Microenvironment Responsive Hydrogel Exerting Inhibition of Cascade Immune Activation and Elimination of Synovial Fibroblasts for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.

A novel treatment modality for rheumatoid arthritis: Inflammation-targeted multifunctional metal-organic frameworks with synergistic phototherapy and chemotherapy.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease with complex pathogenesis. Single chemotherapy struggles to eliminate the disease permanently and reduce the pain owing to drug resistance and inadequate delivery to target cells. This study developed hyaluronic acid (HA)-modified and methotrexate (MTX)-load metal-organic frameworks (denoted as FT-HA-MTX NPs), combining photothermal therapy (PTT), photodynamic therapy (PDT), and chemotherapy to inhibit the progression of RA. In vitro experiments proved that the obtained NPs exhibited good biocompatibility and commendable photothermal conversion efficiency of 36.3 %. Additionally, they promoted ∙OH and O2 production via the Fenton reaction, which dramatically alleviated hypoxia and enhanced ROS generation, and induced substantial mortality in activated RAW 264.7 cells, with cell viability of 31.72 %. Cellular uptake and in vivo imaging confirmed that the modification of HA enabled the NPs to specifically target activated macrophage, ensured prolonged retention of NPs in inflamed synovial tissues, and reduced systemic toxicity. In vivo, after FT-HA-MTX NPs treatment with laser irradiation, the levels of TNF-α and IL-1ß in the synovial tissue were reduced by approximately 50 % compared to those in the inflamed synovium, demonstrating a significant enhancement in the anti-inflammatory effect (p < 0.001). In conclusion, FT-HA-MTX NPs are promising inflammation-targeted multifunctional nanoparticles that combine PTT, PDT, and chemotherapy, thereby significantly inhibiting the progression of RA while reducing systemic toxicity.

Automatic planning of maxillary anterior dental implant based on prosthetically guided and pose evaluation indicator.

PURPOSE: Preoperative planning of maxillary anterior dental implant is a prerequisite to ensuring that the implant achieves the proper three-dimensional (3D) pose, which is essential for its long-term stability. However, the current planning process is labor-intensive and subjective, relying heavily on the surgeon's experience. Consequently, this paper proposes an automatic method for computing the optimal pose of the dental implant. METHODS: The method adopts the principle of prosthetically guided dental implant placement. Initially, the prosthesis coordinate system is established to determine the implant candidate orientations. Subsequently, virtual slices of the maxilla in the buccal-palatal direction are generated according to the prosthesis position. By extracting feature points from the virtual slices, the implant candidate starting points are acquired. Then, a candidate pose set is obtained by combining these candidate starting points and orientations. Finally, a pose evaluation indicator is introduced to determine the optimal implant pose from this set. RESULTS: Twenty-two cases were utilized to validate the method. The results show that the method could determine an ideal pose for the dental implant, with the average minimum distance between the implant and the left tooth root, the right tooth root, the palatal side, and the buccal side being 2.57 ± 0.53 mm, 2.59 ± 0.65 mm, 0.74 ± 0.19 mm, 1.83 ± 0.16 mm, respectively. The planning time was less than 9 s. CONCLUSION: Unlike manual planning, the proposed method can efficiently and accurately complete maxillary anterior dental implant planning, providing a theoretical analysis of the success rate of the implant. Thus, it has great potential for future clinical application.

Learning curve of dynamic navigation-assisted zygomatic implant surgery: An in vitro study.

STATEMENT OF PROBLEM: Dynamic computer-assisted zygomatic implant surgery (dCAZIS) has been reported to provide clinical efficacy with high accuracy and low risk of complications. However, the learning curve before performing dCAZIS effectively is unknown. PURPOSE: The purpose of this in vitro study was to explore the learning curve of dCAZIS in dentists with different levels of experience in implant dentistry and navigation surgery. MATERIAL AND METHODS: Six senior dental students were randomly divided into 3 groups for initial training (FH-CI group: pretraining on freehand conventional implant surgery; FH-ZI group: pretraining on freehand ZI surgery; DN-CI group: pretraining on conventional implant surgery under dynamic navigation). Then, every operator conducted 6 repeated dCAZIS training sessions on edentulous 3-dimensional (3D) printed skull models and was asked to complete a self-report questionnaire after each training session. A total of 36 postoperative cone beam computed tomography (CBCT) scans with 144 ZI osteotomy site preparations were obtained and superimposed over the preoperative design for accuracy measurements. The operation time, 3D deviations, and results of the self-reports were recorded. Comparisons among groups were analyzed with independent-sample Kruskal-Wallis tests (α=.05), and correlations between study outcomes and the number of practices were calculated. RESULTS: Operator experience and increased practice times did not significantly affect the accuracy of dCAZIS (P>.05). However, the operation time varied among groups (P<.001), and significantly shortened with more practice, reaching 11.51 ±1.68 minutes at the fifth attempt in the FH-CI group (P<.001 compared with the first practice), 14.48 ±3.07 minutes at the third attempt in the FH-ZI group (P=.038), and 8.68 ±0.58 minutes at the sixth attempt in the DN-CI group (P<.001). All groups reached their own learning curve plateau stage within 6 practice sessions. As the number of practice sessions increased, the results from the self-report questionnaires gradually improved. CONCLUSIONS: Among dentists with different levels of experience in implant dentistry and navigation surgery, dCAZIS was found to have a learning curve with respect to operation time but not implant accuracy. Experience in ZI surgery had little impact on the learning curve of dCAZIS, but experience in navigation surgery was a key factor.

A new approach for vertical bone augmentation: Reconstructing bony peaks before GBR with a customized titanium mesh.

This image article presents a single patient receiving a reconstructed fibular bony peak (BP) for guided bone regeneration (GBR) with a customized titanium mesh. The patient was informed and understood the objectives and signed a written informed consent document before surgery.

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.

Identification of a novel de novo mutation in SOX4 for syndromic tooth agenesis.

OBJECTIVES: Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms. MATERIALS AND METHODS: We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4. RESULTS: A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing. CONCLUSIONS: Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis. CLINICAL RELEVANCE: This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.

Comparison of self-efficacy among graduate teaching assistants before and after training.

BACKGROUND: Teaching assistants (TAs) play a crucial role in pedagogical practices, and the TA training has emerged as a vital strategy for enhancing teaching quality and fostering effective interactions. The self-efficacy of TAs can substantially impact their performance. Nevertheless, little research has focused on the change in TAs' self-efficacy following their training. METHODS: A self-control quasi-experiment was conducted to examine shifts in the self-efficacy of Tas at Peking University before and after their TA training. A questionnaire was used to assess the change, and the reliability and validity of the questionnaire was also calculated. A paired data rank sum test was used to analysis the changes in TA self-efficacy before and after training. RESULTS: A total of 372 TAs from School of Basic Medicine (N = 173), School of Pharmacy (N = 112), School of Public Health (N = 69), and other schools (N = 18) submitted complete questionnaires. The questionnaire showed a good performance in internal reliability and validity test (Cronbach's alpha index = 0.906, and KMO value was 0.903). Participants had a median total self-efficacy score of 88 and 85 before and after the TA training, respectively, which shows a lack in the total TA self-efficacy score following the TA training (P < 0.001). TAs who have no desire to becoming a college instructor have a higher self-efficacy when compared to TAs who have expressed neutral attitudes in becoming college instructors. CONCLUSION: The participated TAs display a lack of self-efficacy after attending the TA training at Peking University. Therefore, it is necessary to establish and strengthen TA's self-efficacy beyond academic skills when designing and delivering TA training programs at Peking University.

Influence of a mesial cantilever on stress, strain, and axial force in fixed partial dentures with a distally tilted implant in the atrophic posterior maxilla.

PURPOSE: This study aimed to investigate whether the presence of a mesial cantilever influences the biomechanical behavior and screw loosening in fixed partial dentures (FPDs) with a distally tilted implant in the atrophic posterior maxilla and where to best place the distal implant. METHODS: Two configurations of implant-supported four-unit FPDs were modelled using finite element analysis. Five interabutment distances were considered. The stress and strain distributions in the implants, abutments, and prosthetic screws were verified under occlusal loading. The development of the axial force on the abutments and screws was also examined. Two-sample t-tests were used to identify differences (P < 0.05). RESULTS: The von Mises stress distributions of the components in the two configurations were similar, as were the maximum plastic strains of the distal prosthetic screws, distal implants, and 30° abutments. The difference in the maximum plastic strains of the straight abutments was statistically significant. The preload of the 30° abutment screws was significantly reduced after the initial loading. In the absence of a mesial cantilever, the axial force on the straight abutments increased. However, when a mesial cantilever was used, the preload of the straight abutments was maintained, and the axial force on the prosthetic screws fluctuated less. The axial force fluctuation of the abutments gradually decreased as the interabutment distance increased. CONCLUSIONS: Mesial cantilever usage had minimal effect on stress or strain distribution in FPD implants, abutments, or prostheses. However, it helped resist screw loosening. The distal screw access hole was preferably positioned close to the prosthetic end.

A hybrid robotic system for zygomatic implant placement based on mixed reality navigation.

BACKGROUNDS: Zygomatic implant (ZI) placement surgery is a viable surgical option for patients with severe maxillary atrophy and insufficient residual maxillary bone. Still, it is difficult and risky due to the long path of ZI placement and the narrow field of vision. Dynamic navigation is a superior solution, but it presents challenges such as requiring operators to have advanced skills and experience. Moreover, the precision and stability of manual implantation remain inadequate. These issues are anticipated to be addressed by implementing robot-assisted surgery and achieved by introducing a mixed reality (MR) navigation-guided hybrid robotic system for ZI placement surgery. METHODS: This study utilized a hybrid robotic system to perform the ZI placement surgery. Our first step was to reconstruct a virtual 3D model from preoperative cone-beam CT (CBCT) images. We proposed a series of algorithms based on coordinate transformation, which includes image-phantom registration, HoloLens-tracker registration, drill-phantom calibration, and robot-implant calibration, to unify all objects within the same coordinate system. These algorithms enable real-time tracking of the surgical drill's position and orientation relative to the patient phantom. Subsequently, the surgical drill is directed to the entry position, and the planned implantation paths are superimposed on the patient phantom using HoloLens 2 for visualization. Finally, the hybrid robot system performs the processed of drilling, expansion, and placement of ZIs under the guidance of the MR navigation system. RESULTS: Phantom experiments of ZI placement were conducted using 10 patient phantoms, with a total of 40 ZIs inserted. Out of these, 20 were manually implanted, and the remaining 20 were robotically implanted. Comparisons between the actual implanted ZI paths and the preoperatively planned ZI paths showed that our MR navigation-guided hybrid robotic system achieved a coronal deviation of 0.887 ± 0.213 mm, an apical deviation of 1.201 ± 0.318 mm, and an angular deviation of 3.468 ± 0.339° This demonstrates significantly better accuracy and stability than manual implantation. CONCLUSION: Our proposed hybrid robotic system enables automated ZI placement surgery guided by MR navigation, achieving greater accuracy and stability compared to manual operations in phantom experiments. Furthermore, this system is expected to apply to animal and cadaveric experiments, to get a good ready for clinical studies.

Comparison of the accuracy of dental implant placement using dynamic and augmented reality-based dynamic navigation: An in vitro study.

Background/purpose: Augmented reality has been gradually applied in dental implant surgery. However, whether the dynamic navigation system integrated with augmented reality technology will further improve the accuracy is still unknown. The purpose of this study is to investigate the accuracy of dental implant placement using dynamic navigation and augmented reality-based dynamic navigation systems. Materials and methods: Thirty-two cone-beam CT (CBCT) scans from clinical patients were collected and used to generate 64 phantoms that were allocated to the augmented reality-based dynamic navigation (ARDN) group or the conventional dynamic navigation (DN) group. The primary outcomes were global coronal, apical and angular deviations, and they were measured after image fusion. A linear mixed model with a random intercept was used. A P value < 0.05 was considered to indicate statistical significance. Results: A total of 242 dental implants were placed in two groups. The global coronal, apical and angular deviations of the ARDN and DN groups were 1.31 ± 0.67 mm vs. 1.18 ± 0.59 mm, 1.36 ± 0.67 mm vs. 1.39 ± 0.55 mm, and 3.72 ± 2.13° vs. 3.1 ± 1.56°, respectively. No significant differences were found with regard to coronal and apical deviations (P = 0.16 and 0.6, respectively), but the DN group had a significantly lower angular deviation than the ARDN group (P = 0.02). Conclusion: The augmented reality-based dynamic navigation system yielded a similar accuracy to the conventional dynamic navigation system for dental implant placement in coronal and apical points, but the augmented reality-based dynamic navigation system yielded a higher angular deviation.

Detecting Gene-Gene Interaction among DNA Repair Genes in Chinese non-Syndromic Cleft lip with or Without Palate Trios.

OBJECTIVE: The objective of this study is to investigate the gene-gene interactions associated with NSCL/P among DNA repair genes. DESIGN: This study included 806 NSCL/P case-parent trios from China. Quality control process was conducted for genotyped single nucleotide polymorphisms (SNPs) located in six DNA repair genes (ATR, ERCC4, RFC1, TYMS, XRCC1 and XRCC3). We tested gene-gene interactions with Cordell's method using statistical package TRIO in R software. Bonferroni corrected significance level was set as P = 4.24 × 10-4. We also test the robustness of the interactions by permutation tests. SETTING: Not applicable. PATIENTS/PARTICIPANTS: A total of 806 NSCL/P case-parent trios (complete trios: 682, incomplete trios: 124) with Chinese ancestry. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Not applicable. RESULTS: A total of 118 SNPs were extracted for the interaction tests. Fourteen pairs of significant interactions were identified after Bonferroni correction, which were confirmed in permutation tests. Twelve pairs were between ATR and ERCC4 or XRCC3. The most significant interaction occurred between rs2244500 in TYMS and rs3213403 in XRCC1(P = 8.16 × 10-15). CONCLUSIONS: The current study identified gene-gene interactions among DNA repair genes in 806 Chinese NSCL/P trios, providing additional evidence for the complicated genetic structure underlying NSCL/P. ATR, ERCC4, XRCC3, TYMS and RFC1 were suggested to be possible candidate genes for NSCL/P.

[Association between insomnia and type 2 diabetes: A two-sample Mendelian rando-mization study].

OBJECTIVE: To explore the robust relationship between insomnia and type 2 diabetes mellitus by two-sample Mendelian randomization analysis to overcome confounding factors and reverse causality in observational studies. METHODS: We identified strong, independent single nucleotide polymorphisms (SNPs) of insomnia from the most up to date genome wide association studies (GWAS) within European ancestors and applied them as instrumental variable to GWAS of type 2 diabetes mellitus. After excluding SNPs that were significantly associated with smoking, physical activity, alcohol consumption, educational attainment, obesity, or type 2 diabetes mellitus, we assessed the impact of insomnia on type 2 diabetes mellitus using inverse variance weighting (IVW) method. Weighted median and MR-Egger regression analysis were also conducted to test the robustness of the association. We calculated the F statistic of the selected SNPs to test the applicability of instrumental variable and F statistic over than ten indicated that there was little possibility of bias of weak instrumental variables. We further examined the existence of pleiotropy by testing whether the intercept term in MR-Egger regression was significantly different from zero. In addition, the leave-one-out method was used for sensitivity analysis to verify the stability and reliability of the results. RESULTS: We selected 248 SNPs independently associated with insomnia at the genome-wide level (P<5×10-8) as a preliminary candidate set of instrumental variables. After clumping based on the reference panel from 1000 Genome Project and removing the potential pleiotropic SNPs, a total of 167 SNPs associated with insomnia were included as final instrumental variables. The F statistic of this study was 39. 74, which was in line with the relevance assumption of Mendelian randomization. IVW method showed insomnia was associated with higher risk of type 2 diabetes mellitus that po-pulation with insomnia were 1. 14 times more likely to develop type 2 diabetes mellitus than those without insomnia (95% CI: 1.09-1.21, P<0.001). The weighted median estimator (WME) method and MR-Egger regression showed similar causal effect of insomnia on type 2 diabetes mellitus. And MR-Egger regression also showed that the effect was less likely to be triggered by pleiotropy. Sensitivity analyses produced directionally similar estimates. CONCLUSION: Insomnia is a risk factor of type 2 diabetes mellitus, which has positively effects on type 2 diabetes mellitus. Our study provides further rationale for indivi-duals at risk for diabetes to keep healthy lifestyle.

Eight EDA mutations in Chinese patients with tooth agenesis and genotype-phenotype analysis.

OBJECTIVE: Tooth agenesis is a common craniofacial malformation, which is often associated with gene mutations. The purpose of this research was to investigate and uncover ectodysplasin A (EDA) gene variants in eight Chinese families affected with tooth agenesis. METHODS: Genomic DNA was extracted from tooth agenesis families and sequenced using whole-exome sequencing. The expression of ectodysplasin A1 (EDA1) protein was studied by western blot, binding activity with receptor was tested by pull-down and the NF-κB transcriptional activity was analyzed by Dual luciferase assay. RESULTS: Eight EDA missense variants were discovered, of which two (c.T812C, c.A1073G) were novel. The bioinformatics analysis indicated that these variants might be pathogenic. The tertiary structure analysis revealed that these eight variants could cause structural damage to EDA proteins. In vitro functional studies demonstrated that the variants greatly affect protein stability or impair the EDA-EDAR interaction; thereby significantly affecting the downstream NF-κb transcriptional activity. In addition, we summarized the genotype-phenotype correlation caused by EDA variants and found that EDA mutations leading to NSTA are mostly missense mutations located in the TNF domain. CONCLUSION: Our results broaden the variant spectrum of the EDA gene associated with tooth agenesis and provide valuable information for future genetic counseling.

Long-term survival and complications of Quad Zygoma Protocol with Anatomy-Guided Approach in severely atrophic maxilla: A retrospective follow-up analysis of up to 17 years.

INTRODUCTION: The objective of the study was to provide long-term clinical outcomes and complications in the severely atrophic edentulous maxillae treated by means of the quad zygoma protocol (QZP) using the Anatomy-Guided Approach (AGA). METHODS: This was a retrospective cohort study of all consecutive patients with severely atrophic edentulous maxilla and insufficient bone height and width in the anterior and posterior regions bilaterally, who underwent rehabilitation with the QZP between May 2006 and December 2021. All patients were followed for at least 1 year. All zygomatic implants (ZIs) were placed by the same surgeon. The primary endpoint of the study was the implant survival rate. Secondary endpoints were implant success rate, prosthesis success rate, complications, and Oral Health-Related Quality of Life using the OHIP-14 questionnaire. RESULTS: A total of 56 patients (men 16, women 40) with 224 ZIs (Nobel Biocare, n = 204; Straumann, n = 16; Southern Implant, n = 4) placement were included with a mean follow-up period 8.8 ± 3.9 years (range, 1.2-17.0). The survival (success) rate was 97.7%. Five ZIs in four patients failed. The mean time between implant placement and failure was 8.6 years (range, 0.5-13.3). All patients received immediate loading with acrylic prosthesis. The successful rates for the definitive prosthesis were 98.2%. Forty-two patients received posterior cantilever for rehabilitation of fixed definitive prosthesis. Local orofacial inflammation (35.7%) and Sinusitis (12.5%) were the most common complications, occurring at a mean follow-up of 10.0 (range, 4.2-14.9) and 10.3 (range, 4.3-16.2) years, respectively. In 48 patients, the mean score of the OHIP-14 questionnaire was 1.7 ± 2.6 with the follow-up period of 9.0 ± 4.1 years. CONCLUSIONS: The rehabilitation of severely atrophic edentulous maxilla using the QZP has shown a predictable and high survival rate in the long term. The implementation of an immediate loading protocol offers potential benefits in stabilizing ZIs with cross-arch stabilization. Moreover, the use of a posterior cantilever in reconstruction can effectively establish functional occlusion through well-distributed ZIs, eliminating the need for additional implant placement.

Effect of statin therapy patterns on readmission and mortality in patients with intracerebral hemorrhage.

There is limited and inconsistent evidence for the association of statin therapy and statin treatment patterns with the risk of recurrent intracerebral hemorrhage (ICH) in patients with prior ICH. To assess the association of statin therapy and its intensity, type, initiation time, and discontinuation with the risk of recurrent ICH and mortality in Chinese patients with ICH. Patients with newly diagnosed ICH in the Beijing Employee Medical Claims Data database from 2010 to 2017 were included. Post-ICH statin users (post-diagnosis only) and nonusers (never), statin discontinuers (pre-diagnosis only) and continuers (pre- and post-diagnosis) were matched on a 1:1 propensity score, respectively. Adjusted Cox proportional risk models were used to estimate the risk ratios for ICH readmission and mortality under various statin patterns. A total of 2668 post-ICH statin users and 2668 nonusers without a history of statin use were enrolled. Post-ICH statin users had a lower risk of ICH readmission (HR, 0.57; 95% CI 0.48, 0.69) and all-cause death (0.56: 0.49, 0.63) than nonusers. Low/moderate-intensity treatment was associated with a 63% lower risk of recurrent ICH compared with nonusers (0.37: 0.29, 0.46), whereas high-intensity treatment did not reduce the risk (0.93: 0.74, 1.16). Both low/moderate-intensity (0.42: 0.36, 0.48) and high-intensity statins (0.57: 0.48, 0.69) were associated with a lower risk of all-cause mortality. The risk of ICH readmission was 53% (0.47: 0.30, 0.74) lower with adherence to rosuvastatin than with atorvastatin. Only starting medication within 30 days of the first diagnosis of ICH reduced the risk of ICH readmission (0.49: 0.40, 0.60). Among patients with a history of statin use, 1807 discontinuing and 1,807 continuing users of statins were included. The risk of ICH readmission (4.00: 3.32, 4.80) and the risk of all-cause death (4.01: 3.57, 4.50) were substantially increased in statin discontinuation compared with continued statin use. Statin therapy after ICH was associated with lower risks for ICH readmission and all-cause mortality compared with non-statin therapy, especially at low/moderate intensity and early initiation of statins after ICH. Adherence to rosuvastatin was associated with a lower risk of recurrence of ICH than atorvastatin. Among patients with a statin history prior to ICH, discontinuation of statins after ICH was associated with increased risk of ICH recurrence and death.

Computer-assisted preoperative planning system with an automated registration method in prosthesis-driven oral implantology.

PURPOSE: Dentition defect including edentulism is a problem that deserves attention, which requires precise preoperative planning. The trajectories of the implants can be determined using a pre-made radiographic template, which is adopted for prosthesis-driven oral implantology. However, existing solutions for the registration between the radiographic template and the patient's CBCT still require manual operation and cause inadequate accuracy. In this study, a pre-operative planning system for prosthesis-driven oral implantology is developed with a novel automated registration method. METHODS: Based on threshold segmentation and morphological feature filtering, the potential feature points on two sets of CBCTs are, respectively, recognized. The distance features of the point sets are used to predict the optimal solution for point pair matching, after which the automated registration is implemented. The prosthesis-driven planning can be completed according to the results of registration and multi-planar reconstruction. Then, the surgical templates can be designed and fabricated using 3D printing technology based on the planning results and finally used for intra-operative guidance during implant placement. RESULTS: Verification of the proposed method was conducted on three clinical cases. The mean Fiducial Registration Error of 0.13 ± 0.01mm was achieved with great efficiency. The average time was 0.15 s for the automatic registration algorithm, and 15.64 s for the whole procedure. CONCLUSIONS: The proposed method proved to be accurate and robust. The results indicate that it can achieve higher efficiency while maintaining a low error level, which will have great potential clinical applications in the future.

The impact of heat waves and cold spells on pneumonia risk: A nationwide study.

Climate change affects human health and has been linked to several infectious diseases in recent year. However, there is limited assessment on the impact of heat waves and cold spells on pneumonia risk. This study aims to examine the association of heat waves and cold spells with daily pneumonia hospitalizations in 168 cities in China. Data on pneumonia hospitalizations between 2014 and 2017 were extracted from a national claim database of 280 million beneficiaries. We consider combining temperature intensity and duration to define heat waves and cold spells.This association was quantified using a quasi-Poisson generalized linear model combined with a distributed lag nonlinear model. Exposure-response curves and potential effect modifiers were also estimated. We found that the peak relative risk (RR) of cold spells on daily hospitalizations for pneumonia was observed in relatively mild cold spells with a threshold below the 3 days at the 2nd percentile (RR = 1.69, 95% CI: 1.46-1.92). The risk of heat waves increased with the thresholds, and the greatest risk was found for extremely heatwave period of 4 days at the 98th percentile (RR = 1.69, 95% CI: 1.46-1.92). Heat waves and cold spells are more likely to adversely affect women. In conclusion, our study provided novel and strong evidence that exposure to heat waves and cold spells was associate with increased hospital visits for pneumonia, especially in females. This is the first national study in China to comprehensively evaluate the influence of heat waves and cold spells on pneumonia risk, and the findings may offer valuable insights into the impact of climate change on public health.

Identification of genetic loci jointly influencing COVID-19 and coronary heart diseases.

BACKGROUND: Comorbidities of coronavirus disease 2019 (COVID-19)/coronary heart disease (CHD) pose great threats to disease outcomes, yet little is known about their shared pathology. The study aimed to examine whether comorbidities of COVID-19/CHD involved shared genetic pathology, as well as to clarify the shared genetic variants predisposing risks common to COVID-19 severity and CHD risks. METHODS: By leveraging publicly available summary statistics, we assessed the genetically determined causality between COVID-19 and CHD with bidirectional Mendelian randomization. To further quantify the causality contributed by shared genetic variants, we interrogated their genetic correlation with the linkage disequilibrium score regression method. Bayesian colocalization analysis coupled with conditional/conjunctional false discovery rate analysis was applied to decipher the shared causal single nucleotide polymorphisms (SNPs). FINDINGS: Briefly, we observed that the incident CHD risks post COVID-19 infection were partially determined by shared genetic variants. The shared genetic variants contributed to the causality at a proportion of 0.18 (95% CI 0.18-0.19) to 0.23 (95% CI 0.23-0.24). The SNP (rs10490770) located near LZTFL1 suggested direct causality (SNPs → COVID-19 → CHD), and SNPs in ABO (rs579459, rs495828), ILRUN(rs2744961), and CACFD1(rs4962153, rs3094379) may simultaneously influence COVID-19 severity and CHD risks. INTERPRETATION: Five SNPs located near LZTFL1 (rs10490770), ABO (rs579459, rs495828), ILRUN (rs2744961), and CACFD1 (rs4962153, rs3094379) may simultaneously influence their risks. The current study suggested that there may be shared mechanisms predisposing to both COVID-19 severity and CHD risks. Genetic predisposition to COVID-19 is a causal risk factor for CHD, supporting that reducing the COVID-19 infection risk or alleviating COVID-19 severity among those with specific genotypes might reduce their subsequent CHD adverse outcomes. Meanwhile, the shared genetic variants identified may be of clinical implications for identifying the target population who are more vulnerable to adverse CHD outcomes post COVID-19 and may also advance treatments of 'Long COVID-19.'

Deep learning-based automatic segmentation of bone graft material after maxillary sinus augmentation.

OBJECTIVES: To investigate the accuracy and reliability of deep learning in automatic graft material segmentation after maxillary sinus augmentation (SA) from cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: One hundred paired CBCT scans (a preoperative scan and a postoperative scan) were collected and randomly allocated to training (n = 82) and testing (n = 18) subsets. The ground truths of graft materials were labeled by three observers together (two experienced surgeons and a computer engineer). A deep learning model including a 3D V-Net and a 3D Attention V-Net was developed. The overall performance of the model was assessed through the testing data set. The comparative accuracy and inference time consumption of the model-driven and manual segmentation (by two surgeons with 3 years of experience in dental implant surgery) were conducted on 10 CBCT scans from the test samples. RESULTS: The deep learning model had a Dice coefficient (Dice) of 90.36 ± 2.53%, a 95% Hausdorff distance (HD) of 1.59 ± 0.82 mm, and an average surface distance (ASD) of 0.38 ± 0.11 mm. The proposed model only needed 7.2 s, while the surgeon took 19.15 min on average to complete a segmentation task. The overall performances of the model were significantly superior to those of surgeons. CONCLUSIONS: The proposed deep learning model yielded a more accurate and efficient performance of automatic segmentation of graft material after SA than that of the two surgeons. The proposed model could facilitate a powerful system for volumetric change evaluation, dental implant planning, and digital dentistry.