Periodontitis promotes bacterial extracellular vesicle-induced neuroinflammation in the brain and trigeminal ganglion.

Gram-negative bacteria derived extracellular vesicles (EVs), also known as outer membrane vesicles, have attracted significant attention due to their pathogenic roles in various inflammatory diseases. We recently demonstrated that EVs secreted by the periodontopathogen Aggregatibacter actinomycetemcomitans (Aa) can cross the blood-brain barrier (BBB) and that their extracellular RNA cargo can promote the secretion of proinflammatory cytokines, such as IL-6 and TNF-α, in the brain. To gain more insight into the relationship between periodontal disease (PD) and neuroinflammatory diseases, we investigated the effect of Aa EVs in a mouse model of ligature-induced PD. When EVs were administered through intragingival injection or EV-soaked gel, proinflammatory cytokines were strongly induced in the brains of PD mice. The use of TLR (Toll-like receptor)-reporter cell lines and MyD88 knockout mice confirmed that the increased release of cytokines was triggered by Aa EVs via TLR4 and TLR8 signaling pathways and their downstream MyD88 pathway. Furthermore, the injection of EVs through the epidermis and gingiva resulted in the direct retrograde transfer of Aa EVs from axon terminals to the cell bodies of trigeminal ganglion (TG) neurons and the subsequent activation of TG neurons. We also found that the Aa EVs changed the action potential of TG neurons. These findings suggest that EVs derived from periodontopathogens such as Aa might be involved in pathogenic pathways for neuroinflammatory diseases, neuropathic pain, and other systemic inflammatory symptoms as a comorbidity of periodontitis.

Functional modulation of lysophosphatidic acid type 2 G-protein coupled receptor facilitates alveolar bone formation.

Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.

A CT-based Deep Learning Model for Predicting Subsequent Fracture Risk in Patients with Hip Fracture.

Background Patients have the highest risk of subsequent fractures in the first few years after an initial fracture, yet models to predict short-term subsequent risk have not been developed. Purpose To develop and validate a deep learning prediction model for subsequent fracture risk using digitally reconstructed radiographs from hip CT in patients with recent hip fractures. Materials and Methods This retrospective study included adult patients who underwent three-dimensional hip CT due to a fracture from January 2004 to December 2020. Two-dimensional frontal, lateral, and axial digitally reconstructed radiographs were generated and assembled to construct an ensemble model. DenseNet modules were used to calculate risk probability based on extracted image features and fracture-free probability plots were output. Model performance was assessed using the C index and area under the receiver operating characteristic curve (AUC) and compared with other models using the paired t test. Results The training and validation set included 1012 patients (mean age, 74.5 years ± 13.3 [SD]; 706 female, 113 subsequent fracture) and the test set included 468 patients (mean age, 75.9 years ± 14.0; 335 female, 22 subsequent fractures). In the test set, the ensemble model had a higher C index (0.73) for predicting subsequent fractures than that of other image-based models (C index range, 0.59-0.70 for five of six models; P value range, < .001 to < .05). The ensemble model achieved AUCs of 0.74, 0.74, and 0.73 at the 2-, 3-, and 5-year follow-ups, respectively; higher than that of most other image-based models at 2 years (AUC range, 0.57-0.71 for five of six models; P value range, < .001 to < .05) and 3 years (AUC range, 0.55-0.72 for four of six models; P value range, < .001 to < .05). Moreover, the AUCs achieved by the ensemble model were higher than that of a clinical model that included known risk factors (2-, 3-, and 5-year AUCs of 0.58, 0.64, and 0.70, respectively; P < .001 for all). Conclusion In patients with recent hip fractures, the ensemble deep learning model using digital reconstructed radiographs from hip CT showed good performance for predicting subsequent fractures in the short term. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Li and Jaremko in this issue.

Developmental roles of glomerular epithelial protein-1 in mice molar morphogenesis.

Glomerular epithelial protein-1 (Glepp1), a R3 subtype family of receptor-type protein tyrosine phosphatases, plays important role in the activation of Src family kinases and regulates cellular processes such as cell proliferation, differentiation, and apoptosis. In this study, we firstly examined the functional evaluation of Glepp1 in tooth development and morphogenesis. The precise expression level and developmental function of Glepp1 were examined by RT-qPCR, in situ hybridization, and loss and gain of functional study using a range of in vitro organ cultivation methods. Expression of Glepp1 was detected in the developing tooth germs in cap and bell stage of tooth development. Knocking down Glepp1 at E13 for 2 days showed the altered expression levels of tooth development-related signaling molecules, including Bmps, Dspp, Fgf4, Lef1, and Shh. Moreover, transient knock down of Glepp1 revealed alterations in cellular physiology, examined by the localization patterns of Ki67 and E-cadherin. Similarly, knocking down of Glepp1 showed disrupted enamel rod and interrod formation in 3-week renal transplanted teeth. In addition, due to attrition of odontoblastic layers, the expression signals of Dspp and the localization of NESTIN were almost not detected after knock down of Glepp1; however, their expressions were increased after Glepp1 overexpression. Thus, our results suggested that Glepp1 plays modulating roles during odontogenesis by regulating the expression levels of signaling molecules and cellular events to achieve the proper structural formation of hard tissue matrices in mice molar development.

CXCL5/CXCL8 induces neutrophilic inflammation in peri-implantitis.

OBJECTIVE AND BACKGROUND: This research aimed to examine the role of C-X-C motif chemokine ligand 5 (CXCL5) and C-X-C motif chemokine ligand 8 (CXCL8; also known as IL-8) in neutrophilic inflammation triggered by peri-implantitis and to shed light on the underlying mechanisms that link them to the development of this condition. MATERIALS: This study included 40 patients who visited the Department of Periodontology at Kyungpook University Dental Hospital. They were divided into two groups based on their condition: healthy implant (HI) group (n = 20) and peri-implantitis (PI) group (n = 20). Biopsy samples of PI tissue were collected from the patients under local anesthesia. HI tissue was obtained using the same method during the second implant surgery. To construct libraries for control and test RNAs, the QuantSeq 3' mRNA-Seq Library Prep Kit (Lexogen, Inc., Austria) was used according to the manufacturer's instructions. Samples were pooled based on representative cytokines obtained from RNA sequencing results and subjected to Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Hematoxylin and eosin staining, and immunohistochemistry (IHC) analysis were performed to visually assess expression levels and analyze tissue histology. Student's t-test was employed to conduct statistical analyses. RESULTS: Initially, heatmaps were used to examine gene expression variations between the HI and PI groups based on the results of RNA sequencing. Notably, among various cytokines, CXCL5 and CXCL8 had the highest expression levels in the PI group compared with the HI group, and they are known to be associated with inflammatory responses. In the gingival tissues, the expression of genes encoding cytokines such as interleukin (IL)-1ß, tumor necrosis factor-alpha (TNF)-α, interleukin (IL)-6, and CXCL5/CXCL8 was assessed via RT-qPCR. The mRNA expression level of CXCL5/CXCL8 significantly increased in the PI group compared with the HI group (p < .045). Contrarily, the mRNA expression level of interleukin 36 receptor antagonist (IL36RN) significantly decreased (p < .008). IHC enabled examination of the distribution and intensity of CXCL5/CXCL8 protein expression within the tissue samples. Specifically, increased levels of CXCL5/CXCL8 promote inflammatory responses, cellular proliferation, migration, and invasion within the peri-implant tissues. These effects are mediated through the activation of the PI3K/Akt/NF-κB signaling pathway. CONCLUSIONS: This study found that the PI sites had higher gene expression level of CXCL8/CXCL5 in the soft tissue than HI sites, which could help achieve more accurate diagnosis and treatment planning.

Comparison of the Surgical Outcome between the Multiple Screw Fixation and Fixed Angle Devices for the Basicervical Femoral Neck Fractures.

Introduction: Basicervical femoral neck fracture (FNF) is an uncommon type of femoral neck fracture and is associated with an increased risk of fixation failure due to its inherent instability. The purpose of this study was to compare the surgical parameters and reoperation rate between the use of a multiple cannulated screw (MCS) and fixed angle device (FAD) in treating basicervical FNFs. Methods: We retrospectively reviewed the records of 885 patients who underwent internal fixation between May 2004 and August 2019 to determine basicervical FNF with at least 12 months of follow-up. Among the identified 77 patients with basicervical FNF, 17 patients who underwent multiple cannulated screw (MCS) fixation and 36 patients who underwent fixed angle device (FAD) fixation were included. We compared the rates of fracture-site collapse and reoperations according to the fixation device. Results: Among the 53 patients with basicervical FNF, 13 patients (24.5%) sustained surgical complications (8 collapses of fracture site and 5 reoperations). The reoperation rate in the MCS group was significantly higher than that in the FAD group (23.5% vs. 2.8%, p = 0.016), without any significant difference in the collapse of the fracture site (11.8% vs. 16.7%, p = 0.642). Conclusions: Although basicervical FNF was rare among hip fractures, fracture site collapse was prevalent and prone to fixation failure. Surgeons should keep this in mind, and consider FAD for basicervical FNF.

The role of O-GlcNAcylation mediated by OGT during tooth development.

To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O-GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O-GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage-specific immunostaining results against O-GlcNAc and O-GlcNAc transferase (OGT) in developing tooth germs would suggest that O-GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT-mediated O-GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI-1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI-1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real-time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of ß-catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT-inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT-mediated O-GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis.

The risk of osteoporotic fracture in gastric cancer survivors: total gastrectomy versus subtotal gastrectomy versus endoscopic treatment.

PURPOSES: Previous studies have suggested that there is an increased risk of osteoporotic fracture in gastric cancer survivors. However, the data was not classified according to surgery type. This study investigated the cumulative incidence osteoporotic fracture (OF) in gastric cancer survivors according to treatment modality. METHODS: A total of 85,124 gastric cancer survivors during 2008-2016 were included. The type of surgery was classified as total gastrectomy (TG, n = 14,428)/subtotal gastrectomy (SG, n = 52,572)/endoscopic mucosal dissection and endoscopic mucosal resection (ESD/EMR, n = 18,125). The site of osteoporotic fractures included the spine, hip, wrist, and humerus. We examined cumulative incidence using Kaplan-Meier survivor analysis and cox proportional hazards regression analysis to determine the risk factor of OF. RESULTS: The incidence of OF per 100,000 patient year was 2.6, 2.1, 1.8 in TG, SG, ESD/EMR group. The cumulative incidence rate was 2.3% at 3 years, 4.0% at 5 years, and 5.8% at 7 years in gastrectomy group, and 1.8% at 3 years, 3.3% at 5 years in the SG group, and 4.9% at 7 years postoperatively in ESD/EMR group. TG increased the risk of OF compared to patients who underwent SG (HR 1.75, 95% confidence interval [CI] 1.57-1.94), and ESD/EMR (hazard ratio [HR] 2.23, 95% CI 2.14-2.32). CONCLUSION: Gastric cancer survivors who underwent TG had an increased osteoporotic fracture risk than did SG or ESD/EMR in these patients. The amount of gastric resection and accompanying metabolic changes seemed to mediate such risk. Additional research is needed to establish an optimal strategy for each type of surgery.

Comparison between osteonecrosis of the humeral and femoral heads - epidemiological analysis of the surgical trend using the nationwide claims database of the republic of Korea.

BACKGROUNDS: The humeral head is the second most common site of osteonecrosis, after the femoral head. However, compared to osteonecrosis of the femoral head (ONFH), epidemiological information on osteonecrosis of the humeral head (ONHH) is scarce. We hypothesised that different biomechanical properties of the shoulder from the hip joint might present different epidemiological characteristics of ONHH from those of the ONFH. To evaluate epidemiological differences, we compared trends in the surgical treatment of ONHH and ONFH using the nationwide medical claims database of the Republic of Korea (ROK). METHODS: We analysed epidemiological data from the Health Insurance Review and Assessment (HIRA) database of the ROK between 2008 and 2018. HIRA database contains almost all medical information in an anonymised form, including demographics, diagnoses, and types of surgical procedures, generated through healthcare practices in ROK. The annual incidence rates of ONHH and ONFH were calculated based on the total number of the general population. Demographics, annual incidence, and the proportion of post-traumatic osteonecrosis and surgical procedures were compared according to the anatomical site and the affected year. RESULTS: The total number of patients treated for ONHH and ONFH during the study period was 1,028 and 66,260, respectively. Although the incidence of ONHH increased, it is a relatively rare disease compared to ONFH. ONHH occurred more frequently in females, while ONFH occurred predominantly in male patients (p < 0.001). Surgical treatment for ONHH was most frequently performed in older patients (63.7%), whereas middle-aged patients had the largest proportion of ONFH (48.9%, p < 0.001). The proportion of post-traumatic osteonecrosis was significantly higher in the ONHH (5.1%) than in the ONFH (1.9%, p < 0.001). Arthroplasty was performed more frequently in the ONHH (96.0%) than in the ONFH (92.9%, p < 0.001). CONCLUSION: Despite the anatomical similarities between the hip and shoulder joints, the different biomechanical properties, such as weight-bearing functions, might cause epidemiological differences between ONHH and ONFH.

The Korean hip fracture registry study.

BACKGROUND: The purpose of the Korean Hip Fracture Registry (KHFR) Study is to establish a nationwide, hospital-based prospective cohort study of adults with hip fracture to explore the incidence and risk factors of second osteoporotic fractures for a Fracture Liaison Service (FLS) model. METHODS: The KHFR, a prospective multicenter longitudinal study, was launched in 2014. Sixteen centers recruited participants who were treated for hip fracture. The inclusion criteria were patients, who were treated for proximal femur fracture due to low-energy trauma and aged 50 or more at the time of injury. Until 2018, 5,841 patients were enrolled in this study. Follow-up surveys were conducted annually to determine occurrence of second osteoporotic fracture, and 4,803 participants completed at least one follow-up survey. DISCUSSION: KHFR is a unique resource of individual level on osteoporotic hip fracture with radiological, medical, and laboratory information including DXA (dual energy x-ray absorptiometry), bone turnover marker, body composition, and hand grip strength for future analyses for FLS model. Modifiable factors for mortality after hip surgery is planned to be identified with nutritional assessment and multi-disciplinary interventions from hospitalization to follow-ups. The proportions of femoral neck, intertrochanteric, and subtrochanteric fractures were 517 (42.0%), 730 (53.6%), and 60 (4.4%), respectively, from 2014 to 2016, which was similar in other studies. Radiologic definition of atypical subtrochanteric fracture was adopted and 17 (1.2%) fractures among 1,361 proximal femoral fractures were identified. Internal fixation showed higher reoperation rate compared to arthroplasty in unstable intertrochanteric fractures (6.1% vs. 2.4%, p = 0.046) with no significant difference in mortality. The KHFR plans to identify outcomes and risk factors associated with second fracture by conducting a 10-year cohort study, with a follow-up every year, using 5,841 baseline participants. TRIAL REGISTRATION: Present study was registered on Internet-based Clinical Research and Trial management system (iCReaT) as multicenter prospective observational cohort study (Project number: C160022, Date of registration: 22th, Apr, 2016).

GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone.

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor ß (TGF-ß) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality of Gdf11 null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show that Gdf11 null mice, despite significantly down-regulating Mstn expression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed in Mstn null mice that display enhanced bone mass. Mechanistically, Mstn deletion up-regulates Gdf11 expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlike Mstn null mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

Effect of Total Hip Arthroplasty on Ipsilateral Lower Limb Alignment and Knee Joint Space Width: Minimum 5-Year Follow-up.

BACKGROUND: This study aimed to 1) assess the effect of total hip arthroplasty (THA) on coronal limb alignment, namely, the hip-knee-ankle angle (HKA), 2) identify factors that determine changes in the HKA, and 3) determine whether alignment changes influence the knee joint space width. METHODS: We retrospectively evaluated 266 limbs of patients who underwent THA. Three types of prostheses with neck shaft angles (NSAs) of 132°, 135°, and 138° were used. Several radiographic parameters were measured in the preoperative and final radiographs (at least 5 years after THA). A paired t-test was used to confirm the effect of THA on HKA change. Multiple regression analysis was performed to identify radiographic parameters related to HKA changes following THA and changes in knee joint space width. Subgroup analyses were performed to reveal the effect of NSA change on the HKA change, and the proportion of total knee arthroplasty usage and changes in radiographic parameters between maintained joint space and narrowed joint space groups were compared. RESULTS: The preoperative mean HKA was 1.4° varus and increased to 2.7° varus after THA. This change was related to changes in the NSA, lateral distal femoral angle, and femoral bowing angle. In particular, in the group with a decrease in NSA of > 5°, the preoperative mean HKA was largely changed from 1.4° varus to 4.6° varus after THA. The prostheses with NSA of 132° and 135° also led to greater varus HKA changes than those with an NSA of 138°. Narrowing of the medial knee joint space was related to changes in the varus direction of the HKA, decrease in NSA, increase in femoral offset. CONCLUSION: A large reduction in NSA can lead to considerable varus limb alignment after THA, which can have adverse effects on the medial compartment of the ipsilateral knee.

Anterior and Lateral Femoroacetabular Excursion Angles Are Helpful for Assessing Femoroacetabular Impingement Syndrome: A Cross-Sectional Cohort Study.

PURPOSE: To develop a radiographic measurement to evaluate the femoroacetabular space using 3-dimensional (3D) hip models in asymptomatic hips, and to evaluate the reliability and validity of the femoroacetabular excursion angle (FAEA) in symptomatic patients. METHODS: From January 2020 to December 2020, we recruited patients with healthy hips to establish 3D models. Through the simulation of 14 activities of daily living (ADLs), anterior and lateral impingement-free FAEAs were measured. Another cross-sectional cohort was formed from consecutive symptomatic subjects with impingement signs during the same period. In the validation cohort, anterior and lateral FAEAs were assessed on modified Dunn's and anteroposterior views of the hip, respectively. We evaluated the reliability and clinical implications of the FAEAs. RESULTS: In the discovery cohort (n = 33), hips with collisions tended to have smaller computed tomography-based FAEAs than collision-free hips, although alpha and lateral center-edge (CE) angles were comparable. Additionally, hips with a lower quartile of FAEAs had a significantly higher number of ADLs with collisions. In the validation cohort (n = 411), the FAEA measurement was highly reliable (kappa statistics >0.95 for both interobserver and intraobserver reliabilities). The femoroacetabular impingement syndrome (FAIS) group (n = 165) showed significantly smaller anterior and lateral FAEAs than the non-FAIS group (all P < .001, Cramer V = .420). The optimal cut-off values for anterior and lateral FAEAs were 32.6° and 48.9°, respectively. In univariate regression, anterior (odds ratio [OR] = 0.91; 95% confidence interval [CI] = 0.89-0.94) and lateral (OR = 0.91; 95% CI = 0.89-0.93) FAEAs were significantly associated with FAIS. Moreover, in multivariate regression adjusted for alpha and lateral CE angles, anterior FAEA remained a significant predictor (OR = 0.96; 95% CI = 0.93-0.99), and small FAEA was an independent risk factor for FAIS (OR = 1.99; 95% CI = 1.06-3.71) for any small FAEA (OR = 2.88; 95% CI = 1.32-6.31) for both small FAEAs. CONCLUSION: The FAEA is a valid measurement for FAIS with high reliability. Small FAEA was an independent risk factor for FAIS in the multivariate regression model, even after adjusting for alpha and lateral CE angles. LEVEL OF EVIDENCE: Level III, diagnostic study.

Rhein Induces Oral Cancer Cell Apoptosis and ROS via Suppresse AKT/mTOR Signaling Pathway In Vitro and In Vivo.

Oral cancer remains the leading cause of death worldwide. Rhein is a natural compound extracted from the traditional Chinese herbal medicine rhubarb, which has demonstrated therapeutic effects in various cancers. However, the specific effects of rhein on oral cancer are still unclear. This study aimed to investigate the potential anticancer activity and underlying mechanisms of rhein in oral cancer cells. The antigrowth effect of rhein in oral cancer cells was estimated by cell proliferation, soft agar colony formation, migration, and invasion assay. The cell cycle and apoptosis were detected by flow cytometry. The underlying mechanism of rhein in oral cancer cells was explored by immunoblotting. The in vivo anticancer effect was evaluated by oral cancer xenografts. Rhein significantly inhibited oral cancer cell growth by inducing apoptosis and S-phase cell cycle arrest. Rhein inhibited oral cancer cell migration and invasion through the regulation of epithelial-mesenchymal transition-related proteins. Rhein induced reactive oxygen species (ROS) accumulation in oral cancer cells to inhibit the AKT/mTOR signaling pathway. Rhein exerted anticancer activity in vitro and in vivo by inducing oral cancer cell apoptosis and ROS via the AKT/mTOR signaling pathway in oral cancer. Rhein is a potential therapeutic drug for oral cancer treatment.

A 10- to 12-year follow-up study of delta ceramic-on-ceramic total hip arthroplasty.

BACKGROUND: We previously reported five-to-seven-year results of total hip arthroplasty (THA) with the use of delta ceramic-on-ceramic (CoC) bearing. We conducted an extension study with a CT scan at a minimum of 10 years after surgery. METHODS: From March 2009 to March 2011, 273 patients (310 hips) received cementless THA with delta CoC bearing, porous-coated cup and hydroxyapatite-coated stem. In this extended study, 252 patients (144 men and 108 women) (288 hips) with a mean age of 49.7 years (16-83) at surgery were followed for a mean of 10.4 years (10-12) with CT scans in 133 hips (46.2%, 133/288). Clinical and radiographic evaluations were made at each follow-up and Kaplan-Meier survival analysis was performed with revision and reoperation as endpoints. RESULTS: There were no more ceramic fractures. Compared to mid-term results, the incidence of squeaking and RLLs increased to 3.1% (9/288) and 19.4% (56/288), respectively. The RLL progressed to focal osteolysis in 3 hips (5.4%, 3/56). No hip had detectable wear or prosthetic loosening. Two hips were reoperated due to periprosthetic joint infection and periprosthetic femoral fracture in each. The survivorship decreased to 98.3% (96.7-99.9%) at 12 years. CONCLUSION: During the extended follow-up, no additional ceramic fracture occurred, and the incidence of squeak increased by 0.7%. The long-term survivorship of Delta CoC THA was encouraging. However, focal osteolysis occurred around the hydroxyapatite-coated stem in 1% (3/288). LEVEL OF EVIDENCE: II (Prospective cohort study).

The Potential Economic Benefits of an Alarm Service in Order Communication Systems in Korea: a Cost-Effectiveness Analysis of Less-Intensive Fracture Liaison Services Based on a Prospective Cohort Study.

An alarm service in an order communication system (OCS) was found to be effective at increasing the rate of dual-energy X-ray absorptiometry (DXA) testing and treatment in South Korea, but its cost-effectiveness remains unknown. We used a Markov model to determine the cost-effectiveness of the alarm service in the OCS compared to no alarm service for the post-fracture management of subjects aged 50 years and older with fragility fractures. DXA testing and treatment data were collected from a prospective cohort study. The prevalence of osteoporotic fractures, the subsequent risk of hip fracture, and healthcare costs were obtained using Korea National Health Insurance claims data. The lifetime cost and quality-adjusted life-years (QALYs) gained were estimated from a healthcare perspective. A probabilistic sensitivity analysis was performed to examine the uncertainty of the results. The alarm service increased treatment by 125 per 1000 patients and prevented 3 hip fractures per 1000 patients. The alarm service cost an additional 249,393 KRW and resulted in an increase of 0.008 QALYs per patient compared to no alarm service. The incremental cost-effectiveness ratio was 31,174,125 KRW (26,843 USD) per QALY gained. The alarm service was cost-effective than no alarm service if the willingness to pay setting as 1GDP per capita (29,288 USD) per QALY gained. This study shows that less-intensive fracture liaison services, such as an alarm service, are cost-effective for patients aged 50 years and older with osteoporotic fractures in Korea. An intensive model, including enhanced identification and education, could further prevent the risk of refracture and improve cost-effectiveness.

Sarcopenia: an unsolved problem after hip fracture.

INTRODUCTION: Sarcopenia, loss of muscle mass and strength, leads to functional dependence and disability. To date, no study reported the postoperative change of sarcopenia prevalence after hip fractures. Thus, we assessed postoperative changes in the prevalence of osteoporosis and sarcopenia in hip fracture patients. MATERIALS AND METHODS: Among 1159 patients, who underwent surgery for low-energy hip fractures between May 2012 and December 2019, 224 patients (38 men and 186 women with a mean age of 76.8 ± 8.7 years) were studied with preoperative and follow-up dual-energy X-ray absorptiometry (DXA). Bone mineral density (BMD) and skeletal muscle mass were measured on DXA scans. The postoperative changes in the prevalence of osteoporosis and that of the sarcopenia were evaluated as well as Koval grade of the hip fracture patients. RESULTS: While there was no significant change in BMD, SMI significantly decreased postoperatively. Mean decrease of the SMI was 0.53 kg/m2 in men and 0.38 kg/m2 in women. Prevalence of sarcopenia increased from 63 to 89% (p = 0.014) in men and from 45 to 57% (p = 0.006) in women. Lower BMI (Odds ratio (OR) 0.85 (95% confidence interval (CI) 0.76-0.96), p = 0.008) and prior sarcopenia (OR 14.47 (95% CI 5.29-35.39), p < 0.001) were the risk factors for the decrease of SMI after hip fracture. CONCLUSIONS: After hip fracture, osteoporosis seemed to be well managed and the prevalence of osteoporosis did not increase. However, SMI decreased and the prevalence of sarcopenia increased. More active measures are warranted to prevent sarcopenia in elderly hip fracture patients.

High Risk of Neck-liner Impingement and Notching Observed with Thick Femoral Neck Implants in Ceramic-on-ceramic THA.

BACKGROUND: Recently, impingement between the femoral stem and ceramic liner, which appears as a notch in the stem neck on radiographs, has emerged as a new complication. However, the proportion of impingement, potential risk factors, and related complications are poorly elucidated. QUESTION/PURPOSES: In patients who underwent ceramic-on-ceramic (CoC) THA and had at least 10 years of follow-up, we asked: (1) What proportion had radiographic evidence of stem neck-ceramic liner impingement (notching of the stem), and what implant design, implantation factors, or complications such as ceramic fracture or metallosis are associated with impingement? (2) How common are the complications of noise and ceramic fracture? (3) What are the radiologic changes (including fixation of femoral and acetabular components, osteolysis, and heterotopic ossification) and clinical outcomes as determined by the modified Harris hip score (mHHS) for this cohort? (4) What is the survivorship with implant revision as the endpoint and with reoperation for any reason as the endpoint after CoC THA using a thick-neck stem design? METHODS: Between May 2003 and April 2010, 643 patients underwent primary THA at a tertiary referral hospital. After excluding patients with metal-on-polyethylene and with ceramic-on-polyethylene implants, 621 patients were considered eligible for this study. All patients received the same hemispherical titanium cup, a standard-length tapered titanium stem, and a CoC bearing. Of those, 19% (115) were lost to follow-up before 10 years, and 8% (50) were excluded because they died before the minimum follow-up duration of 10 years, leaving 73% (456) for analysis. Patients had a mean age of 50 ± 14 years and were followed for a median (range) of 13 years (10 to 17). The mean cup abduction was 38° ± 5°, and the mean cup anteversion was 26° ± 7°. To determine the proportion of patients with the neck-liner impingement, we analyzed the plain radiographs of every patient during follow-up to detect notches around the stem. The detection of stem neck notches on the radiographs was reliable (intraobserver reliability: κ = 0.963; p < 0.001 and interobserver reliability: κ = 0.975; p < 0.001). To evaluate factors related to notching, we compared the possible confounding factors including gender, age, BMI, implant position, neck length, and head diameter. Complications such as ceramic fracture, noise, dislocation, and periprosthetic joint infection were recorded. Noise was evaluated via interview and with the Hip Noise Assessment Questionnaire, which assessed the noise qualitatively. For clinical outcome, we assessed the mHHS, which includes pain and function scales (0 [worst] to 100 [best]), every visit. Tilting of at least 4° or migration of at least 4 mm was the criteria for cup loosening; subsidence more than 3 mm, any change in position, or a continuous radiolucent line greater than 2 mm was the criteria for stem loosening. To evaluate osteolysis, we performed CT scans in 57% (262 of 456) of patients. Kaplan-Meier survivorship analysis was performed using the endpoints of survivorship free from implant revision and survivorship free from reoperation for any cause. RESULTS: The proportion of stem neck notching was 11% (49 of 456). There were no differences in cup abduction and anteversion between hips with notches and those without notches. Notched hips were more likely to have 28-mm than 32-mm heads (90% [44 of 49] versus 70% [285 of 407]; odds ratio 3.77 [95% CI 1.46 to 9.73]; p = 0.004). None of the 49 notched hips had a ceramic head or liner fracture or evidence of metallosis. A ceramic head fracture was reported in 2% (9 of 456); all fractures occurred in 28-mm short neck heads. A ceramic liner fracture occurred in 0.2% (1 of 456), and noise was noted in 6% (27 of 456). Acetabular osteolysis developed in 2% (7 of 456). The mHHS was 91 ± 12 points at the final follow-up. The survivorship free from implant revision was 97% (95% CI 96% to 99%), and the survivorship free from reoperation for any cause was 96% (95% CI 95% to 98%) at 13 years. CONCLUSION: The proportion of stems with neck-ceramic liner impingement and ceramic component fracture were unacceptably high after the use of a thick-neck stem design, especially when a 28-mm head was used. We have discontinued the use of this stem design and we recommend that such stems should not be used when CoC bearings are used. As these findings might be generalized to other bearing couples, further studies focused on polyethylene liner wear and local metallosis due to thick stem neck are warranted. LEVEL OF EVIDENCE: Level III, therapeutic study.

Do Cementless Short Tapered Stems Reduce the Incidence of Thigh Pain After Hip Arthroplasty? Systematic Review and Meta-Analysis.

BACKGROUND: The purpose of this study was to determine whether short tapered stems reduce the rate of thigh pain through a systematic review and meta-analysis of comparative studies between short tapered stems and standard-length tapered stems. METHODS: We conducted a meta-analysis of comparative studies: 1) retrospective studies and 2) randomized controlled trials (RCTs), on 2 stem designs: short tapered stem versus standard-length tapered stem. Studies were selected by means of the following criteria: 1) study design: retrospective comparative studies, prospective comparative studies, RCTs; 2) study population: patients with total hip arthroplasty or hemiarthroplasty for hip disease or hip fracture; 3) intervention: short tapered stem and standard tapered stem; and 4) outcomes; thigh pain, other clinical results. RESULTS: Among the 250 articles that were identified at the initial search, 6 studies, 4 RCTs and 2 retrospective comparative studies, were included in this meta-analysis. In the analysis of retrospective studies, the short tapered stem reduced the risk of thigh pain compared to the standard tapered stem (risk ratio [RR] = 0.13; 95% confidence interval [CI], 0.02-0.09; Z = -2.07; P = 0.039). However, in the analysis of RCTs, the incidence of thigh pain was similar between the two stem designs (RR = 1.21; 95% CI, 0.76-1.93; Z = 0.82; P = 0.410). Overall meta-analysis including all studies showed that the short tapered stem did not reduce the incidence of thigh pain compared to the standard-length tapered stem (RR = 0.91; 95% CI, 0.59-1.40; Z = -0.44, P = 0.663). CONCLUSIONS: We did not find a significant difference in the incidence of thigh pain between short tapered stem and standard tapered stem in hip arthroplasty. TRIAL REGISTRATION: PROSPERO Identifier: CRD42021231240.

Effectiveness of Online Video Instruction on Time to Start Ambulation and Duration of Hospital Stay, Satisfaction and Functional Recovery in Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: At the end of 2014, we implemented an online video to inform patients of the entire process from admission to rehabilitation after total hip arthroplasty (THA). In this study, we investigated the effectiveness of online video instruction in THA patients. METHODS: Electronic medical records of 184 patients undergoing THA in 2014 (pre-video group) and 182 patients in 2015 (post-video group) were reviewed. We compared 1) the time to start wheelchair ambulation, 2) walker or crutch ambulation, 3) the length of hospital stay, 4) postoperative satisfaction using visual analogue scale (0-10 points), and 5) modified Harris Hip Score (mHHS) at postoperative 6 weeks. RESULTS: In the post-video group, the time to start wheelchair ambulation (1.8 ± 0.6 vs. 2.4 ± 3.2 days, P = 0.021) and walker/crutch ambulation were faster (2.9 ± 1.2 vs. 3.8 ± 1.0 days, P = 0.016), and the hospital stay was shorter (8.2 ± 4.7 vs. 9.9 ± 7.8 days, P = 0.001) compared to the pre-video group. The visual analogue scale for satisfaction (7.84 ± 1.62 vs. 7.68 ± 1.85 points) and mHHS (89.59 ± 9.47 vs. 89.58 ± 8.59) were similar. CONCLUSION: Online video instruction is an effective tool to expedite ambulation and reduce the hospital stay without compromising the clinical outcome and postoperative complications after THA.