Design, Optimization, and Modeling of a Hydraulic Soft Robot for Chronic Total Occlusions.

Chronic total occlusion (CTO) is one of the most severe and sophisticated vascular stenosis because of complete blockage, greater operation difficulty, and lower procedural success rate. This study proposes a hydraulic-driven soft robot imitating the earthworm's locomotion to assist doctors or operators in actively opening thrombi in coronary or peripheral artery vessels. Firstly, a three-actuator bionic soft robot is developed based on earthworms' physiological structure. The soft robot's locomotion gait inspired by the earthworm's mechanism is designed. Secondly, the influence of structure parameters on actuator deformation, stress, and strain is explored, which can help us determine the soft actuators' optimal structure parameters. Thirdly, the relationship between hydraulic pressure and actuator deformation is investigated by performing finite element analysis using the bidirectional fluid-structure interaction (FSI) method. The kinematic models of the soft actuators are established to provide a valuable reference for the soft actuators' motion control.

Parental migration and cyberbullying victimization among Chinese left-behind children: understanding the association and mediating factors.

Introduction: Parental absence is greatly associated with school bullying victimization of left-behind children (LBC) in migrant families. With the increasing popularity of the Internet, little is known about the association between parental migration and cyberbullying victimization, and potential mediators. Methods: We conducted a cross-sectional study in Anhui and Zhejiang Province, China, in 2020. With a sample of 792 currently left-behind children (CLBC), 541 previously left-behind children (PLBC), and 628 never left-behind children (NLBC), path analysis was used to explore the association between parental migration and cyberbullying victimization among children, while considering the independent and sequential mediating roles of parent-child communication, and time spent online. Results: The prevalence of cyberbullying victimization was 29.3% among CLBC, 29.2% among PLBC, and 23.4% among NLBC. Path analysis showed that current left-behind status was positively associated with cyberbullying victimization among children (p = 0.024). Furthermore, current left-behind status was associated with worse parent-child communication, which, in turn, predicted a higher prevalence of cyberbullying victimization [95% CI = (0.007, 0.036)]. Similarly, the previous left-behind experience was associated with worse parent-child communication, which, in turn, predicted a higher prevalence of cyberbullying victimization [95% CI = (0.013, 0.043)]. Current left-behind status was associated with increased time spent online, which, in turn, predicted a higher prevalence of cyberbullying victimization [95% CI = (0.013, 0.038)]. Additionally, the current left-behind status positively predicted cyberbullying victimization among children through the serial mediating roles of parent-child communication and time spent online [95% CI = (0.001, 0.006)]. Similarly, previous left-behind experience positively predicted cyberbullying victimization among children through the serial mediating roles of parent-child communication and time spent online [95% CI = (0.002, 0.007)]. Discussion: We propose that to protect CLBC and PLBC from cyberbullying victimization, it is of great importance for migrant parents to regulate children's time spent online and promote daily parent-child communication.

Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages.

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal immunoglobulin A (IgA) response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal secretory IgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric, and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies (mAbs 01A05, rmAb23, DXP-604, and XG014) targeting the receptor-binding domain of the spike protein. Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2, and BA.4/5 with a 25- to 75-fold increase in potency. In human angiotensin converting enzyme 2 (ACE2) transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by the current circulating subvariants and, potentially, future VOCs.

Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting.

The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on the ancestral (hereafter referred to as WT) strain would compromise the antibody response to Omicron-based boosters1-5. Vaccination strategies to counter immune imprinting are critically needed. Here we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. In mice, the efficacy of single Omicron boosting is heavily limited when using variants that are antigenically distinct from WT-such as the XBB variant-and this concerning situation could be mitigated by a second Omicron booster. Similarly, in humans, repeated Omicron infections could alleviate WT vaccination-induced immune imprinting and generate broad neutralization responses in both plasma and nasal mucosa. Notably, deep mutational scanning-based epitope characterization of 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated from repeated Omicron infection revealed that double Omicron exposure could induce a large proportion of matured Omicron-specific antibodies that have distinct RBD epitopes to WT-induced antibodies. Consequently, immune imprinting was largely mitigated, and the bias towards non-neutralizing epitopes observed in single Omicron exposures was restored. On the basis of the deep mutational scanning profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated that these mutations could further boost the immune-evasion capability of XBB.1.5 while maintaining high ACE2-binding affinity. Our findings suggest that the WT component should be abandoned when updating COVID-19 vaccines, and individuals without prior Omicron exposure should receive two updated vaccine boosters.

Application of Elastic Traction Band Combined with Pain Assessment in Elderly Patients After Hip Replacement.

Objective: This study aims to investigate the use of an elastic traction band in conjunction with pain evaluation in geriatric patients after hip replacement. Methods: Eighty hip arthroplasty cases involving senior patients at our institution were chosen for this study, covering the period from February 2021 to January 2022. They were separated into the control and observation groups using the premise of comparing and contrasting the two groups' shared fundamental characteristics. Traditional nursing care was given to the control group, while the observation group got an elastic stretch traction belt and pain assessment nursing care. The application effect of the two groups was observed. Results: Before surgery, there was no statistically significant difference in the Harris hip function score between the two groups (P > .05). Harris scores for research items in both groups improved 6 months after surgery, compared to scores obtained before surgery (P < .05), and the increase was greater in the observation group than in the control group (P < .05). Self-efficacy for physical activity, coping, and the overall SER scale were all greater in the observation group than in the control group (P < .05). There was no statistically significant difference between the two groups on any measure of material wellbeing (P > .05). Mental and physical health scores were better in the observation group than in the control group (P < .05). Patients' social dimensions were compared to those of two control groups, and the results showed no statistically significant difference in terms of social function aspects (P > .05), although the control group reported much lower levels of enjoyment, learning, and work, the observation group reported significantly greater levels (P < .05). Patient treatment compliance study using a rank sum test revealed that the observation group's postoperative exercise compliance was considerably greater than that of the control group. Observation group members were more compliant than control group members, with an average rank of 30.829 compared to 40.171 for both groups (P < .05). Conclusion: Patients who have had hip arthroplasty may benefit from using an elastic traction belt in conjunction with pain assessment to increase the likelihood that they would participate in rehabilitation exercises, so enhancing their self-efficacy, hip function, and quality of life.

Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice.

Olfactory receptor (OR) choice represents an example of genetically hardwired stochasticity, where every olfactory neuron expresses one out of ~2000 OR alleles in the mouse genome in a probabilistic, yet stereotypic fashion. Here, we propose that topographic restrictions in OR expression are established in neuronal progenitors by two opposing forces: polygenic transcription and genomic silencing, both of which are influenced by dorsoventral gradients of transcription factors NFIA, B, and X. Polygenic transcription of OR genes may define spatially constrained OR repertoires, among which one OR allele is selected for singular expression later in development. Heterochromatin assembly and genomic compartmentalization of OR alleles also vary across the axes of the olfactory epithelium and may preferentially eliminate ectopically expressed ORs with more dorsal expression destinations from this 'privileged' repertoire. Our experiments identify early transcription as a potential 'epigenetic' contributor to future developmental patterning and reveal how two spatially responsive probabilistic processes may act in concert to establish deterministic, precise, and reproducible territories of stochastic gene expression.

Single-cell bisulfite-free 5mC and 5hmC sequencing with high sensitivity and scalability.

Existing single-cell bisulfite-based DNA methylation analysis is limited by low DNA recovery, and the measurement of 5hmC at single-base resolution remains challenging. Here, we present a bisulfite-free single-cell whole-genome 5mC and 5hmC profiling technique, named Cabernet, which can characterize 5mC and 5hmC at single-base resolution with high genomic coverage. Cabernet utilizes Tn5 transposome for DNA fragmentation, which enables the discrimination between different alleles for measuring hemi-methylation status. Using Cabernet, we revealed the 5mC, hemi-5mC and 5hmC dynamics during early mouse embryo development, uncovering genomic regions exclusively governed by active or passive demethylation. We show that hemi-methylation status can be used to distinguish between pre- and post-replication cells, enabling more efficient cell grouping when integrated with 5mC profiles. The property of Tn5 naturally enables Cabernet to achieve high-throughput single-cell methylome profiling, where we probed mouse cortical neurons and embryonic day 7.5 (E7.5) embryos, and constructed the library for thousands of single cells at high efficiency, demonstrating its potential for analyzing complex tissues at substantially low cost. Together, we present a way of high-throughput methylome and hydroxymethylome detection at single-cell resolution, enabling efficient analysis of the epigenetic status of biological systems with complicated nature such as neurons and cancer cells.

A Novel Spatial Position Prediction Navigation System Makes Surgery More Accurate.

During intravascular interventional surgery, the 3D surgical navigation system can provide doctors with 3D spatial information of the vascular lumen, reducing the impact of missing dimension caused by digital subtraction angiography (DSA) guidance and further improving the success rate of surgeries. Nevertheless, this task often comes with the challenge of complex registration problems due to vessel deformation caused by respiratory motion and high requirements for the surgical environment because of the dependence on external electromagnetic sensors. This article proposes a novel 3D spatial predictive positioning navigation (SPPN) technique to predict the real-time tip position of surgical instruments. In the first stage, we propose a trajectory prediction algorithm integrated with instrumental morphological constraints to generate the initial trajectory. Then, a novel hybrid physical model is designed to estimate the trajectory's energy and mechanics. In the second stage, a point cloud clustering algorithm applies multi-information fusion to generate the maximum probability endpoint cloud. Then, an energy-weighted probability density function is introduced using statistical analysis to achieve the prediction of the 3D spatial location of instrument endpoints. Extensive experiments are conducted on 3D-printed human artery and vein models based on a high-precision electromagnetic tracking system. Experimental results demonstrate the outstanding performance of our method, reaching 98.2% of the achievement ratio and less than 3 mm of the average positioning accuracy. This work is the first 3D surgical navigation algorithm that entirely relies on vascular interventional robot sensors, effectively improving the accuracy of interventional surgery and making it more accessible for primary surgeons.

Therapeutic targeting of mitochondria-proteostasis axis by antioxidant polysaccharides in neurodegeneration.

Aging is a major risk factor for many age-associated disorders, including neurodegenerative diseases. Both mitochondrial dysfunction and proteostatic decline are well-recognized hallmarks of aging and age-related neurodegeneration. Despite a lack of therapies for neurodegenerative diseases, a number of interventions promoting mitochondrial integrity and protein homeostasis (proteostasis) have been shown to delay aging-associated neurodegeneration. For example, many antioxidant polysaccharides are shown to have pharmacological potentials in Alzheimer's, Parkinson's and Huntington's diseases through regulation of mitochondrial and proteostatic pathways, including oxidative stress and heat shock responses. However, how mitochondrial and proteostatic mechanisms work together to exert the antineurodegenerative effect of the polysaccharides remains largely unexplored. Interestingly, recent studies have provided a growing body of evidence to support the crosstalk between mitostatic and proteostatic networks as well as the impact of the crosstalk on neurodegeneration. Here we summarize the recent progress of antineurodegenerative polysaccharides with particular attention in the mitochondrial and proteostatic context and provide perspectives on their implications in the crosstalk along the mitochondria-proteostasis axis.

High-resolution feature based central venous catheter tip detection network in X-ray images.

Hospital patients can have catheters and lines inserted during the course of their admission to give medicines for the treatment of medical issues, especially the central venous catheter (CVC). However, malposition of CVC will lead to many complications, even death. Clinicians always detect the malposition based on position detection of CVC tip via X-ray images. To reduce the workload of the clinicians and the percentage of malposition occurrence, we propose an automatic catheter tip detection framework based on a convolutional neural network (CNN). The proposed framework contains three essential components which are modified HRNet, segmentation supervision module, and deconvolution module. The modified HRNet can retain high-resolution features from start to end, ensuring the maintenance of precise information from the X-ray images. The segmentation supervision module can alleviate the presence of other line-like structures such as the skeleton as well as other tubes and catheters used for treatment. In addition, the deconvolution module can further increase the feature resolution on the top of the highest-resolution feature maps in the modified HRNet to get a higher-resolution heatmap of the catheter tip. A public CVC Dataset is utilized to evaluate the performance of the proposed framework. The results show that the proposed algorithm offering a mean Pixel Error of 4.11 outperforms three comparative methods (Ma's method, SRPE method, and LCM method). It is demonstrated to be a promising solution to precisely detect the tip position of the catheter in X-ray images.

Post-exposure prophylaxis with SA58 (anti-SARS-COV-2 monoclonal antibody) nasal spray for the prevention of symptomatic COVID-19 in healthy adult workers: a randomized, single-blind, placebo-controlled clinical study.

Monoclonal antibodies (mAbs) and the post-exposure prophylaxis (PEP) with mAbs represent a very important public health strategy against coronavirus disease 2019 (COVID-19). This study has assessed a new Anti-SARS-COV-2 mAb (SA58) Nasal Spray for PEP against COVID-19 in healthy adults aged 18 years and older within three days of exposure to a SARS-CoV-2 infected individual. Recruited participants were randomized in a ratio of 3:1 to receive SA58 or placebo. Primary endpoints were laboratory-confirmed symptomatic COVID-19 within the study period. A total of 1222 participants were randomized and dosed (SA58, n = 901; placebo, n = 321). Median of follow-up was 2.25 and 2.79 days for SA58 and placebo, respectively. Adverse events occurred in 221 of 901 (25%) and 72 of 321 (22%) participants with SA58 and placebo, respectively. All adverse events were mild in severity. Laboratory-confirmed symptomatic COVID-19 developed in 7 of 824 participants (0.22 per 100 person-days) in the SA58 group vs. 14 of 299 (1.17 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 80.82% (95%CI 52.41%-92.27%). There were 32 SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) positives (1.04 per 100 person-days) in the SA58 group vs. 32 (2.80 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 61.83% (95%CI 37.50%-76.69%). A total of 21 RT-PCR positive samples were sequenced and all were the Omicron variant BF.7. In conclusion, SA58 Nasal Spray showed favourable efficacy and safety in preventing symptomatic COVID-19 or SARS-CoV-2 infection in adults who had exposure to SARS-CoV-2 within 72 h.

Safety and Effectiveness of SA58 Nasal Spray Against COVID-19 Infection in Medical Personnel: An Open-Label, Blank-Controlled Study - Hohhot City, Inner Mongolia Autonomous Region, China, 2022.

What is already known about this topic?: The active ingredient of the SA58 Nasal Spray is a broad-spectrum neutralizing antibody with a high neutralizing capacity against different Omicron sub-variants in vitro studies. What is added by this report?: This study demonstrated the safety and effectiveness of SA58 Nasal Spray against coronavirus disease 2019 (COVID-19) infection in medical personnel for the first time. What are the implications for public health practice?: This study provides an effective approach for the public to reduce their risk of COVID-19 infection. The findings of this research have the potential to significantly reduce the risk of infection and limit human-to-human transmission in the event of a COVID-19 outbreak.

To Explore the Mechanism of "Fuzi-Guizhi" for the Treatment of Osteoarthritis on the Basis of Network Pharmacology and Molecular Docking.

OBJECTIVE: The objective of this study is to analyze and verify the main drug components and targets of "Fuzi-Guizhi" in the treatment of osteoarthritis by using the network pharmacology platform. METHODS: The integrated pharmacology of "Fuzi-Guizhi" was analyzed by using the platform of integrated pharmacology of traditional Chinese medicine to explore its mechanism in the treatment of osteoarthritis. By establishing an arthritis model in vitro, the pharmacological effect of "aconitecassia twigs" on articular cartilage was evaluated and conducted for molecular docking. RESULTS: 28 candidate active components, 37 compound targets, and 583 osteoarthritis-related potential targets were screened, and 10 key target processes were screened in the protein interaction network model. Enrichment analysis showed that the 10 core targets involved 958 GO biologic function items and 76 KEGG signal pathways, which were mainly related to apoptosis and mitochondrial functional metabolism and "Fuzi-Guizhi" drug-containing serum inhibited the expression of Caspase-3 mRNA and protein in chondrocytes and promoted the synthesis of ATP. CONCLUSION: Our research is preliminary that the mechanism of action of "Fuzi-Guizhi" may inhibit chondrocyte degeneration by resisting mitochondrial apoptosis, and further experimental research is required to determine.

Learning Skill Characteristics From Manipulations.

Percutaneous coronary intervention (PCI) has increasingly become the main treatment for coronary artery disease. The procedure requires high experienced skills and dexterous manipulations. However, there are few techniques to model PCI skill so far. In this study, a learning framework with local and ensemble learning is proposed to learn skill characteristics of different skill-level subjects from their PCI manipulations. Ten interventional cardiologists (four experts and six novices) were recruited to deliver a medical guidewire to two target arteries on a porcine model for in vivo studies. Simultaneously, translation and twist manipulations of thumb, forefinger, and wrist are acquired with electromagnetic (EM) and fiber-optic bend (FOB) sensors, respectively. These behavior data are then processed with wavelet packet decomposition (WPD) under 1-10 levels for feature extraction. The feature vectors are further fed into three candidate individual classifiers in the local learning layer. Furthermore, the local learning results from different manipulation behaviors are fused in the ensemble learning layer with three rule-based ensemble learning algorithms. In subject-dependent skill characteristics learning, the ensemble learning can achieve 100% accuracy, significantly outperforming the best local result (90%). Furthermore, ensemble learning can also maintain 73% accuracy in subject-independent schemes. These promising results demonstrate the great potential of the proposed method to facilitate skill learning in surgical robotics and skill assessment in clinical practice.

Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution.

Continuous evolution of Omicron has led to a rapid and simultaneous emergence of numerous variants that display growth advantages over BA.5 (ref. 1). Despite their divergent evolutionary courses, mutations on their receptor-binding domain (RBD) converge on several hotspots. The driving force and destination of such sudden convergent evolution and its effect on humoral immunity remain unclear. Here we demonstrate that these convergent mutations can cause evasion of neutralizing antibody drugs and convalescent plasma, including those from BA.5 breakthrough infection, while maintaining sufficient ACE2-binding capability. BQ.1.1.10 (BQ.1.1 + Y144del), BA.4.6.3, XBB and CH.1.1 are the most antibody-evasive strains tested. To delineate the origin of the convergent evolution, we determined the escape mutation profiles and neutralization activity of monoclonal antibodies isolated from individuals who had BA.2 and BA.5 breakthrough infections2,3. Owing to humoral immune imprinting, BA.2 and especially BA.5 breakthrough infection reduced the diversity of the neutralizing antibody binding sites and increased proportions of non-neutralizing antibody clones, which, in turn, focused humoral immune pressure and promoted convergent evolution in the RBD. Moreover, we show that the convergent RBD mutations could be accurately inferred by deep mutational scanning profiles4,5, and the evolution trends of BA.2.75 and BA.5 subvariants could be well foreseen through constructed convergent pseudovirus mutants. These results suggest that current herd immunity and BA.5 vaccine boosters may not efficiently prevent the infection of Omicron convergent variants.

Correlated gene modules uncovered by high-precision single-cell transcriptomics.

Correlations in gene expression are used to infer functional and regulatory relationships between genes. However, correlations are often calculated across different cell types or perturbations, causing genes with unrelated functions to be correlated. Here, we demonstrate that correlated modules can be better captured by measuring correlations of steady-state gene expression fluctuations in single cells. We report a high-precision single-cell RNA-seq method called MALBAC-DT to measure the correlation between any pair of genes in a homogenous cell population. Using this method, we were able to identify numerous cell-type specific and functionally enriched correlated gene modules. We confirmed through knockdown that a module enriched for p53 signaling predicted p53 regulatory targets more accurately than a consensus of ChIP-seq studies and that steady-state correlations were predictive of transcriptome-wide response patterns to perturbations. This approach provides a powerful way to advance our functional understanding of the genome.