Medical-engineering Cross-innovation Postgraduate Talent Training

At the beginning of the new year of 2020, the new coronavirus swept across the motherland. Scientific researchers throughout the country overcame scientific difficulties and wrote papers for the motherland. Under the challenge of the epidemic situation, medical workers in the front saved the dying and healed the wounded, while the scientific researchers in the rear tackled scientific and technological problems. The two sides cooperated sincerely to unify medical practice and theoretical development, and effectively improved the scientific and technological level of China's medical industry. Health care is closely related to human survival, development and quality of life. At present, mankind is still facing the threat of major diseases, and the development of medical and health services has increasingly shown strategic significance to national security, social stability and even national survival. This article introduces a new model of talent cultivation at the graduate level. The cross-dissolution of clinical medicine and manufacturing engineering produces novel ideas and new technologies.

A global optimization feedback model with PSO for large scale group decision making in hesitant fuzzy linguistic environments

In an increasingly complex and uncertain decision-making environment, large-scale group decision-making (LSGDM) can offer a more efficient method, allowing a large number of decision-makers (DMs) to truly participate in the decision-making process. The consensus-reaching process (CRP) is an effective method for resolving conflicting opinions among large-scale DMs. However, in the existing CRP of LSGDM, the new consensus state and the adjustment cost borne by inconsistent DMs after implementing feedback suggestions are not taken into consideration. To address this issue, this paper proposes a global optimization feedback model with particle swarm optimization (PSO) for LSGDM in hesitant fuzzy linguistic environments. An improved density-based spatial clustering of applications with noise (DBSCAN) on hesitant fuzzy linguistic term sets (HFLTSs) is introduced to classify large-scale DMs into several clusters, and a weight determination method that combines cluster size and intra-cluster tightness is also presented. The consensus degree of clusters is calculated at two levels: intra-consensus and inter-consensus. To improve the global consensus level with minimum cost, a global optimization feedback model is established to generate recommendation advice for inconsistent DMs, and the model is solved by PSO. A numerical example related to "COVID-19” and some comparisons are provided to verify the feasibility and advantages of the proposed method.

Perceptions towards online learning among medical students during the COVID-19 pandemic.

Social distancing has been essential during the COVID-19 pandemic to slow the spread of the disease. Online learning ensures students can participate in learning activities while also maintaining a physical distance from other students. Although online learning was used to prevent the spread of COVID-19, the development of online learning has also been promoted. Here, we sought to explore the perceptions and responses of students to online learning during the pandemic using a cross-sectional study. Electronic questionnaire was used for data collection. Statistical analyses were performed for 1614 valid questionnaires and P < 0.05 was considered statistically significant. Overall, COVID-19 had more effect on female students, such as fear of COVID-19 (2.4 times higher than the number of male students) and length of time spent learning (H = 42.449, P < 0.05). However, the higher the students' grades were, the less the impact of COVID-19. For the style of lessons, all students would prefer shorter lessons (P < 0.05). Female and fifth-grade students were more prefer combined online and face-to-face learning, and male and freshmen students were more likely to prefer face-to-face learning after the pandemic. More than 50% of students thought the main advantage of online learning was convenience, with low efficiency being a disadvantage. The main factors negatively influencing online learning were eyestrain, poor network connections, and poor learning environments at home. In conclusion, synchronous online and face-to-face learning may become more common in future curricula, however the efficiency of online learning and the female students more attentions.

Data-Driven Building Energy Consumption Prediction Model Based on VMD-SA-DBN

Prediction of building energy consumption using mathematical modeling is crucial for improving the efficiency of building energy utilization, assisting in building energy consumption planning and scheduling, and further achieving the goal of energy conservation and emission reduction. In consideration of the non-linear and non-smooth characteristics of building energy consumption time series data, a short-term, hybrid building energy consumption prediction model combining variational mode decomposition (VMD), a simulated annealing (SA) algorithm, and a deep belief network (DBN) is proposed in this study. In the proposed VMD-SA-DBN model, the VMD algorithm decomposes the time series into different modes to reduce the fluctuation of the data. The SA-DBN prediction model is built for each mode separately, and the DBN network structure parameters are optimized by the SA algorithm. The prediction results of each model are aggregated and reconstructed to obtain the final prediction output. The validity and prediction performance of the proposed model is evaluated on a publicly available dataset, and the results show that the proposed new model significantly improves the accuracy and stability of building energy consumption prediction compared with several typical machine learning methods. The mean absolute percent error (MAPE) of the VMD-SA-DBN model is 63.7%, 65.5%, 46.83%, 64.82%, 44.1%, 36.3%, and 28.3% lower than that of the long short-term memory (LSTM), gated recurrent unit (GRU), VMD-LSTM, VMD-GRU, DBN, SA-DBN, and VMD-DBN models, respectively. The results will help managers formulate more-favorable low-energy emission reduction plans and improve building energy efficiency.

Adsorption of Different Pollutants by Using Microplastic with Different Influencing Factors and Mechanisms in Wastewater: A Review.

The studies on microplastics are significant in the world. According to the literature, microplastics have greatly specific surface areas, indicating high adsorption capacities for highly toxic pollutants in aquatic and soil environments, and these could be used as adsorbents. The influencing factors of microplastic adsorption, classification of microplastics, and adsorption mechanisms using microplastics for adsorbing organic, inorganic, and mixed pollutants are summarized in the paper. Furthermore, the influence of pH, temperature, functional groups, aging, and other factors related to the adsorption performances of plastics are discussed in detail. We found that microplastics have greater advantages in efficient adsorption performance and cost-effectiveness. In this paper, the adsorptions of pollutants by microplastics and their performance is proposed, which provides significant guidance for future research in this field.

Peritoneal M2 macrophage-derived extracellular vesicles as natural multitarget nanotherapeutics to attenuate cytokine storms after severe infections.

Cytokine storms are a primary cause of multiple organ damage and death after severe infections, such as SARS-CoV-2. However, current single cytokine-targeted strategies display limited therapeutic efficacy. Here, we report that peritoneal M2 macrophage-derived extracellular vesicles (M2-EVs) are multitarget nanotherapeutics that can be used to resolve cytokine storms. In detail, primary peritoneal M2 macrophages exhibited superior anti-inflammatory potential than immobilized cell lines. Systemically administered M2-EVs entered major organs and were taken up by phagocytes (e.g., macrophages). M2-EV treatment effectively reduced excessive cytokine (e.g., TNF-α and IL-6) release in vitro and in vivo, thereby attenuating oxidative stress and multiple organ (lung, liver, spleen and kidney) damage in endotoxin-induced cytokine storms. Moreover, M2-EVs simultaneously inhibited multiple key proinflammatory pathways (e.g., NF-κB, JAK-STAT and p38 MAPK) by regulating complex miRNA-gene and gene-gene networks, and this effect was collectively mediated by many functional cargos (miRNAs and proteins) in EVs. In addition to the direct anti-inflammatory role, human peritoneal M2-EVs expressed angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2 spike protein, and thus could serve as nanodecoys to prevent SARS-CoV-2 pseudovirus infection in vitro. As cell-derived nanomaterials, the therapeutic index of M2-EVs can be further improved by genetic/chemical modification or loading with specific drugs. This study highlights that peritoneal M2-EVs are promising multifunctional nanotherapeutics to attenuate infectious disease-related cytokine storms.

Clinical Study of Human Coronavirus NL63, OC43, 229E, HKU1 Infentions in Hospitalized Children from 2015 to 2020

Objective This study aims to analyze the clinical characteristics of hospitalized children infected with HCoV-NL63, OC43, 229E, HKU1 and provide the basis for disease diagnosis and treatment. Methods A retrospective analysis was conducted on clinical manifestations, imaging data, and treatment measures of hospitalized children with positive HCoV-NL63, OC43, 229E, HKU1 from 2015 to 2020. Results A total of 1062 children aged 33 days to 12 years were analyzed, including 879 (82.77%) between 33 days to three years. Lower respiratory tract infections were the most common in 698 children positive for HCoVs (65.72%). The incidences of runny nose, cough, pharyngeal hyperemia, and fine crackles in the mild case group (n = 894, 84.18%) were significantly higher than in the severe case group, and the differences were statistically significant (P < 0.01). The incidences of gasp, stridor, and convulsions, the proportion of underlying diseases, such as congenital heart disease, laryngomalacia, and general developmental disorders, anemia, and abnormal liver function, and mixed infections in the severe group (n = 168, 15.82%) were significantly higher than in the mild group, and the differences were statistically significant (P < 0.01 or P < 0.05). Imaging manifestations differed. Pleural effusion and atelectasis occurred in the severe cases. After treatment, patients fully recovered or improved and were discharged from the hospital. There were no deaths. Conclusion HCoV-NL63, OC43, 229E, HKU1 infection is most common in children under three years old, and the infection site is mainly the lower respiratory tract. The main clinical manifestations include fever, cough, and runny nose. Inspiratory three concave signs, respiratory failure, and heart failure occurred in the severe cases, with pleural effusion and atelectasis possibly occurring at the same time. Severe cases should be identified early so that they may be given comprehensive treatment in time to improve the prognosis.

Weakly-Supervised Network for Detection of COVID-19 in Chest CT Scans.

Deep Learning-based chest Computed Tomography (CT) analysis has been proven to be effective and efficient for COVID-19 diagnosis. Existing deep learning approaches heavily rely on large labeled data sets, which are difficult to acquire in this pandemic situation. Therefore, weakly-supervised approaches are in demand. In this paper, we propose an end-to-end weakly-supervised COVID-19 detection approach, ResNext+, that only requires volume level data labels and can provide slice level prediction. The proposed approach incorporates a lung segmentation mask as well as spatial and channel attention to extract spatial features. Besides, Long Short Term Memory (LSTM) is utilized to acquire the axial dependency of the slices. Moreover, a slice attention module is applied before the final fully connected layer to generate the slice level prediction without additional supervision. An ablation study is conducted to show the efficiency of the attention blocks and the segmentation mask block. Experimental results, obtained from publicly available datasets, show a precision of 81.9% and F1 score of 81.4%. The closest state-of-the-art gives 76.7% precision and 78.8% F1 score. The 5% improvement in precision and 3% in the F1 score demonstrate the effectiveness of the proposed method. It is worth noticing that, applying image enhancement approaches do not improve the performance of the proposed method, sometimes even harm the scores, although the enhanced images have better perceptual quality.

The impact of the COVID-19 Pandemic on rhegmatogenous retinal detachment treatment patterns.

BACKGROUNDS: To describe changes in rhegmatogenous retinal detachment (RRD) surgical procedures in Beijing during the COVID-19 Pandemic. METHODS: A retrospective cohort of RRD patients was analyzed. Patients were divided into the COVID-19 pandemic group and pre-COVID-19 group according to their presentation. The presurgery characteristics, surgical procedures, and surgery outcomes were collected. The potential factors related to the choice of pars plana vitrectomy (PPV) or scleral buckling (SB) were analyzed using logistic regression. The differences in the procedure choice under specific conditions were compared. Surgery outcomes were compared between the two groups. RESULTS: In the COVID-19 pandemic group, less patients received SB (27.8, 41.3%, p = 0.02) while more patients received PPV (72.2, 58.6%, p = 0.02); in patients who received SB, fewer patients received subretinal fluid drainage (45.4,75.7%, p = 0.01); in patients who received PPV, fewer patients received phacovitrectomy (7.0, 21.0%, p = 0.02). The choice of PPV was related to older age (1.03, p = 0.005), the presence of RRD with choroidal detachment (RRD-CD) (2.92, p = 0.03), pseudophakia (5.0, p = 0.002), retinal breaks located posterior to the equator (4.87, p < 0.001), macular holes (9.76, p = 0.005), and a presurgery visual acuity (VA) less than 0.02 (0.44, p = 0.03). Fewer phakia patients with retinal breaks located posterior to the equator (1/28, 11/30, p = 0.01) and fewer patients with chronic RRD and subretinal strand (1/9, 9/16, p = 0.03) received SB in the COVID-19 pandemic group. There were more patients with improved VA (55.7, 40.2%, p = 0.03) in the COVID-19 pandemic group. The overall single-surgery retinal attachment rate was similar in the two groups (94.9, 94.5%, p = 0.99). CONCLUSIONS: During the COVID-19 Pandemic, the main reason for the increased number of PPV in RRD treatment was that more complicated cases were presented. However, the surgeons were conservative in procedure choice in specific cases. The adjustments on RRD treatments lead to comparable surgery outcomes.

The impact of the COVID-19 pandemic lockdown on rhegmatogenous retinal detachment services-Experiences from the Tongren eye center in Beijing.

PURPOSE: To investigate the impact on services for rhegmatogenous retinal detachment (RRD) patients during the COVID-19 (2019coronal virus disease) pandemic in one tertiary center in Beijing. METHODS: A retrospective cohort study. Two reviewed consecutive RRD patients cohorts of the same length were treated during two different periods: the COVID-19 pandemic and the pre-COVID-19 group. The characteristics of patients, surgery, anesthesia methods, length of hospital stay, and the latest follow-up were recorded and analyzed. RESULTS: There were 79 patients in the COVID-19 pandemic group with a 55.9% reduction (179). Compared to patients in the pre-COVID-19, patients in the COVID-19 pandemic had a longer presurgical waiting times (28days, 3days, p<0.001), a higher percentage of patients with presurgical poor (less than 0.02) visual acuity (55.7%, 32.4%, p = 0.009), and a higher percentage of patients with presurgical choroidal detachment (34.2%, 19.6%, p = 0.01). There was no significant difference in the severity of presurgical proliferative vitreoretinopathy between the two groups (p = 0.64). Surgeries on pathological myopia patients with macular hole retinal detachment were postponed in the COVID-19 pandemic. There was a lower percentage of scleral buckling (27.8%, 41.3%, p = 0.02) and a lower rate of subretinal fluid drainage (45.4%, 75.7%, p = 0.01) in the COVID-19 pandemic. There was no significant difference in either postoperative visual acuity (p = 0.73) or the rate of single-surgery retinal attachment (p = 1) between the two groups. Patients in the COVID-19 pandemic had a shorter length of hospital stay (3hours, 35 hours, p<0.001), and a lower percentage of patients received general anesthesia (48.1%, 83.2%, p<0.001). None was infected with COVID-19 disease during the pandemic. CONCLUSION: The COVID-19 pandemic lockdown caused prolonged presurgical waiting times, shorter hospital stays, less general anesthesia, and a significant reduction of RRD surgeries. The RD were more complicated, the surgeons were more conservative on procedures and patients selection, while the surgery outcomes were comparable.

Structural dynamics of single SARS-CoV-2 pseudoknot molecules reveal topologically distinct conformers.

The RNA pseudoknot that stimulates programmed ribosomal frameshifting in SARS-CoV-2 is a possible drug target. To understand how it responds to mechanical tension applied by ribosomes, thought to play a key role during frameshifting, we probe its structural dynamics using optical tweezers. We find that it forms multiple structures: two pseudoknotted conformers with different stability and barriers, and alternative stem-loop structures. The pseudoknotted conformers have distinct topologies, one threading the 5' end through a 3-helix junction to create a knot-like fold, the other with unthreaded 5' end, consistent with structures observed via cryo-EM and simulations. Refolding of the pseudoknotted conformers starts with stem 1, followed by stem 3 and lastly stem 2; Mg2+ ions are not required, but increase pseudoknot mechanical rigidity and favor formation of the knot-like conformer. These results resolve the SARS-CoV-2 frameshift signal folding mechanism and highlight its conformational heterogeneity, with important implications for structure-based drug-discovery efforts.

The risk factors of the progression of rhegmatogenous retinal detachment on patients with the fourteen-day quarantine in the early period of COVID-19 outbreak.

BACKGROUNDS: The COVID-19 Pandemic has a great impact on hospitals and patients. The 14-day quarantine caused surgery of rhegmatogenous retinal detachment (RRD) postponed. We aimed to explore the risk factors of RRD progression in a group of patients whose surgery was postponed during the top-level emergency response of COVID-19. METHODS: A retrospective case series. Medical records of all consecutive patients with a diagnosis of RRD who underwent a surgical treatment at Beijing Tongren Hospital's retina service from February 16, 2020, to April 30, 2020 have been reviewed retrospectively. Medical history, symptoms, and clinical signs of progression of RRD were recorded. RRD progression was defined as the presence of either choroidal detachment or proliferative vitreoretinopathy (PVR) progression during the quarantine period. Risk factors were analyzed using the Cox proportional hazards model, survival analysis, and logistic regression. RESULTS: Seventy-nine eyes of 79 patients met the inclusion criteria and were included in the study. The median time from the patients' presentation at the clinic to admission for surgery was 14 days (3-61 days). There were 70 cases (88.6%) who did not present to the hospital within 1 week of the onset of visual symptoms. There were 69 (87.3%) macular-off cases at the presentation and 27 (34.2%) cases combined with choroidal detachment. There were 49 (62.0%) cases with PVR B, 22 (27.8%) cases with PVR C, 4 (5.1%) cases with PVR D, and 4 (5.1%) cases with anterior PVR. After the 14-day quarantine, 21 (26.6%) cases showed RRD progression, and 9 cases showed RRD regression at the time of surgery. Neither the time of onset of the visual symptom (p = 0.46) nor the time between presentation and admission (p = 0.31) was significantly different between the patients with RRD progression and patients without RRD progression. The combination of choroidal detachment (3.07, 1.68-5.60, p<0.001) and retinal breaks located posterior to the equator (3.79, 1.21-11.80, p=0.02) were factors related to the progression of RRD. CONCLUSIONS: In our study during the COVID-19 outbreak, the RRD progression risk factors included a combination of choroidal detachment and retinal breaks posterior to the equator. Ophthalmologists should schedule the surgeries for RRD patients with these signs as soon as possible.

Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials.

BACKGROUND: The therapeutic evidence collected from well-designed studies is needed to help manage the global pandemic of the coronavirus disease 2019 (COVID-19). Evaluating the quality of therapeutic data collected during this most recent pandemic is important for improving future clinical research under similar circumstances. OBJECTIVE: To assess the methodological quality and variability in implementation of randomized controlled trials (RCTs) for treating COVID-19, and to analyze the support that should be provided to improve data collected during an urgent pandemic situation. SEARCH STRATEGY: PubMed, Excerpta Medica Database, China National Knowledge Infrastructure, Wanfang, and Chongqing VIP, and the preprint repositories including Social Science Research Network and MedRxiv were systematically searched, up to September 30, 2020, using the keywords "coronavirus disease 2019 (COVID-19)," "2019 novel coronavirus (2019-nCoV)," "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)," "novel coronavirus pneumonia (NCP)," "randomized controlled trial (RCT)" and "random." INCLUSION CRITERIA: RCTs studying the treatment of COVID-19 were eligible for inclusion. DATA EXTRACTION AND ANALYSIS: Screening of published RCTs for inclusion and data extraction were each conducted by two researchers. Analysis of general information on COVID-19 RCTs was done using descriptive statistics. Methodological quality was assessed using the risk-of-bias tools in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Variability in implementation was assessed by comparing consistency between RCT reports and registration information. RESULTS: A total of 5886 COVID-19 RCTs were identified. Eighty-one RCTs were finally included, of which, 45 had registration information. Methodological quality of the RTCs was not optimal due to deficiencies in five main domains: allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Comparisons of consistency between published protocols and registration information showed that the 45 RCTs with registration information had common deviations in seven items: inclusion and exclusion criteria, sample size, outcomes, research sites of recruitment, interventions, and blinding. CONCLUSION: The methodological quality of COVID-19 RCTs conducted in early to mid 2020 was consistently low and variability in implementation was common. More support for implementing high-quality methodology is needed to obtain the quality of therapeutic evidence needed to provide positive guidance for clinical care. We make an urgent appeal for accelerating the construction of a collaborative sharing platform and preparing multidisciplinary talent and professional teams to conduct excellent clinical research when faced with epidemic diseases of the future. Further, variability in RCT implementation should be clearly reported and interpreted to improve the utility of data resulting from those trials.

Effects of early-life exposure to Western diet and voluntary exercise on adult activity levels, exercise physiology, and associated traits in selectively bred High Runner mice.

Exercise behavior is under partial genetic control, but it is also affected by numerous environmental factors, potentially including early-life experiences whose effects persist into adulthood. We studied genetic and early-life environmental effects on wheel-running behavior in a mouse model that includes four replicate high runner (HR) lines selectively bred for increased voluntary wheel running as young adults and four non-selected control (C) lines. In a full factorial design, mice from each line were granted wheel access or not and administered either standard or Western diet (WD) from weaning (3 weeks old) to 6 weeks of age (sexual maturity). In addition to acute effects, after a washout period of 8 weeks (∼6 human years) in which all mice had standard diet and no wheel access, we found both beneficial and detrimental effects of these early-life exposures. During the first week of treatments, WD increased distance run by 29% in C mice and 48% in HR mice (significant Diet × Linetype interaction), but diet effects disappeared by the third week. Across the three weeks of juvenile treatment, WD significantly increased fat mass (with lean mass as a covariate). Tested as adults, early-life exercise increased wheel running of C mice but not HR mice in the first week. Early-life exercise also reduced adult anxiety-like behavior and increased adult fasted blood glucose levels, triceps surae mass, subdermal fat pad mass, and brain mass, but decreased heart ventricle mass. Using fat mass as a covariate, early-life exercise treatment increased adult leptin concentration. In contrast, early-life WD increased adult wheel running of HR mice but not C mice. Early-life WD also increased adult lean mass and adult preference for Western diet in all groups. Surprisingly, early-life treatment had no significant effect on adult body fat or maximal aerobic capacity (VO2max). No previous study has tested for combined or interactive effects of early-life WD and exercise. Our results demonstrate that both factors can have long-lasting effects on adult voluntary exercise and related phenotypes, and that these effects are modulated by genetic background. Overall, the long-lasting effects of early-life exercise were more pervasive than those of WD, suggesting critical opportunities for health intervention in childhood habits, as well as possible threats from modern challenges. These results may be relevant for understanding potential effects of activity reductions and dietary changes associated with the obesity epidemic and COVID-19 pandemic.

A Direct Injection Technique to Improve Biosafety to Analyze Levetiracetam Concentrations in Human Serum and Its Application in Therapeutic Drug Monitoring.

BACKGROUND: With the outbreak of COVID-19, it has become very important to improve biosafety measures taken by medical staff. Fewer pretreatment steps correspond to lower chances of infection. The authors established a direct injection technique to analyze levetiracetam (LEV) concentrations in human serum and studied its application in therapeutic drug monitoring. METHODS: Serum samples were prepared by hollow fiber centrifugal ultrafiltration and the filtrate was directly injected into a ultra-high performance liquid chromatography apparatus (Waters UPLC BEH C18 column: 50 × 2.1 mm, 1.7 µm) for analysis. The mobile phase consisted of acetonitrile and water (8:92) at a flow rate of 1.0 mL/min. The column temperature was maintained at 30°C. The detected wavelength was 210 nm. RESULTS: A linear relationship was obtained for LEV from 0.625 to 80 mcg/mL (r2 = 0.999). The limit of detection for the analysis of LEV was 0.125 mcg/mL. The analysis time was shortened to 4 minutes. The recovery rate of LEV based on the current method was 96.6%-100.1%, whereas the absolute recovery rate was 93.2%-96.8%. The relative SD of intraday and interday precision was <7.3%. Stability was achieved at room temperature for 24 hours after 3 freeze-thaw cycles and at -80°C for 21 days. The method was successfully applied to determine LEV concentrations in the serum of 19 patients. CONCLUSIONS: The present method is simple, accurate, and sensitive, and can improve biosafety with the direct injection technique. It is suitable for the analysis of LEV concentrations in therapeutic drug monitoring.

Tocilizumab for treating COVID-19: a systemic review and meta-analysis of retrospective studies.

OBJECTIVES: COVID-19 has become a global epidemic, and effective therapies have not been discovered up to now. We conducted this study to explore the effectiveness and safety of tocilizumab recently used for treating COVID-19. METHOD: A comprehensive search was conducted (up to September 27, 2020), and 19 eligible records were identified according to the inclusion and exclusion criteria. The data of the studies were extracted by 2 independent reviewers and were analyzed to evaluate the safety and availability of tocilizumab for treating COVID-19. RESULTS: Thirteen retrospective case-control studies (n = 2285 patients) and 6 retrospective single-armed studies (n = 208) were retrieved in this study. In the comparison of tocilizumab treatment group (TCZ) and standard treatment group (ST), significant associations with a lower risk of admission to ICU, use of ventilation, and mortality (OR, 95% CI: 0.53, 0.26~1.09; 0.66, 0.46~0.94; 0.44, 0.36~0.55) were found in the tocilizumab treatment group. What is more, patients treated with tocilizumab had better clinical improvement compared with the patients treated with ST (OR, 1.24; 95% CI, 0.96~1.62). After taking tocilizumab, the patients had lower C-reactive protein (CRP), white blood cell count (WBC), aspartate aminotransferase (AST) (WMD, 95% CI: - 99.66, - 156.24~- 43.09; - 0.95, - 1.8~- 0.11; - 12.58, - 18.88~-6.29) but higher troponin (WMD, 7.61; 95% CI, 3.06~12.15) than before. In addition, tocilizumab did not have significant influence on patients' neutrophil count (Neut), lymphocyte count (Lymp), platelet count (Plt), alanine aminotransferase (ALT), and creatine (WMD, 95% CI: - 0.29, - 2.91~2.33; 0.42, - 0.23~1.07; 5.2, - 2.85~13.25; 22.49, - 2.73~47.7; - 44.78, - 93.37~3.81). CONCLUSION: Tocilizumab may have potential effectiveness to treat COVID-19 according to the results of this study. However, more large-scale studies are needed for more accurate conclusions.

Multifaceted Optimization of MSC-Based Formulation upon Sodium Iodoacetate-Induced Osteoarthritis Models by Combining Advantageous HA/PG Hydrogel and Fluorescent Tracer

Owing to the boundedness of conventional remedies upon articular cartilage for self-rehabilitation and the incrementally senior citizens, the incidence of osteoarthritis (OA) is increasing worldwide. Empirical studies have revealed the advantageous and promising potentials of mesenchymal stem/stromal cells (MSCs) on the refractory OA, whereas the deficiency of systematic and detailed exploration of MSC-based therapy largely hampers the large-scale applications in regenerative medicine. Herein, we initially utilized the monosodium iodoacetate- (MIA-) induced OA rabbit models and investigated the therapeutic effect of human umbilical cord-derived UC-MSCs at serial dose gradients with the splendid hyaluronic acid and/or propylene glycol hydrogels (HA, HA/PG), respectively. Afterwards, we turned to a dual-luciferase reporter tracing system and evaluated the spatiotemporal distribution and metabolokinetics of bifluorescence expressing UC-MSCs (BF-MSCs) in OA rats. Of the aforementioned trials, we verified that the combination of HA/PG and middle-dose MSCs (0.5×107 cells/ml) eventually manifested the optimal efficacy on OA rabbits. Furthermore, with the aid of the bioluminescence imaging (BLI) technology for dynamic in vitro and in vivo tracking, we intuitively delineated the spatiotemporal distribution and therapeutic process of BF-MSCs in OA rats, which substantially confirmed the reinforcement of HA/PG on BF-MSCs for OA treatment. Collectively, our data conformably demonstrated that the middle dose of UC-MSCs combined with HA/PG hydrogel was sufficient for optimal MSC-based formulation for blocking OA progression and promoting cartilage repair, which supplied overwhelming new references and enlightened MSC-based therapeutic strategies for cartilage defects.

Modeling the structure of the frameshift-stimulatory pseudoknot in SARS-CoV-2 reveals multiple possible conformers.

The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses -1 programmed ribosomal frameshifting (-1 PRF) to control the relative expression of viral proteins. As modulating -1 PRF can inhibit viral replication, the RNA pseudoknot stimulating -1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by µs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through junctions formed between two helices. These structural models may help interpret future experiments and support efforts to discover ligands inhibiting -1 PRF in SARS-CoV-2.

Anti-Frameshifting Ligand Active against SARS Coronavirus-2 Is Resistant to Natural Mutations of the Frameshift-Stimulatory Pseudoknot.

SARS-CoV-2 uses -1 programmed ribosomal frameshifting (-1 PRF) to control expression of key viral proteins. Because modulating -1 PRF can attenuate the virus, ligands binding to the RNA pseudoknot that stimulates -1 PRF may have therapeutic potential. Mutations in the pseudoknot have occurred during the pandemic, but how they affect -1 PRF efficiency and ligand activity is unknown. Studying a panel of six mutations in key regions of the pseudoknot, we found that most did not change -1 PRF levels, even when base-pairing was disrupted, but one led to a striking 3-fold decrease, suggesting SARS-CoV-2 may be less sensitive to -1 PRF modulation than expected. Examining the effects of a small-molecule -1 PRF inhibitor active against SARS-CoV-2, it had a similar effect on all mutants tested, regardless of basal -1 PRF efficiency, indicating that anti-frameshifting activity can be resistant to natural pseudoknot mutations. These results have important implications for therapeutic strategies targeting SARS-CoV-2 through modulation of -1 PRF.