Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Radiomics using CT images for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma: a multi-centric study.

OBJECTIVES: To develop a CT-based radiomics model for preoperative prediction of lymph node (LN) metastasis in perihilar cholangiocarcinoma (pCCA). METHODS: The study enrolled consecutive pCCA patients from three independent Chinese medical centers. The Boruta algorithm was applied to build the radiomics signature for the primary tumor and LN. The k-means algorithm was employed to cluster the selected LNs based on the radiomics signature LN. Support vector machines were used to construct the prediction models. The diagnostic efficiency was measured by the area under the receiver operating characteristic curve (AUC). The optimal model was evaluated in terms of calibration, clinical usefulness, and prognostic value. RESULTS: A total of 214 patients were included in the study (mean age: 61.6 years ± 9.4; 130 male). The selected LNs were classified into two clusters, which were significantly correlated with LN metastasis in all cohorts (p < 0.001). The model incorporated the clinical risk factors, radiomics signature primary tumor, and the LN cluster obtained the best discrimination, with AUC values of 0.981 (95% CI: 0.962-1), 0.896 (95% CI: 0.810-0.982), and 0.865 (95% CI: 0.768-0.961) in the training, internal validation, and external validation cohorts, respectively. High-risk patients predicted by the optimal model had shorter overall survival than low-risk patients (median, 13.7 vs. 27.3 months, p < 0.001). CONCLUSIONS: The study proposed a radiomics model with good performance to predict LN metastasis in pCCA. As a noninvasive preoperative prediction tool, this model may help in patient risk stratification and personalized treatment. CLINICAL RELEVANCE STATEMENT: A CT-based radiomics model accurately predicts lymph node metastasis in perihilar cholangiocarcinoma patients. This noninvasive preoperative tool can aid in patient risk stratification and personalized treatment, potentially improving patient outcomes. KEY POINTS: • The radiomics model based on contrast-enhanced CT is a useful tool for preoperative prediction of lymph node metastasis in perihilar cholangiocarcinoma. • Radiomics features extracted from lymph nodes show great potential for predicting lymph node metastasis. • The study is the first to identify a lymph node phenotype with a high probability of metastasis based on radiomics.

SARS-CoV-2 hijacks macropinocytosis to facilitate its entry and promote viral spike-mediated cell-to-cell fusion.

Revealing the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and cell-to-cell spread might provide insights for understanding the underlying mechanisms of viral pathogenesis, tropism, and virulence. The signaling pathways involved in SARS-CoV-2 entry and viral spike-mediated cell-to-cell fusion remain elusive. In the current study, we found that macropinocytosis inhibitors significantly suppressed SARS-CoV-2 infection at both the entry and viral spike-mediated cell-to-cell fusion steps. We demonstrated that SARS-CoV-2 entry required the small GTPase Rac1 and its effector kinase p21-activated kinase 1 by dominant-negative and RNAi assays in human embryonic kidney 293T-angiotensin-converting enzyme 2 cells and that the serine protease transmembrane serine protease 2 reversed the decrease in SARS-CoV-2 entry caused by the macropinocytosis inhibitors. Moreover, in the cell-to-cell fusion assay, we confirmed that macropinocytosis inhibitors significantly decreased viral spike-mediated cell-to-cell fusion. Overall, we provided evidence that SARS-CoV-2 utilizes a macropinocytosis pathway to enter target cells and to efficiently promote viral spike-mediated cell-to-cell fusion.

Neuropilin-1 Facilitates Pseudorabies Virus Replication and Viral Glycoprotein B Promotes Its Degradation in a Furin-Dependent Manner.

Pseudorabies virus (PRV), which is extremely infectious and can infect numerous mammals, has a risk of spillover into humans. Virus-host interactions determine viral entry and spreading. Here, we showed that neuropilin-1 (NRP1) significantly potentiates PRV infection. Mechanistically, NRP1 promoted PRV attachment and entry, and enhanced cell-to-cell fusion mediated by viral glycoprotein B (gB), gD, gH, and gL. Furthermore, through in vitro coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC) assays, NRP1 was found to physically interact with gB, gD, and gH, and these interactions were C-end Rule (CendR) motif independent, in contrast to currently known viruses. Remarkably, we illustrated that the viral protein gB promotes NRP1 degradation via a lysosome-dependent pathway. We further demonstrate that gB promotes NRP1 degradation in a furin-cleavage-dependent manner. Interestingly, in this study, we generated gB furin cleavage site (FCS)-knockout PRV (Δfurin PRV) and evaluated its pathogenesis; in vivo, we found that Δfurin PRV virulence was significantly attenuated in mice. Together, our findings demonstrated that NRP1 is an important host factor for PRV and that NRP1 may be a potential target for antiviral intervention. IMPORTANCE Recent studies have shown accelerated PRV cross-species spillover and that PRV poses a potential threat to humans. PRV infection in humans always manifests as a high fever, tonic-clonic seizures, and encephalitis. Therefore, understanding the interaction between PRV and host factors may contribute to the development of new antiviral strategies against PRV. NRP1 has been demonstrated to be a receptor for several viruses that harbor CendR, including SARS-CoV-2. However, the relationships between NRP1 and PRV are poorly understood. Here, we found that NRP1 significantly potentiated PRV infection by promoting PRV attachment and enhanced cell-to-cell fusion. For the first time, we demonstrated that gB promotes NRP1 degradation via a lysosome-dependent pathway. Last, in vivo, Δfurin PRV virulence was significantly attenuated in mice. Therefore, NRP1 is an important host factor for PRV, and NRP1 may be a potential target for antiviral drug development.

Management of fear and anxiety in dental treatments: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: This systematic review was to compare the effects of interventions for the management of fear and anxiety for dental treatments. METHODS: This research project was applied to PubMed, CENTRAL, Web of Science, Cochrane library databases. The last search was run on March 31st, 2021. A list of references of relevant articles and previous reviews were checked. Qualitative and quantitative analyses were performed. RESULTS: A total of 20 eligible randomized controlled trials were included, and 969 participations in experimental group and 892 participations in the control group were involved. Anxiety levels decreased more in intervention groups than in control groups (Z = 3.47, P = 0.0005, SMD = - 0.62, 95% CI - 0.98 to - 0.27). For adults, there was statistical difference between experimental and control groups [Z = 2.14, P = 0.03, 95% CI - 0.54 (- 1.03, - 0.04)], while there was not no such statistical difference in children and adolescents [Z = 1.62, P = 0.11, 95% CI - 0.60 (- 1.32, 0.13)]. Patients experienced a significant decrease in anxiety level using sedation drugs [Z = 2.44, P = 0.01, 95% CI - 0.61 (- 1.10, - 0.12)] and audio-visual distractions [Z = 3.1, P = 0.002, 95% CI - 0.86 (- 1.40, - 0.32)]. For the informative intervention groups, patients did not show significant difference than control groups [Z = 1.22, P = 0.22, 95% CI - 0.55 (- 1.43, 0. 33)]. There was no statistical difference in vital signs [Z = 1.39, P = 0.16, 95% CI - 0.25 (- 0.61, 0.10)] and pain levels [Z = 0.69, P = 0.49; SMD = - 0.06, 95% CI (0.27, 0.11)] between intervention and control groups. CONCLUSIONS: Interventions should be used in managing anxiety and fear for dental treatment. It might be effective for anxiety alleviating for adults, but there was a low certainty of evidence that interventions could reduce anxiety level in children and adolescents. Sedation drugs and audio-visual distractions might be useful for managing dental fear and anxiety. Pain levels and vital signs could not be improved form our study. High-quality randomized clinical trials are required for further study.

Evaluating angiotensin-converting enzyme 2-mediated SARS-CoV-2 entry across species.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic represents a global threat, and the interaction between the virus and angiotensin-converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, is a key determinant of the range of hosts that can be infected by the virus. However, the mechanisms underpinning ACE2-mediated viral entry across species remains unclear. Using infection assay, we evaluated SARS-CoV-2 entry mediated by ACE2 of 11 different animal species. We discovered that ACE2 of Rhinolophus sinicus (Chinese rufous horseshoe bat), Felis catus (domestic cat), Canis lupus familiaris (dog), Sus scrofa (wild pig), Capra hircus (goat), and Manis javanica (Malayan pangolin) facilitated SARS-CoV-2 entry into nonsusceptible cells. Moreover, ACE2 of the pangolin also mediated SARS-CoV-2 entry, adding credence to the hypothesis that SARS-CoV-2 may have originated from pangolins. However, the ACE2 proteins of Rhinolophus ferrumequinum (greater horseshoe bat), Gallus gallus (red junglefowl), Notechis scutatus (mainland tiger snake), or Mus musculus (house mouse) did not facilitate SARS-CoV-2 entry. In addition, a natural isoform of the ACE2 protein of Macaca mulatta (rhesus monkey) with the Y217N mutation was resistant to SARS-CoV-2 infection, highlighting the possible impact of this ACE2 mutation on SARS-CoV-2 studies in rhesus monkeys. We further demonstrated that the Y217 residue of ACE2 is a critical determinant for the ability of ACE2 to mediate SARS-CoV-2 entry. Overall, these results clarify that SARS-CoV-2 can use the ACE2 receptors of multiple animal species and show that tracking the natural reservoirs and intermediate hosts of SARS-CoV-2 is complex.

Fabrication of Multilayered Biofunctional Material with an Enamel-like Structure.

The oral cavity is an environment with diverse bacteria; thus, antibacterial materials are crucial for treating and preventing dental diseases. There is a high demand for materials with an enamel-like architecture because of the high failure rate of dental restorations, due to the physical differences between dental materials and enamel. However, recreating the distinctive apatite composition and hierarchical architecture of enamel is challenging. The aim of this study was to synthesize a novel material with an enamel-like structure and antibacterial ability. We established a non-cell biomimetic method of evaporation-based bottom-up self-assembly combined with a layer-by-layer technique and introduced an antibacterial agent (graphene oxide) to fabricate a biofunctional material with an enamel-like architecture and antibacterial ability. Specifically, enamel-like graphene oxide-hydroxyapatite crystals, formed on a customized mineralization template, were assembled into an enamel-like prismatic structure with a highly organized orientation preferentially along the c-axis through evaporation-based bottom-up self-assembly. With the aid of layer-by-layer absorption, we then fabricated a bulk macroscopic multilayered biofunctional material with a hierarchical enamel-like architecture. This enamel-inspired biomaterial could effectively resolve the problem in dental restoration and brings new prospects for the synthesis of other enamel-inspired biomaterials.

Effects of graphene oxide and graphene quantum dots on enhancing CPP-ACP anti-caries ability of enamel lesion in a biofilm-challenged environment.

OBJECTIVE: To investigate the anticaries effects of graphene oxide (GO) and graphene quantum dots (GQDs) combined with casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on enamel in a biofilm-challenged environment. MATERIAL AND METHODS: GO and GQDs were synthesised using citric acid. The antibiofilm and biofilm inhibition effects for Streptococcus mutans were evaluated by scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and colony-forming units (CFU). Remineralisation ability was determined by assessing mineral loss, calcium-to-phosphorus ratio, and surface morphology. To create a biofilm-challenged environment, enamel blocks were immersed in S. mutans to create the lesion and then subjected to artificial saliva/biofilm cycling for 7 days. Anticaries effects of GO, GQDs, GQDs@CPP-ACP, GO@CPP-ACP, and CPP-ACP were determined by broth pH and mineral changes after 7-day pH cycling. Biocompatibility was tested using a Cell Counting Kit-8 (CCK8) assay for human gingival fibroblasts (HGF-1). RESULTS: GQDs and GO presented significant antibiofilm and biofilm inhibition effects compared to the CPP-ACP and control groups (P < 0.05). The enamel covered by GQDs and GO showed better crystal structure formation and less mineral loss (P < 0.05) than that covered by CPP-ACP alone. After 7 days in the biofilm-challenged environment, the GO@CPP-ACP group showed less lesion depth than the CPP-ACP and control groups (P < 0.05). GO and GQDs showed good biocompatibility compared to the control group by CCK8 (P > 0.05) within 3 days. CONCLUSION: GO and GQDs could improve the anti-caries effects of CPP-ACP, and CPP-ACP agents with GO or GQDs could be a potential option for enamel lesion management. CLINICAL SIGNIFICANCE: GO and GQDs have demonstrated the potential to significantly enhance the anticaries effects of CPP-ACP. Incorporating these nanomaterials into CPP-ACP formulations could provide innovative and effective options for the management of enamel lesions, offering improved preventive and therapeutic strategies in dental care.

Effects of T2DM on cancer progression: pivotal precipitating factors and underlying mechanisms.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting people worldwide. It is characterized by several key features, including hyperinsulinemia, hyperglycemia, hyperlipidemia, and dysbiosis. Epidemiologic studies have shown that T2DM is closely associated with the development and progression of cancer. T2DM-related hyperinsulinemia, hyperglycemia, and hyperlipidemia contribute to cancer progression through complex signaling pathways. These factors increase drug resistance, apoptosis resistance, and the migration, invasion, and proliferation of cancer cells. Here, we will focus on the role of hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with T2DM in cancer development. Additionally, we will elucidate the potential molecular mechanisms underlying their effects on cancer progression. We aim to identify potential therapeutic targets for T2DM-related malignancies and explore relevant directions for future investigation.

An enamel-inspired bioactive material with multiscale structure and antibacterial adhesion property.

Conventional dental materials lack of the hierarchical architecture of enamel that exhibits excellent intrinsic-extrinsic mechanical properties. Moreover, restorative failures frequently occur due to physical and chemical mismatch between artificial materials and native dental hard tissue followed by recurrent caries which is caused by sugar-fermenting, acidogenic bacteria invasion of the defective cite. In order to resolve the limitations of the conventional dental materials, the aim of this study was to establish a non-cell-based biomimetic strategy to fabricate a novel bioactive material with enamel-like structure and antibacterial adhesion property. The evaporation-based, bottom-up and self-assembly method with layer-by-layer technique were used to form a large-area fluorapatite crystal layer containing antibacterial components. The multilayered structure was constructed by hydrothermal growth of the fluorapatite crystal layer and highly conformal adsorption to the crystal surface of a polyelectrolyte matrix film. Characterization and mechanical assessment demonstrated that the synthesized bioactive material resembled the native enamel in chemical components, mechanical properties and crystallographic structure. Antibacterial and cytocompatibility evaluation demonstrated that this material had the antibacterial adhesion property and biocompatibility. In combination with the molecular dynamics simulations to reveal the effects of variables on the crystallization mechanism, this study brings new prospects for the synthesis of enamel-inspired materials.

Synthesis of a graphene oxide/agarose/hydroxyapatite biomaterial with the evaluation of antibacterial activity and initial cell attachment.

Various materials are used in bone tissue engineering (BTE). Graphene oxide (GO) is a good candidate for BTE due to its antibacterial activity and biocompatibility. In this study, an innovative biomaterial consists of GO, agarose and hydroxyapatite (HA) was synthesized using electrophoresis system. The characterization of the synthesized biomaterial showed that needle-like crystals with high purity were formed after 10 mA/10 h of electrophoresis treatment. Furthermore, the calcium-phosphate ratio was similar to thermodynamically stable HA. In the synthesized biomaterial with addition of 1.0 wt% of GO, the colony forming units test showed significantly less Staphylococcus aureus. Initial attachment of MC3T3-E1 cells on the synthesized biomaterial was observed which showed the safety of the synthesized biomaterial for cell viability. This study showed that the synthesized biomaterial is a promising material that can be used in BTE.

Senecavirus A Entry Into Host Cells Is Dependent on the Cholesterol-Mediated Endocytic Pathway.

Senecavirus A (SVA), an important member of the Picornaviridae family, causes vesicular disease in pigs. Here, we generated an EGFP-expressing recombinant SVA re-SVA-EGFP, which exhibited similar growth kinetics to its parental virus. The reporter SVA was used to study the role of pig ANTXR1 (pANTXR1) in SVA infection in a porcine alveolar macrophage cell line (PAM-Tang cells). Knockdown of the pANTXR1 significantly reduced SVA infection and replication in PAM-Tang cells, while re-expression of the pANTXR1 promoted the cell susceptibility to SVA infection. The results indicated that pANTXR1 is a crucial receptor mediating SVA infection. Subsequently, the viral endocytosis pathways for SVA entry into pig cells were investigated and the results showed that cholesterol played an essential role in receptor-mediated SVA entry. Together, these results demonstrated that SVA entered into host cells through the pANTXR1-mediated cholesterol pathway. Our findings provide potential targets to develop antiviral drugs for the prevention of SVA infection in the pig population.

CRISPR-Cas13d Exhibits Robust Antiviral Activity Against Seneca Valley Virus.

In recent years, Seneca Valley virus (SVV) as a newly identified pathogen of porcine vesicular disease spread quickly and has posed a potential threat to the swine industry in several countries resulting in economic losses. Considering the evolution of SVV, attention should be given to controlling SVV epidemics. So far there are no commercial vaccines or drugs available to combat SVV. Therefore, development of strategies for preventing and controlling SVV infection should be taken into account. In the current study, we evaluated whether the CRISPR-Cas13d system could be used as a powerful tool against SVV infection. Besides, selected crRNAs showed different capacity against SVV infection. Our study suggests the CRISPR-Cas13d system significantly inhibited SVV replication and exhibited potent anti-SVV activity. This knowledge may provide a novel alternative strategy to control epidemics of SVV in the future.

A Nomogram to Predict the Risk of Stent Dysfunction After TIPS in Patients with Hepatitis B Cirrhosis.

RATIONALE AND OBJECTIVES: To develop and validate a nomogram for the prediction of stent dysfunction after transjugular intrahepatic portosystemic shunt (TIPS) placement in patients with hepatitis B cirrhosis. MATERIALS AND METHODS: From 2012 to 2020, 355 patients with hepatitis B cirrhosis who underwent TIPS placements were enrolled in this study. A multivariable logistic regression analysis was applied to determine independent risk factors for the nomogram construction. Discrimination, calibration, and clinical usefulness of the prediction model were assessed by using receiver operating characteristic curves, calibration scatter plots, and a decision curve analysis (DCA). RESULTS: Independent factors for TIPS stent dysfunction included diabetes, previous splenectomy, the shunting branch of the portal vein, and stent position, which were used to construct the nomogram. The AUC values in the training and validation cohorts were 0.817 (95% CI: 0.731-0.903) and 0.804 (95% CI: 0.673-0.935), respectively, which suggested a good predictive ability. The calibration curves in both cohorts revealed good agreement between the predictions and actual observations. The DCA curve indicated that when the threshold probability ranged from 2% to 88%, the nomogram could provide clinical usefulness and a net benefit. CONCLUSION: The nomogram that we developed could be conveniently used to predict TIPS stent dysfunction in patients with hepatitis B cirrhosis.

Electrophoresis-Aided Biomimetic Mineralization System Using Graphene Oxide for Regeneration of Hydroxyapatite on Dentin.

Graphene oxide (GO) is an emerging luminescent carbon nanomaterial with the ability to foster hydroxyapatite (HA). A specially designed electrophoresis system can be used to accelerate the mineralization process. The aim of this study was to promote HA crystal growth on demineralized dentin using a GO incorporated electrophoresis system. GO was successfully synthesized by carbonization of citric acid and its presence was confirmed by Fourier transform infrared and UV-visible spectrophotometry evaluation. Dentin slices were placed in demineralized solution and divided into control (without the electrophoresis system) and experimental group. Demineralized dentin slices in the experimental group were remineralized using the electrophoresis system for 8 h/1.0 mA, with one subgroup treated without GO and the other with GO. Energy dispersive spectroscopy evaluation showed that the calcium/phosphate ratio of the crystal formed in control and experimental group with addition of GO was close to natural hydroxyapatite. However, scanning electron microscopy evaluation showed that the exposed dentinal tubules were occluded with rod-like crystals, which is similar to native enamel morphology, in the experimental group with addition of GO compared to the flake-like crystal in the control group. Mechanical evaluation revealed that the nanohardness and modulus of remineralized dentin were significantly higher in the experimental group. In conclusion, GO is a promising material to remineralize dentin and the introduction of an electrophoresis system can accelerate its process.

Clinical Characteristics and Long-Term Prognosis of Elderly Valvular Heart Disease Patients with Diabetes Mellitus: Five-Year Experience from a Single-Center Study of Southern China.

BACKGROUND: Diabetes mellitus (DM) is a prognostic marker in elderly patients with cardiovascular diseases, but its predictive value in elderly valvular heart disease (VHD) patients is unclear. This study aimed to investigate the effect of DM on the long-term outcome of elderly VHD patients. METHODS: This single-center, observational study enrolled patients aged 65 and older consecutively with confirmed VHD using echocardiography. Patients, divided into the DM group and non-DM group, were followed up for major adverse cardiac and cerebrovascular events (MACCEs), including all-cause death, ischemic stroke, and heart failure rehospitalization. RESULTS: Our study consisted of 532 patients over a median follow-up of 52.9 months. Compared with the non-DM group (n = 377), the DM group (n = 155) had higher incidences of ischemic stroke (25.2% vs. 13.5%, P=0.001), heart failure rehospitalization (37.4% vs. 20.7%, P < 0.001), and MACCEs (60.0% vs. 35.8%, P < 0.001). After adjustment of confounders by the multivariable cox regression, DM appeared as an independent predictor for MACCEs (adjusted hazard ratio, aHR: 1.88; 95% confidence interval 1.42-2.48; P < 0.001). In the subgroup analysis of VHD etiology and functional style, conversely, DM was a protective factor for MACCEs in the patients with rheumatic VHD compared with those without rheumatic VHD (aHR: 0.43 vs. 2.27, P=0.004). CONCLUSIONS: DM was an independent predictor for ischemic stroke and heart failure rehospitalization in elderly VHD patients undergoing conservative treatment.

Dental fear association between mothers and adolescents-a longitudinal study.

AIM: To assess the longitudinal association between adolescents' and their mothers' dental fear. STUDY DESIGN: A longitudinal questionnaire survey study. METHODS: A randomized sample of 12-year-old adolescents were selected from local Hong Kong schools. Adolescents and their mothers self-completed the Modified Dental Anxiety Scale (MDAS). The sociodemographic background of the mothers and the oral health habits of the adolescents were also collected and these measurements were repeated at 15- and 18-years-old. Non-parametric tests (Mann-Whitney U test/Kruskall Wallis test) were used to test associations between MDAS dental fear items and independent variables. Logistic regression (adjusted for family's sociodemographic background and adolescent's oral health habits) was performed to evaluate the longitudinal association between adolescents' and mothers' dental fear. RESULTS: A total of 212 mother-child pairs were recruited at baseline (12-year-old adolescents). In the first and second follow-ups (15- and 18-years-old), 195 and 182 mother-child pairs completed the survey. Significant associations between mother's and child's scores in "feeling about having their teeth scraped and polished", "having teeth drilled", and 'having an injection in the gum' were found when adolescents were 12- years-old (P < 0.01) and 18-years-old (P < 0.05), but not at 15-years-old. CONCLUSION: Adolescents' and mothers' dental fear is associated at 12-years-old and 18-years-old, but not at 15-years-old, which is likely specific to the Hong Kong context but may be extrapolated to other industrialized countries with caution.

Constructing an Antibiofouling and Mineralizing Bioactive Tooth Surface to Protect against Decay and Promote Self-Healing.

Numerous methods have been investigated to manage dental caries, one of the top three diseases threatening human health as reported by the World Health Organization. An innovative strategy was proposed to prevent dental caries and achieve self-healing of the decayed tooth, and a novel bioactive peptide was designed and synthesized to construct an antibiofouling and mineralizing dual-bioactive tooth surface. Compared to its original endogenous peptide, the synthesized bioactive peptide showed statistically significantly higher binding affinity to the tooth surface, stronger suppression of demineralization, and a certain promotion of tooth remineralization. The abilities of the peptide to inhibit Streptococcus mutans (S. mutans) biofilm formation and S. mutans adhesion on the tooth surface were not affected after synthesis. Biocompatibility tests revealed the safety of the synthesized bioactive peptide. Interaction mechanisms between the synthesized bioactive peptide and tooth surface were also explained by molecular dynamic simulation analysis. In summary, the synthesized bioactive peptide could be applied safely to prevent dental caries and effectively induce in situ self-healing remineralization for treatment of the decayed tooth.

Repair of dentine-related lesions without a drill or injection.

For covering the shortages of traditional treatments, a novel and non-invasive system was developed with the simple adaption of nature's own repair process, while an extrinsic electric field was introduced to improve its remineralization kinetics. In an in vivo study, acid-etched rabbit dentine was used to evaluate the remineralization efficacy and safety of the system. The exposed dentine tubules were fully occluded after 5 hours/1.0 mA and 8 hours/0.5 mA of remineralization. After 5 hours of remineralization (1.0 mA), the micro-hardness of the demineralized dentine was fully recovered, equal to native rabbit dentine. Haematoxylin-eosin staining demonstrated no obvious inflammatory reaction. This study provides a feasible solution to realize rapid repair of dentine.