Autophagy activated by GR/miR-421-3p/mTOR pathway as a compensatory mechanism participates in chondrodysplasia induced by prenatal caffeine exposure in male fetal rats.

Autophagy has been implicated in the developmental toxicity of multiple organs in offspring caused by adverse environmental conditions during pregnancy. We have previously found that prenatal caffeine exposure (PCE) can cause fetal overexposure to maternal glucocorticoids, leading to chondrodysplasia. However, whether autophagy is involved and what role it plays has not been reported. In this study, a PCE rat model was established by gavage of caffeine (120 mg/kg.d) on gestational day 9-20. The results showed that reduced cartilage matrix synthesis in male fetal rats in the PCE group was accompanied by increased autophagy compared to the control group. Furthermore, the expression of mTOR, miR-421-3p, and glucocorticoid receptor (GR) in male fetal rat cartilage of PCE group was increased. At the cellular level, we confirmed that corticosterone inhibited matrix synthesis in fetal chondrocytes while increasing autophagic flux. However, administration of autophagy enhancer (rapamycin) or inhibitor (bafilomycin A1 or 3-methyladenine) partially increased or further decreased aggrecan expression respectively. At the same time, we found that corticosterone could increase the expression of miR-421-3p through GR and target to inhibit the expression of mTOR, thereby enhancing autophagy. In conclusion, PCE can cause chondrodysplasia and autophagy enhancement in male fetal rats. Intrauterine high corticosterone activates GR/miR-421-3p signaling and down-regulates mTOR signaling in fetal chondrocytes, resulting in enhanced autophagy, which can partially compensate for corticosterone-induced fetal chondrodysplasia. This study confirmed the compensatory protective effect of autophagy on the developmental toxicity of fetal cartilage induced by PCE and its epigenetic mechanism, providing novel insights for exploring the early intervention and therapeutic target of fetal-originated osteoarthritis.

Effects of the timing of maternal SARS-CoV-2 infection and vaccination status on placental transfer of antibodies to neonates: A cross-sectional study.

OBJECTIVES: To assess the effects of timing of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination status on placental transfer of antibodies to neonates. METHODS: In this cross-sectional study, chemiluminescence was employed to measure SARS-CoV-2 IgG antibody titers in paired maternal-infant samples from women infected during pregnancy who were vaccinated or unvaccinated. Generalized linear regression assessed factors affecting antibody transfer in infected pregnant women and neonatal titers. RESULTS: The group with ≥90 days between infection and delivery showed a higher antibody transfer rate than the <90 days group (ß= 0.33, 95%CI: 0.01-0.65). Neonatal IgG titers correlated significantly with maternal titers and with maternal infections more than 90 days before delivery. Among infected pregnant women, those who had received 2 or 3 doses of vaccine before pregnancy had higher neonatal antibody titers than those who were not vaccinated (ß = 57.70, 95%CI: 31.33-84.07). CONCLUSION: Neonates born to pregnant women who were vaccinated before infection showed higher antibody titers than neonates of pregnant women who were not vaccinated before infection. The transfer rate is higher in pregnant women with ≥90 days from infection to delivery than in those with <90 days. These findings highlight the importance of timely maternal vaccination to optimize maternal and infant immunity.

Correction: Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis.

Correction for 'Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis' by Yi Zhang et al., J. Mater. Chem. B, 2023, 11, 11344-11356, https://doi.org/10.1039/D3TB01726E.

Public acceptance of COVID-19 control measures and associated factors during Omicron-dominant period in China: a cross-sectional survey.

OBJECTIVES: This study aims to evaluate the public acceptance of coronavirus disease 2019 (COVID-19) control measures during the Omicron-dominant period and its associated factors. METHODS: A cross-sectional design was conducted and 1391 study participants were openly recruited to participate in the questionnaire survey. Logistic regression model was performed to assess the association between the public acceptance and potential factors more specifically. RESULTS: By August 26, 2022, 58.9% of the study participants were less acceptive of the control measures while 41.1% expressed higher acceptance. Factors associated with lower acceptance included young age, such as < 18 (OR = 8.251, 95% CI: 2.009 to 33.889) and 18-29 (OR = 2.349, 95% CI: 1.564 to 3.529), and household per capita monthly income lower than 5000 yuan (OR = 1.512, 95% CI: 1.085 to 2.105). Furthermore, individuals who perceived that the case fatality rate (CFR) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was very low (OR = 6.010, 95% CI: 2.475 to 14.595) and that the restrictions could be eased once the CFR dropped to 2-3 times of the influenza (OR = 2.792, 95% CI: 1.939 to 4.023) showed greater oppositional attitudes. Likewise, respondents who were dissatisfied with control measures (OR = 9.639, 95% CI: 4.425 to 20.998) or preferred fully relaxation as soon as possible (OR = 13.571, 95% CI: 7.751 to 23.758) had even lower acceptability. By contrast, rural residents (OR = 0.683, 95% CI: 0.473 to 0.987), students (OR = 0.510, 95% CI: 0.276 to 0.941), public (OR = 0.417, 95% CI: 0.240 to 0.727) and private (OR = 0.562, 95% CI: 0.320 to 0.986) employees, and vaccinated participants (OR = 0.393, 95% CI: 0.204 to 0.756) were more compliant with control measures. CONCLUSION: More than half of the Chinese public were less supportive of COVID-19 control measures during Omicron-dominant period, which varied based on their different demographic characteristics, cognition and overall attitude towards SARS-CoV-2 infection. Control measures that struck a balance between public safety and individual freedom would be more acceptable during the pandemic.

Development of bioactive and ultrasound-responsive microdroplets for preventing ovariectomy (OVX)-induced osteoporosis.

As a common bone disease in the elderly population, osteoporosis-related bone loss and bone structure deterioration represent a major public health problem. Therapeutic strategies targeting excessive osteoclast formation are frequently used for osteoporosis treatment; however, potential side effects have been recorded. Here, we have developed a novel therapeutic strategy using microdroplets (MDs) encapsulated with NFATc1-siRNA and investigated the role of bioactive MDs-NFATc1 biocompatibility in RAW 264.7 macrophages and human mesenchymal stem cells (hBMSCs), respectively. Its role in regulating osteoclast differentiation and formation was also investigated in vitro. We first fabricated MDs with spherical morphology along with a well-defined core-shell structure. The ultrasound-responsive study demonstrated time-dependent responsive structural changes following ultrasound stimulation. The internalization study into unstimulated macrophages, inflammatory macrophages, and hBMSCs indicated good delivery efficiency. Furthermore, the results from the MTT assay, the live/dead assay, and the cellular morphological analysis further indicated good biocompatibility of our bioactive MDs-NFATc1. Following MDs-NFATc1 treatment, the number of osteoclasts was greatly reduced, indicating their inhibitory effect on osteoclastogenesis and osteoclast formation. Subsequently, osteoporotic rats that underwent ovariectomy (OVX) were used for the in vivo studies. The rats treated with MDs-NFATc1 exhibited significant resistance to bone loss induced by OVX. In conclusion, our results demonstrate that MDs-NFATc1 could become an important regulator in osteoclast differentiation and functions, thus having potential applications in osteoclast-related bone diseases.

Maternal antibody transfer rate of vaccination against SARS-CoV-2 before or during early pregnancy and its protective effectiveness on offspring.

This study focuses on maternal antibody transfer following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before or during early pregnancy and its potential protective effects on infants, providing scientific evidence for vaccination strategies. This prospective study tested the samples for SARS-CoV-2 IgG antibody titers and neutralizing capacity and tracked the infections after birth. Perform multivariate analysis of factors influencing antibody transfer rate, newborn antibody titers, and infant infection. Total 87.1% (122/140) women received coronavirus disease 2019 (COVID-19) vaccine before or during early pregnancy, and 28 of them had breakthrough infection. The maternal and neonatal IgG positive rates at delivery were 60.7% (85/140) and 60.8% (87/143), respectively. A positive correlation was found between neonatal and maternal IgG antibody titers. Compared with the median IgG antibody transfer rate of infected pregnant women, that of vaccinated but not infected pregnant women was higher (1.21 versus: 1.53 [two doses], 1.71 [three doses]). However, neonatal IgG antibodies were relatively low (174.91 versus: 0.99 [two doses], 8.18 [three doses]), and their neutralizing capacity was weak. The overall effectiveness of maternal vaccination in preventing infant infection was 27.0%, and three doses had higher effectiveness than two doses (64.3% vs. 19.6%). Multivariate analysises showed that in vaccination group women receiving three doses or in infection group women with longer interval between infection and delivery had a higher antibody transfer rate and neonatal IgG antibody titer. More than half of women vaccinated before or during early pregnancy can achieve effective antibody transfer to newborns. However, the neonatal IgG antibody titer is low and has a weak neutralizing capacity, providing limited protection to infants.

Cathepsin D mediates prenatal caffeine exposure-caused NAFLD susceptibility in male rat offspring by regulating autophagy.

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to ß-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.

Effectiveness of Maternal Inactivated COVID-19 Vaccination against Omicron Infection in Infants during the First 12 Months of Life: A Test-Negative Case-Control Study.

This study aims to evaluate the effectiveness of maternal inactivated COVID-19 vaccination before delivery for infants against Omicron infection in Guangzhou, China. A test-negative case-control design was conducted. This study selected infants born from 1 November 2021 to 23 November 2022 and tested for SARS-CoV-2 between 13 April 2022 and 30 November 2022 during outbreaks in Guangzhou. Multivariable logistic regression was performed to compare the maternal vaccination status of inactivated COVID-19 vaccines before delivery in cases and controls to estimate vaccine effectiveness (VE) for infants within 12 months. According to eligibility criteria, we finally selected 205 test-positive and 114 test-negative infants, as well as their mothers. The effectiveness of inactivated COVID-19 vaccines among fully vaccinated mothers was 48.4% (7.3% to 71.7%) for infants within 12 months, with the effectiveness of partial and booster vaccination showing no significant difference. Effectiveness for full vaccination presented a slight increase according to infants' age at testing, with 49.6% (-12.3% to 78.4%) for 0-6 months and 59.9% (-0.6% to 84.4%) for over 6 months. A greater protective effect of two-dose vaccination was manifested in infants whose mother had received the second dose during the first trimester (65.9%, 95% CI: 7.7% to 87.9%) of pregnancy rather than preconception (43.5%, 95% CI: -8.7% to 71.1%). Moreover, VE could be improved to 77.1% (11.1% to 95.3%) when mothers received two doses both during pregnancy and 91.8% (41.1% to 99.6%) with receipt of a booster dose during pregnancy. Maternal vaccination with two doses of inactivated COVID-19 vaccines before delivery was moderately effective against Omicron infection in infants during the first 12 months of life. Full vaccination or a booster dose during pregnancy could confer better protection against Omicron for infants, although it might be overestimated due to the insufficient sample size in subgroups.

Combining MOE Bioinformatics Analysis and In Vitro Pseudovirus Neutralization Assays to Predict the Neutralizing Ability of CV30 Monoclonal Antibody on SARS-CoV-2 Variants.

Combining bioinformatics and in vitro cytology assays, a predictive method was established to quickly evaluate the protective effect of immunity acquired through SARS-CoV-2 infection against variants. Bioinformatics software was first used to predict the changes in the affinity of variant antigens to the CV30 monoclonal antibody by integrating bioinformatics and cytology assays. Then, the ability of the antibody to neutralize the variant antigen was further verified, and the ability of the CV30 to neutralize the new variant strain was predicted through pseudovirus neutralization experiments. The current study has demonstrated that when the Molecular Operating Environment (MOE) predicts |ΔBFE| ≤ 3.0003, it suggests that the CV30 monoclonal antibody exhibits some affinity toward the variant strain and can potentially neutralize it. However, if |ΔBFE| ≥ 4.1539, the CV30 monoclonal antibody does not display any affinity for the variant strain and cannot neutralize it. In contrast, if 3.0003 < |ΔBFE| < 4.1539, it is necessary to conduct a series of neutralization tests promptly with the CV30 monoclonal antibody and the variant pseudovirus to obtain results and supplement the existing method, which is faster than the typical procedures. This approach allows for a rapid assessment of the protective efficacy of natural immunity gained through SARS-CoV-2 infection against variants.

[Research updates of osteoimmunomodulation in osteogenesis].

The gold-standard for bone substitution of large bone defects continues to be autogenous bone graft. Artificial bone substitutes are difficult to replace the autogenous bone grafting due to excessive immune response, fast biodegradation characteristics and inappropriate biocompatibility. Given these drawbacks, osteoimmunology and its advanced functional biomaterials have gained growing attention in recent years. Immune system plays an essential role during bone healing via regulating the shift from inflammatory to anti-inflammation phenotype, and inflammatory cytokines response. The inflammatory reaction mainly include infiltration of immune cells (such as macrophages, neutrophils, T cells, B cells, etc) and release of inflammatory factors (such as IL-1ß, IL-6, TNF-α, etc.) at the bone defects, which subsequently affect the step-wised process of bone healing rejuvenation. Hence, advanced bone biomaterials with immunomodulatory properties is of great significance for the treatment of patients with recalcitrant bone defects, especially for delayed healing or non-union. The reciprocal mechanism of immuno-modulated bone healing, however, is not fully understood and more research is required in the future.

Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats.

Autophagy inhibition is known to be involved in the development of adult osteoarthritis. Dexamethasone, as a synthetic glucocorticoid, is widely used for premature delivery and related pregnancy diseases in clinics. We have previously shown that prenatal dexamethasone exposure (PDE) was associated with increased susceptibility to postnatal osteoarthritis in offspring. However, whether the occurrence of fetal-originated adult osteoarthritis induced by PDE is related to autophagy remains unclear. In this study, we first found that PDE could increase the mRNA and protein expression of cartilage matrix-degrading enzymes (MMP3, MMP13, and ADAMTS5) and decrease the cartilage matrix contents in adult offspring, and the in vitro results suggested that this might be related to the autophagy inhibition of chondrocytes. Further, we demonstrated a persistent autophagy inhibition with autolysosome accumulation, low expression of cathepsin D (CTSD), increased H3K9ac level, and expression of miR-1912-3p in the cartilage of PDE offspring from fetus to adulthood. In vitro experiments showed that dexamethasone inhibited autophagy flux and CTSD expression in fetal chondrocytes, while overexpression of CTSD could alleviate the inhibition of autophagic flux induced by dexamethasone. Finally, we confirmed that dexamethasone increased the H3K9ac level and expression of miR-1912-3p through activation of the glucocorticoid receptor (GR), resulting in the decreased expression of CTSD and inhibition of autophagy flux in fetal chondrocytes. In conclusion, intrauterine miR-1912-3p/CTSD programming-mediated autophagy inhibition promoted the susceptibility to osteoarthritis in PDE adult offspring rats. This study provides new ideas for exploring early prevention and therapeutic targets in fetal-originated osteoarthritis.

Advances of Blood Coagulation Factor XIII in Bone Healing.

The biologic process of bone healing is complicated, involving a variety of cells, cytokines, and growth factors. As a result of bone damage, the activation of a clotting cascade leads to hematoma with a high osteogenic potential in the initial stages of healing. A major factor involved in this course of events is clotting factor XIII (FXIII), which can regulate bone defect repair in different ways during various stages of healing. Autografts and allografts often have defects in clinical practice, making the development of advanced materials that support bone regeneration a critical requirement. Few studies, however, have examined the promotion of bone healing by FXIII in combination with biomaterials, in particular, its effect on blood coagulation and osteogenesis. Therefore, we mainly summarized the role of FXIII in promoting bone regeneration by regulating the extracellular matrix and type I collagen, bone-related cells, angiogenesis, and platelets, and described the research progress of FXIII = related biomaterials on osteogenesis. This review provides a reference for investigators to explore the mechanism by which FXIII promotes bone healing and the combination of FXIII with biomaterials to achieve targeted bone tissue repair.

Fabrication of Interleukin-4 Encapsulated Bioactive Microdroplets for Regulating Inflammation and Promoting Osteogenesis.

Background: Despite the inherent regenerative ability of bone, large bone defect regeneration remains a major clinical challenge for orthopedic surgery. Therapeutic strategies medicated by M2 phenotypic macrophages or M2 macrophage inducer have been widely used to promote tissue remodeling. In this study, ultrasound-responsive bioactive microdroplets (MDs) encapsulated with bioactive molecule interleukin-4 (IL4, hereafter designated MDs-IL4) were fabricated to regulate macrophage polarization and potentiate the osteogenic differentiation of human mesenchymal stem cells (hBMSCs). Materials and Methods: The MTT assay, live and dead staining, and phalloidin/DAPI dual staining were used to evaluate biocompatibility in vitro. H&E staining was used to evaluate biocompatibility in vivo. Inflammatory macrophages were further induced via lipopolysaccharide (LPS) stimulation to mimic the pro-inflammatory condition. The immunoregulatory role of the MDs-IL4 was tested via macrophage phenotypic marker gene expression, pro-inflammatory cytokine level, cell morphological analysis, and immunofluorescence staining, etc. The immune-osteogenic response of hBMSCs via macrophages and hBMSCs interactions was further investigated in vitro. Results: The bioactive MDs-IL4 scaffold showed good cytocompatibility in RAW 264.7 macrophages and hBMSCs. The results confirmed that the bioactive MDs-IL4 scaffold could reduce inflammatory phenotypic macrophages, as evidenced by changing in morphological features, reduction in pro-inflammatory marker gene expression, increase of M2 phenotypic marker genes, and inhibition of pro-inflammatory cytokine secretion. Additionally, our results indicate that the bioactive MDs-IL4 could significantly enhance the osteogenic differentiation of hBMSCs via its potential immunomodulatory properties. Conclusion: Our results demonstrate that the bioactive MDs-IL4 scaffold could be used as novel carrier system for other pro-osteogenic molecules, thus having potential applications in bone tissue regeneration.

The role of autophagy in bone metabolism and clinical significance.

The skeletal system is the basis of the vertebral body composition, which affords stabilization sites for muscle attachment, protects vital organs, stores mineral ions, supplies places to the hematopoietic system, and participates in complex endocrine and immune system. Not surprisingly, bones are constantly reabsorbed, formed, and remodeled under physiological conditions. Once bone metabolic homeostasis is interrupted (including inflammation, tumors, fractures, and bone metabolic diseases), the body rapidly initiates bone regeneration to maintain bone tissue structure and quality. Macroautophagy/autophagy is an essential metabolic process in eukaryotic cells, which maintains metabolic energy homeostasis and plays a vital role in bone regeneration by controlling molecular degradation and organelle renewal. One relatively new observation is that mesenchymal cells, osteoblasts, osteoclasts, osteocytes, chondrocytes, and vascularization process exhibit autophagy, and the molecular mechanisms and targets involved are being explored and updated. The role of autophagy is also emerging in degenerative diseases (intervertebral disc degeneration [IVDD], osteoarthritis [OA], etc.) and bone metabolic diseases (osteoporosis [OP], osteitis deformans, osteosclerosis). The use of autophagy regulators to modulate autophagy has benefited bone regeneration, including MTOR (mechanistic target of rapamycin kinase) inhibitors, AMPK activators, and emerging phytochemicals. The application of biomaterials (especially nanomaterials) to trigger autophagy is also an attractive research direction, which can exert superior therapeutic properties from the material-loaded molecules/drugs or the material's properties such as shape, roughness, surface chemistry, etc. All of these have essential clinical significance with the discovery of autophagy associated signals, pathways, mechanisms, and treatments in bone diseases in the future.Abbreviations: Δψm: mitochondrial transmembrane potential AMPK: AMP-activated protein kinase ARO: autosomal recessive osteosclerosis ATF4: activating transcription factor 4 ATG: autophagy-related ß-ECD: ß-ecdysone BMSC: bone marrow mesenchymal stem cell ER: endoplasmic reticulum FOXO: forkhead box O GC: glucocorticoid HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha HSC: hematopoietic stem cell HSP: heat shock protein IGF1: insulin like growth factor 1 IL1B/IL-1ß: interleukin 1 beta IVDD: intervertebral disc degradation LPS: lipopolysaccharide MAPK: mitogen-activated protein kinase MSC: mesenchymal stem cell MTOR: mechanistic target of rapamycin kinase NP: nucleus pulposus NPWT: negative pressure wound therapy OA: osteoarthritis OP: osteoporosis PTH: parathyroid hormone ROS: reactive oxygen species SIRT1: sirtuin 1 SIRT3: sirtuin 3 SQSTM1/p62: sequestosome 1 TNFRSF11B/OPG: TNF receptor superfamily member 11b TNFRSF11A/RANK: tumor necrosis factor receptor superfamily, member 11a TNFSF11/RANKL: tumor necrosis factor (ligand) superfamily, member 11 TSC1: tuberous sclerosis complex 1 ULK1: unc-51 like autophagy activating kinase 1.

Protective Effect of Inactivated COVID-19 Vaccines against Omicron BA.2 Infection in Guangzhou: A Test-Negative Case-Control Real-World Study.

This study aims to explore the relationship between the doses of inactivated COVID-19 vaccines received and SARS-CoV-2 Omicron infection in the real-world setting, so as to preliminarily evaluate the protective effect induced by COVID-19 vaccination. We conducted a test-negative case-control study and recruited the test-positive cases and test-negative controls in the outbreak caused by Omicron BA.2 in April 2022 in Guangzhou, China. All the participants were 3 years and older. The vaccination status between the case group and the control group was compared in the vaccinated and all participants, respectively, to estimate the immune protection of inactivated COVID-19 vaccines. After adjusting for sex and age, compared with a mere single dose, full vaccination of inactivated COVID-19 vaccines (OR = 0.191, 95% CI: 0.050 to 0.727) and booster vaccination (OR = 0.091, 95% CI: 0.011 to 0.727) had a more superior protective effect. Compared with one dose, the second dose was more effective in males (OR = 0.090), as well as two doses (OR = 0.089) and three doses (OR = 0.090) among individuals aged 18-59. Whereas, when compared with the unvaccinated, one dose (OR = 7.715, 95% CI: 1.904 to 31.254) and three doses (OR = 2.055, 95% CI: 1.162 to 3.635) could contribute to the increased risk of Omicron infection after adjusting for sex and age. Meanwhile, by contrast with unvaccinated individuals, the result of increased risk was also manifested in the first dose in males (OR = 12.400) and one dose (OR = 21.500), two doses (OR = 1.890), and a booster dose (OR = 1.945) in people aged 18-59. In conclusion, the protective effect of full and booster vaccination with inactivated COVID-19 vaccines exceeded the incomplete vaccination, of which three doses were more effective. Nevertheless, vaccination may increase the risk of Omicron infection compared with unvaccinated people. This may result from the transmission traits of BA.2, the particularity and stronger protection awareness of the unvaccinated population, as well as the ADE effect induced by the decrease of antibody titers after a long time of vaccination. It is crucial to explore this issue in depth for the formulation of future COVID-19 vaccination strategies.

Neutralization Effect of Sera against Delta and Omicron in Patients Recovering from COVID-19 and Inactivated Vaccine Recipients.

This study aims to analyze the serum neutralization capacity against Delta and Omicron variants in three clusters of individuals, including those who had recovered from COVID-19 and those who had received two and three doses of inactivated vaccine. Pseudovirus neutralization tests were performed on serum samples. The neutralizing titers between different groups were compared using the Wilcoxon's signed-rank test. Among the two-dose vaccinees, the neutralization titers of the Omicron variant were reduced by approximately 3.1-fold compared to the wild-type virus (p < 0.05). Meanwhile, among the three-dose vaccinees, the neutralization titers for Delta and Omicron variants were 3.5-fold (p < 0.05) and 5.0-fold (p < 0.05) lower, respectively, as compared to the wild-type virus. In addition, among the recovering patients, the neutralization titers for Delta and Omicron variants were 3.9-fold (p < 0.05) and 29.1-fold (p < 0.05) lower, respectively, as compared to the wild-type virus. Overall, only 12.0% (11/92) of participants showed neutralizing titers against Omicron above the detection limit. The ability to neutralize wild-type pseudovirus was significantly boosted in three-dose vaccinees as compared to two-dose vaccinees. Sera from recovered patients showed greater neutralizing titers for the wild-type and Delta pseudoviruses than the two- and three-dose inactivated vaccine groups. The present study revealed a loss of neutralizing activity against the Omicron variant in almost all samples. Moreover, the immunization effect obtained through natural infection is more robust than that from the active immunization method of vaccination.

MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure.

Mounting evidence indicates that adverse intrauterine conditions increase offspring's hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Effect of Vaccination Time Intervals on SARS-COV-2 Omicron Variant Strain Infection in Guangzhou: A Real-World Matched Case-Control Study.

In April 2022, a COVID-19 outbreak caused by the Omicron variant emerged in Guangzhou. A case-control study was conducted to explore the relationship between vaccination intervals and SARS-CoV-2 infection in the real world. According to the vaccination dose and age information of the cases, a 1:4 matched case-control sample was established, finally including n = 242 for the case group and n = 968 for the control group. The results indicated that among the participants who received three vaccine doses, those with an interval of more than 300 days between the receipt of the first vaccine dose and infection (or the first contact with a confirmed case) were less likely to be infected with SARS-CoV-2 than those with an interval of less than 300 days (OR = 0.67, 95% CI = 0.46-0.99). After age-stratified analysis, among participants aged 18-40 years who received two doses of vaccine, those who received the second dose more than 30 days after the first dose were less likely to be infected with SARS-CoV-2 (OR = 0.53, 95% CI = 0.30-0.96). Our findings suggest that we need to extend the interval between the first dose and the second dose and further explore the optimal interval between the first and second and between the second and third doses in order to improve vaccine efficacy.

Impact of Vaccination and Control Measures on the Fatality of COVID-19: An Ecological Study.

BACKGROUND: During the COVID-19 pandemic, reducing the case fatality rate (CFR) becomes an urgent goal. OBJECTIVE: This study explored the effect of vaccination and variants on COVID-19 fatality and provide a basis for the adjustment of control measures. METHODS: This study collected epidemiological information on COVID-19 from January to October 2021. By setting different lag times, we calculated the adjusted CFR. The Spearman correlation coefficient and beta regression were used to explore factors that may affect COVID-19 fatality. RESULTS: Every 1% increase in the percentage of full vaccinations may reduce the 3 weeks lagging CFR by 0.66%. Increasing the restrictions on internal movement from level 0 to 1, restrictions on international travel controls from level 2 to 3, and stay-at-home restrictions from level 0 to 2 were associated with an average reduction in 3 weeks lagging CFR of 0.20%, 0.39%, and 0.36%, respectively. Increasing strictness in canceling public events from level 0 to 1 and 2 may reduce the 3 weeks lagging CFR by 0.49% and 0.37, respectively. Increasing the severity of school and workplace closures from level 1 or level 0 to 3 may increase the 3 weeks lagging CFR of 0.39% and 0.83, respectively. Every 1-point increase in the Global Health Security (GHS) index score may increase the 3 weeks lagging CFR by 0.12%. CONCLUSION: A higher percentage of full vaccinations, higher levels of internal movement restrictions, international travel control restrictions, cancelations of public events, and stay-at-home restrictions are factors that may reduce the adjusted CFR.

Does potential antibody-dependent enhancement occur during SARS-CoV-2 infection after natural infection or vaccination? A meta-analysis.

Coronavirus disease 2019 (COVID-19) continues to constitute an international public health emergency. Vaccination is a prospective approach to control this pandemic. However, apprehension about the safety of vaccines is a major obstacle to vaccination. Amongst health professionals, one evident concern is the risk of antibody-dependent enhancement (ADE), which may increase the severity of COVID-19. To explore whether ADE occurs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and increase confidence in the safety of vaccination, we conducted a meta-analysis to investigate the relationship between post-immune infection and disease severity from a population perspective. Databases, including PubMed, EMBASE, Chinese National Knowledge Infrastructure, SinoMed, Scopus, Science Direct, and Cochrane Library, were searched for articles on SARS-CoV-2 reinfection published until 25 October 2021. The papers were reviewed for methodological quality, and a random effects model was used to analyse the results. Heterogeneity was assessed using the I2 statistic. Publication bias was evaluated using a funnel plot and Egger's test. Eleven studies were included in the final meta-analysis. The pooled results indicated that initial infection and vaccination were protective factors against severe COVID-19 during post-immune infection (OR = 0.55, 95%CI = 0.31-0.98). A subgroup (post-immune infection after natural infection or vaccination) analysis showed similar results. Primary SARS-CoV-2 infection and vaccination provide adequate protection against severe clinical symptoms after post-immune infection. This finding demonstrates that SARS-CoV-2 may not trigger ADE at the population level.