Convolutional Neural Networks Enable Highly Accurate and Automated Subvisible Particulate Classification of Biopharmaceuticals.

Quantification of subvisible particles, which are generally defined as those ranging in size from 2 to 100 µm, is important as critical characteristics for biopharmaceutical formulation development. Micro Flow Imaging (MFI) provides quantifiable morphological parameters to study both the size and type of subvisible particles, including proteinaceous particles as well as non-proteinaceous features incl. silicone oil droplets, air bubble droplets, etc., thus enabling quantitative and categorical particle attribute reporting for quality control. However, limitations in routine MFI image analysis can hinder accurate subvisible particle classification. In this work, we custom-built a subvisible particle-aware Convolutional Neural Network, SVNet, which has a very small computational footprint, and achieves comparable performance to prior state-of-art image classification models. SVNet significantly improves upon current standard operating procedures for subvisible particulate assessments as confirmed by thorough real-world validation studies.

Correction: Li et al. Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3ß Signaling. Molecules 2019, 24, 110.

The authors wish to make the following corrections to this paper [...].

[Development of a Multi-parameter Pulmonary Function Test System].

To comprehensively evaluate the human body's respiratory, circular metabolism and other functions, and to diagnose lung disease, an accurate and reliable pulmonary function test (PFT) is developed. The system is divided into two parts:hardware and software. It realizes the collection of respiratory, pulse oxygen, carbon dioxide, oxygen and other signals, and draws flow-volume curve (FV curve), volume-time curve (VT curve), respiratory waveform, pulse wave, carbon dioxide and oxygen waveform in real time on the upper computer of the PFT system, and conducts signal processing and parameter calculation for each signal. The experimental results prove that the system is safe and reliable, it can accurately measure the basic functions of human body, and provide reliable parameters, and has good application prospects.

[Design and Implementation of Urodynamic Monitoring System].

In order to assess and diagnose lower urinary tract dysfunction in patients and help patients with lower urinary tract rehabilitation training, an accurate and reliable urodynamic monitoring and automatic voiding system was designed. The system realizes the signal acquisition circuit of bladder pressure, abdominal pressure and urine volume based on the pressure sensor of urinary catheter and the load sensor. Meanwhile, the dynamic waveforms of urinary flow rate, bladder pressure and abdominal pressure are drawn in real time on the software of urodynamic monitoring. Signal processing and analysis of each signal are carried out, and the system performance is verified by building a simulation experiment. The experimental results show that the system is stable, reliable, accurate and meets the expected design goals, which can provide support for subsequent engineering design and clinical applications.

Protective Effect of Topiroxostat on Myocardial Injury Induced by Lipopolysaccharide.

BACKGROUND: Myocardial injury induced by sepsis is the most common cause of death. Topiroxostat has been found to have organ protective effects, but its role in septic shock-related cardiomyocyte damage is still unclear and needs further study. MATERIAL AND METHODS: An endotoxemic shock model in rats was constructed. After topiroxostat treatment, hemodynamic parameters, myocardial injury marker enzymes, oxidative stress, myocardial injury, and apoptosis were measured by polyphysiograph, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, TUNEL staining, and western blot. During in vitro experiments, the effect of topiroxostat on cell vitality, oxidative stress, inflammatory factors, apoptosis-related markers, phosphorylated-p65 (p-p65) and p65 expressions were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. RESULTS: Topiroxostat improved myocardial dysfunction and superoxide dismutase activity while suppressing levels of creatine kinase, lactate dehydrogenase and malondialdehyde in serum of endotoxemic shock rats. Additionally, topiroxostat augmented dry-wet weight ratios of the hearts in rats. Meanwhile, topiroxostat was proved to alleviate interstitial edema and apoptosis in myocardial tissues of endotoxemic shock rats. During in vitro experiments, topiroxostat pretreatment elevated lipopolysaccharide (LPS)-induced H9c2 cell vitality, and alleviated oxidative stress and inflammation. Moreover, topiroxostat pretreatment downregulated apoptosis-related markers, p-p65, and p-p65/p65 levels in LPS-induced H9c2 cells. CONCLUSIONS: Topiroxostat attenuated LPS-induced myocardial injury via repressing apoptosis and oxidative stress.

Prevalence and predictors of depression among emergency physicians: a national cross-sectional study.

BACKGROUND: Physicians' depression can damage their physical and mental health and can also lead to prescribing errors and reduced quality of health care. Emergency physicians are a potentially high-risk community, but there have been no large-sample studies on the prevalence and predictors of depression among this population. METHODS: A nationally representative cross-sectional survey of 15,243 emergency physicians was conducted in 31 provinces across China between July and September 2019. Multivariable logistic regression analysis was performed to identify predictors of depression. RESULTS: A total of 35.59% of emergency physicians suffered from depression. Emergency physicians who were male (OR=0.91) and older [>37 and ≤43 (OR=0.83) or >43 (OR=0.71)], had high (OR=0.63) or middle (OR=0.70) level income, and participated in physical inactivity (OR=0.85) were not more likely to suffer depression. Meanwhile, those who were unmarried (OR=1.13) and smokers (OR=1.12) had higher education levels [Bachelor's degree (OR=1.57) or Master's degree or higher (OR=1.82)], long work tenure [>6 and ≤11 (OR=1.15) or >11;11 (OR=1.19)], poorer health status [fair (OR=1.67) or poor (OR=3.79)] and sleep quality [fair (OR=2.23) or poor (OR=4.94)], a history of hypertension (OR=1.13) and coronary heart disease (OR=1.57) and experienced shift work (OR=1.91) and violence (OR=4.94)]. CONCLUSION: Nearly one third of emergency physicians in China suffered from depression. Targeted measures should be taken to reduce the prevalence of depression to avoid a decline in health care quality and adversely impact the supply of emergency medical services.

Safety and efficacy of new oral anticoagulants compared to those of warfarin in AF patients with cancer: a meta-analysis of randomized clinical trials and observational studies.

BACKGROUND: Data on the efficacy and safety of nonvitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with cancer are limited. Therefore, we conducted a meta-analysis to compare the efficacy and safety between NOACs and warfarin in this population. METHODS: A comprehensive search of the PubMed, Embase, and Cochrane databases for articles published through July 2020 was performed. An evaluation of each study was conducted, and data were extracted. Pooled odds ratio (OR) estimates and 95% CIs were calculated. RESULTS: Eight studies (3 randomized controlled trials (RCTs) and 5 retrospective cohort studies) involving a total of 24,665 patients were included. Among the RCTs, there were no significant differences in the rates of stroke or systemic embolism (OR=0.69; 95% CI, 0.45-1.06; P=0.09), venous thromboembolism (OR=0.91; 95% CI, 0.33-2.52; P=0.86), myocardial infarction (OR=0.74; 95% CI, 0.44-1.23; P=0.24), major bleeding (OR=0.81; 95% CI, 0.61-1.06; P=0.12), or major or nonmajor clinically relevant bleeding (OR= 0.98; 95% CI, 0.82-1.19; P=0.86) between the NOAC and warfarin groups. Among the observational studies, patients who used NOACs had a significantly lower risk than those who used warfarin. The prevalence rates of ischemic stroke (OR=0.51; 95% CI, 0.28-0.92; P=0.02), VTE (OR=0.50; 95% CI, 0.41-0.60; P<0.00001), major bleeding (OR=0.28; 95% CI, 0.14-0.55; P=0.0002), and intracranial or gastrointestinal bleeding (OR=0.59; 95% CI, 0.37-0.92; P=0.02) were significantly reduced in the NOAC group. CONCLUSION: Our meta-analysis confirms that NOACs are as safe and effective as warfarin and can be applied in the real world; this data can serve as a reference for clinical doctors for formulating treatment strategies.

A Novel EMG-Based Hand Gesture Recognition Framework Based on Multivariate Variational Mode Decomposition.

Surface electromyography (sEMG) is a kind of biological signal that records muscle activity noninvasively, which is of great significance in advanced human-computer interaction, prosthetic control, clinical therapy, and biomechanics. However, the number of hand gestures that can be recognized is limited and the recognition accuracy needs to be further improved. These factors lead to the fact that sEMG products are not widely used in practice. The main contributions of this paper are as follows. Firstly, considering the increasing number of gestures to be recognized and the complexity of gestures, an extensible two-stage machine learning lightweight framework was innovatively proposed for multi-gesture task recognition. Secondly, the multivariate variational mode decomposition (MVMD) is applied to extract the spatial-temporal features from the multiple channels to the EMG signals, and the separable convolutional neural network is used for modelling. In this work, the experimental results for 52 hand gestures recognition task show that the average accuracy on each stage is about 90%. The potential movement information is mainly contained in the low-frequency oscillator of the sEMG signal, and the model performs better with the low-frequency oscillation from the MVMD algorithm on the second stage classification than that of other decomposition methods.

Sesamin suppresses NSCLC cell proliferation and induces apoptosis via Akt/p53 pathway.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a disappointing prognosis. The aim of this study was to investigate the anticancer effect of sesamin and the underlying mechanism. The MTT assay was used to detect the proliferation of NSCLC cells. The cell cycle and apoptosis were analyzed by flow cytometry. The protein levels of Akt, p-Akt (Ser473), p53, cyclin D1, CDK2, MDM2, p-MDM2 (Ser166) were detected by western blotting. The expression of p-Akt (Ser473), p53 and Ki67 in vivo was analyzed by IHC. Histopathologic analyses of major organs (heart, liver, spleen, lung and kidney) were performed by H&E staining. The results show that sesamin suppressed cell proliferation and induced apoptosis of NSCLC cells (A549 and H1792) in a dose-dependent manner. Treatment with sesamin caused cell cycle arrest at G1 phase and inhibited cyclin D1 and CDK2 expression. In addition, sesamin inhibited Akt activity and upregulated p53 expression both in vivo and in vitro. When Akt and p53 were suppressed by LY294002 and PFTα, respectively, sesamin exerted no additional effects. The in vivo results mostly matched the in vitro findings. Specifically, sesamin exerted little damage to major organs. Taken together, this study demonstrates that sesamin suppresses NSCLC cell proliferation by induction of G1 phase cell cycle arrest and apoptosis via Akt/p53 pathway. Therefore, sesamin may be a promising adjuvant treatment for NSCLC therapy.

[Design of Low Power Multi-parameter Monitoring System Based on Bluetooth].

This paper designs a bluetooth-based low-power multi-parameter monitoring system. The system is mainly composed of ECG signal acquisition, respiratory signal acquisition, body temperature acquisition, bluetooth 4.0 transmission module and Android mobile phone APP display. The system collects the corresponding physiological signals through various collection parts, and can realize the monitoring of three physiological signals of electrocardiogram, respiration and body temperature. The Android mobile APP can display ECG, respiratory waveform and temperature data in real time. The system is small in size and low in power consumption, and has a good application prospect in portable and wearable medical applications.

[Design of Multi-parameter Monitoring System Based on Embedded Linux+Qt].

OBJECTIVE: To establish the system software of multi-parameter monitoring by embedded Linux kernel and Qt library. METHODS: To determine the hardware system needed for the development of the system, carry out system Bootloader (Bootloader), Linux kernel, file system and Qt/Embedded (QtE) tailoring and transplantation and application development on the basis of the hardware system, and achieve the characteristic UI design. RESULTS: The changes of physiological parameters were observed in real time to improve the stability and real-time performance of the whole system and increase users' experience with QtE. CONCLUSIONS: The embedded Linux+Qt multi-reference monitoring system can improve the stability, operability and functionality of real-time monitoring and multi-physiological information, and has good extensibility and maintainability.

[Design of Treatment System for Poor Peripheral Circulation Using Air Wave Pressure Based on STM32 Microprocessor].

This study designs an intermittent pneumatic pressurization device with STM32 series single chip as the core. The working state of the air pump and the plurality of air chambers is controlled by the IO port of the single chip microcomputer, and the circulating inflation of the plurality of air bags is realized. The pressure monitoring system consists of a silicon piezoresistive pressure sensor, a high-precision operational amplifier and a 12-bit AD converter which monitors the gas pressure of each gas path in real time to ensure the safety of the equipment. The system is easy to operate, simple in function, and has strong practicability.

Discovery of 2-phenylthiazole-4-carboxylic acid, a novel and potent scaffold as xanthine oxidase inhibitors.

The xanthine oxidase (XO) plays an important role in producing uric acid, and therefore XO inhibitors are considered as one of the promising therapies for hyperuricemia and gout. We have previously reported a series of XO inhibitors with pyrazole scaffold to extend the chemical space of current XO inhibitors. Herein, we describe further structural optimization to explore the optimal heterocycle by replacing the thiazole ring of Febuxostat with 5 heterocycle scaffolds unexplored in this field. All of these efforts resulted in the identification of compound 8, a potent XO inhibitor (IC50 = 48.6 nM) with novel 2-phenylthiazole-4-carboxylic acid scaffold. Moreover, lead compound 8 exhibited hypouricemic effect in potassium oxonate-hypoxanthine-induced hyperuricemic mice. These results promote the understanding of ligand-receptor interaction and might help to design more promising XO inhibitors.

[Design of Cardiac Pacemaker Based on Low Power MCU].

In order to improve the accuracy of the pacemaker's parameter adjustment and to avoid the surgical replacement of the pacemaker when the battery is exhausted, this paper designs a novel single-chamber pacemaker circuit based on low-power single-chip microcomputer. The circuit uses digital control to accurately control the amplitude, pulse width and frequency of the pacing pulse. The circuit is also designed with wireless charging function, and wireless communication with the programmer can wirelessly charge the pacemaker and know the charging information in real time. Wireless charging function can reduce the number of times the patient replaces the pacemaker or even completely avoid it.

Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma.

BACKGROUND: Distinctive exosomal contents could be useful for cancer diagnosis and prognosis. However, little is known about whether serum exosomal heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) mRNA is a satisfactory biomarker for hepatocellular carcinoma (HCC). METHODS: Two hundred and ninety-one participants divided into four age- and gender-matched groups, including a HCC group (n=88), a liver cirrhosis (LC) group (n=67), a chronic hepatitis B (CHB) group (n=68) and a healthy control group (n=68), were enrolled. Serum exosomal hnRNPH1 mRNA and GAPDH mRNA were measured using TaqMan real-time PCR, and the relative expression levels were calculated. Receiver operating characteristic (ROC) curves were constructed to evaluate the effectiveness of hnRNPH1 mRNA alone and in combination with α-fetoprotein (AFP) in the diagnosis of HCC. The correlation between hnRNPH1 mRNA levels and clinicopathological characteristics and overall survival (OS) in HCC was determined. RESULTS: The serum exosomal hnRNPH1 mRNA levels in HCC patients were remarkably higher than in the other groups (p<0.05). The hnRNPH1 mRNA discriminated HCC from CHB with an area under the ROC curve (AUC) of 0.865, with sensitivity of 85.2% and specificity of 76.5% at cut-off value of 0.670. The AUC for hnRNPH1 mRNA in combination with AFP was further improved. The exosomal hnRNPH1 mRNA levels in HCC patients were associated with the Child-Pugh classification, portal vein tumor emboli, lymph node metastasis, TNM stage and OS (p<0.05). CONCLUSIONS: These findings suggested that serum exosomal hnRNPH1 mRNA could be an effective marker for HCC in high HBV prevalence areas.

Structure-based design of free fatty acid receptor 1 agonists bearing non-biphenyl scaffold.

The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co-crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced-fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and δ-π interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket.

Shikonin Attenuates Acetaminophen-Induced Hepatotoxicity by Upregulation of Nrf2 through Akt/GSK3ß Signaling.

Acetaminophen (APAP) overdose-induced acute liver damage is mostly due to overwhelmingly increased oxidative stress. Nuclear factor-erythroid 2-related factor2 (Nrf2) plays an important role in alleviating APAP hepatic toxicity. Shikonin (SHK) enhances Nrf2 in multiple lines of normal cells. Nevertheless, whether SHK protects against APAP-induced liver toxicity remains undefined. This study found SHK defended APAP-induced liver toxicity, as well as reversed the levels of serum alanine/aspartate aminotransferases (ALT/AST), liver myeloperoxidase (MPO) activity, and reactive oxygen species (ROS), while it enhanced the liver glutathione (GSH) level in APAP-treated mice. SHK rescued the cell viability and GSH depletion, but neutralized oxidative stress in APAP-treated human normal liver L-02 cells. Mechanically, SHK increased Nrf2 expression in the exposure of APAP at the protein level but not at the mRNA level. Inhibition of Nrf2 blocked the SHK effect in APAP-treated hepatocytes. Furthermore, SHK improved Nrf2 stability through stimulating PI3K/Akt pathway, thus inhibiting GSK-3ß. In vivo studies confirmed the close correlation of liver protection of SHK against APAP and Akt/GSK-3ß/Nrf2 pathway. In conclusion, this study reveals that SHK prevents APAP hepatotoxicity by upregulation of Nrf2 via PI3K/Akt/GSK-3ß pathway. Therefore, SHK may be a promising candidate against APAP-induced liver injury.

Wald tests for variance-adjusted equivalence assessment with normal endpoints.

Equivalence tests may be tested with mean difference against a margin adjusted for variance. The justification of using variance adjusted non-inferiority or equivalence margin is for the consideration that a larger margin should be used with large measurement variability. However, under the null hypothesis, the test statistic does not follow a t-distribution or any well-known distribution even when the measurement is normally distributed. In this study, we investigate asymptotic tests for testing the equivalence hypothesis. We apply the Wald test statistic and construct three Wald tests that differ in their estimates of variances. These estimates of variances include the maximum likelihood estimate (MLE), the uniformly minimum variance unbiased estimate (UMVUE), and the constrained maximum likelihood estimate (CMLE). We evaluate the performance of these three tests in terms of type I error rate control and power using simulations under a variety of settings. Our empirical results show that the asymptotic normalized tests are conservative in most settings, while the Wald tests based on ML- and UMVU-method could produce inflated significance levels when group sizes are unequal. However, the Wald test based on CML-method provides an improvement in power over the other two Wald tests for medium and small sample size studies.

[Research progress on the technique and materials for three-dimensional bio-printing].

Three-dimensional (3D) bio-printing is a novel engineering technique by which the cells and support materials can be manufactured to a complex 3D structure. Compared with other 3D printing methods, 3D bio-printing should pay more attention to the biocompatible environment of the printing methods and the materials. Aimed at studying the feature of the 3D bio-printing, this paper mainly focuses on the current research state of 3D bio-printing, with the techniques and materials of the bio-printing especially emphasized. To introduce current printing methods, the inkjet method, extrusion method, stereolithography skill and laser-assisted technique are described. The printing precision, process, requirements and influence of all the techniques on cell status are compared. For introduction of the printing materials, the cross-link, biocompatibility and applications of common bio-printing materials are reviewed and compared. Most of the 3D bio-printing studies are being remained at the experimental stage up to now, so the review of 3D bio-printing could improve this technique for practical use, and it could also contribute to the further development of 3D bio-printing.

Testing for polygenic effects in genome-wide association studies.

To confirm associations with a large number of single nucleotide polymorphisms (SNPs), each with only a small effect size, as hypothesized in the polygenic theory for schizophrenia, the International Schizophrenia Consortium (2009, Nature 460:748-752) proposed a polygenic risk score (PRS) test and demonstrated its effectiveness when applied to psychiatric disorders. The basic idea of the PRS test is to use a half of the sample to select and up-weight those more likely to be associated SNPs, and then use the other half of the sample to test for aggregated effects of the selected SNPs. Intrigued by the novelty and increasing use of the PRS test, we aimed to evaluate and improve its performance for GWAS data. First, by an analysis of the PRS test, we point out its connection with the Sum test [Chapman and Whittaker, Genet Epidemiol 32:560-566; Pan, Genet Epidemiol 33:497-507]; given the known advantages and disadvantages of the Sum test, this connection motivated the development of several other polygenic tests, some of which may be more powerful than the PRS test under certain situations. Second, more importantly, to overcome the low statistical efficiency of the data-splitting strategy as adopted in the PRS test, we reformulate and thus modify the PRS test, obtaining several adaptive tests, which are closely related to the adaptive sum of powered score (SPU) test studied in the context of rare variant analysis [Pan et al., 2014, Genetics 197:1081-1095]. We use both simulated data and a real GWAS dataset of alcohol dependence to show dramatically improved power of the new tests over the PRS test; due to its superior performance and simplicity, we recommend the whole sample-based adaptive SPU test for polygenic testing. We hope to raise the awareness of the limitations of the PRS test and potential power gain of the adaptive SPU test.