The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway.

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-kappaB signaling pathway

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg.kg-1), and positive control sildenafil group (100 mg.kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% +/- 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF- kappaB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF- kappaB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-kappaB and signal transducer and activator of transcription 3 (STAT3) by DYY.Copyright © 2023, Chinese Pharmaceutical Association. All rights reserved.

Accurate prediction of molecular properties and drug targets using a self-supervised image representation learning framework

The clinical efficacy and safety of a drug is determined by its molecular properties and targets in humans. However, proteome-wide evaluation of all compounds in humans, or even animal models, is challenging. In this study, we present an unsupervised pretraining deep learning framework, named ImageMol, pretrained on 10 million unlabelled drug-like, bioactive molecules, to predict molecular targets of candidate compounds. The ImageMol framework is designed to pretrain chemical representations from unlabelled molecular images on the basis of local and global structural characteristics of molecules from pixels. We demonstrate high performance of ImageMol in evaluation of molecular properties (that is, the drug's metabolism, brain penetration and toxicity) and molecular target profiles (that is, beta-secretase enzyme and kinases) across 51 benchmark datasets. ImageMol shows high accuracy in identifying anti-SARS-CoV-2 molecules across 13 high-throughput experimental datasets from the National Center for Advancing Translational Sciences. Via ImageMol, we identified candidate clinical 3C-like protease inhibitors for potential treatment of COVID-19. Predicting the properties of a molecule from its structure with high accuracy is a crucial problem in digital drug design. Instead of sequence features, Zeng and colleagues use an image representation of a large collection of bioactive molecules to pretrain a model that can be fine-tuned on specific property prediction tasks.

Antibody Response to 3-Dose SARS-CoV-2 mRNA Vaccination in Pediatric Solid Organ Transplant Recipients

Purpose: We report the immunogenicity and safety of a third BNT162b2 vaccine in pediatric solid organ transplant recipients (pSOTRs). Method(s): Samples from pSOTRs (12-18 years) enrolled in our multicenter, observational study (COVID-19 Antibody Testing of Recipients of Solid Organ Transplants and Patients with Chronic Diseases) who received a third vaccine (V3) were analyzed for antibodies to SARS-CoV-2 spike protein receptor-binding domain, with a positive cutoff of >=0.8 and maximum titer of >2500 U/mL. Pre-V3 samples were 1-3 months after vaccine 2, and post-V3 were 1 month after vaccine 3. Result(s): Thirty-seven pSOTRs (46% heart, 24% liver, 27% kidney, 3% multi) received V3. Median (interquartile range [IQR]) age was 15 (14-16) years;42% were male and 78% white. pSOTRs were median (IQR) 9 (6-13) years from transplant. Four (11%) patients had prior SARS-CoV-2 infection. Antibody titers were positive in 26/37 (70%) patients pre-V3 and 32/37 (86%) post-V3 (Figure). Median (IQR) antibody titers were higher post-V3 (2500 [1581-2500] U/mL) than pre-V3 (211 [0.8-2500] U/mL) in paired analysis (p<0.001). 6/11 (55%) pSOTRs with negative pre-V3 titers seroconverted, with a post-V3 median (IQR) titer of 418 (132-1581) U/ mL. Transplant within 3 years was associated with negative post-V3 titer (p=0.037). Main side effects after V3 were pain (71%) and fatigue (50%). No patients reported allergic reaction, myocarditis, or rejection. One patient tested positive for SARSCoV- 2 between vaccines 2 and 3, with negative pre- and post-V3 titers. At time of first vaccine, this patient was transplanted a year ago, treated for rejection recently, and taking 3 immunosuppression agents including an antimetabolite. Conclusion(s): In this limited cohort, 86% of pSOTRs had a positive antibody response after three SARS-CoV-2 vaccines with no adverse events. Importantly, 55% of pSOTRs with prior negative response seroconverted post-V3, and 100% of pSOTRs with positive response increased their antibody titer or remained at maximum titer. Our preliminary results suggest the benefit of a third vaccine for adolescent pSOTRs based on antibody response;larger studies are needed to assess vaccine effectiveness.

Higher Proinflammatory Cytokines Are Associated with Increased Antibody Titer After a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients

Purpose: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if pre-vaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Method(s): A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, with comparison to 16 healthy controls (HCs). Anti-spike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detectionbased multiplexed sandwich immunoassays were used to quantify plasma cytokine and chemokine concentrations (n=20 analytes). Concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine, were compared using Wilcoxon-rank-sum test with false discovery rates (FDR) computed to correct for multiple comparisons. Result(s): In the study population, 100% of HCs, 59% of SOTRs after two doses and 63% of SOTRs after three doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in cytokine levels between SOTRs with high vs low-titer antibodies after two doses of vaccine. However, as compared to poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher pre-third dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1alpha, and TNF-alpha (FDR <0.05). Conclusion(s): A specific inflammatory profile or immune state may identify which SOTRs are likely to develop stronger sero-response and possible protection after a third dose of SARS-CoV-2 vaccine.

B Cells Fit for Germinal Center Activity Predict Response to a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients

Purpose: While SARS-CoV-2 vaccination has dramatically reduced COVID-19 severity in the general population, fully vaccinated solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates. Furthermore, a third vaccine dose only increases antibody and T cell responses in a proportion of SOTRs. We sought to investigate the underlying mechanisms resulting in varied humoral responses in SOTRs. Method(s): Within a longitudinal prospective cohort of SOTRs, anti-spike IgG, total and spike-specific B cells were evaluated in 44 SOTR participants before and after a third vaccine dose using high dimensional flow cytometry to assess immunologic and metabolic phenotypes. B cell phenotypes were compared to those of 10 healthy controls who received a standard two-dose mRNA series. Result(s): Notably, even in the absence anti-spike antibody after two doses, spikespecific B cells were detectable in most SOTRs (76%). While 15% of participants were seropositive before the third dose, 72% were seropositive afterward. B cells, however, were differentially skewed towards non-class switched B cells in SOTRs as compared to healthy control B cells. Expansion of spike-specific class-switched B cells in SOTRs following a third vaccine dose correlated with increased classswitched (IgG) antibody titers. Antibody response to a third vaccine dose was associated with expanded populations of germinal center-like (CD10+CD27+) B cells, as well as CD11c+ alternative lineage B cells with specific upregulation of CPT1a, the rate limiting enzyme of fatty acid oxidation and a preferred energy source of germinal center B cells. Conclusion(s): This analysis defines a distinct B cell phenotype in SOTRs who respond to a third SARS-CoV-2 vaccine dose, specifically identifying fatty acid oxidation as pathway that could be targeted to improve vaccine response such as through targeted immunosuppressive modulation. (Figure Presented).

Post-Acute Sequelae of Sars-Cov-2 Infection in Solid Organ Transplant Recipients

Purpose: Post-acute sequelae of SARS-CoV-2 infection (PASC) is an increasingly recognized phenomenon manifested by long lasting cognitive, mental, and physical symptoms. We aimed to estimate the prevalence of PASC symptoms in solid organ transplant recipients (SOTRs) in the short (1- 6 months) and long-term (> 6 months) periods after SARS-CoV-2 infection. We also compared the prevalence of these symptoms between those with SARS-CoV-2 infection requiring hospitalization and those not requiring hospitalization. Method(s): We surveyed 111 SOTRs with self-reported SARS-CoV-2 infection diagnosed more than 4 weeks prior to survey administration. The survey consisted of 7 validated questionnaires ("Quick Dementia Rating System (QDRS)", "Patient Health Questionnaire (PHQ9)", "Generalized Anxiety Disorder 7 (GAD-7)", "Impact of Events Scale (IES-6)", "EuroQol- 5 Dimension (EQ-5D)", "PROMIS global physical health scale (GHS) "and "Breathlessness, Cough and Sputum Scale (BCSS)"). Result(s): Of the 111 survey participants, 32 (33%) had been hospitalized and 35 (36%) had SARS-CoV-2 infection >6 months ago. Median (IQR) age was 58 years (46, 65). Median time from SARS-CoV-2 diagnosis was 167 days (138, 221). Cognitive impairment, anxiety, depression, insomnia, feeling of trauma, fatigue, pain, breathing problems, cough, abnormal smell, abnormal taste, and diarrhea were reported by 40%, 23%, 36%, 55%, 53%, 41%, 19%, 33%, 33%, 21%, 22%, and 32% of patients respectively. Hospitalized patients had poorer scores in cognition (QDRS survey score of 2 versus 0.75, p=0.048) (Figure 1), quality of life (EQ-5D survey score of 2 versus 1, p=0.043), physical health (PROMIS GHS survey score of 10 versus 11, p=0.013), respiratory status (BCSS survey score of 1 versus 0, p=0.056), and pain (Pain score of 3 versus 0, p 0.006). Among patients who had SARS-CoV-2 infection >6 months ago, abnormal breathing, cough, abnormal smell, abnormal taste, and diarrhea continued to be reported by 31%, 31%, 29%, 32%, and 32% of patients respectively. Conclusion(s): After SARS-CoV-2 infection, SOTRs had a high prevalence of PASC symptoms. Some of the symptoms are more severe in patients who had required hospitalization and persist beyond 6 months. Further studies are needed to understand the long term sequalae of SARS-CoV-2 infection in SOTRs and to develop an evidence-based multidisciplinary approach for caring for these patients beyond the acute phase. (Table Presented).

[Study of transmissibility of 2019-nCoV Omicron variant in Beijing].

Objective: To evaluate the transmissibility of 2019-nCoV Omicron variant under the current prevention and control strategy in Beijing, and provide evidence for the prevention and control of COVID-19. Methods: The information of 78 Omicron variant infection cases involved in clear transmission chains in Beijing during 7-25 March, 2022 were collected, the incubation period and serial interval of the disease were fitted by using Gamma and Weibull distribution. Markov Chain Monte Carlo approach was used to estimate the time-varying reproduction number (Rt). Results: The median of the incubation period (Q1, Q3) of Omicron variant infection was 4.0 (3.0, 6.0) days, and the serial interval was 3.0 (2.0, 5.0) days. The median of the serial interval (Q1, Q3) was 2.0 (1.0, 4.0) days in unvaccinated cases and 4.0 (2.0, 6.0) days in vaccinated cases (Z=-2.12, P=0.034), and 2.0 (1.5, 3.0) days in children and 4.0 (2.0, 6.0) days in adults, respectively (Z=-2.02,P=0.044), the differences were significant. The mean of Rt was estimated to be 4.98 (95%CI: 2.22-9.04) for Omicron variant in this epidemic. Conclusion: Omicron variant has stronger transmissibility compared with Delta variant. It is necessary to strengthen the routine prevention and control COVID-19, promote the vaccination and pay close attention to susceptible population, such as children.

Research progress on risk communication of public health emergencies

Risk communication is essential in dealing with public health emergencies. By collecting relevant literature at home and abroad, this paper summarized the development history, communication process and theoretical models of risk communication, focusing on the application of risk communication in public health emergencies. Theoretical research and practical experience have shown that risk communication should follow a specific process and adopt corresponding communication strategies according to the characteristics before, during, and after the public health event. After the outbreak of SARS in 2003, the risk communication mechanism in China has been continuously improved, and it has shown a good effect on coping with the epidemic of influenza A and COVID-19. However, public health emergencies frequently occur in the world, and the demand for risk communication is increasing. There are still deficiencies in the theory and practice of risk communication in China, which needs continuous improvement.

Advancing COVID-19 diagnosis with privacy-preserving collaboration in artificial intelligence

Artificial intelligence provides a promising solution for streamlining COVID-19 diagnoses;however, concerns surrounding security and trustworthiness impede the collection of large-scale representative medical data, posing a considerable challenge for training a well-generalized model in clinical practices. To address this, we launch the Unified CT-COVID AI Diagnostic Initiative (UCADI), where the artificial intelligence (AI) model can be distributedly trained and independently executed at each host institution under a federated learning framework without data sharing. Here we show that our federated learning framework model considerably outperformed all of the local models (with a test sensitivity/specificity of 0.973/0.951 in China and 0.730/0.942 in the United Kingdom), achieving comparable performance with a panel of professional radiologists. We further evaluated the model on the hold-out (collected from another two hospitals without the federated learning framework) and heterogeneous (acquired with contrast materials) data, provided visual explanations for decisions made by the model, and analysed the trade-offs between the model performance and the communication costs in the federated training process. Our study is based on 9,573 chest computed tomography scans from 3,336 patients collected from 23 hospitals located in China and the United Kingdom. Collectively, our work advanced the prospects of utilizing federated learning for privacy-preserving AI in digital health. The COVID-19 pandemic sparked the need for international collaboration in using clinical data for rapid development of diagnosis and treatment methods. But the sensitive nature of medical data requires special care and ideally potentially sensitive data would not leave the organization which collected it. Xiang Bai and colleagues present a privacy-preserving AI framework for CT-based COVID-19 diagnosis and demonstrate it on data from 23 hospitals in China and the United Kingdom.

A Deep Convolutional Neural Network to Limit Virus Spread Using Facial Mask Segmentation

Due to the recent COVID-19 outbreak the world has experienced many challenges. Limit and control the virus spread rate is one of them. This letter focuses on limiting the speed of virus spreading by monitoring the use of facial mask in crowded public environments such as tourism places, commercial centres, etc. The proposed method first accurately localizes faces using a state-of-the-art approach and, segments facial mask in a second step. The facial mask segmentation allows to distinguish whether the current subject is wearing a facial mask or not but also if it is properly covering the human face. Indeed, most recent face detection algorithms provide as output a set of facial features such as nose tip and mouth corners. By combining these facial features with facial mask segmentation, the proposed method detects real-time subjects that indirectly encourage virus spread in crowded environments. The proposed facial mask segmentation model is trained with pairs of RGB images and its corresponding alpha image created by extending the publicly available real-world masked face dataset. Further, the proposed model is pruned and optimized using the TensorRt library to be usable for real-world applications.