Dimethyloxalylglycine Attenuates Steroid-Associated Endothelial Progenitor Cell Impairment and Osteonecrosis of the Femoral Head by Regulating the HIF-1α Signaling Pathway.

Endothelial impairment and dysfunction are closely related to the pathogenesis of steroid-associated osteonecrosis of the femoral head (SONFH). Recent studies have showed that hypoxia inducible factor-1α (HIF-1α) plays a crucial role in endothelial homeostasis maintenance. Dimethyloxalylglycine (DMOG) could suppress HIF-1 degradation and result in nucleus stabilization by repressing prolyl hydroxylase domain (PHD) enzymatic activity. Our results showed that methylprednisolone (MPS) remarkably undermined biological function of endothelial progenitor cells (EPC) by inhibiting colony formation, migration, angiogenesis, and stimulating senescence of EPCs, while DMOG treatment alleviated these effects by promoting HIF-1α signaling pathway, as evidenced by senescence-associated ß-galactosidase (SA-ß-Gal) staining, colony-forming unit, matrigel tube formation, and transwell assays. The levels of proteins related to angiogenesis were determined by ELISA and Western blotting. In addition, active HIF-1α bolstered the targeting and homing of endogenous EPCs to the injured endothelium in the femoral head. Histopathologically, our in vivo study showed that DMOG not only alleviated glucocorticoid-induced osteonecrosis but also promoted angiogenesis and osteogenesis in the femoral head as detected by microcomputed tomography (Micro-CT) analysis and histological staining of OCN, TRAP, and Factor Ⅷ. However, all of these effects were impaired by an HIF-1α inhibitor. These findings demonstrate that targeting HIF-1α in EPCs may constitute a novel therapeutic approach for the treatment of SONFH.

Intramedullary spinal cavernous malformations with high ossification: a case report and review of the literature.

BACKGROUND: Cavernous malformations of the spinal cord are a rare type of vascular malformation, comprising approximately 5 to 16% of all vascular lesions in the spinal cord. Depending on their origin position, these malformations can be distributed in different locations within the spinal canal. Although intramedullary cavernous malformations have been reported in the literature, they are exceedingly rare. Furthermore, highly calcified or ossified intramedullary cavernous spinal malformations are even rarer. CASE PRESENTATION: Here, we present a case report of a 28-year-old woman diagnosed with a thoracic intramedullary cavernous malformation. The patient had been experiencing progressive numbness in her distal limbs for a period of 2 months. During routine lung computed tomography screening for COVID-19, a hyperdense mass was noted in the patient's spinal canal. Magnetic resonance imaging revealed a mulberry-shaped intramedullary mass at the T1-2 level. The patient underwent surgical treatment, during which the entire lesion was successfully removed, resulting in a gradual improvement of her symptoms. Histological examination confirmed the presence of cavernous malformations with calcification. CONCLUSIONS: Intramedullary cavernous malformations with calcification are rare and special type that should be treated surgically in the early stage without significant neurological impairment before rebleeding or enlargement of the lesion can occur.

Comprehensive analysis of clinical indications and viral strain variants among patients infected with SARS-CoV-2 in Inner Mongolia, China.

Since the first appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, the virus is still evolving and mutating until now. In this study, we collected 6 throat swabs from patients who diagnosed with COVID-19 in Inner Mongolia, China, to understand the entry of multiple SARS-CoV-2 variants into Inner Mongolia and analyze the relationships between variants and clinical features observed in infected patients. In addition, we performed a combined analysis of clinical parameters associated with SARS-CoV-2 variants of interest, pedigree analysis, and detection of single-nucleotide polymorphisms. Our results showed that the clinical symptoms were generally mild although some patients demonstrated some degree of liver function abnormalities, and the SARS-CoV-2 strain was related to the Delta variant (B.1.617.2), AY.122 lineage. The epidemiological investigations and clinical manifestations confirmed that the variant exhibits strong transmission, a high viral load, and moderate clinical symptoms. SARS-CoV-2 has undergone extensive mutations in various hosts and countries. Timely monitoring of virus mutation can help to monitor the spread of infection and characterize the diversity of genomic variants, thus limiting future waves of SARS-CoV-2 infection.

Single-cell transcriptome atlas reveals protective characteristics of COVID-19 mRNA vaccine.

Messenger RNA (mRNA) vaccines are promising alternatives to conventional vaccines in many aspects. We previously developed a lipopolyplex (LPP)-based mRNA vaccine (SW0123) that demonstrated robust immunogenicity and strong protective capacity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in mice and rhesus macaques. However, the immune profiles and mechanisms of pulmonary protection induced by SW0123 remain unclear. Through high-resolution single-cell analysis, we found that SW0123 vaccination effectively suppressed SARS-CoV-2-induced inflammatory responses by inhibiting the recruitment of proinflammatory macrophages and increasing the frequency of polymorphonuclear myeloid-derived suppressor cells. In addition, the apoptotic process in both lung epithelial and endothelial cells was significantly inhibited, which was proposed to be one major mechanism contributing to vaccine-induced lung protection. Cell-cell interaction in the lung compartment was also altered by vaccination. These data collectively unravel the mechanisms by which the SW0123 protects against lung damage caused by SARS-CoV-2 infection.

A hepatitis B virus core antigen-based virus-like particle vaccine expressing SARS-CoV-2 B and T cell epitopes induces epitope-specific humoral and cell-mediated immune responses but confers limited protection against SARS-CoV-2 infection.

The hepatitis B virus core antigen (HBcAg) tolerates insertion of foreign epitopes and maintains its ability to self-assemble into virus-like particles (VLPs). We constructed a ∆HBcAg-based VLP vaccine expressing three predicted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B and T cell epitopes and determined its immunogenicity and protective efficacy. The recombinant ∆HBcAg-SARS-CoV-2 protein was expressed in Escherichia coli, purified, and shown to form VLPs. K18-hACE2 transgenic C57BL/6 mice were immunized intramuscularly with ∆HBcAg VLP control (n = 15) or ∆HBcAg-SARS-CoV-2 VLP vaccine (n = 15). One week after the 2nd booster and before virus challenge, five ∆HBcAg-SARS-CoV-2 vaccinated mice were euthanized to evaluate epitope-specific immune responses. There is a statistically significant increase in epitope-specific Immunoglobulin G (IgG) response, and statistically higher interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) expression levels in ∆HBcAg-SARS-CoV-2 VLP-vaccinated mice compared to ∆HBcAg VLP controls. While not statistically significant, the ∆HBcAg-SARS-CoV-2 VLP mice had numerically more memory CD8+ T-cells, and 3/5 mice also had numerically higher levels of interferon gamma (IFN-γ) and tumor necrosis factor (TNF). After challenge with SARS-CoV-2, ∆HBcAg-SARS-CoV-2 immunized mice had numerically lower viral RNA loads in the lung, and slightly higher survival, but the differences are not statistically significant. These results indicate that the ∆HBcAg-SARS-CoV-2 VLP vaccine elicits epitope-specific humoral and cell-mediated immune responses but they were insufficient against SARS-CoV-2 infection.

Effects and safety of auricular acupressure on depression and anxiety in isolated COVID-19 patients: A single-blind randomized controlled trial.

Objective: Psychological distress such as depression and anxiety resulted from coronavirus disease 2019 (COVID-19) have attracted increasing attention. The aim of this randomized controlled trial is to evaluate the effects and safety of auricular acupressure on depression and anxiety in isolated COVID-19 patients. Methods: 68 participants diagnosed with COVID-19 pneumonia (18-80 years old, SDS ≥ 50, SAS ≥ 45) were recruited and randomly allocated to the auricular acupressure group and the sham auricular acupressure group by a computer-generated random number sequence from 9th June to 30th June 2022. The group allocation was only blinded to the participants. Those in the auricular acupressure group were attached magnetic beads against 4 auricular points Shenmen, Subcortex, Liver and Endocrine, while sham group used four irrelevant auricular points. Outcomes were measured by Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Depression Scale (SAS) before and after treatment in both groups through electronic questionnaire in mobile phones. Results: After treatment, statistically significant differences were found in scores of SAS in both groups (P < 0.001 in auricular acupressure group; P = 0.003 in sham group), and SDS scores reduced significantly in the auricular acupressure group (P = 0.002). Significant reduced SAS and SDS scores were achieved in the auricular acupressure group than that in the sham group (F = 4.008, P = 0.049, MD -7.70 95% CI: -9.00, -6.40, SMD -2.79 95% CI: -3.47, -2.11 in SDS; F = 10.186, P = 0.002, MD -14.00 95% CI: -15.47, -12.53, SMD -4.46 95% CI: -5.37, -3.56 in SAS). No adverse events were found in either group during the whole study. Conclusion: Auricular acupressure is an effective and safe treatment for alleviating symptoms of depressive and anxiety in patients with COVID-19. Clinical trial registration: https://www.chictr.org.cn//, identifier ChiCTR2200061351.

Third dose of anti-SARS-CoV-2 inactivated vaccine for patients with RA: Focusing on immunogenicity and effects of RA drugs.

Objectives: To evaluate the immunogenicity of the third dose of inactivated SARS-CoV-2 vaccine in rheumatoid arthritis (RA) patients and explore the effect of RA drugs on vaccine immunogenicity. Methods: We recruited RA patients (n = 222) and healthy controls (HC, n = 177) who had been injected with a third dose of inactivated SARS-CoV-2 vaccine, and their neutralizing antibody (NAb) titer levels were assessed. Results: RA patients and HC were age- and gender-matched, and the mean interval between 3rd vaccination and sampling was comparable. The NAb titers were significantly lower in RA patients after the third immunization compared with HC. The positive rate of NAb in HC group was 90.4%, while that in RA patients was 80.18%, and the difference was significant. Furthermore, comparison of NAb titers between RA treatment subgroups and HC showed that the patients in the conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) group exhibited no significant change in NAb titers, while in those receiving the treatment of biological DMARDs (bDMARDs), Janus Kinase (JAK) inhibitors, and prednisone, the NAb titers were significantly lower. Spearman correlation analysis revealed that NAb responses to SARS-CoV-2 in HC did differ significantly according to the interval between 3rd vaccination and sampling, but this finding was not observed in RA patients. In addition, NAb titers were not significantly correlated with RA-related laboratory indicators, including RF-IgA, RF-IgG, RF-IgM, anti-CCP antibody; C-RP; ESR; NEUT% and LYMPH%. Conclusion: Serum antibody responses to the third dose of vaccine in RA patients were weaker than HC. Our study will help to evaluate the efficacy and safety of booster vaccination in RA patients and provide further guidance for adjusting vaccination strategies.

Human antibody BD-218 has broad neutralizing activity against concerning variants of SARS-CoV-2.

As SARS-CoV-2 variants of concern (VOC) reduce the effectiveness of existing anti-COVID therapeutics, it is increasingly critical to identify highly potent neutralizing antibodies (nAbs) that bind to conserved regions across multiple variants, especially beta, delta, and omicron variants. Using single-cell sequencing with biochemical methods and pseudo-typed virus neutralization experiments, here we report the characterization of a potent nAb BD-218, identified from an early screen of patients recovering from the original virus. We have determined the cryo-EM structure of the BD-218/spike protein complex to define its epitope in detail, which revealed that BD-218 interacts with a novel epitope on the receptor-binding domain (RBD) of the spike protein. We concluded that BD-218 is a highly effective and broadly active nAb against SARS-CoV-2 variants with promising potential for therapeutic development.

Effects of airway pressure release ventilation on multi-organ injuries in severe acute respiratory distress syndrome pig models.

BACKGROUND: Extra-pulmonary multi-organ failure in patients with severe acute respiratory distress syndrome (ARDS) is a major cause of high mortality. Our purpose is to assess whether airway pressure release ventilation (APRV) causes more multi-organ damage than low tidal volume ventilation (LTV). METHODS: Twenty one pigs were randomized into control group (n = 3), ARDS group (n = 3), LTV group (n = 8) and APRV group (n = 7). Severe ARDS model was induced by repeated bronchial saline lavages. Pigs were ventilated and monitored continuously for 48 h. Respiratory data, hemodynamic data, serum inflammatory cytokines were collected throughout the study. Histological injury and apoptosis were assessed by two pathologists. RESULTS: After severe ARDS modeling, pigs in ARDS, LTV and APRV groups experienced significant hypoxemia and reduced lung static compliance (Cstat). Oxygenation recovered progressively after 16 h mechanical ventilation (MV) in LTV and APRV group. The results of the repeated measures ANOVA showed no statistical difference in the PaO2/FiO2 ratio between the APRV and LTV groups (p = 0.54). The Cstat showed a considerable improvement in APRV group with statistical significance (p < 0.01), which was significantly higher than in the LTV group since 16 h (p = 0.04). Histological injury scores showed a significantly lower injury score in the middle and lower lobes of the right lung in the APRV group compared to LTV (pmiddle = 0.04, plower = 0.01), and no significant increase in injury scores for extra-pulmonary organs, including kidney (p = 0.10), small intestine (p = 1.0), liver (p = 0.14, p = 0.13) and heart (p = 0.20). There were no significant differences in serum inflammatory cytokines between the two groups. CONCLUSION: In conclusion, in the experimental pig models of severe ARDS induced by repetitive saline lavage, APRV improved lung compliance with reduced lung injury of middle and lower lobes, and did not demonstrate more extra-pulmonary organ injuries as compared with LTV.

Implementing a school-based HIV prevention program during public health emergencies: lessons learned in The Bahamas.

BACKGROUND: Natural disasters and public health crises can disrupt communities' capacities to implement important public health programs. A nationwide implementation of an evidence-based HIV prevention program, Focus on Youth in The Caribbean (FOYC) and Caribbean Informed Parents and Children Together (CImPACT), in The Bahamas was disrupted by Hurricane Dorian and the COVID-19 pandemic, especially in its more remote, Family Islands. We explored the teacher- and school-level factors that affected implementation of the program in these islands during those disruptions. METHODS: Data were collected from 47 Grade 6 teachers and 984 students in 34 government elementary schools during the 2020-2021 school year. Teachers completed a pre-implementation questionnaire to record their characteristics and perceptions that might affect their implementation fidelity and an annual program training workshop. School coordinators and high-performing teachers acting as mentors received additional training to provide teachers with monitoring, feedback, and additional support. Teachers submitted data on their completion of the 9 sessions and 35 core activities of FOYC + CImPACT. The fidelity outcomes were the number of sessions and core activities taught by teachers. RESULTS: On average, teachers taught 60% of sessions and 53% of core activities. Teachers with "very good" school coordinators (34% of teachers) taught more activities than those with "satisfactory" (43%) or no (34%) school coordinator (27.5 vs. 16.8 vs. 14.8, F = 12.86, P < 0.001). Teachers who had attended online training or both online and in-person training taught more sessions (6.1 vs. 6.2 vs. 3.6, F = 4.76, P < 0.01) and more core activities (21.1 vs. 20.8 vs. 12.6, F = 3.35, P < 0.05) than those who received no training. Teachers' implementation was associated with improved student outcomes (preventive reproductive health skills, self-efficacy, and intention). CONCLUSIONS: The Hurricane Dorian and the COVID-19 pandemic greatly disrupted education in The Bahamas Family Islands and affected implementation of FOYC + CImPACT. However, we identified several strategies that supported teachers' implementation following these events. Teacher training and implementation monitoring increased implementation fidelity despite external challenges, and students achieved the desired learning outcomes. These strategies can better support teachers' implementation of school-based interventions during future crises.

The discrepancies in the impacts of COVID-19 lockdowns on electricity consumption in China: Is the short-term pain worth it?

The COVID-19 pandemic caused severe economic contraction and paralyzed industrial activity. Despite a growing body of literature on the impacts of COVID-19 mitigation measures, scant evidence currently exists on the impacts of lockdowns on the economic and industrial activities of developing countries. Our study provides an empirical assessment of lockdown measures using 298,354 data points on daily electricity consumption in 396 sub-industries. To infer causal relationships, we employ difference-in-differences models that compare cities with and without lockdown policies and provide quantitative evidence on whether the long-term gain of lockdowns outweighs the short-term loss. The results show that lockdown policies led to a significant short-term drop in electricity consumption of 15.2% relative to the control group. However, the electricity loss under the no-lockdown scenario is 2.6 times larger than that under the strict lockdown scenario within 4 months of the outbreak. Discrepancies in the impacts among industries are identified, and even within the same industry, lockdowns have heterogeneous effects. The impact of lockdowns on small and medium-sized enterprises in developing countries is seriously underestimated, raising concerns about the distributional impact of subsidy measures. This study serves as a crucial reference for the government when facing public health emergencies and shocks to support better policies.

A biomarker assay to risk-stratify patients with symptoms of respiratory tract infection.

BACKGROUND: Patients who present to an emergency department with respiratory symptoms are often conservatively triaged in favour of hospitalization. We sought to determine if an inflammatory biomarker panel that identifies the host response better predicts hospitalization in order to improve the precision of clinical decision-making in the emergency department. PATIENTS AND METHODS: From April 2020 to March 2021, plasma samples of 641 patients with symptoms of respiratory illness were collected from emergency departments in an international multicentre study: Canada (n=310), Italy (n=131), and Brazil (n=200). Patients were followed prospectively for 28 days. Subgroup analysis was conducted on confirmed COVID-19 patients (n=245). An inflammatory profile was determined using a rapid, 50-minute, biomarker panel: Rapid Acute Lung Injury Diagnostic (RALI-Dx), which measures IL-6, IL-8, IL-10, sTNFR1, and sTREM1. RESULTS: RALI-Dx biomarkers were significantly elevated in patients who required hospitalization across all three sites. A machine learning algorithm that was applied to predict hospitalization using RALI-Dx biomarkers had an area under the receiver operating characteristic curve of 76±6% (Canada), 84±4% (Italy), and 86±3% (Brazil). Model performance in COVID-19 patients was 82±3% and 87±7% for patients with a confirmed pneumonia diagnosis. CONCLUSIONS: The rapid diagnostic biomarker panel accurately identified the need for inpatient care in patients presenting with respiratory symptoms, including COVID-19. The RALI-Dx test is broadly and easily applicable across many jurisdictions and represents an important diagnostic adjunct to advance emergency department decision-making protocols.

Systematic comparison of ranking aggregation methods for gene lists in experimental results.

MOTIVATION: A common experimental output in biomedical science is a list of genes implicated in a given biological process or disease. The gene lists resulting from a group of studies answering the same, or similar, questions can be combined by ranking aggregation methods to find a consensus or a more reliable answer. Evaluating a ranking aggregation method on a specific type of data before using it is required to support the reliability since the property of a dataset can influence the performance of an algorithm. Such evaluation on gene lists is usually based on a simulated database because of the lack of a known truth for real data. However, simulated datasets tend to be too small compared to experimental data and neglect key features, including heterogeneity of quality, relevance and the inclusion of unranked lists. RESULTS: In this study, a group of existing methods and their variations that are suitable for meta-analysis of gene lists are compared using simulated and real data. Simulated data were used to explore the performance of the aggregation methods as a function of emulating the common scenarios of real genomic data, with various heterogeneity of quality, noise level and a mix of unranked and ranked data using 20 000 possible entities. In addition to the evaluation with simulated data, a comparison using real genomic data on the SARS-CoV-2 virus, cancer (non-small cell lung cancer) and bacteria (macrophage apoptosis) was performed. We summarize the results of our evaluation in a simple flowchart to select a ranking aggregation method, and in an automated implementation using the meta-analysis by information content algorithm to infer heterogeneity of data quality across input datasets. AVAILABILITY AND IMPLEMENTATION: The code for simulated data generation and running edited version of algorithms: https://github.com/baillielab/comparison_of_RA_methods. Code to perform an optimal selection of methods based on the results of this review, using the MAIC algorithm to infer the characteristics of an input dataset, can be downloaded here: https://github.com/baillielab/maic. An online service for running MAIC: https://baillielab.net/maic. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of an antiviral drug control and its variable order fractional network in host COVID-19 kinetics.

In December 2019, a novel coronavirus disease (COVID-19) appeared in Wuhan, China. After that, it spread rapidly all over the world. Novel coronavirus belongs to the family of Coronaviridae and this new strain is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epithelial cells of our throat and lungs are the main target area of the SARS-CoV-2 virus which leads to COVID-19 disease. In this article, we propose a mathematical model for examining the effects of antiviral treatment over viral mutation to control disease transmission. We have considered here three populations namely uninfected epithelial cells, infected epithelial cells, and SARS-CoV-2 virus. To explore the model in light of the optimal control-theoretic strategy, we use Pontryagin's maximum principle. We also illustrate the existence of the optimal control and the effectiveness of the optimal control is studied here. Cost-effectiveness and efficiency analysis confirms that time-dependent antiviral controlled drug therapy can reduce the viral load and infection process at a low cost. Numerical simulations have been done to illustrate our analytical findings. In addition, a new variable-order fractional model is proposed to investigate the effect of antiviral treatment over viral mutation to control disease transmission. Considering the superiority of fractional order calculus in the modeling of systems and processes, the proposed variable-order fractional model can provide more accurate insight for the modeling of the disease. Then through the genetic algorithm, optimal treatment is presented, and its numerical simulations are illustrated.