High-Dose Compound Betamethasone Used in Local Infiltration Analgesia Does Not Increase Reinfection Rates Following Periprosthetic Joint Infection Treatment.

BACKGROUND: The administration of cocktails that contain glucocorticoids for local infiltration analgesia (LIA) is highly advocated and has been shown to be effective in managing pain in total joint arthroplasty (TJA). However, it remains ambiguous whether this protocol maintains its safety and efficacy in the treatment of periprosthetic joint infection (PJI), a devastating complication of TJA. METHODS: A comprehensive retrospective study was carried out on 299 single-stage revision cases for PJI spanning the years 2010 to 2021. Of these, 127 received LIAs containing high-dose compound betamethasone (CB) were termed the CB group, and the other 172 were termed the non-CB group. The rates of reinfection and other postoperative complications, along with postoperative visual analog scale (VAS) scores, and opioid consumption were compared. RESULTS: During minimum 2-year follow-up, there was no significant difference in the reinfection rate between the non-CB and CB groups (9.3 versus 8.7%; P = 0.85), consistent within the subsets of hip (8.4 versus 4.5%; P = 0.51) and knee (10.4 versus 13.3%; P = 0.60) PJIs individually. The administration of high-dose CB was neither an independent risk factor for reinfection (P > 0.05; 95% CI [confidence interval] including 1) nor was it associated with the occurrence of reinfection (P > 0.05). The incidence of postoperative nausea and vomiting (PONV) was significantly lower in the CB group (P < 0.05). In the initial 48-hour postoperative period, the CB group exhibited lower mean scores in both resting and movement VAS evaluations (P < 0.05). Notably, the movement VAS scores of the CB group remained lower even at 72 hours post-surgery for knee PJIs (P < 0.001). Furthermore, within the first 72 hours post-surgery, the necessity for additional opioid analgesics in the CB group was significantly reduced compared to the non-CB group (P < 0.05). CONCLUSION: A LIA with a high-dose compound betamethasone reduces postoperative pain, opioid consumption, and the incidence of PONV following a single-stage revision without affecting reinfection and other complication rates.

Efficacy and safety of intra-articular-only meropenem after one-stage revision for treating Escherichia coli-induced periprosthetic joint infection in a rat model.

Aims: The optimum type of antibiotics and their administration route for treating Gram-negative (GN) periprosthetic joint infection (PJI) remain controversial. This study aimed to determine the GN bacterial species and antibacterial resistance rates related to clinical GN-PJI, and to determine the efficacy and safety of intra-articular (IA) antibiotic injection after one-stage revision in a GN pathogen-induced PJI rat model of total knee arthroplasty. Methods: A total of 36 consecutive PJI patients who had been infected with GN bacteria between February 2015 and December 2021 were retrospectively recruited in order to analyze the GN bacterial species involvement and antibacterial resistance rates. Antibiotic susceptibility assays of the GN bacterial species were performed to screen for the most sensitive antibiotic, which was then used to treat the most common GN pathogen-induced PJI rat model. The rats were randomized either to a PJI control group or to three meropenem groups (intraperitoneal (IP), IA, and IP + IA groups). After two weeks of treatment, infection control level, the side effects, and the volume of antibiotic use were evaluated. Results: Escherichia coli was the most common pathogen in GN-PJI, and meropenem was the most sensitive antibiotic. Serum inflammatory markers, weightbearing activity, and Rissing score were significantly improved by meropenem, especially in the IA and IP + IA groups ( p < 0.05). Meropenem in the IA group eradicated E. coli from soft-tissue, bone, and prosthetic surfaces, with the same effect as in the IP + IA group. Radiological results revealed that IA and IP + IA meropenem were effective at relieving bone damage. Haematoxylin and eosin staining also showed that IA and IP + IA meropenem improved synovial inflammation and bone destruction. No pathological changes in the main organs or abnormal serum markers were observed in any of the meropenem-treated rats. The IA group required the lowest amount of meropenem, followed by the IP and IP + IA groups. Conclusion: IA-only meropenem with a two-week treatment course was effective and safe for PJI control following one-stage revision in a rat model, with less meropenem use.

High-Entropy Materials for Application: Electricity, Magnetism, and Optics.

High-entropy materials (HEMs) have recently emerged as a prominent research focus in materials science, gaining considerable attention because of their complex composition and exceptional properties. These materials typically comprise five or more elements mixed approximately in equal atomic ratios. The resultant high-entropy effects, lattice distortions, slow diffusion, and cocktail effects contribute to their unique physical, chemical, and optical properties. This study reviews the electrical, magnetic, and optical properties of HEMs and explores their potential applications. Additionally, it discusses the theoretical calculation methods and preparation techniques for HEMs, thereby offering insights and prospects for their future development.

The effects of ambient temperature on non-accidental mortality in the elderly hypertensive subjects, a cohort-based study.

BACKGROUND: The association between ambient temperature and mortality has yielded inconclusive results with previous studies relying on in-patient data to assess the health effects of temperature. Therefore, we aimed to estimate the effect of ambient temperature on non-accidental mortality among elderly hypertensive patients through a prospective cohort study conducted in northeastern China. METHODS: A total of 9634 elderly hypertensive patients from the Kailuan research who participated in the baseline survey and follow-up from January 1, 2006 to December 31, 2017, were included in the study. We employed a Poisson generalized linear regression model to estimate the effects of monthly ambient temperature and temperature variations on non-accidental mortality. RESULTS: After adjusting for meteorological parameters, the monthly mean temperature (RR = 0.989, 95% CI: 0.984-0.993, p < 0.001), minimum temperature (RR = 0.987, 95% CI: 0.983-0.992, p < 0.001) and maximum temperature (RR = 0.989, 95% CI: 0.985-0.994, p < 0.001) exhibited a negative association with an increased risk of non-accidental mortality. The presence of higher monthly temperature variation was significantly associated with an elevated risk of mortality (RR = 1.097, 95% CI:1.051-1.146, p < 0.001). Further stratified analysis revealed that these associations were more pronounced during colder months as well as among male and older individuals. CONCLUSIONS: Decreased temperature and greater variations in ambient temperature were observed to be linked with non-accidental mortality among elderly hypertensive patients, particularly notable within aging populations and males. These understanding regarding the effects of ambient temperature on mortality holds clinical significance for appropriate treatment strategies targeting these individuals while also serving as an indicator for heightened risk of death.

Vegetation restoration enhancing soil carbon sequestration in karst rocky desertification ecosystems: A meta-analysis.

Vegetation restoration measures have been increasingly employed to alleviate rocky desertification in karst ecosystems. However, the comprehensive effects of these interventions on soil properties and soil organic carbon (SOC) remain poorly understood. Herein, we gathered 644 paired observations from 68 studies and conducted a meta-analysis to quantify the performance of different vegetation restoration measures including moss (MS), grassland (GL), cash crop (CP), shrub (SH), and secondary forest (SF) through soil properties and SOC. Our results demonstrated significant effects of MS, GL, CP, SH, and SF on soil biotic and abiotic factors, each with distinct response characteristics. Particularly, MS significantly enhanced all soil properties (excluding a slight decrease in soil pH by 10.8%). Moreover, MS, GL, CP, SH, and SF could elevate SOC by 32.1%, 17.6%, 24.9%, 59.2%, and 48.7% respectively. Utilizing random forest and linear regression models, we identified primary drivers for SOC in MS, GL, CP, SH, and SF as soil moisture content, arbuscular mycorrhizal fungi, soil microbial phosphorus, total nitrogen, and ß-1,4-glucosidase, respectively. This meta-analysis underlined the varied effects of vegetation restoration measures on soil properties and advocates for restoration measures that prioritize plant productivity and reduce soil temperature during the karst rocky desertification restoration process. Additionally, this study underscores the pivotal role of vegetation rehabilitation in environmental conservation and carbon sequestration of ecologically vulnerable regions.

[Medium- and long-term effectiveness of hip revision with SL-PLUS MIA stem in patients with Paprosky type â - â ¢ femoral bone defect].

Objective: To investigate the medium- and long-term effectiveness of hip revision with SL-PLUS MIA stem in patients with Paprosky typeⅠ-Ⅲ femoral bone defect. Methods: Between June 2012 and December 2018, 44 patients with Paprosky typeⅠ-Ⅲ femoral bone defect received hip revision using SL-PLUS MIA stem. There were 28 males and 16 females, with an average age of 57.7 years (range, 31-76 years). Indications for revision comprised aseptic loosening (27 cases) and periprosthetic joint infection (17 cases). The Harris hip scores were 54 (48, 60) and 43 (37, 52) in patients with aseptic loosening and periprosthetic joint infection, respectively. The preoperative femoral bone defects were identified as Paprosky type Ⅰ in 32 cases, type Ⅱ in 9 cases, type ⅢA in 2 cases, and type ⅢB in 1 case. Operation time and intraoperative blood transfusion volume were recorded. During follow-up after operation, the hip joint function were evaluated by Harris hip score and X-ray films, the femoral stem survival was analyzed, and the surgical related complications were recorded. Results: The operation time of infected patients was 95-215 minutes, with an average of 125.0 minutes. The intraoperative blood transfusion volume was 400-1 800 mL, with an average of 790.0 mL. The operation time of patients with aseptic loosening was 70-200 minutes, with an average of 121.0 minutes. The intraoperative blood transfusion volume was 400-1 400 mL, with an average of 721.7 mL. All patients were followed up 5.3-10.0 years (mean, 7.4 years). At last follow-up, the Harris hip scores were 88 (85, 90) and 85 (80, 88) in patients with aseptic loosening and periprosthetic joint infection, respectively, both of which were significantly higher than those before operation ( P<0.05). Radiological examination results showed that the distal end of the newly implanted femoral stem did not cross the distal end of the original prosthesis in 25 cases, and all femoral stems obtained bone fixation. Two cases experienced femoral stem subsidence and 1 case had a translucent line on the lateral side of the proximal femoral stem. When aseptic loosening was defined as the end event, the 10-year survival rate of the SL-PLUS MIA stem was 100%. When treatment failure due to any reason was defined as the end event, the survival time of the prosthesis was (111.70±3.66) months, and the 7-year survival rate was 95.5%. The 7-year survival rates were 94.1% and 96.3% in patients with aseptic loosening and periprosthetic joint infection, respectively. The incidence of postoperative complications was 9.1% (4/44), among which the prosthesis related complications were 4.5% (2/44), 1 case of dislocation and 1 case of infection recurrence. Conclusion: Hip revision with SL-PLUS MIA stem has the advantages of simple operation and few postoperative complications in the patients with Paprosky type Ⅰ-Ⅲ femoral bone defect, and the medium- and long-term effectiveness is reliable.

Conservative femoral revision using short cementless stems with a tapered rectangular shape for selected Paprosky II-IV bone defects: an average seven-year follow-up.

BACKGROUND: The use of long stems for severe femoral bone defects is suggested by many scholars, but it is associated with further bone loss, intraoperative fracture, increased surgical trauma, and complications. With better bone retention, simple and quick surgical procedures, and minimal complications, the short cementless stems with a tapered rectangular shape may be an alternative for femoral revision. This study aimed to evaluate the results of this type of stem in treating selected Paprosky II-IV bone defects. METHODS: This retrospective study included 73 patients (76 hips involved) who underwent conservative femoral revision using the short cementless stems with a tapered rectangular shape between January 2012 and December 2020. The preoperative femoral bone defects were identified as follows: 54 cases of type II, 11 cases of type IIIA, 7 cases of type IIIB, and 4 cases of type IV. Indications for revision included aseptic loosening (76.3%) and prosthetic joint infection (23.7%). Six cementless stems with a tapered rectangular shape from three companies were used in all patients. Among them, SLR-Plus, SL-Plus MIA, and Corail stems were employed in most patients (40.8%, 23.7%, and 17.1%, respectively). The average length of these stems measured 171.7 mm (SD 27 mm; 122-215 mm). Radiographic results, Harris hip scores (HHS), complications, and survivorship were analyzed. The follow-up lasted for 7 years on average (range 3-11 years). RESULTS: The subsidence was observed in three hips (3.9%), and all stems achieved stable bone ingrowth. Proximal femoral bone restoration in the residual osteolytic area was found in 67 hips (88.2%), constant defects in nine hips (11.8%), and increasing defects in 0 cases. There was no evidence of stem fractures and stem loosening in this series. The mean HHS significantly improved from 32 (range 15-50) preoperatively to 82 (range 68-94) at the last follow-up (t = - 36.297, P < 0.001). Five hips developed prosthesis-related complications, including three infection and two dislocation cases. The mean 5- and 10-year revision-free survivorships for any revision or removal of an implant and reoperation for any reason were 94.6% and 93.3%, respectively. Both mean 5- and 10-year revision-free survivorships for aseptic femoral loosening were 100%. CONCLUSION: Conservative femoral revision using short cementless stems with a tapered rectangular shape can provide favorable radiographic outcomes, joint function, and mid-term survivorship with minimal complications. Of note, a sclerotic proximal femoral bone shell with continued and intact structure and enough support strength is the indication for using these stems.

Rocky desertification succession alters soil microbial communities and survival strategies in the karst context.

Rocky desertification is one of the most ecological problems in the karst context. Although extensive research has been conducted to explore how to restore and protect, the responses of soil fungi and archaea to rocky desertification succession remain limited. Here, four grades of rocky desertification in a karst ecosystem were selected, amplicon sequencing analysis was conducted to investigate fungal and archaeal community adaptation in response to rocky desertification succession. Our findings revealed that the diversity and community structure of fungi and archaea in soils declined with the aggravation of rocky desertification. As the rocky desertification succession intensified, microbial interactions shifted from cooperation to competition. Microbial survival strategies were K-strategist and r-strategist dominated in the early and late stages of succession, respectively. Additionally, the driving factors affecting microorganisms have shifted from vegetation diversity to soil properties as the intensification of rocky desertification. Collectively, our study highlighted that plant diversity and soil properties play important roles on soil microbiomes in fragile karst ecosystems and that environmental factors induced by human activities might still be the dominant factor exacerbating rocky desertification, which could significantly enrich our understanding of microbial ecology within karst ecosystems.

Correlation analysis of serum TLR4 protein levels and TLR4 gene polymorphisms in gouty arthritis patients.

OBJECTIVE: The Toll-like receptor (TLR) 4-mediated nuclear factor kappa B (NF-κB) signaling pathway regulates the production of inflammatory factors and plays a key role in the pathogenesis of gouty arthritis. The aim of the present study was to investigate the link among TLR4 gene polymorphisms at various loci, protein expression, and gouty arthritis susceptibility. METHODS: Between 2016 and 2021, a case-control study was used to collect a total of 1207 study subjects, including 317 male patients with gouty arthritis (gout group) and 890 healthy males (control group). The association between gout susceptibility and different genetic models was analyzed by typing three loci of the TLR4 gene (rs2149356, rs2737191, and rs10759932) using a multiplex point mutation rapid assay, and the association between protein expression and gout was confirmed by measuring TLR4 protein concentrations using enzyme-linked immunosorbent assays (ELISAs). RESULTS: In a codominant models AA and AG, the rs2737191 polymorphism in the gout group increased the risk of gout compared to the AA genotype (OR = 2.249, 95%CI 1.010~5.008), and the risk of gout was higher for those carrying the G allele compared to the A allele (OR = 2.227, 95%CI 1.006~4.932). TLR4 protein expression was different between the two groups with different locus genotypes. The differences in TLR4 protein expression between the gout group and control group were statistically significant between the following genotypes: the GG and GT genotypes of the rs2149356 polymorphism; the AA and AG genotypes of the rs2737191 polymorphism; and the TT and TC genotypes of the rs10759932 polymorphism(P<0.05). The TLR4 protein level in the gout group (19.19±3.09 ng/ml) was significantly higher than that in the control group (15.85±4.75 ng/ml). CONCLUSION: The AG genotype of the TLR4 gene rs2737191 polymorphism may be correlated with the development of gouty arthritis. The level of TLR4 protein expression is significantly higher in patients with gouty arthritis than in controls, and there is a correlation between high TLR4 protein expression and the development of gouty arthritis.

Iron decoration in binary graphene oxide and copper iron sulfide nanocomposites boosting catalytic antibacterial activity in acidic microenvironment against antimicrobial resistance.

The strong antimicrobial resistance (AMR) of multidrug-resistant (MDR) bacteria and biofilm, especially the biofilm with extracellular polymeric substance (EPS) protection and persister cells, not only renders antibiotics ineffective but also causes chronic infections and makes the infectious tissue difficult to repair. Considering the acidic properties of bacterial infection microenvironment and biofilm, herein, a binary graphene oxide and copper iron sulfide nanocomposite (GO/CuFeSx NC) is synthesized by a surfactant free strategy and utilized as an alternative smart nanozyme to fight against the MDR bacteria and biofilm. For the GO/CuFeSx NC, the iron decoration facilitates the well distribution of bimetallic CuFeSx NPs on the GO surfaces compared to monometallic CuS NPs, providing synergistically enhanced peroxidase (POD)-like activity in acidic medium (pH 4 âˆ¼ 5) and intrinsic strong near infrared (NIR) light responsive photothermal activity, while the ultrathin and sharp structure of 2D GO nanosheet allows the GO/CuFeSx NC to strongly interact with the bacteria and biofilm, facilitating the catalytic and photothermal attacks on the bacterial surfaces. In addition, the GO in GO/CuFeSx NC exhibits a "Pseudo-Photo-Fenton" effect to promote the ROS generation. Therefore, the GO/CuFeSx NC can effectively kill bacteria and biofilm both in vitro and in vivo, finally eliminating the infections and accelerating the tissue repair when treating the biofilm-infected wound. This work paves a new way to the design of novel nanozyme for smart antibacterial therapy against antimicrobial resistance.

Multiparametric MRI-based radiomics combined with pathomics features for prediction of the efficacy of neoadjuvant chemotherapy in breast cancer.

Purpose: The aim of this study is to investigate a new method that combines radiological and pathological breast cancer information to predict discrepancies in pathological responses for individualized treatment planning. We used baseline multiparametric magnetic resonance imaging and hematoxylin and eosin-stained biopsy slides to extract quantitative feature information and predict the pathological response to neoadjuvant chemotherapy in breast cancer patients. Methods: We retrospectively collected data from breast cancer patients who received neoadjuvant chemotherapy in our hospital from August 2016 to January 2018; multiparametric magnetic resonance imaging (contrast-enhanced T1-weighted imaging and diffusion-weighted imaging) and whole slide image of hematoxylin and eosin-stained biopsy sections were collected. Quantitative imaging features were extracted from the multiparametric magnetic resonance imaging and the whole slide image were used to construct a radiopathomics signature model powered by machine learning methods. Models based on multiparametric magnetic resonance imaging or whole slide image alone were also constructed for comparison and referred to as the radiomics signature and pathomics signature models, respectively. Four modeling methods were used to establish prediction models. Model performances were evaluated using receiver operating characteristic curve analysis and the area under the curve, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. Results: The radiopathomics signature model had favourable performance for the prediction of pathological complete response in the training set (the best value: area under the curve 0.83, accuracy 0.84, and sensitivity 0.87), and in the test set (the best value: area under the curve 0.91, accuracy 0.90, and sensitivity 0.88). In the test set, the radiopathomics signature model also significantly outperformed the radiomics signature (the best value: area under the curve 0.83, accuracy 0.64, and sensitivity 0.62), pathomics signature (the best value: area under the curve 0.60, accuracy 0.74, and sensitivity 0.62) (p > 0.05). Decision curve analysis and calibration curves confirmed the excellent performance of these prediction models in discrimination, calibration, and clinical usefulness. Conclusions: The results of this study suggest that radiopathomics, the combination of both radiological information regarding the whole tumor and pathological information at the cellular level, could potentially predict discrepancies in pathological response and provide evidence for rational treatment plans.

Intensive N2 fixation accelerates microbial turnover in cropland soils.

Biological nitrogen fixation (BNF) is strongly affected by the carbon (C) and nitrogen (N) stoichiometry in soil and depends on the input of organic C. Due to the high metabolic costs of nitrogenase activity, however, the response of BNF to organic C input and its impact on microbial turnover remain unclear. To address this knowledge gap, we combined 15N2 tracing with high-throughput sequencing by adding glucose or glucose plus mineral N fertilizer for a 12-day incubation in three cropland soils. Glucose addition alone strongly changed the BNF activity (0.76-2.51 mg N kg-1 d-1), while BNF was completely absent after mineral N fertilization. This switch-on of BNF by glucose addition supported equally high rates of microbial growth and organic C mineralization compared with the direct mineral N assimilation by microorganisms. Glucose-induced BNF was predominantly catalyzed by Azotobacter-affiliated free-living diazotrophs (>50 % of the total nifH genes), which increased with diverse nondiazotrophs such as Nitrososphaera, Bacillus and Pseudoxanthomonas. Structural equation models (SEMs) and random forest (RF) analyses consistently revealed that the soil C:N ratio and Azotobacter-affiliated diazotrophic abundances were the key factors affecting glucose-induced BNF. Our findings emphasize the importance of free-living diazotrophs for microbial turnover of organic C in soil.

[Effectiveness of one-stage total knee arthroplasty in treatment of advanced active knee tuberculosis].

Objective: To investigate the effectiveness of one-stage total knee arthroplasty (TKA) in the treatment of advanced active knee tuberculosis. Methods: The clinical data of 38 patients with advanced active knee tuberculosis who received one-stage TKA between January 2011 and December 2020 were retrospectively analyzed. There were 20 males and 18 females. The age ranged from 20 to 84 years, with an average of 52.8 years. The body mass index ranged from 17 to 36 kg/m 2, with an average of 23.05 kg/m 2. The preoperative C reactive protein (CRP) was (23.49±4.72) mg/L, erythrocyte sedimentation rate (ESR) was (45.95±8.82) mm/1 h. The Hospital for Special Surgery (HSS) score was 48.8±9.1. During the operation, the infected lesions of the knee joint were completely removed, and the operative area was repeatedly soaked with 3% hydrogen peroxide solution and 0.5% povidone iodine solution. The intraoperative pathological examination confirmed the tuberculosis of the knee joint, and systemic anti-tuberculosis treatment was performed. The operation time, postoperative hospitalization stay, postoperative anti-tuberculosis chemotherapy time, and complications were recorded. CRP and ESR were recorded and compared before and after operation. Anteroposterior and lateral X-ray films of the knee joint were taken to evaluate whether the prosthesis had signs of loosening and sinking, and to determine whether there was recurrence of tuberculosis. The knee joint function was evaluated by HSS score. With treatment failure due to any reason as the end event, the survival time of prosthesis was analyzed by Kaplan-Meier survival curve. Results: All operations were successfully completed without fracture, vascular and nerve injury, deep vein thrombosis, and other complications. All incisions healed by first intention after operation. The operation time ranged from 80 to 135 minutes, with an average of 102.76 minutes; postoperative hospitalization stay was 5-16 days, with an average of 9.7 days; the duration of postoperative anti-tuberculosis chemotherapy ranged from 1 to 18 months, and the median duration was 12 months. All 38 cases were followed up 3-133 months (mean, 63.7 months). At last follow-up, CRP was (4.88±1.24) mg/L and ESR was (13.00±2.97) mm/1 h, both of which were significantly lower than those before operation ( t=20.647, P<0.001; t=20.886, P<0.001). During the follow-up, 3 patients (7.89%) had tuberculosis recurrence. Two patients had tuberculosis recurrence due to withdrawal of anti-tuberculosis chemotherapy at 1 and 2 months after operation, respectively. One patient was cured after debridement, preservation of prosthesis and anti-tuberculosis chemotherapy for 12 months, and 1 patient was cured after oral administration of anti-tuberculosis drugs for 12 months. Another 1 patient had recurrent tuberculosis and mixed infection ( Corynebacterium gehreni) at 2 months after operation, and the infection was not controlled after debridement, and finally the thigh was amputated. Except for the patients with recurrent infection, no complications such as prosthesis loosening, periprosthetic fracture, and periprosthetic infection were found. At last follow-up, the HSS score of the knee joint was 86.8±4.8, and the knee joint function significantly improved when compared with that before operation ( t=-31.198, P<0.001). Prosthesis survival time was (122.57±5.77) months [95% CI (111.25, 133.88) months], and the 10-year survival rate was 92.1%. Conclusion: One-stage TKA combined with postoperative antituberculous chemotherapy in the treatment of advanced active knee tuberculosis can achieve satisfactory infection control and joint function.

METTL3 (Methyltransferase Like 3)-Dependent N6-Methyladenosine Modification on Braf mRNA Promotes Macrophage Inflammatory Response and Atherosclerosis in Mice.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, in which macrophages determine the progression of atherosclerotic plaques. However, no studies have investigated how METTL3 (methyltransferase like 3) in macrophages affects atherosclerotic plaque formation in vivo. Additionally, whether Braf mRNA is modified by METTL3-dependent N6-methyladenosine (m6A) methylation remains unknown. METHODS: We analyzed single-cell sequencing data of atherosclerotic plaques in mice fed with a high fat diet for different periods. Mettl3fl/fl Lyz2cre Apoe-/- mice and littermate control Mettl3fl/fl Apoe-/- mice were generated and fed high fat diet for 14 weeks. In vitro, we stimulated peritoneal macrophages with ox-LDL (oxidized low-density lipoprotein) and tested the mRNA and protein expression levels of inflammatory factors and molecules regulating ERK (extracellular signal-regulated kinase) phosphorylation. To find METTL3 targets in macrophages, we performed m6A-methylated RNA immunoprecipitation sequencing and m6A-methylated RNA immunoprecipitation-qPCR. Further, point mutation experiments were used to explore m6A-methylated adenine. Using RNA immunoprecipitation assay, we explored m6A methylation-writing protein bound to Braf mRNA. RESULTS: In vivo, METTL3 expression in macrophages increased with the progression of atherosclerosis. Myeloid cell-specific METTL3 deletion negatively regulated atherosclerosis progression and the inflammatory response. In vitro, METTL3 knockdown or knockout in macrophages attenuated ox-LDL-mediated ERK phosphorylation rather than JNK (c-Jun N-terminal kinase) and p38 phosphorylation and reduced the level of inflammatory factors by affecting BRAF protein expression. The negative regulation of inflammation response caused by METTL3 knockout was rescued by overexpression of BRAF. In mechanism, METTL3 targeted adenine (39725126 in chromosome 6) on the Braf mRNA. Then, YTHDF1 could bind to m6A-methylated Braf mRNA and promoted its translation. CONCLUSIONS: Myeloid cell-specific Mettl3 deficiency suppressed hyperlipidemia-induced atherosclerotic plaque formation and attenuated atherosclerotic inflammation. We identified Braf mRNA as a novel target of METTL3 in the activation of the ox-LDL-induced ERK pathway and inflammatory response in macrophages. METTL3 may represent a potential target for the treatment of atherosclerosis.

Effects of Adding Morphine to Periarticular Infiltration Analgesia Combined with Single Dose Epidural Morphine in Total Knee Arthroplasty: A Randomized Controlled Study.

OBJECTIVE: Morphine plays an important role in postoperative analgesia after total knee arthroplasty (TKA). However, there are limited data that investigate the administration ways of morphine. To evaluate the efficacy and safety of adding morphine to periarticular infiltration analgesia (PIA) combined with single-dose epidural morphine for the patients undergoing TKA. METHODS: In total, 120 patients with knee osteoarthritis who underwent the primary TKA from April 2021 and March 2022 were randomized into three groups (a cocktail containing morphine with single-dose epidural morphine [Group A]; a cocktail containing morphine [Group B]; and a cocktail free of morphine [Group C]). The three groups were compared based on the Visual Analog Score at rest and during motion, requirement of tramadol, functional recovery including quadriceps strength and range of motion, and adverse events including nausea and vomiting and local and systemic adverse events. The repetitive measure analysis of variance and chi-square test among three groups were used to analyze the results. RESULTS: Analgesia strategy in Group A (0.4 ± 0.8, and 0.9 ± 1.0 points, respectively) significantly reduced rest pain at 6 and 12 h after surgery relative to Group B (1.6 ± 1.2, and 2.2 ± 1.4 points, respectively) (p < 0.001), and the analgesic effect of Group B was stronger than that of Group C (2.1 ± 0.9, and 2.6 ± 0.9 points, respectively) (p < 0.05). Rest pain at 24 h after surgery was significantly lower in Group A (2.5 ± 0.8 points) and B (1.9 ± 1.0 points) than in Group C (2.5 ± 0.8) (p < 0.05). Within 24 h after surgery, the requirements for tramadol in Group A (0.25 g) and Group B (0.35 g) were significantly lower than those in Group C (0.75 g) (p < 0.05). Within 4 days of surgery, the quadriceps strength in the three groups increased gradually, and no statistical significance was noted among the three groups (p > 0.05). From the second day to the fourth day after surgery, although the three groups showed no statistical difference in the range of motion, the result of Group C was inferior to that of the other two groups. There were no significant differences in the incidence of postoperative nausea and vomiting and metoclopramide consumption among the three groups (p > 0.05). CONCLUSION: PIA combined with single-dose epidural morphine effectively reduces early postoperative pain and tramadol requirement as well as few complications, which can become a safe and effective measure to improve postoperative pain after TKA.

One-stage revision using intra-articular carbapenem infusion effectively treats chronic periprosthetic joint infection caused by Gram-negative organisms.

Gram-negative periprosthetic joint infection (PJI) has been poorly studied despite its rapidly increasing incidence. Treatment with one-stage revision using intra-articular (IA) infusion of antibiotics may offer a reasonable alternative with a distinct advantage of providing a means of delivering the drug in high concentrations. Carbapenems are regarded as the last line of defense against severe Gram-negative or polymicrobial infection. This study presents the results of one-stage revision using intra-articular carbapenem infusion for treating Gram-negative PJI, and analyzes the characteristics of bacteria distribution and drug sensitivity. We retrospectively reviewed 32 patients (22 hips and 11 knees) who underwent single-stage revision combined with IA carbapenem infusion between November 2013 and March 2020. The IA and intravenous (IV) carbapenem infusions were administered for a single Gram-negative infection, and IV vancomycin combined with IA carbapenems and vancomycin was applied for polymicrobial infection including Gram-negative bacteria. The bacterial community distribution, drug sensitivity, infection control rate, functional recovery, and complications were evaluated. Reinfection or death caused by PJI was regarded as a treatment failure. Gram-negative PJI was mainly caused by Escherichia coli (8/34), Enterobacter cloacae (7/34), and Klebsiella pneumoniae (5/34). Seven cases (7/32) involved polymicrobial PJIs. The resistance rates of penicillin, cephalosporin, quinolones, and sulfonamides were > 10%, and all penicillin and partial cephalosporins (first and second generation) were > 30%. Of 32 cases, treatment failed to eradicate infection in only three cases (9.4%), at a mean follow-up of 55.1 months (SD 25 to 90). The mean postoperative Harris Hip Score and Hospital for Special Surgery knee score at the most recent follow-up were 81 (62 to 91) and 79 (56 to 89), respectively. One patient developed a fistula, and another presented with a local rash on an infected joint. The use of IA carbapenem delivered alongside one-stage revision effectively controlled Gram-negative infection and obtained acceptable clinical outcomes with few complications. Notably, first- and second-generation cephalosporins and penicillin should be administrated with caution, due to a high incidence of resistance.

Prediction of brain age using quantitative parameters of synthetic magnetic resonance imaging.

Objective: Brain tissue changes dynamically during aging. The purpose of this study was to use synthetic magnetic resonance imaging (syMRI) to evaluate the changes in relaxation values in different brain regions during brain aging and to construct a brain age prediction model. Materials and methods: Quantitative MRI was performed on 1,000 healthy people (≥ 18 years old) from September 2020 to October 2021. T1, T2 and proton density (PD) values were simultaneously measured in 17 regions of interest (the cerebellar hemispheric cortex, pons, amygdala, hippocampal head, hippocampal tail, temporal lobe, occipital lobe, frontal lobe, caudate nucleus, lentiform nucleus, dorsal thalamus, centrum semiovale, parietal lobe, precentral gyrus, postcentral gyrus, substantia nigra, and red nucleus). The relationship between the relaxation values and age was investigated. In addition, we analyzed the relationship between brain tissue values and sex. Finally, the participants were divided into two age groups: < 60 years old and ≥ 60 years old. Logistic regression analysis was carried out on the two groups of data. According to the weight of related factors, a brain age prediction model was established and verified. Results: We obtained the specific reference value range of different brain regions of individuals in different age groups and found that there were differences in relaxation values in brain tissue between different sexes in the same age group. Moreover, the relaxation values of most brain regions in males were slightly higher than those in females. In the study of age and brain relaxation, it was found that brain relaxation values were correlated with age. The T1 values of the centrum semiovale increased with age, the PD values of the centrum semiovale increased with age, while the T2 values of the caudate nucleus and lentiform nucleus decreased with age. Seven brain age prediction models were constructed with high sensitivity and specificity, among which the combined T1, T2 and PD values showed the best prediction efficiency. In the training set, the area under the curve (AUC), specificity and sensitivity were 0.959 [95% confidence interval (CI): 0.945-0.974], 91.51% and 89.36%, respectively. In the test cohort, the above indicators were 0.916 (95% CI: 0.882-0.951), 89.24% and 80.33%, respectively. Conclusion: Our study provides specific reference ranges of T1, T2, and PD values in different brain regions from healthy adults of different ages. In addition, there are differences in brain relaxation values in some brain regions between different sexes, which help to provide new ideas for brain diseases that differ according to sex. The brain age model based on synthetic MRI is helpful to determine brain age.

High expression of TTC21A predicts unfavorable prognosis and immune infiltrates in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is the most common pathological type of renal cell carcinoma. Tetratricopeptide repeat domain 21A (TTC21A), known as a component of intraflagellar transport complex A which is essential for the function of cilia, However, the role of TTC21A remains unclear in ccRCC. For the first time, we explore the role and potential mechanism of TTC21A in ccRCC based on multiple databases. Methods: TTC21A expression across all TCGA tumor was analyzed via Tumor Immune Estimation Resource (TIMER) site. The correlation between TTC21A and clinicopathologic characteristics of ccRCC was analyzed with TCGA database. The diagnostic and prognostic value of TTC21A was evaluated by receiver operation characteristic curve, Kaplan-Meier plotter and Cox regression respectively. Moreover, functional enrichment analysis of TTC21A and the co-expression genes were performed by Gene Set Enrichment Analysis. The correlation of TTC21A and immune infiltration were evaluated by single sample Gene Set Enrichment Analysis. Results: Pan-cancer analysis indicated that TTC21A was highly expressed in ccRCC and other cancer. In addition, elevated expression of TTC21A was associated with worse overall survival in ccRCC patients. Functional enrichment analysis showed that TTC21A and the co-expressed genes enriched in glucose metabolism and energy metabolism. Moreover, TTC21A expression was associated with infiltrating levels of dendritic cell, nature killer cell and other immune marker sets. Conclusion: The results of analysis indicate that expression of TTC21A is associated with poor prognosis and immune infiltrating in ccRCC, which suggested TTC21A might be used as a potential predictor and target of treatment in ccRCC.

Clinical benefits of therapeutic drug monitoring of vancomycin therapy in patients with postoperative intracerebral hemorrhage: a retrospective cohort study.

OBJECTIVE: The objective of this study was to investigate the clinical efficacy and safety of conducting therapeutic drug monitoring (TDM) of vancomycin in patients with postoperative intracerebral haemorrhage. METHODS: We conducted a retrospective analysis of 435 patients who experienced postoperative cerebral haemorrhage and were treated with vancomycin in the Department of Neurosurgery of Inner Mongolia Autonomous Region People's Hospital from January 2017 to December 2021. Patients were then matched using the propensity score matching method in a ratio of 1:1. Ninety-two pairs of cases were successfully matched, and the data before and after performing vancomycin TDM were analysed. RESULTS: After PSM, the baseline data of the two groups were balanced. There were no significant differences in the 14-day mortality and length of hospital stay (p>0.05) between the two groups. Compared with the non-TDM group, the TDM group had a higher proportion of patients with normal white blood cells (83.7% vs 56.5%, p=0.000), neutrophil count (57.6% vs 25.0%, p=0.000) and attaining desirable reductions of 80% in procalcitonin (65.2% vs 10.9%, p=0.000) and C-reactive protein (78.3% vs 41.3%, p=0.000) levels. At US$15.82 per additional TDM, TDM significantly promoted patient outcomes, as seen in improvements in the proportion of patients attaining desirable levels of white blood cells, neutrophil count, procalcitonin and C-reactive protein. CONCLUSIONS: Vancomycin TDM is a safe and effective approach for the treatment of patients with postoperative intracerebral haemorrhage. The empirical use of TDM of vancomycin significantly improved normal values of white blood cells and neutrophil count, achieved desirable reductions of 80% in procalcitonin and C-reactive protein, and reduced nephrotoxicity in patients with postoperative intracerebral haemorrhage.