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The membrane-disruptive activity of PEG-PAEMA nanoparticles are silenced at physiological pH, while activated by characteristic tumor acidity via protonation of the PAEMA block, resulting in high selectivity towards tumors.

Metformin hydrochloride enteric-coated capsule (MH-EC) is a commonly used clinical drug for the treatment of type 2 diabetes. In this study, we described a metformin hydrochloride mucosal nanoparticles enteric-coated capsule (MH-MNPs-EC) based on metformin hydrochloride chitosan mucosal nanoparticles (MH-CS MNPs) and its preparation method to improve the bioavailability and hypoglycemic effect duration of MH-EC. In intestinal adhesion study, the residue rates of free drugs and mucosal nanoparticles were 10.52% and 67.27%, respectively after cleaned with PBS buffer. MH-CS MNPs could significantly improve the efficacy of MH and promote the rehabilitation of diabetes rats. In vitro release test of MH-MNPs-EC showed continuous release over 12 h, while commercial MH-EC released completely within about 1 h in intestinal environment (pH 6.8). Pharmacokinetic study was performed in beagle dogs compared to the commercial MH-EC. The durations of blood MH concentration above 2 μg/mL were 9 h for MH-MNPs-EC versus 2 h for commercial MH-EC. The relative bioavailability of MH-MNPs-EC was determined as 185.28%, compared with commercial MH-EC. In conclusion, MH-CS MNPs have good intestinal adhesion and can significantly prolong the residence time of MH in the intestine. MH-MNPs-EC has better treatment effect compared with MH-EC, and it is expected to be a potential drug product for the treatment of diabetes because of its desired characteristics.

In this article we present our results from the SC19 Student Cluster Competition Reproducibility Challenge. The challenge entails reproducing the article entitled “Computing Planetary Interior Normal Modes with A Highly Parallel Polynomial Filtering Eigensolver” presented at SC’18, which proposes a parallel polynomial filtered Lanczos algorithm to directly calculate the planetary normal modes of heterogeneous planets. The proposed algorithm showed excellent performance with relatively low memory consumption and high parallel efficiency. In this work, we reproduce the scaling tests in that article on a cluster using Intel Cascade Lake architecture and use the proposed algorithm to illustrate specific normal modes of Mars. We compare the results obtained on our cluster with those in the original article. We also design a new metric to better analyze the results. In addition, we use the profiling tool Intel VTune Amplifier to explain our discoveries. Our results demonstrate that the given models show great scalability, which is similar to the original article. The required normal modes of Mars are also successfully calculated and visualized.

China's manufacturing sector is pursuing the connotative growth of service-oriented transformation. The vigorous development of digital finance has effectively promoted manufacturing upgrading. Using the 2011–2018 data for listed enterprises and the Peking University Digital Financial Inclusion Index, we exploited the causal effect of digital finance on manufacturing servitization. The results showed that digital finance has a significant positive impact on the servitization of manufacturing industry in China. And we investigated how digital finance may promote manufacturing servitization through increasing the intensity of innovation and enhancing the level of digitalization. Furthermore, we found that digital finance has better promoted the servitization of enterprises in the central and west region, labor-intensive industries, high-tech sector, and private-owned ones. In closing, we articulated enterprises' willingness and dynamic time effect of manufacturing servitization. The role of digital finance is in line with the law of diminishing marginal utility, but an obvious superimposing effect is formed in the lagging three-period timeline.

Electrocardiogram (ECG) signal plays a key role in the diagnosis of arrhythmia, which will pose a great threat to human health. As an effective feature extraction method, deep learning has shown excellent results in processing ECG signals. However, most of these methods neglect the cooperation between the multi-lead ECG series correlation and intra-series temporal patterns. In this work, a multi-domain collaborative analysis and decision approach is proposed, which makes the classification and diagnosis of arrhythmia more accurate. With this decision, we can realize the transition from the spatial domain to the spectral domain, and from the time domain to the frequency domain, and make it possible that ECG signals can be more clearly detected by convolution and sequential learning modules. Moreover, instead of the prior method, the self-attention mechanism is used to learn the relation matrix between the sequences automatically in this paper. We conduct extensive experiments on eight advanced models in the same field to demonstrate the effectiveness of our method.

The rectal enemas of berberine hydrochloride (BH) have emerged as one of the most effective strategies in the clinical treatment of ulcerative colitis (UC). However, oral dosages of BH exhibit a poor anti-inflammatory effect of UC, which may attribute to premature absorption of BH by the upper gastrointestinal tract. Moreover, the thick colonic mucus layer obstructs the penetration of the drug, resulting in low bioavailability to the inflammatory site of the colon. The aim of this study was to develop the mucus-penetrating sodium alginate-chitosan nanoparticles (SA-CS NPs) for oral delivery of BH to the site of colonic ulcer lesions. BH-loaded SA-CS NPs were developed through the ionic gelation method and analyzed for physicochemical characteristics, release performance, penetrability, site retention, and therapeutic efficacy. The results showed that the NPs have a particle size of 257 nm with a negative charge, presenting desired pH-dependent release behavior. The permeation studies elucidated that negatively charged SA-CS NPs had 2.9 times higher mucus penetration ability than positively charged CS NPs. An ex vivo retention study indicated the high retention of BH-SA-CS NPs at the colon site for more than 16 h. In vivo therapeutic effectiveness demonstrated that the prepared NPs could not only alleviate colonic injury by decreasing the disease activity index and colon mucosa damage index, but also improve the immunologic function by decreasing the spleen index. In conclusion, the BH-SA-CS NPs could enhance the mucus permeability and deliver drugs to the colonic inflammation site, providing new insights into improving the therapeutic effect of UC.

Liver cancer, one of the most common types of cancer in the world, is the second leading cause of death for cancer patients. For liver cancer, there is an urgent need for an effective treatment with no or less toxic side effects. Lactonic sophorolipids (LSL), as a potential anticancer drug, has attracted wide attention of pharmaceutical researchers with its good biological activities. The effects of LSL and cell death inhibitors were measured by MTT test on HepG2 cells. Meanwhile, the morphology of the cells was observed under a microscope. The apoptosis rate was detected by flow cytometry, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 were measured by detection kits. Meanwhile, mRNA levels of Apaf-1, Caspase-3, Bax, and Bcl-2 were measured by quantitative real-time RT-PCR; protein levels of Caspase-3, Cleaved Caspase-3, Bax, and Bcl-2 were measured by western blot. LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in cells. The HepG2 cells with LSL co-culture exhibited typical apoptotic morphology, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 increased (P< 0.05). We also found that LSL increases cell apoptosis rate and regulates the expression of genes and proteins associated with apoptosis through the Caspase-3 pathway. These results indicate that LSL may be one of the potential drug candidates to inhibit the proliferation and induce apoptosis in HepG2 cells.Key points• LSL, which is of good biological activities such as anti-bacterium, virus elimination, and inflammatory response elimination, has been firstly used to intervene in vitro to investigate its effect on HepG2 cell proliferation.• LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in HepG2 cells through the Caspase-3 pathway.• The mechanism of LSL action on HepG2 cell proliferation was firstly also discussed, which provides a certain experimental reference for the clinical treatment of liver cancer.

Real world evidence (RWE) and real-world data (RWD) are drawing ever-increasing attention in the pharmaceutical industry and drug regulatory authorities (DRAs) all over the world due to their paramount role in supporting drug development and regulatory decision making. However, there is little systematic documentary analysis about how RWE was integrated for the use by the DRAs in evaluating new treatment approaches and monitoring post-market safety. This study aimed to analyze and discuss the integration of RWE into regulatory decision-making process from the perspective of DRAs. Different development strategies to develop and adopt RWE by the DRAs in the US, Europe, and China were reviewed and compared, and the challenges encountered were discussed. It was found that different strategies on development of RWE were applied by FDA, EMA, and NMPA. The extent to which RWE was adopted in China was relatively limited compared to that in the US and EU, which was highly related to the national pharmaceutical environment and development stages. A better understanding of the overall goals, inputs, activities, outputs, and outcomes in developing RWE will help inform actions to harness RWD and leverage RWE for better health care decisions.

Pre-trained Language Models (PLMs) have proven to be beneficial for various downstream NLP tasks. Recently, GPT-3, with 175 billion parameters and 570 GB training data, drew a lot of attention due to the capacity of few-shot (even zero-shot) learning. However, applying GPT-3 to address Chinese NLP tasks is still challenging, as the training corpus of GPT-3 is primarily English, and the parameters are not publicly available. In this technical report, we release the Chinese Pre-trained Language Model (CPM) with generative pre-training on large-scale Chinese training data. To the best of our knowledge, CPM, with 2.6 billion parameters and 100 GB Chinese training data, is the largest Chinese pre-trained language model, which could facilitate several downstream Chinese NLP tasks, such as conversation, essay generation, cloze test, and language understanding. Extensive experiments demonstrate that CPM achieves strong performance on many NLP tasks in the settings of few-shot (even zero-shot) learning. The code and parameters are available at https://github.com/TsinghuaAI/CPM .

Chronic obstructive pulmonary disease (COPD) is the fourth major cause of mortality and morbidity worldwide and is projected to be the third by 2030. However, there is little evidence available on the associations of COPD hospitalizations with meteorological factors and air pollutants in developing countries/regions of Asia. In particular, no study has been done in western areas of China considering the nonlinear and lagged effects simultaneously. This study aims to evaluate the nonlinear and lagged associations of COPD hospitalizations with meteorological factors and air pollutants using time-series analysis. The modified associations by sex and age were also investigated. The distributed lag nonlinear model was used to establish the association of daily COPD hospitalizations of all 441 public hospitals in Chengdu, China from Jan/2015–Dec/2017 with the ambient meteorological factors and air pollutants. Model parameters were optimized based on quasi Akaike Information Criterion and model diagnostics was conducted by inspecting the deviance residuals. Subgroup analysis by sex and age was also performed. Temperature, relative humidity, wind and Carbon Monoxide (CO) have statistically significant and consistent associations with COPD hospitalizations. The cumulative relative risk (RR) was lowest at a temperature of 19℃ (relative humidity of 67%). Both extremely high and low temperature (and relative humidity) increase the cumulative RR. An increase of wind speed above 4 mph (an increase of CO above 1.44 mg/m3) significantly decreases (increases) the cumulative RR. Female populations were more sensitive to low temperature and high CO level; elderly (74+) populations are more sensitive to high relative humidity; younger populations (3. Therefore, people with COPD should avoid exposure to adverse environmental conditions of extreme temperatures and relative humidity, low wind speed and high CO level, especially for female and elderly patients who were more sensitive to extreme temperatures and relative humidity.

Borneol can enhance the bioavailability of several other drugs by opening the blood-brain barrier and inhibiting P-glycoprotein (P-gp) efflux. However, whether borneol will impact the bioavailability and the mechanism of compound Danshen colon-specific osmotic pump capsule (CDCOPC) remains unclear. This study aimed to determine the effects of borneol on the in vitro release and in vivo pharmacokinetic characteristics of CDCOPC. Besides, the in vitro release behavior of CDCOPC was further assessed by chromatographic fingerprints. The in vitro release studies showed that borneol followed the zero-order release and hardly impacted the in vitro release of Salvia miltiorrhiza and Panax notoginseng in CDCOPC. Moreover, as revealed from the similarity results of fingerprints, the in vitro release of different components of CDCOPC was almost simultaneous. Compared with the commercially available tablets, the pharmacokinetics studies suggested that both CDCOPCs containing and lacking borneol could significantly prolong the retention time of these effective components; their average relative bioavailability values increased to 448.70% and 350.97%, respectively. Notably, borneol significantly improved the relative bioavailability of some components of CDCOPC, such as salvianolic acid B (SAB), tanshinone IIA (Tan IIA), notoginsenoside R1 (R1), ginsenoside Rg1 (Rg1), and ginsenoside Re (Re) from CDCOPC, while it slightly impacted ginsenoside Rb1 (Rb1) and ginsenoside Rd (Rd). Summarily, borneol is capable of improving the bioavailability of some effective components in CDCOPC, which is critical to design with CDCOPC for enhanced bioavailability. This study could also help reveal the composition principle of the compound Danshen formula (CDF).

To provide more discriminative feedback for the second language (L2) learners to better identify their mispronunciation, we propose a method for exaggerated visual-speech feedback in computer-assisted pronunciation training (CAPT). The speech exaggeration is realized by an emphatic speech generation neural network based on Tacotron, while the visual exaggeration is accomplished by ADC Viseme Blending, namely increasing Amplitude of movement, extending the phone's Duration and enhancing the color Contrast. User studies show that exaggerated feedback outperforms non-exaggerated version on helping learners with pronunciation identification and pronunciation improvement.

Liver cancer, one of the most common types of cancer in the world, is the second leading cause of death for cancer patients. For liver cancer, there is an urgent need for an effective treatment with no or less toxic side effects. Lactonic sophorolipids (LSL), as a potential anticancer drug, has attracted wide attention of pharmaceutical researchers with its good biological activities. The effects of LSL and cell death inhibitors were measured by MTT test on HepG2 cells. Meanwhile, the morphology of the cells was observed under a microscope. The apoptosis rate was detected by flow cytometry, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 were measured by detection kits. Meanwhile, mRNA levels of Apaf-1, Caspase-3, Bax, and Bcl-2 were measured by quantitative real-time RT-PCR; protein levels of Caspase-3, Cleaved Caspase-3, Bax, and Bcl-2 were measured by western blot. LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in cells. The HepG2 cells with LSL co-culture exhibited typical apoptotic morphology, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 increased (P0.05). We also found that LSL increases cell apoptosis rate and regulates the expression of genes and proteins associated with apoptosis through the Caspase-3 pathway. These results indicate that LSL may be one of the potential drug candidates to inhibit the proliferation and induce apoptosis in HepG2 cells.Key points• LSL, which is of good biological activities such as anti-bacterium, virus elimination, and inflammatory response elimination, has been firstly used to intervene in vitro to investigate its effect on HepG2 cell proliferation.• LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in HepG2 cells through the Caspase-3 pathway.• The mechanism of LSL action on HepG2 cell proliferation was firstly also discussed, which provides a certain experimental reference for the clinical treatment of liver cancer.

BACKGROUND Internet hospitals have been encouraged by the Chinese government to develop an innovative medical service model that mainly uses new internet-based technologies to increase access to health care and improve the quality and efficiency of health care delivery. However, the academic exploration of the institutional and sectoral development of internet hospitals in China is scarce in the existing literature. OBJECTIVE This study aimed to investigate the policy interventions, development trends, and service innovations of internet hospitals in China. It is expected that the findings from this study will contribute to the further innovation of internet hospitals in China and provide references for the international development of internet hospitals for personalized digital health and patient-centric services. METHODS This study analyzed official policies related to internet hospitals that were implemented by the government in China since 2005. The data of formally approved internet hospitals were collected from official websites to analyze development trends. In-depth semistructured interviews were conducted with 58 key stakeholders who represented comprehensive viewpoints about the service innovations of internet hospitals between March and November 2019. RESULTS In total, 25 policies that promoted the development of internet hospitals in China were identified. These policies encompassed informatization infrastructure construction, medical resource integration, development model design, service model design, and payment model design. Of the 268 internet hospitals that had received an official license from the government, 153 public internet hospitals had been built mainly by medical institutions. Public tertiary hospitals were the main actors in founding internet hospitals that were created to provide services that targeted patients with common diseases or chronic diseases or patients living in remote and rural areas. Promoting convenient access to high-quality medical resources and saving patients’ and their families’ time were the key values of internet hospitals. CONCLUSIONS The policy interventions strongly promoted the development of internet hospitals in China. Public tertiary hospitals led the development of internet hospitals. However, internet hospitals in China have mainly played roles that are complementary to those of physical medical institutions. The service model of internet hospitals needs more distinguished innovations to provide personalized digital health and patient-centric services.

Background Internet hospitals have been encouraged by the Chinese government to develop an innovative medical service model that mainly uses new internet-based technologies to increase access to health care and improve the quality and efficiency of health care delivery. However, the academic exploration of the institutional and sectoral development of internet hospitals in China is scarce in the existing literature. Objective This study aimed to investigate the policy interventions, development trends, and service innovations of internet hospitals in China. It is expected that the findings from this study will contribute to the further innovation of internet hospitals in China and provide references for the international development of internet hospitals for personalized digital health and patient-centric services. Methods This study analyzed official policies related to internet hospitals that were implemented by the government in China since 2005. The data of formally approved internet hospitals were collected from official websites to analyze development trends. In-depth semistructured interviews were conducted with 58 key stakeholders who represented comprehensive viewpoints about the service innovations of internet hospitals between March and November 2019. Results In total, 25 policies that promoted the development of internet hospitals in China were identified. These policies encompassed informatization infrastructure construction, medical resource integration, development model design, service model design, and payment model design. Of the 268 internet hospitals that had received an official license from the government, 153 public internet hospitals had been built mainly by medical institutions. Public tertiary hospitals were the main actors in founding internet hospitals that were created to provide services that targeted patients with common diseases or chronic diseases or patients living in remote and rural areas. Promoting convenient access to high-quality medical resources and saving patients’ and their families’ time were the key values of internet hospitals. Conclusions The policy interventions strongly promoted the development of internet hospitals in China. Public tertiary hospitals led the development of internet hospitals. However, internet hospitals in China have mainly played roles that are complementary to those of physical medical institutions. The service model of internet hospitals needs more distinguished innovations to provide personalized digital health and patient-centric services.

Evolving graphs in the real world are large-scale and constantly changing, as hundreds of thousands of updates may come every second. Monotonic algorithms such as Reachability and Shortest Path are widely used in real-time analytics to gain both static and temporal insights and can be accelerated by incremental computing. Existing streaming systems adopt the incremental computing model and achieve either low latency or high throughput, but not both. However, both high throughput and low latency are required in real scenarios such as financial fraud detection. This paper presents RisGraph, a real-time streaming system that provides low-latency analysis for each update with high throughput. RisGraph addresses the challenge with localized data access and inter-update parallelism. We propose a data structure named Indexed Adjacency Lists and use sparse arrays and Hybrid Parallel Mode to enable localized data access. To achieve inter-update parallelism, we propose a domain-specific concurrency control mechanism based on the classification of safe and unsafe updates. Experiments show that RisGraph can ingest millions of updates per second for graphs with several hundred million vertices and billions of edges, and the P999 processing time latency is within 20 milliseconds. RisGraph achieves orders-of-magnitude improvement on throughput when analyses are executed for each update without batching and performs better than existing systems with batches of up to 20 million updates.

Background: This study aimed to explore the intellectual landscape of the studies investigating the clinical application of enteral nutrition (EN) in patients with ventilator associated pneumonia (VAP), and to identify thematic development trends and research frontiers in this area. Methods: Scientometric research was conducted by analyzing bibliographic records retrieved from the Web of Science Core Collection Database dated between 1996 and 2018. Reference co-citation analysis, key words co-occurrence analysis and cooperation network analysis were performed using CiteSpace software. Results: A total of 124 valid records were included in the final dataset. It was found that early studies were mainly focused on the feeding pathways of EN among VAP patients. The risks associated with EN intervention in VAP patients, including gastric nutrition intolerance and aspiration pneumonia, were extensively investigated and reported. While aspiration pneumonia has remained a long-term active research area in the field of EN interventions for VAP patients, with recent research focused more on interventions aiming to improve EN support and to optimize the use of EN for VAP patients. It seems that clinical guidelines on EN interventions for VAP patients need to be established. Conclusion: The advantages of EN for VAP patients have been recognized but still require further investigation on standardizing the use. Strategic cooperation among hospital physicians, university researchers and industrial product developers is required to establish clinical guidelines and to continue developing innovative EN products to tackle VAP.

Huperzine A (hup A), extracted from the Chinese medicinal plant Huperzia serrata, is a reversible and highly selective second-generation acetylcholine esterase (AchE) inhibitor for treating Alzheimer’s disease (AD), but it suffers from low bioavailability in the brain. This study aimed to develop a nasal temperature and pH dual-responsive in situ gel delivery system based on microemulsion of hup A (hup A-M-TPISG). The optimal formulation was obtained by central composite design and response surface methodology. The optimized mucoadhesive formulation, hup A-M-TPISG, was composed of pluronic F127 (20.80%), pluronic F68 (2.8%), and chitosan (0.88%) as the gel matrix, which could gelatinize under physiological conditions (29–34°C, pH 6.5) because of its temperature and pH responsiveness. The optimized hup A-M-TPISG formulation was further evaluated by in vitro release and in vivo pharmacokinetic studies via microdialysis. The in vitro release study showed continuous and steady drug release from hup A-M-TPISG, which was in accordance with the first-order model. Moreover, the pharmacokinetic results revealed that the optimized formulation for nasal administration, with convenient administration and improved patient compliance, could achieve similar brain-targeting properties as intravenous administration. In conclusion, the hup A-M-TPISG for intranasal administration, as an effective and safe vehicle, could enhance the absorption of hup A in vivo and would be a promising noninvasive alternative for partially improving brain-targeting therapy.

Meng Li,1 Fengyan Wang,2 Rongchang Chen,2 Zhenyu Liang,2 Yumin Zhou,2 Yuqiong Yang,2 Shengqi Chen,1 Carolina Oi Lam Ung,1 Hao Hu1 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou China Purpose: Hospitalization brings considerable economic pressure on COPD patients in China. A clear understanding of hospitalization costs for patients with COPD is warranted to improve treatment strategies and to control costs. Currently, investigation on factors contributing to hospitalization costs for patients with COPD in China is limited. This study aimed to measure the hospitalization costs of COPD and to determine the contributing factors. Patients and methods: Medical record data from the First Affiliated Hospital of Guangzhou Medical University from January 2016 to December 2016 were used for a retrospective analysis. Patients who were hospitalized with a diagnosis of COPD were included. Patient characteristics, medical treatment, and hospitalization costs were analyzed by descriptive statistics and multivariable regression. Results: Among the 1,943 patients included in this study, 87.85% patients were male; the mean (SD) age was 71.15 (9.79) years; 94.49% patients had comorbidities; and 82.30% patients had health insurance. Regarding medical treatment, the mean (SD) length of stay was 9.38 (7.65) days; 11.12% patients underwent surgery; 87.91% used antibiotics; and 4.53% underwent emergency treatment. For hospitalization costs, the mean (SD) of the total costs per COPD patient per admission was 24,372.75 (44,173.87) CNY (3,669.33 [6,650.38] USD), in which Western medicine fee was the biggest contributor (45.53%) followed by diagnosis fee (27.00%) and comprehensive medical fee (12.04%). Regression found that reimbursement (-0.032; 95% CI -0.046 to 0.007), length of stay (0.738; 95% CI 0.832–0.892), comorbidity (0.044; 95% CI 0.029–0.093), surgery (0.145; 95% CI 0.120–0.170), antibiotic use (0.086; 95% CI 0.060–0.107), and emergency treatment (0.121; 95% CI 0.147–0.219) were significantly (P