Safety and efficacy of rimegepant orally disintegrating tablet for the acute treatment of migraine in China and South Korea: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: No acute treatments targeting calcitonin gene-related peptide (CGRP) have been approved for use in China or South Korea. We aimed to compare the efficacy and safety of rimegepant-an orally administered small molecule CGRP antagonist-with placebo in the acute treatment of migraine among adults in these countries. METHODS: This double-blind, randomised, placebo-controlled, multicentre phase 3 trial was done at 86 outpatient clinics at hospitals and academic medical centres (73 in China and 13 in South Korea). Participants were adults (≥18 years) with at least a 1-year history of migraine who had two to eight moderate or severe attacks per month and fewer than 15 headache days per month within the 3 months before the screening visit. Participants were randomly assigned (1:1) to 75 mg rimegepant or placebo to treat a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use of preventive medication and by country. The allocation sequence was generated and implemented by study personnel using an interactive web-response system accessed online from each study centre. All participants, investigators, and the sponsor were masked to treatment assignment. The coprimary endpoints of freedom from pain and freedom from the most bothersome symptom (nausea, phonophobia, or photophobia) 2 h after dosing were assessed in the modified intention-to-treat (mITT) population (randomly assigned participants who took study medication for a migraine attack of moderate or severe pain intensity, and provided at least one efficacy datapoint after treatment) using Cochran-Mantel Haenszel tests. Safety was assessed in all participants who received rimegepant or placebo. The study is registered with ClinicalTrials.gov, number NCT04574362, and is completed. FINDINGS: 1431 participants were randomly assigned (716 [50%] to rimegepant and 715 [50%] to placebo). 668 (93%) participants in the rimegepant group and 674 (94%) participants in the placebo group received treatment. 1340 participants were included in the mITT analysis (666 [93%] in the rimegepant group and 674 [94%] in the placebo group). 2 h after dosing, rimegepant was superior to placebo for pain freedom (132 [20%] of 666 vs 72 [11%] of 674, risk difference 9·2, 95% CI 5·4-13·0; p<0·0001) and freedom from the most bothersome symptom (336 [50%] of 666 participants vs 241 [36%] of 674 participants, 14·8, 9·6-20·0; p<0·0001). The most common (≥1%) adverse events were protein in urine (8 [1%] of 668 participants in the rimepegant group vs 7 [1%] of 674 participants in the placebo group), nausea (7 [1%] of 668 vs 18 [3%] of 674), and urinary tract infection (5 [1%] of 668 vs 8 [1%] of 674). There were no rimegepant-related serious adverse events. INTERPRETATION: Among adults living in China or South Korea, a single dose of 75 mg rimegepant was effective for the acute treatment of migraine. Safety and tolerability were similar to placebo. Our findings suggest that rimegepant might be a useful new addition to the range of medications for the acute treatment of migraine in China and South Korea, but further studies are needed to support long-term efficacy and safety and to compare rimegepant with other medications for the acute treatment of migraine in this population. FUNDING: BioShin Limited. TRANSLATIONS: For the Chinese and Korean translations of the abstract see Supplementary Materials section.

Enhancing thoracic disease detection using chest X-rays from PubMed Central Open Access.

Large chest X-rays (CXR) datasets have been collected to train deep learning models to detect thorax pathology on CXR. However, most CXR datasets are from single-center studies and the collected pathologies are often imbalanced. The aim of this study was to automatically construct a public, weakly-labeled CXR database from articles in PubMed Central Open Access (PMC-OA) and to assess model performance on CXR pathology classification by using this database as additional training data. Our framework includes text extraction, CXR pathology verification, subfigure separation, and image modality classification. We have extensively validated the utility of the automatically generated image database on thoracic disease detection tasks, including Hernia, Lung Lesion, Pneumonia, and pneumothorax. We pick these diseases due to their historically poor performance in existing datasets: the NIH-CXR dataset (112,120 CXR) and the MIMIC-CXR dataset (243,324 CXR). We find that classifiers fine-tuned with additional PMC-CXR extracted by the proposed framework consistently and significantly achieved better performance than those without (e.g., Hernia: 0.9335 vs 0.9154; Lung Lesion: 0.7394 vs. 0.7207; Pneumonia: 0.7074 vs. 0.6709; Pneumothorax 0.8185 vs. 0.7517, all in AUC with p< 0.0001) for CXR pathology detection. In contrast to previous approaches that manually submit the medical images to the repository, our framework can automatically collect figures and their accompanied figure legends. Compared to previous studies, the proposed framework improved subfigure segmentation and incorporates our advanced self-developed NLP technique for CXR pathology verification. We hope it complements existing resources and improves our ability to make biomedical image data findable, accessible, interoperable, and reusable.

The Relationship between Nurses' Perceptions of Spirituality and Spiritual Care and Perceived Professional Benefits: A Correlation Study

Purpose. This study aimed to investigate nurses' perceptions of spirituality and spiritual care and perceived professional benefits in China and reveal the relationship between them. Design and Methods. In this study, 372 nurses (response rate: 93.47%) from a number of hospitals across China were surveyed using convenience sampling. The data were collected through online questionnaires, including a sociodemographic characteristics form, the Chinese version of the Spiritual Care-Giving Scale (C-SCGS), and the Nurses' Perceived Professional Benefits Questionnaire (NPPBQ). Findings. The total score of the NPPBQ was 136.88 ± 20.13. A statistically significant relationship was found between the total score and subscale score of the C-SCGS and the total score and subscale score of the NPPBQ (R = 0.217–0.475, P < 0.01). Practice Implications. Nursing managers and educators should pay attention to improving nurses' perceptions of spirituality and spiritual care in order to help nurses gain more perceived professional benefits.

Increasing hand-hygiene compliance in clinical settings using a baby-eyes sticker

This double-blind field study tested the effectiveness of a baby-eyes image in promoting healthcare workers' hand-hygiene compliance in a hospital setting. Adults are inclined to take care of babies and aspire to be their role models;therefore, they should wash their hands thoroughly when being watched by babies. Participants were healthcare workers from the obstetrical and neonatology units of a women's hospital in Hangzhou. We recorded and coded 3,360 hours and 10,325 hand-hygiene events over a five-week period—from 16 October to 20 November 2018. Three types of stickers, depicting baby eyes, adult eyes, or flowers, were placed above handwashing basins to compare hand-hygiene behavior between the three conditions. Each condition continued for one week, and experimenters interchanged the stickers in each unit to control for the location and sequence effects. Participants in the baby-eyes condition (72.9%) were more likely to use sanitizer than those in the flowers condition (69.4%;χ2 = 9.74, p < .01, φc = 0.034). Moreover, participants in the baby-eyes condition were more likely to use sanitizer than those in the adult-eyes condition (70.8%);however, the difference only trended towards significance (χ2 = 2.38, p = .066, φc = 0.023). The mean handwashing time between the three conditions was significant (Welch's F(2, 3488.436) = 3.50, p < .05, η2 = 0.001). Washing time in the baby-eyes condition (17.41 ± 12.02) was significantly longer than in the adult-eyes condition (16.36 ± 11.47;p < .05). The presence of a baby-eyes image promoted hand-hygiene compliance in the hospital environment. This finding can be adopted to change public health behaviors. It also holds theoretical implications that enhance our understanding of how being monitored by children can enhance responsible behaviors.

Taking control of violence against doctors

Violence against healthcare professionals is a serious but understudied global problem and one that lacks evidence‐based solutions. The current research offers a novel explanation and intervention for addressing this issue: We propose that low feelings of control among patients and their family members play an important role in shaping doctor‐patient relationships. To regain a sense of control, we suggest that patients attribute responsibility to doctors for their suffering, which may in turn lead to aggressive behavioural intentions against one's doctors. We conducted three studies to understand whether individuals with low perceived control blame doctors more, and whether threats to their sense of control cause participants to attribute more responsibility to doctors. Study 1 found that feelings of lack of control were an important predictor of attributing responsibility for negative illness‐related incidents to doctors in a manner consistent with blame. Study 2 specified that the chaotic and unpredictable nature of illness, and not just its negative valence, is what drives attributions of increased responsibility to doctors. Study 3, which utilized a field setting in hospitals, found that an experimental intervention to increase feelings of control decreased frustration against (Study 3a/3b) and intention to harm doctors (Study 3b). These findings suggest that increasing feelings of control among patients can improve patient‐doctor relationships. We also discuss the role of control and scapegoating during the COVID‐19 pandemic.

IBV QX affects the antigen presentation function of BMDCs through non-structural protein16

The gamma-coronavirus infectious bronchitis virus (IBV) has a high mutation rate and mainly invades the respiratory mucosa, making it difficult to prevent and causing great economic losses. Non-structural protein 16 (NSP16) of IBV QX also not only plays an indispensable role in virus invading but also might hugely influence the antigen's recognition and presentation ability of host BMDCs. Hence, our study tries to illustrate the underline mechanism of how NSP16 influences the immune function of BMDCs. Initially, we found that NSP16 of the QX strain significantly inhibited the antigen presentation ability and immune response of mouse BMDCs, which was stimulated by Poly (I:C) or AIV RNA. Besides mouse BMDCs, we also found that NSP16 of the QX strain also significantly stimulated the chicken BMDCs to activate the interferon signaling pathway. Furthermore, we preliminarily demonstrated that IBV QX NSP16 inhibits the antiviral system by affecting the antigen-presenting function of BMDCs.

IBV QX affects the antigen presentation function of BMDCs through nonstructural protein16.

The gamma-coronavirus infectious bronchitis virus (IBV) has a high mutation rate and mainly invades the respiratory mucosa, making it difficult to prevent and causing great economic losses. Nonstructural protein 16 (NSP16) of IBV QX also not only plays an indispensable role in virus invading but also might hugely influence the antigen's recognition and presentation ability of host BMDCs. Hence, our study tries to illustrate the underline mechanism of how NSP16 influences the immune function of BMDCs. Initially, we found that NSP16 of the QX strain significantly inhibited the antigen presentation ability and immune response of mouse BMDCs, which was stimulated by Poly (I:C) or AIV RNA. Besides mouse BMDCs, we also found that NSP16 of the QX strain also significantly stimulated the chicken BMDCs to activate the interferon signaling pathway. Furthermore, we preliminarily demonstrated that IBV QX NSP16 inhibits the antiviral system by affecting the antigen-presenting function of BMDCs.

A Beta Strain-Based Spike Glycoprotein Vaccine Candidate Induces Broad Neutralization and Protection against SARS-CoV-2 Variants of Concern.

The coronavirus disease 2019 (COVID-19) pandemic is still ongoing. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) are circulating worldwide, making it resistant to existing vaccines and antiviral drugs. Therefore, the evaluation of variant-based expanded spectrum vaccines to optimize the immune response and provide broad protectiveness is very important. In this study, we expressed spike trimer protein (S-TM) based on the Beta variant in a GMP-grade workshop using CHO cells. Mice were immunized twice with S-TM protein combined with aluminum hydroxide (Al) and CpG Oligonucleotides (CpG) adjuvant to evaluate its safety and efficacy. BALB/c immunized with S-TM + Al + CpG induced high neutralizing antibody titers against the Wuhan-Hu-1 strain (wild-type, WT), the Beta and Delta variants, and even the Omicron variant. In addition, compared with the S-TM + Al group, the S-TM + Al + CpG group effectively induced a stronger Th1-biased cell immune response in mice. Furthermore, after the second immunization, H11-K18 hACE2 mice were well protected from challenge with the SARS-CoV-2 Beta strain, with a 100% survival rate. The virus load and pathological lesions in the lungs were significantly reduced, and no virus was detected in mouse brain tissue. Our vaccine candidate is practical and effective for current SARS-CoV-2 VOCs, which will support its further clinical development for potential sequential immune and primary immunization. IMPORTANCE Continuous emergence of adaptive mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the use and development of existing vaccines and drugs. The value of variant-based vaccines that are capable of inducing a higher and broader protection immune response against SARS-CoV-2 variants is currently being evaluated. This article shows that a recombinant prefusion spike protein based on a Beta variant was highly immunogenic and could induced a stronger Th1-biased cell immune response in mice and was effectively protective against challenge with the SARS-CoV-2 Beta variant. Importantly, this Beta-based SARS-CoV-2 vaccine could also offer a robust humoral immune response with effectively broad neutralization ability against the wild type and different variants of concern (VOCs): the Beta, Delta, and Omicron BA.1 variants. To date, the vaccine described here has been produced in a pilot scale (200L), and the development, filling process, and toxicological safety evaluation have also been completed, which provides a timely response to the emerging SARS-CoV-2 variants and vaccine development.

How does digitalisation influence supply chain performance? Evidence from a supply chain risk management perspective

This study explores the contribution of supply chain digitalisation (SCD) to supply chain performance (SCP) via the mediating roles of SC responsiveness, resilience, and restoration (SC 3Rs) and examines the moderating effects of the COVID-19 pandemic from a risk management perspective. We surveyed 215 Chinese companies from January to April 2021 and examined the hypothesised relationships in a moderated mediation model. We find that SCD positively affects SC 3Rs, which in turn play positive mediating roles in the relationship between SCD and SCP, and that the mediating effects are stronger when pandemic impact is higher. The results of post-hoc analyses indicate that the mediating role of SC resilience is stronger than those of SC responsiveness and SC restoration. These findings enrich our understanding of how the roles of SCD and SC 3Rs vary in a turbulent context, contributing to both academic research and practice on digitalisation for a sustainable SC.

A network analysis of anxiety and depression symptoms among Chinese nurses in the late stage of the COVID-19 pandemic.

Background: Nurses are at high risk for depression and anxiety symptoms after the outbreak of the COVID-19 pandemic. We aimed to assess the network structure of anxiety and depression symptoms among Chinese nurses in the late stage of this pandemic. Method: A total of 6,183 nurses were recruited across China from Oct 2020 to Apr 2021 through snowball sampling. We used Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder scale-7 (GAD-7) to assess depression and anxiety, respectively. We used the Ising model to estimate the network. The index "expected influence" and "bridge expected influence" were applied to determine the central symptoms and bridge symptoms of the anxiety-depression network. We tested the stability and accuracy of the network via the case-dropping procedure and non-parametric bootstrapping procedure. Result: The network had excellent stability and accuracy. Central symptoms included "restlessness", "trouble relaxing", "sad mood", and "uncontrollable worry". "Restlessness", "nervous", and "suicidal thoughts" served as bridge symptoms. Conclusion: Restlessness emerged as the strongest central and bridge symptom in the anxiety-depression network of nurses. Intervention on depression and anxiety symptoms in nurses should prioritize this symptom.

The prevalence and risk factors of mental problems in medical students during COVID-19 pandemic: A systematic review and meta-analysis.

BACKGROUND: This meta-analysis and systematic review aimed to evaluate the global prevalence and risk factors of mental problems (i.e., depression, anxiety, stress, sleep disorder, posttraumatic stress disorder (PTSD), burnout, psychological distress, and suicidal ideation) among medical students during the COVID-19 pandemic. METHOD: We searched PubMed, Embase, Web of Science, psycARTICLES, PsycINFO, CNKI, and Wan Fang for studies on the prevalence of mental problems among medical students from January 1, 2020, to April 1, 2022. The pooled prevalence was calculated by random-effect models. We performed a narrative review to identify the risk factors. RESULTS: The meta-analysis included 201 studies (N = 198,000). The prevalence of depression (41 %, 95 % CI, 37-45 %,), anxiety (38 %,95 % CI, 34 %-42 %), stress (34 %, 95 % CI, 27 %-42 %), sleep disorder (52 %, 95 % CI, 44 %-60 %), psychological distress (58 %, 95 % CI, 51 %-65 %), PTSD (34 %, 95 % CI, 22 %-46 %), suicidal ideation (15 %, 95 % CI, 11 %-18 %) and burnout (38 %, 95 % CI, 25 %-50 %) was high. The major risk factors were being female, being junior or preclinical students, exposure to COVID-19, academic stress, psychiatric or physical disorders history, economic trouble, fear of education impairment, online learning trouble, fear of infection, loneliness, low physical activity, low social support, problematic internet or smartphone use, and young age. LIMITATIONS: Most studies were cross-sectional. Few studies provided a reasonable response rate, suggesting potential selection bias. CONCLUSIONS: The study demonstrated a high prevalence and risk factors for mental problems during COVID-19, calling for mental health services. Our findings are valuable for college and health authorities to identify high-risk students and provide targeted intervention.

Establishment of ELISA for detecting porcine epidemic diarrhea virus specific SIgA in mucus

The aim of this study is to establish an indirect ELISA technique for detecting the SIgA antibody against porcine epidemic diarrhea virus (PEDV) to evaluate its mucosal immunity. Firstly, the S1D gene (534-789 aa) of PEDV was cloned into the pET-28a(+) vector, and induced in Escherichia coli BL21 (DE3) by IPTG, the product of which was in the form of inclusion bodies. According to Western-blot, the target protein S1D with antigenic activity was 32 ku in molecular weight and could be well detected. Then, the S1D protein was denatured by 8 mol/L urea, purified and gradient as the coating antigen to establish an indirect ELISA for detecting the PEDV specific SIgA antibody in nasal or oral mucus by optimizing conditions. And the optimal antigen coating concentration of ELISA was 2 micro g mL, the working concentrations of nasal mucus was 1:1 and the optimal blocking solution was 50 g/L skimmed milk, while the working concentrations and optimal blocking solution were 1:2 and 30 g/L BSA in oral mucus, the working concentrations of the enzyme-labeled antibody was 1:2 000 in nasal and oral mucus. Finally, 84 samples of oral and nasal mucus from immunized pigs were detected by S1D of ELISA, and the coincidence rate could reach 95.2% compared with purified PEDV of ELISA. In conclusion, the indirect ELISA established in this study provided a quick, simple, sensitive, and specific method to detect PEDV specific SigA for evaluating the level of PEDV mucosal immunity.

Transcriptome and targeted metabolome analysis revealed the effects of combined red and blue light on the growth and secondary metabolism of Scutellaria baicalensis Georgi

Scutellaria baicalensis Georgi is a medicinal plant commonly used in China and other parts of East Asia. A high flavonoid content endows it with multiple beneficial biological activities that have anti-inflammatory, antibacterial, antiviral, and anti-COVID19 properties. Light-emitting diodes (LEDs) have been recognized as effective artificial lights to enhance plant growth and the accumulation of secondary metabolites for commercial plant production. However, little is known regarding the effects of LEDs on S. baicalensis. Here, we explored the effects of monochromatic blue light (B, 460 nm), monochromatic red light (R, 660 nm), white light (CK), and different combinations of R and B (R9B1, R7B3, R5B5, R3B7, and R1B9) on the growth of, and flavonoid accumulation in S. baicalensis. The results revealed that under R:B ratios of 9:1 or 7:3, the whole plant and roots of S. baicalensis seedlings had a higher biomass and flavonoid content. Targeted metabolomics analysis showed that 48 differentially expressed metabolites (DEMs) were verified between different groups, and the number of upregulated DEMs, particularly flavonoids, were higher in the R9B1 and R7B3 groups compared with the CK. Transcriptome data identified 1412 and 1508 differentially expressed genes (DEGs) in the R9B1 and R7B3 groups, respectively, in contrast to the CK. KEGG pathway analysis indicated that DEGs in both the R9B1 and R7B3 groups were primarily enriched in the phenylpropane biosynthesis, plant hormone signal transduction, flavonoid biosynthesis, starch and sucrose metabolism, galactose metabolism, cartenoid biosynthesis, zeatin biosynthesis, and nitrogen metabolism pathways. The qRT-PCR results showed that SbPAL, SbCLL-7, SbCHI, SbFNS, and SbOMT encoding enzymes for the flavonoid biosynthesis pathway were significantly upregulated in S. baicalensis, which was consistent with the transcriptome data. Finally, based on correlation analysis between the main flavonoids in S. baicalensis and the genes encoding transcription factors and enzymes for the flavonoid metabolism pathway, a co-expression network map was developed, which provided a basis for the mining of light responsive genes related to flavonoids biosynthesis in S. baicalensis. This is the first report to articulate how the combination of red light and blue light influences the growth and secondary metabolism of S. baicalensis.

Calpain-1: a Novel Antiviral Host Factor Identified in Porcine Small Intestinal Mucus.

The thick mucus layer covering of the intestinal epithelium has received increasing attention, owing to its protective role in intestinal infection. However, the exact mechanisms by which the mucus increases intestinal resistance against viral infection remain largely unclear. Here, we identify prominent antiviral activity of the small intestinal mucus and extracted total mucus proteins, as evidenced by their inhibitory effects against porcine epidemic diarrhea virus (PEDV) infection. Of all the extracted mucus proteins, mucin 2 and fraction III (~70 kDa) exhibited potent antiviral activity. We further evaluated the antiviral effects of three candidate factors in fraction III and found that calpain-1 contributed substantially to its antiviral activity. In vivo studies demonstrated that oral administration of calpain-1 provided effective protection against intestinal PEDV infection. As a calcium-activated cysteine protease, calpain-1 inhibited viral invasion by binding to and hydrolyzing the S1 domain of the viral spike protein. The region between amino acids 297 and 337 in the b domain of PEDV S1 protein was critical for calpain-1-mediated hydrolysis. Further investigation indicated that calpain-1 could be produced by goblet cells between intestinal epithelia. Taken together, the results of our study revealed calpain-1 to be a novel antiviral protein in porcine small intestinal mucus, suggesting that calpain-1 has potential for defending against intestinal infections. IMPORTANCE Although the antiviral activity of the intestinal mucus was recognized 20 years ago, the antiviral active ingredients in the mucus are poorly understood. Currently, most research on antiviral molecules in the intestinal mucus remains limited to members of the mucin family. This study identified the cysteine protease calpain-1 as a novel antiviral protein in porcine small intestinal mucus and revealed its underlying protective mechanism for the first time. This mechanism involves inhibiting porcine epidemic diarrhea virus (PEDV) invasion by binding and hydrolyzing the S1 domain of the viral spike protein. Furthermore, the results of our PEDV-challenge experiment in piglets indicated that calpain-1 provides effective protection against intestinal PEDV infection. Our findings provide new insights into the protective function of the small intestinal mucus. In addition to potential therapeutic implications for the swine industry, our analysis of antiviral proteins in the small intestinal mucus may have implications for the prevention and control of coronavirus infection in humans.

Non-Viral Delivery of Gene Therapy to the Tendon.

The tendon, as a compact connective tissue, is difficult to treat after an acute laceration or chronic degeneration. Gene-based therapy is a highly efficient strategy for diverse diseases which has been increasingly applied in tendons in recent years. As technology improves by leaps and bounds, a wide variety of non-viral vectors have been manufactured that attempt to have high biosecurity and transfection efficiency, considered to be a promising treatment modality. In this review, we examine the unwanted biological barriers, the categories of applicable genes, and the introduction and comparison of non-viral vectors. We focus on lipid-based nanoparticles and polymer-based nanoparticles, differentiating between them based on their combination with diverse chemical modifications and scaffolds.