Dual targeting non-overlapping epitopes in HER2 domain IV substantially enhanced HER2/HER2 homodimers and HER2/EGFR heterodimers internalization leading to potent antitumor activity in HER2-positive human gastric cancer.

BACKGROUND: Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer. METHODS: We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. RESULTS: HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-ß-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo. CONCLUSIONS: These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.

Lithium prevents glucocorticoid-induced osteonecrosis of the femoral head by regulating autophagy.

Autophagy may play an important role in the occurrence and development of glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH). Lithium is a classical autophagy regulator, and lithium can also activate osteogenic pathways, making it a highly promising therapeutic agent for GC-ONFH. We aimed to evaluate the potential therapeutic effect of lithium on GC-ONFH. For in vitro experiments, primary osteoblasts of rats were used for investigating the underlying mechanism of lithium's protective effect on GC-induced autophagy levels and osteogenic activity dysfunction. For in vivo experiments, a rat model of GC-ONFH was used for evaluating the therapeutic effect of oral lithium on GC-ONFH and underlying mechanism. Findings demonstrated that GC over-activated the autophagy of osteoblasts and reduced their osteogenic activity. Lithium reduced the over-activated autophagy of GC-treated osteoblasts through PI3K/AKT/mTOR signalling pathway and increased their osteogenic activity. Oral lithium reduced the osteonecrosis rates in a rat model of GC-ONFH, and restrained the increased expression of autophagy related proteins in bone tissues through PI3K/AKT/mTOR signalling pathway. In conclusion, lithium can restrain over-activated autophagy by activating PI3K/AKT/mTOR signalling pathway and up-regulate the expression of genes for bone formation both in GC induced osteoblasts and in a rat model of GC-ONFH. Lithium may be a promising therapeutic agent for GC-ONFH. However, the role of autophagy in the pathogenesis of GC-ONFH remains controversial. Studies are still needed to further explore the role of autophagy in the pathogenesis of GC-ONFH, and the efficacy of lithium in the treatment of GC-ONFH and its underlying mechanisms.

Effects of a Modified Long-Acting Cocktail on Analgesia and Enhanced Recovery After Total Hip Arthroplasty: A Double-Blinded Randomized Clinical Trial.

BACKGROUND: We compared the efficacy and safety of a modified cocktail for postoperative analgesia and early functional rehabilitation in patients undergoing total hip arthroplasty (THA). METHODS: Magnesium sulfate and sodium bicarbonate were added to a cocktail of ropivacaine, epinephrine, and dexamethasone. Primary outcome measures were visual analog scale (VAS) pain scores at various intervals after surgery, morphine consumption for rescue analgesia after surgery, and time to first rescue analgesia. Secondary outcomes were hip function after surgery, daily walking distance, quadriceps muscle strength, and the incidence of postoperative adverse reactions. RESULTS: Morphine consumption was significantly lower in the modified cocktail group than in the control group in the first 24 hours after surgery (6.2 ± 6.0 versus 14.2 ± 6.4 mg, P < .001), as was total morphine consumption (10.0 ± 8.6 versus 19.2 ± 10.1 mg, P < .001). The duration of the first rescue analgesia was significantly prolonged (23.7 ± 10.3 versus 11.9 ± 5.8 mg, P < .001). Morphine consumption was also reduced in the magnesium sulfate and sodium bicarbonate groups over a 24-hour period compared to the control group (P < .001). The modified cocktail group had significantly lower resting VAS pain scores than the control group within 24 hours after surgery (P < .050). The VAS pain scores during movement within 12 hours after surgery were also lower (P < .050). The experimental groups showed better hip range of motion (P < .050) and longer walking distance (P < .050) on the first postoperative day, and levels of inflammatory markers were significantly reduced. The incidence of postoperative adverse reactions was similar among the 4 groups. CONCLUSIONS: The modified cocktail with a new adjuvant can prolong the duration of postoperative analgesia, reduce the dosage of rescue analgesics, and accelerate early postoperative functional recovery in patients undergoing THA.

Hypobaric hypoxia aggravates osteoarthritis via the alteration of the oxygen environment and bone remodeling in the subchondral zone.

A high prevalence of osteoarthritis (OA) has been observed among individuals living at high altitudes, and hypobaric hypoxia (HH) can cause bone mass and strength deterioration. However, the effect of HH on OA remains unclear. In this study, we aimed to explore the impact of HH on OA and its potential mechanisms. A rat knee OA model was established by surgery, and the rats were bred in an HH chamber simulating a high-altitude environment. Micro-computed tomography (Micro-CT), histological analysis, and RNA sequencing were performed to evaluate the effects of HH on OA in vivo. A hypoxic co-culture model of osteoclasts and osteoblasts was also established to determine their effects on chondrogenesis in vitro. Cartilage degeneration significantly worsened in the HH-OA group compared to that in the normoxia-OA (N-OA) group, 4 weeks after surgery. Micro-CT analysis revealed more deteriorated bone mass in the HH-OA group than in the N-OA group. Decreased hypoxia levels in the cartilage and enhanced hypoxia levels in the subchondral bone were observed in the HH-OA group. Furthermore, chondrocytes cultured in a conditioned medium from the hypoxic co-culture model showed decreased anabolism and extracellular matrix compared to those in the normoxic model. RNA sequencing analysis of the subchondral bone indicated that the glycolytic signaling pathway was highly activated in the HH-OA group. HH-related OA progression was associated with alterations in the oxygen environment and bone remodeling in the subchondral zone, which provided new insights into the pathogenesis of OA.

Prevalence and risk factors of osteoporotic fracture among the elderly population in China: a multicenter cross-sectional study.

PURPOSE: Prevalence of osteoporotic fracture (OPF) is increasing with ageing, resulting in a significant financial burden for healthcare. However, research on the nationwide epidemiological data of OPF in Chinese elderly is still scarce. The aim of this study was to investigate the prevalence and risk factors of OPF in Chinese population aged 60 years or order. METHODS: A cross-sectional survey was conducted in an elderly Chinese population in five centres. Questionnaire investigation and imaging examination were taken in all participants to identify OPF prevalence and risk factors. Diagnosis of OPF was determined based on imaging of vertebral fractures or history of fall-related fractures. We then used multivariate logistic regression model to analyze the associations between the potential risk factors and OPF. RESULTS: The overall prevalence of OPF in population aged 60 years or older was 24.7% (1,071/4,331), showing an increasing trend with age (P < 0.001). The prevalence of OPF was geographically distinct (P < 0.001), but similar between men and women (P > 0.05). Up to 96.8% of OPFs consisted of vertebral fractures, especially involving T11, T12, and L1 segments. Advanced age (≥ 80), vision loss, severe hearing loss, multiple exercise forms, chronic kidney disease, osteoarthritis, and trauma-related vertebral fractures were significantly associated with risk factors, while education level and vitamin D supplementation were associated with protective factors of OPF. CONCLUSION: High prevalence of OPF is a serious threat to bone health among elderly people in China. There is an urgent need for effective strategies to diagnose, prevent, and treat OPF in elderly adults.

Immune regulation enhances osteogenesis and angiogenesis using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA) delivery for osteonecrosis.

Osteonecrosis is a devastating orthopedic disease in clinic that generally occurs in the femoral head associating with corticosteroid use up to 49 % in patients. In particular, glucocorticoids induced osteonecrosis of the femoral head is closely related to the local immune response that characterized by abnormal macrophage activation and inflammatory cell infiltration at the necrotic site, forming a pro-inflammatory microenvironment dominated by M1 macrophages, and thus leads to failure of bone repair and regeneration. Here, we report a bone regeneration strategy that constructs an immune regulatory biomaterial platform using an injectable thiolated hyaluronic acid hydrogel with lithium-doped nano-hydroxyapatite (Li-nHA@Gel) delivery for osteonecrosis treatment. Li-nHA@Gel achieved a sustain and longterm release of Li ions, which might enhance M2 macrophage polarization through the activation of the JAK1/STAT6/STAT3 signaling pathway, and the following induced pro-repair immune microenvironment mediated the enhancement of the osteogenic and angiogenic differentiation. Moreover, both in vitro and in vivo studies indicated that Li-nHA@Gel enhanced M2 macrophage polarization, osteogenesis, and angiogenesis, and thus promoted the bone and blood vessel formation. Taken together, this novel bone immunomodulatory biomaterial platform that promotes bone regeneration by enhancing M2 macrophage polarization, osteogenesis, and angiogenesis could be a promising strategy for osteonecrosis treatment.

Comparison between Ultrasound-Guided Pericapsular Nerve Group Block and Local Infiltration Analgesia for Postoperative Analgesia after Total Hip Arthroplasty: A Prospective Randomized Controlled Trial.

OBJECTIVES: Pericapsular nerve group (PENG) blocking is a novel nerve block modality for analgesia after total hip arthroplasty (THA); however, its analgesic efficacy is unclear. We aimed to compare the analgesic effect of ultrasound-guided PENG blocking and periarticular local infiltration analgesia after THA. METHODS: This study involved patients undergoing unilateral primary THA at our institution between October 2022 and December 2022. Based on a prospective double-blind, randomized approach, patients were randomly divided into two groups: the PENG and infiltration groups. The former received ultrasound-guided pericapsular nerve block before surgery while the latter received local anesthesia and local infiltration analgesia during surgery. The primary outcome was the amount of morphine used for rescue analgesia within 48 h after surgery and the visual analog scale (VAS) pain score at 3, 6, 12, 24, and 48 h after surgery. Secondary outcomes consisted of postoperative hip function on the first and second postoperative days, including hip extension angle and flexion, as well as distance traveled by the patient. Tertiary outcomes included length of hospital stay and postoperative adverse reactions. The data were analyzed using SPSS 26.0. Using the appropriate statistical methodology, continuous and categorical data were analyzed, and p < 0.05 was considered statistically significant. RESULTS: There was no clear difference in morphine requirements during the first 24 hours postoperatively (5.8 ± 5.9 vs. 6.0 ± 6.3, p = 0.910), in the total postoperative morphine consumption (7.5 ± 6.3 vs. 7.8 ± 6.6, p = 0.889), and in the postoperative resting VAS pain scores (p > 0.05). However, the exercise VAS score in the PENG group was significantly higher than that in the infiltration group within 12 hours after surgery (6.1 + 1.2 vs. 5.4 + 1.0, p = 0.008). There was no significant difference in hip function, length of hospital stay, or incidence of complications between the two groups. CONCLUSION: The analgesic effect and functional recovery of ultrasound-guided pericapsular nerve block for THA was not superior to that of periarticular local infiltration analgesia.

Comparative study of carbazochrome sodium sulfonate and tranexamic acid in reducing blood loss and inflammatory response following direct anterior total hip arthroplasty: a prospective randomized controlled trial.

PURPOSE: Carbazochrome sodium sulfonate (CSS) is a haemostatic agent. However, its hemostatic and anti-inflammatory effects in patients undergoing total hip arthroplasty (THA) via a direct anterior approach (DAA) are unknown. We investigated the efficacy and safety of CSS combined with tranexamic acid (TXA) in THA using DAA. METHODS: This study enrolled 100 patients who underwent primary, unilateral THA through a direct anterior approach. Patients were randomly divided into two groups: Group A used a combination of TXA and CSS, while Group B used TXA only. The primary outcome was total perioperative blood loss. The secondary outcomes were hidden blood loss, postoperative blood transfusion rate, inflammatory reactant levels, hip function, pain score, venous thromboembolism (VTE), and incidence of associated adverse reactions. RESULTS: The total blood loss (TBL) in group A was significantly lower than in group B. The levels of inflammatory reactants and the rate of blood transfusion were also significantly lower. However, the two groups had no significant differences in intraoperative blood loss, postoperative pain score, or joint function. There were no significant differences in VTE or postoperative complications between the groups. CONCLUSION: As a haemostatic agent, CSS combined with TXA can reduce postoperative blood loss in patients undergoing THA via DAA and seems to have an anti-inflammatory effect. Moreover, it did not increase the incidence of VTE or its related complications.

Activated intestinal microbiome-associated tryptophan metabolism upregulates aryl hydrocarbon receptor to promote osteoarthritis in a rat model.

OBJECTIVE: To evaluate the role of aryl hydrocarbon receptor in the pathogenesis of osteoarthritis (OA) and its association with intestinal microbiome-related tryptophan metabolism. METHODS: Cartilage was isolated from OA patients undergoing total knee arthroplasty and analyzed for expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 of family 1, subfamily A, and polypeptide 1 (CyP1A1). To gain mechanistic insights, OA model was induced in Sprague Dawley rats after antibiotic pretreatment combined with a tryptophan-rich diet (or not). The severity of OA was assessed eight weeks after surgery according to the Osteoarthritis Research Society International grading system. Expression of AhR, CyP1A1 as well as markers of bone and cartilage metabolism, inflammation, and intestinal microbiome-related tryptophan metabolism was assessed. RESULTS: Severity of OA in cartilage from patients positively correlated with expression of AhR and CyP1A1 in chondrocytes. In the rat model of OA, antibiotic pretreatment led to lower expression of AhR and CyP1A1 and lower serum levels of lipopolysaccharide (LPS). Conversely, antibiotics upregulated Col2A1 and SOX9 in cartilage, which mitigated the cartilage damage and synovitis, reduced the relative abundance of Lactobacillus. Additional tryptophan supplementation activated intestinal microbiome-related tryptophan metabolism, antagonizing the effects of antibiotics, exacerbating OA synovitis. CONCLUSION: Our study established an underlying intestinal microbiome associated tryptophan metabolism-OA connection which sets a new target for exploring OA pathogenesis. The alteration of tryptophan metabolism might prompt the activation and synthesis of AhR, accelerating the development of OA.

Different Doses of Intravenous Tranexamic Acid in Revision Total Knee Arthroplasty: A Retrospective Study.

PURPOSE: This article assessed the efficacy and safety of different doses of intravenous tranexamic acid (TXA) in revision total knee arthroplasty (TKA). METHODS: We retrospectively identified 122 patients in our institution who underwent revision TKA with a history of perioperative intravenous TXA utilization. According to the sum of intravenous TXA documented, all patients were divided into three groups: 1 g intravenous TXA, 2 g intravenous TXA, and equal or greater than 3 g intravenous TXA. The primary outcomes included total blood loss (TBL), hidden blood loss (HBL), transfusion rate, and the incidence of symptomatic venous thromboembolism among the three groups. A correlation analysis was conducted to analyze the correlation between the dose of TXA and the blood loss. RESULTS: In total, there was no significance difference in TBL and revised HBL (rHBL) between the first two groups (1 g/dL for intravenous TXA, 2 g/dL for intravenous TXA; p = 0.486; p = 0.525). Equal or greater than 3 g intravenous TXA (≥3 g/dL for intravenous TXA) reached a significant reduction in TBL, rHBL, and length of stay compared with the first two groups (p = 0.01; p = 0.01; p = 0.01). The rate of transfusion between the three groups did not differ significantly (p = 0.21). Due to the limitations in sample size, only one symptomatic venous thromboembolism was reported in the 1 g intravenous TXA group. CONCLUSION: Applying the dose of intravenous TXA equal or greater than 3 g in revision TKA might further reduce the blood loss and shorten the length of stay.

Does living at high altitude increase the risk of bleeding events after total knee arthroplasty? A retrospective cohort study.

OBJECTIVE: Post-operative bleeding after total knee arthroplasty (TKA) is a frequent cause of post-operative complications. This study compared blood loss and indicators of coagulation and fibrinolysis between TKA patients living at low or high altitudes. METHODS: We retrospectively analyzed 120 patients at our institution who underwent primary TKA from May 2019 to March 2020, and we divided them into those living in areas about 500 m or > 3000 m above sea level. We compared the primary outcome of total blood loss between them. We also compared them in terms of several secondary outcomes: coagulation and fibrinolysis parameters, platelet count, reduction in hemoglobin, hidden blood loss, intra-operative blood loss, transfusion rate, and incidence of thromboembolic events and other complications. RESULTS: Total blood loss was significantly higher in the high-altitude group than in the low-altitude group (mean, 748.2 mL [95% CI, 658.5-837.9] vs 556.6 mL [95% CI, 496.0-617.1]; p = 0.001). The high-altitude group also showed significantly longer activated partial thromboplastin time, prothrombin time, and thrombin time before surgery and on post-operative day one, as well as increased levels of fibrinogen/fibrin degradation product on post-operative days one and three. Ecchymosis was significantly more frequent in the high-altitude group (41.7 vs 21.7%; relative risk (RR) = 1.923 [95% CI, 1.091-3.389]; p = 0.019). The two groups showed similar transfusion rates, and none of the patients experienced venous thromboembolism, pulmonary embolism, or infection. CONCLUSION: High altitude may alter coagulation and fibrinolysis parameters in a way that increases risk of blood loss after TKA. Such patients may benefit from special management to avoid bleeding events.

Improving target-disease association prediction through a graph neural network with credibility information.

Identifying effective target-disease associations (TDAs) can alleviate the tremendous cost incurred by clinical failures of drug development. Although many machine learning models have been proposed to predict potential novel TDAs rapidly, their credibility is not guaranteed, thus requiring extensive experimental validation. In addition, it is generally challenging for current models to predict meaningful associations for entities with less information, hence limiting the application potential of these models in guiding future research. Based on recent advances in utilizing graph neural networks to extract features from heterogeneous biological data, we develop CreaTDA, an end-to-end deep learning-based framework that effectively learns latent feature representations of targets and diseases to facilitate TDA prediction. We also propose a novel way of encoding credibility information obtained from literature to enhance the performance of TDA prediction and predict more novel TDAs with real evidence support from previous studies. Compared with state-of-the-art baseline methods, CreaTDA achieves substantially better prediction performance on the whole TDA network and its sparse sub-networks containing the proteins associated with few known diseases. Our results demonstrate that CreaTDA can provide a powerful and helpful tool for identifying novel target-disease associations, thereby facilitating drug discovery.

Imbalanced T-Cell Subsets May Facilitate the Occurrence of Osteonecrosis of the Femoral Head.

Background: Osteonecrosis of the femoral head (ONFH) is a complex disease resulting in degeneration of the hip joint. The pathogenesis of ONFH is largely unknown, but alterations in immunological factors have been proposed to play a role. Methods: We included 109 patients with ONFH and 109 age-, sex-, and body mass index-matched healthy controls in this study. The percentage of circulating CD3+, CD4+, and CD8+ lymphocytes among the total lymphocytes was identified by flow cytometry and compared between the cases and controls. Subgroup analysis within each etiological group and correlation analysis of T-cell subset levels with disease duration were performed. Furthermore, we compared the expression patterns of CD4, RANKL, and FoxP3 in the femoral head of healthy and glucocorticoid (GC)-treated ONFH rats. Results: The results showed that CD3+ and CD4+ T-cell counts and the CD4+/CD8+ ratio were significantly higher in patients with ONFH and that CD3+ lymphocyte levels were negatively correlated with disease duration. The CD4+ T-cell levels and CD4+/CD8+ ratios in the GC-ONFH etiological group were lower than those in the idiopathic-, traumatic-, and alcoholic-ONFH groups, while the CD8+ T-cell levels were higher. Furthermore, the CD3+, CD4+, and CD8+ T-cell counts and the CD4+/CD8+ ratio were higher in the GC-ONFH group than in the control group. Finally, we observed diminished levels of FoxP3/CD4 double-positive T regulatory cells and increased RANKL+ T-cell levels in the bone marrow of the femoral head in GC-ONFH rats. Conclusion: The imbalance of T-cell subsets might be involved in the pathophysiological process of ONFH, and diminished CD4+/FoxP3+ T regulatory cells may be associated with increased RANKL+ T cells in the bone marrow of the femoral head in GC-ONFH, which may facilitate bone resorption and collapse of the femoral head. Trial Registration: This study was registered in the Chinese Clinical Trial Registry (Registration number: ChiCTR2100042642).

Copper-Lithium-Doped Nanohydroxyapatite Modulates Mesenchymal Stem Cells Homing to Treat Glucocorticoids-Related Osteonecrosis of the Femoral Head.

In situ tissue regeneration has been demonstrated to promote bone repair. To identify a better approach for treating osteonecrosis of the femoral head (ONFH), we prepared scaffolds using copper-lithium-doped nanohydroxyapatite (Cu-Li-nHA), which has the potential to modulate mesenchymal stem cells (MSCs) homing. The scaffold was fabricated using the gas foaming method and the migration, angiogenesis, and osteogenesis activities of MSCs were detected using Transwell assays, tube formation assays, alkaline phosphatase and alizarin red S staining, respectively. We then implanted the Cu-Li-nHA scaffold into the femoral heads of ONFH rabbits, and CFSE labeled exogenous MSCs were injected intravenously to verify cell homing. The repair effect was subsequently examined using micro-CT and histological analysis in vivo. The results showed that Cu-Li-nHA significantly promoted MSCs migration and homing by upregulating the HIF-1α/SDF-1 pathway. The Cu-Li-nHA group showed optimal osteogenesis and angiogenesis and greater improvements in new bone formation in ONFH rabbits. To summarize, Cu-Li-nHA promoted homing and induced the osteogenic differentiation of MSCs, thereby enhancing bone regeneration during ONFH repair. Thus, Cu-Li-nHA implantation may serve as a potential therapeutic strategy for ONFH in the future.

The effects of body mass index on insulin resistance in patients undergoing total hip arthroplasty: a pilot study.

PURPOSE: We aimed to examine the effects of body mass index (BMI) on insulin resistance (IR), glycaemic control and adverse events in patients undergoing total hip arthroplasty (THA). METHODS: A total of 118 patients undergoing THA were enrolled in this prospective cohort study and divided into two groups based on their BMI: Group A (n = 50, 18.5 ≤ BMI < 24 kg/m2) and Group B (n = 68, BMI ≥ 24 kg/m2). IR was calculated using Homeostasis Model Assessment 2 (HOMA2). Insulin resistance indicators, fasting plasma glucose (FPG), inflammatory markers, blood loss, length of stay and complications were compared between the two groups. RESULTS: Multivariate analysis using generalized estimating equations revealed that BMI and surgery stress were risk factors for IR (P < 0.001). These two factors exhibited significant interactions for HOMA2-IR on post-operative day one (Exp (B) = 1.880, P = 0.003), accompanied by a higher level of FPG (Group B versus Group A, P = 0.004). Furthermore, subgroup analysis based on the IR value demonstrated that patients in Group B with a HOMA2-IR greater than 2.25 after surgery were at increased risk of wound complications (P = 0.045). Similarly, our results showed that the rate of post-operative hyperglycaemia was notably higher in Group B than in Group A (P = 0.013). CONCLUSION: Patients with high BMI may experience significantly elevated IR and increased risk of hyperglycaemia and wound complications after THA. Therefore, routine glycaemia monitoring should be suggested for those patients during peri-operative period to optimize surgical stress management.

Porous tantalum shell and augment for acetabular defect reconstruction in revision total hip arthroplasty: a mid-term follow-up study.

AIM: The use of porous tantalum trabecular metal (TM) shell and augment to reconstruct acetabular defects in revision total hip arthroplasty (THA) is a reliable technique. We evaluated the mid-term implant survival, clinical, and radiological outcomes of our first 48 revisions using this technique. PATIENTS AND METHODS: A total of 45 patients (48 hips) who had acetabular revision of THA between 2011 and 2017 using TM shell and augment with possible mid-term follow-up were included. Twenty-two patients were men (49%) and 23 were women (51%), mean age was 62.5 years (34 to 85) and mean follow-up was 75 months (54 to 125). Twenty-four hips (50%) had a Paprosky IIIA defect, 14 (29.2%) had a type IIIB defect, six (12.5%) had a type IIC defect, and four hips (8.3%) had a type IIB defect. None of the patients had pelvic discontinuity (PD). RESULTS: At a mean 6.25 years follow-up, all hips remained well-fixed and implant survival of 100% with the need of re-revision as the end point. Screw fixation was used for all shells; augments and the shell-augment interface was cemented. Excellent pain relief (mean WOMAC score pain 90.5, (38.3 to 100)), and functional outcomes (mean WOMAC function 88.3 (31.9 to 100), mean OHS 89.2 (31.8 to 100)) were noted. Patient satisfaction scores were excellent. CONCLUSION: This study demonstrated satisfactory mid-term clinical and radiological outcomes of using TM shell and augment for reconstructing major acetabular defects without PD in revision THA.

Intrahepatic microbes govern liver immunity by programming NKT cells.

The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from that of the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically the bacteroidetes species. Targeting bacteroidetes with oral antibiotics reduced hepatic immune cells by approximately 90%, prevented antigen-presenting cell (APC) maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial/glycosphingolipid/NKT/CCL5 axis that underlies hepatic immunity.

Additional nerve blocks are not superior to multiple-site infiltration analgesia in total knee arthroplasty under adductor canal block.

BACKGROUND: Adductor canal block (ACB) with additional nerve blocks (ANBs) is reported to provide adequate analgesia and enhanced functional rehabilitation in total knee arthroplasty (TKA). The present study aims to evaluate whether ANBs are superior to multiple-site infiltration analgesia (MIA) in patients undergoing TKA under ACB. METHODS: We enrolled 530 patients undergoing primary TKA from 2015 to 2019 at our institution in this retrospective cohort study. Patients were divided into two groups: Group A was treated with ANBs + ACB; Group B was treated with MIA + ACB. Primary outcomes were pain scores and morphine consumption. Functional recovery was the secondary outcome. Other outcomes included satisfaction score, cost-effectiveness, adverse events, and length of hospital stay (LOS). RESULTS: Pain scores at rest and morphine consumption were slightly lower in the ANBs + ACB group than in the MIA + ACB group. No significant difference was found in functional recovery, post-operative complications or LOS between the groups. Meanwhile, the cost of analgesic intervention in the MIA + ACB group was less than that in the ANBs + ACB group. CONCLUSION: The present study suggests that ANBs do not provide superior pain relief compared to MIA for patients undergoing TKA under ACB. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100043227. Registered 9 February 2021, https://www.chictr.org.cn/showproj.aspx?proj=121745 .

Meta-analysis of retrospective studies suggests that the pre-operative opioid use is associated with an increased risk of adverse outcomes in total hip and or knee arthroplasty.

BACKGROUND: Opioid use is prevalent in the general population. This systematic review and meta-analysis sought to evaluate whether it affects patient-reported outcomes (PROs) following total hip or knee arthroplasty. METHODS: The following databases were systematically searched on February 5, 2020: Medline, Embase (Ovid), Cochrane Library, and Web of Science. Studies were included if they compared patients who received opioids or not before total hip or knee arthroplasty. Outcomes of interest were rates of post-operative revision, peri-prosthetic infection, and readmission. RESULTS: Ten retrospective studies were included for review. Pre-operative opioid use was identified as a risk factor for post-operative revision [odds ratio (OR) 1.58, 95% confidence interval (CI) 1.15-1.73, p<0.01], peri-prosthetic infection (OR 1.36, 95% CI 1.08-1.71, p=0.01), and readmission (OR 1.41, 95% CI 1.20-1.75, p<0.01). CONCLUSION: The available evidence indicates that pre-operative opioid use increases the risk of adverse outcomes following total hip or knee arthroplasty. Orthopedic physicians should consider these risks when treating their patients.

Comparison of Postoperative Outcomes Between Traditional Longitudinal Incision and Bikini Incision in Total Hip Arthroplasty via Direct Anterior Approach: A Randomized Controlled Trial.

BACKGROUND: The purpose of this study is to compare a traditional longitudinal incision to an oblique "bikini" incision during total hip arthroplasty (THA) via direct anterior approach (DAA), in terms of the aesthetic appearance of the scar, postoperative functional recovery, and complications. METHODS: This study is a single-surgeon experience in the Chinese population. Patients who came to our institute needing a THA via DAA were enrolled in our randomized controlled trial and randomly allocated to undergo traditional longitudinal incision (control) or bikini incision. Primary outcomes were measured using the scar cosmesis assessment and rating scale, the visual analog scale for pain, Oxford hip score, and University of California Los Angeles activity-level rating. Secondary outcomes were postoperative serum markers of muscle damage, inflammation, hemoglobin drop, and implant stability. The occurrence of postoperative complications, such as nerve and wound healing, was also recorded. RESULTS: There were no differences in demographic or clinical characteristics before surgery. A greater proportion of patients in the bikini group were satisfied with the appearance of their scar, giving significantly better scar cosmesis assessment and rating scores. There was no difference in postoperative functional recovery, levels of serum markers, or positioning of the implant components. Incision type had no effect on duration of hospitalization. The incidence of complications did not differ significantly between groups. CONCLUSION: The bikini incision can improve patients' subjective satisfaction with scar aesthetics after THA via DAA and does not detract from a quick functional recovery. Studies with larger sample sizes should be conducted to further investigate associated complications. THE CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR1900022870.