGAN, Pix2pix and U-Net models were used to generate the sCT images. The Mean Absolute Error (MAE), Root Mean Squared Error (RMSE), Peak Signal to Noise Ratio (PSNR), and Structural Similarity Index (SSIM) were used to quantify the accuracy of the proposed models in a testing cohort of 34 patients. Radiation dose were calculated on pCT and sCT following the same protocol. Dose distributions were evaluated for 4 patients by comparing the dose-volume-histogram (DVH) and 2D gamma index analysis. Results: The average MAE and RMSE values between sCT by three models and pCT reduced by 15.4 HU and 26.8 HU at least, while the mean PSNR and SSIM metrics between sCT by different models and pCT added by 10.6 and 0.05 at most, respectively. There were only slight differences for DVH of selected contours between different plans. The passing rates of 2D gamma index analysis under 3 mm/3% 3 mm/2%, 2 mm/3%and 2 mm/2% criteria were all higher than 95%. Conclusions: All the sCT had achieved better evaluation metrics than those of original CBCT, while the performance of CycleGAN model was proved to be best among three methods. The dosimetric agreement confirmed the HU accuracy and consistent anatomical structures of sCT by deep learning methods.
Summary Background The 2013–15 Ebola virus disease epidemic in west Africa greatly accelerated the development of Ebola vaccine. We aimed to analyse the immune persistence induced by one shot of an ...adenovirus type-5 vector-based Ebola virus vaccine up to 6 months and the effect of boosting with a homologous vector in healthy adults in China. Methods In a randomised, double-blind, placebo-controlled, phase 1 clinical trial in one site in Jiangsu Province, China, 120 healthy adults aged 18–60 years received an initial dose of intramuscular adenovirus type-5 Ebola virus vaccine of 4·0 × 1010 viral particles, 1·6 × 1011 viral particles, or placebo, and were followed up to day 168. Participants were subsequently re-recruited to receive a booster dose of the same vaccine or placebo, in the same dose, at month 6. Women who were pregnant, breastfeeding, or planned to become pregnant during the next month were excluded. Randomisation was conducted by computer-generated block randomisation. Randomisation data were unmasked for interim analysis of the data obtained between days 0–28 but not disclosed to participants or site staff. Safety and immunogenicity analysis were done on the intention-to-treat population. We aimed to assess the safety profile of the experimental vaccine and the immunity responses to a single-dose immunisation or a homologous prime-boost regimen. Primary outcomes were Ebola glycoprotein-specific ELISA antibody responses 28 days post-boost and the occurrences of adverse reactions post-boost. The original trial and the extended booster study were registered with ClinicalTrials.gov , numbers NCT02326194 and NCT02533791 , respectively. Findings Between Dec 28, 2014, and Jan 9, 2015, we enrolled 210 volunteers. 90 participants were not randomised due to not meeting inclusion criteria (61), meeting exclusion criteria (4), or withdrawal of consent (25). 120 people were randomly assigned to receive intramuscular Ebola vaccine at 4·0 × 1010 viral particles (low dose, n=40), Ebola vaccine at 1·6 × 1011 viral particles (high dose, n=40), or placebo (n=40, in two groups of 20). After prime vaccination, the geometric mean titer (GMT) of ELISA EC90 peaked at 682·7 (95% CI 424·3–1098·5) in the low-dose vaccine group and 1305·7 (970·1–1757·2) in the high-dose vaccine group at day 28, and then fell gradually through the next a few months to 575·5 (394·8–838·8) in the high-dose vaccine group and 197·9 (107·9–362·7) in the low-dose vaccine group at day 168. No specific response was recorded in the placebo group with a GMT of 5·0. Of the 120 participants involved in the initial trial, ten participants declined to participate, and 110 were included in the boost immunisation: 38 received the low dose, 35 received the high dose, and 37 received the placebo. At day 28 after boost vaccination, the ELISA EC90 titres rapidly rose to 6110 (95% CI 4705–7935) in the low-dose group and to 11825 (8904–15705) in the high dose group. 78 of 110 participants reported at least one solicited adverse reaction within the first 7 days after booster administration. Both of the groups who received vaccine showed significantly higher incidence of mild or moderate solicited adverse reactions than did the placebo group. Interpretation The adenovirus 5-vectored Ebola vaccine of 1·6 × 1011 viral particles was highly immunogenic and safe. The lower dose of 4·0 × 1010 viral particles was also safe, but immunogenicity seemed to be more vulnerable to the pre-existing immunity of adenovirus 5. A homologous priming-boosting regimen with adenovirus type-5 Ebola vaccine at 6 months interval was able to elicit greater antibody responses with longer duration. These results support an immunisation strategy to implement a booster injection for a more durable protection against Ebola virus disease. Funding Chinese Ministry of Science and Technology and The National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology.
Abstract Background Increasing evidence has suggested that botulinum toxin A (BoNT/A) can inhibit the release of selected neuropepetide transmitters from primary sensory neurons. Thus, intraarticular ...(IA) injection therapies with BoNT/A may reduce pain in patients with knee osteoarthritis (OA). Objective To investigate the effects of landmark-guided IA injection of BoNT/A on patients with knee OA. Design A prospective randomized controlled trial. Setting A rehabilitation clinic of a private teaching hospital. Patients A total of 46 patients with symptomatic knee OA (mostly Kellgren/Lawrence grade 2-3). Methods The patients were randomly assigned to 1 of the following groups: BoNT/A group (BoNT/A injection; n = 21) or control group (education only; n = 20). The patients in the BoNT/A group received an IA injection of 100 units of BoNT/A into the affected knee. Main Outcome Measures The short-term (1 week posttreatment) and long-term (6 months posttreatment) effects were evaluated using a pain visual analogue scale (VAS) and questionnaires concerning functional status, including the Lequesne and Western Ontario and McMaster Universities (WOMAC) indexes. Results The between-group comparison revealed significant differences with regard to the pain VAS score at 1 week ( P < .001) and at 6 months ( P = .001) posttreatment. Similar findings for the between-group comparison were observed for the WOMAC and Lequesne indexes at 6 months ( P < .05) posttreatment. The pain VAS score in the BoNT/A group significantly decreased from 5.05 ± 1.12 (pretreatment) to 2.89 ± 1.04 at 1 week ( P < .001) and 3.45 ± 1.70 at 6 months posttreatment ( P < .001) but not in the control group ( P = .476). Conclusions The IA injection of BoNT/A provided pain relief and improved functional abilities in patients with knee OA in both the short- and long-term follow-up.
Background A prospective multicenter survey was conducted to assess the rational use of antibiotics in clean and clean-contaminated elective surgical procedures applied in 53 grade III first class ...hospitals in Shandong Province, China, from 2006 to 2011. The survey was designed to examine the prevalence of antibiotic prophylaxis, evaluate the quality of perioperative antibiotic prophylaxis (PAP) prescriptions, and investigate the risk factors associated with inappropriate indication for antibiotic prophylaxis. Methods Medication charts and medical, anesthetic, and nursing records were reviewed. Antibiotic prescriptions were compared with the Chinese National Antibiotic Guideline on indication, antibiotic combination, antibiotic choice, dose, dosing interval, route of administration, timing of first administration, and duration of prophylaxis. Results 14,261 of 14,525 procedures (98.2%) receiving antibiotic prophylaxis. The most frequently encountered noncompliance types were PAP indications (18.6%), duration of prophylaxis (26.7%), and timing of first administration (30.3%). The steps of PAP were justified and correct only in 9.4% of procedures. Risk factors independently associated with inappropriate indication for antibiotic prophylaxis were seen in age, hospital type, hospital size, surgical disciplines, and surgical duration. Conclusion Results showed a significantly high rate of antibiotic prophylaxis in clean and clean-contaminated elective surgery and also a high prevalence of inappropriate indication prescriptions. These findings suggest important areas for intervention and implementation of antibiotic stewardship policies in Shandong Province hospitals.
Background CASP7 plays a crucial role in cancer development and chemotherapy efficacy. We, therefore, explored whether single nucleotide polymorphisms (SNPs) of the CASP7 gene can modulate outcomes ...of patients with advanced non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. Methods We systematically genotyped 17 SNPs of CASP7 first in a discovery set of 279 patients with advanced NSCLC treated with platinum-based chemotherapy and then replicated the results in an independent set of 384 patients, in whom we evaluated associations with overall survival (OS) and progress-free survival (PFS) by Kaplan-Meier analysis and Cox hazards regression analysis. Results In both discovery and validation sets as well as in the pooled analysis, heterozygotes of CASP7 rs2227310 and rs4353229 as well as rs12415607 variant allele were strongly associated with a better OS of NSCLC (in the pooled sample: adjusted hazard ratio HR, 0.73; 95% CI = 0.59–0.90; P = .003; HR, 0.72; 95% CI = 0.59–0.89; P = .002; and HR, 0.76; 95% CI = 0.62–0.94; P = .009; respectively). In stratified analyses of the pooled data set, treated with paclitaxel, individuals carrying variant allele of rs2227310, rs4353229, and rs12415607 had significantly improved OS (HR, 0.60; 95% CI = 0.41–0.87; P = .008; HR, 0.58; 95% CI = 0.39–0.84; P = .004; and HR, 0.61; 95% CI = 0.42–0.89; P = .010; respectively). Conclusions This study provides evidence that genetic variations of CASP7 may modulate OS and PFS of patients with advanced NSCLC treated with platinum-based chemotherapy.
Background A sequenced house dust mite (HDM) genome would advance our understanding of HDM allergens, a common cause of human allergies. Objective We sought to produce an annotated Dermatophagoides ...farinae draft genome and develop a combined genomic-transcriptomic-proteomic approach for elucidation of HDM allergens. Methods A D farinae draft genome and transcriptome were assembled with high-throughput sequencing, accommodating microbiome sequences. The allergen gene structures were validated by means of Sanger sequencing. The mite's microbiome composition was determined, and the predominant genus was validated immunohistochemically. The allergenicity of a ubiquinol-cytochrome c reductase binding protein homologue was evaluated with immunoblotting, immunosorbent assays, and skin prick tests. Results The full gene structures of 20 canonical allergens and 7 noncanonical allergen homologues were produced. A novel major allergen, ubiquinol-cytochrome c reductase binding protein–like protein, was found and designated Der f 24. All 40 sera samples from patients with mite allergy had IgE antibodies against rDer f 24. Of 10 patients tested, 5 had positive skin reactions. The predominant bacterial genus among 100 identified species was Enterobacter (63.4%). An intron was found in the 13.8-kDa D farinae bacteriolytic enzyme gene, indicating that it is of HDM origin. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed a phototransduction pathway in D farinae , as well as thiamine and amino acid synthesis pathways, which is suggestive of an endosymbiotic relationship between D farinae and its microbiome. Conclusion An HDM genome draft produced from genomic, transcriptomic, and proteomic experiments revealed allergen genes and a diverse endosymbiotic microbiome, providing a tool for further identification and characterization of HDM allergens and development of diagnostics and immunotherapeutic vaccines.
Summary Background Asian HIV epidemics are concentrated among particular behavioural groups, but large variations exist in epidemic types, timing, and geographical spread between countries and within ...countries, especially in China. We aimed to understand the complexity of HIV epidemics in China by systematically analysing prevalence trends by data source, region, population group, and time period. Methods We collected HIV prevalence data from official national sentinel surveillance sites at the provincial level from Jan 1, 1995, to Dec 31, 2010. We also searched PubMed, VIP Chinese Journal Database (VIP), China National Knowledge Infrastructure, and Wanfang Data from Jan 1, 1990, to Dec 31, 2012, for independent studies of HIV prevalence. We integrated both sets of data, and used an intraclass correlation coefficient test to assess the similarity of geographical pattern of HIV disease burden across 31 Chinese provinces in 2010. We investigated prevalence trends (and 95% CIs) to infer corresponding incidence by region, population group, and year. Findings Of 6850 articles identified by the search strategy, 821 studies (384 583 drug users, 52 356 injecting drug users, 186 288 female sex workers, and 87 834 men who have sex with men) met the inclusion criteria. Official surveillance data and findings from independent studies showed a very similar geographical distribution and magnitude of HIV epidemics across China. We noted that HIV epidemics among injecting drug users are decreasing in all regions outside southwest China and have stabilised at a high level in northwest China. Compared with injecting drug users, HIV prevalence in female sex workers is much lower and has stabilised at low levels in all regions except in the southwest. In 2010, national HIV prevalence was 9·08% (95% CI 8·04–10·52) in injecting drug users and 0·36% (0·12–0·71) in female sex workers, whereas incidence in both populations stabilised at rates of 0·57 (0·43–0·72) and 0·02 (0·01–0·04) per 100 person-years, respectively. By comparison, HIV prevalence in men who have sex with men increased from 1·77% (1·26–2·57) in 2000, to 5·98% (4·43–8·18) in 2010, with a national incidence of 0·98 (0·70–1·25) per 100 person-years in 2010. We recorded strong associations between HIV prevalence among at-risk populations in each province, supporting the existence of overlap in risk behaviours and mixing among these populations. Interpretation HIV epidemics in China remain concentrated in injecting drug users, female sex workers, and men who have sex with men. HIV prevalence is especially high in southwest China. Sex between men has clearly become the main route of HIV transmission. Funding The World Bank Group, the Australian Research Council, the University of New South Wales, and Chinese Center for Disease Control and Prevention.
Abstract Background Acute myocardial infarction (AMI) has become a major cause of hospitalization and mortality in China. There has been limited data to date available to characterize AMI ...presentation, contemporary patterns of medical care, and outcomes in China. Aims The China acute myocardial infarction (CAMI) registry is a national project with the objectives to timely obtain real-world knowledge about AMI patients, and to provide the platform for clinical research, guide preventive measures and care quality improvement efforts in China. Methods and progress The CAMI registry is a prospective, nationwide, multicenter observational study for AMI patients. The registry includes three levels of hospitals (representing typical Chinese governmental and administrative models) from all provinces and municipalities throughout Mainland China. Sites were instructed to enroll consecutive patients with a primary diagnosis of AMI. Clinical data, treatments, outcomes and cost are collected by local investigators and captured electronically, with a standardized set of variables and standard definitions, and rigorous data quality control. Post-discharge patient follow-up to 2 years is planned. The CAMI Registry was launched in January 2013. A total of 108 hospitals have participated in the registry so far. As of September 2014, 26,103 patients with AMI were registered. Conclusions The CAMI registry represents a well-supported and the largest national long-term registry-research-education platform for surveillance, research, prevention and care improvement for AMI in China, the world’s most populous nation. The broad representation of all provinces and different-level hospitals will allow for the exploration of AMI across diverse geographic regions and economic circumstances.
Abstract Environment-responsive near-infrared (NIR) aza-BODIPY dyes capable of fluorescence quenching in water were explored to visualize the in vivo fate of model lipid-based nanocarriers, solid ...lipid nanoparticles (SLNs). The water-quenching effect of the dyes was confirmed to be sensitive and remained stable for at least 24 h. In vitro lipolysis measured by fluorescence quenching completed within 20 min, which was in correlation with alkaline compensation results. In vivo live imaging indicated predominant digestion of SLNs within 2 h and complete digestion within 4 h, which correlated well to in vitro data. Rekindling of quenched dyes by mixed micelles was observed in vitro , but not in vivo . In sharp contrast, SLNs encapsulating another NIR dye DiR showed persistent fluorescence both in vitro and in vivo despite significant lipolysis. It was envisaged that water-quenching fluorescence dyes can be used as probes to monitor the in vivo fate of lipid-based nanocarriers. From the Clinical Editor Lipid-based drug delivery systems can provide an excellent nanocarrier platform for the delivery of poorly water-soluble drugs. Nonetheless, the mechanism of oral absorption and subsequent kinetics is poorly understood. In this article, the authors studied the novel use of near-infrared (NIR) aza-BODIPY dyes to visualize the fate of these lipid-based nanocarriers. The positive finding means that this approach may be useful for in-vivo monitoring of lipid-based nanocarriers.
PDF
