Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.

Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1ß (IL-1ß) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.

MiR-106a-5p targets PFKFB3 and improves sepsis through regulating macrophage pyroptosis and inflammatory response.

The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is a critical regulator of glycolysis and plays a key role in modulating the inflammatory response, thereby contributing to the development of inflammatory diseases such as sepsis. Despite its importance, the development of strategies to target PFKFB3 in the context of sepsis remains challenging. In this study, we employed a miRNA-based approach to decrease PFKFB3 expression. Through multiple meta-analyses, we observed a downregulation of miR-106a-5p expression and an upregulation of PFKFB3 expression in clinical sepsis samples. These changes were also confirmed in blood monocytes from patients with early sepsis and from a mouse model of lipopolysaccharide (LPS)-induced sepsis. Overexpression of miR-106a-5p significantly decreased the LPS-induced increase in glycolytic capacity, inflammatory response, and pyroptosis in macrophages. Mechanistically, we identified PFKFB3 as a direct target protein of miR-106a-5p and demonstrated its essential role in LPS-induced pyroptosis and inflammatory response in macrophages. Furthermore, treatment with agomir-miR-106a-5p conferred a protective effect in an LPS mouse model of sepsis, but this effect was attenuated in myeloid-specific Pfkfb3 KO mice. These findings indicate that miR-106a-5p inhibits macrophage pyroptosis and inflammatory response in sepsis by regulating PFKFB3-mediated glucose metabolism, representing a potential therapeutic option for the treatment of sepsis.

Improving artificial intelligence pipeline for liver malignancy diagnosis using ultrasound images and video frames.

Recent developments of deep learning methods have demonstrated their feasibility in liver malignancy diagnosis using ultrasound (US) images. However, most of these methods require manual selection and annotation of US images by radiologists, which limit their practical application. On the other hand, US videos provide more comprehensive morphological information about liver masses and their relationships with surrounding structures than US images, potentially leading to a more accurate diagnosis. Here, we developed a fully automated artificial intelligence (AI) pipeline to imitate the workflow of radiologists for detecting liver masses and diagnosing liver malignancy. In this pipeline, we designed an automated mass-guided strategy that used segmentation information to direct diagnostic models to focus on liver masses, thus increasing diagnostic accuracy. The diagnostic models based on US videos utilized bi-directional convolutional long short-term memory modules with an attention-boosted module to learn and fuse spatiotemporal information from consecutive video frames. Using a large-scale dataset of 50 063 US images and video frames from 11 468 patients, we developed and tested the AI pipeline and investigated its applications. A dataset of annotated US images is available at https://doi.org/10.5281/zenodo.7272660.

Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in Acinetobacter baumannii and Escherichia coli.

Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in de novo guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: Acinetobacter baumannii and Escherichia coli. Specifically, the GuaB inhibitor G6 rapidly kills A. baumannii but only kills E. coli after 24 h. After exposure to G6, the expression of genes involved in purine biosynthesis and stress responses change in opposite directions while siderophore biosynthesis is downregulated in both species. Our results suggest that different species respond to GuaB inhibition using distinct regulatory programs and possibly explain the different bactericidal kinetics upon GuaB inhibition. The comparison highlights opportunities for developing GuaB inhibitors as novel antibiotics.IMPORTANCEA. baumannii is a priority bacterial pathogen for which development of new antibiotics is urgently needed due to the emergence of multidrug resistance. We recently developed a series of specific inhibitors against GuaB, a bacterial inosine 5'-monophosphate dehydrogenase, and achieved sub-micromolar minimum inhibitory concentrations against A. baumannii. GuaB catalyzes the rate-limiting step of de novo guanine biosynthesis and is highly conserved across bacterial pathogens. This study shows that inhibition of GuaB induced a bacterial morphological profile distinct from that of other classes of antibiotics, highlighting a novel mechanism of action. Moreover, our transcriptomic analysis showed that regulation of de novo purine biosynthesis and stress responses of A. baumannii upon GuaB inhibition differed significantly from that of E. coli.

Estrogen Oppositely Regulates Pulmonary Hypertension via METTL3/PFKFB3 Under Normoxia and Hypoxia.

Despite extensive investigation into estrogen's role in pulmonary hypertension (PH) development, its effects-whether beneficial or detrimental-remains contentious. This study aimed to elucidate estrogen's potential role in PH under normoxic and hypoxic conditions. Utilizing norfenfluramine- and hypoxia-induced rat models of PH, the study evaluated the impact of 17ß-estradiol (E2) on PH progression. E2 promoted PH development under normoxia while providing protection under hypoxia. Mechanistically, under normoxia, E2 upregulated methyltransferase-like 3 (METTL3) gene transcription and protein via an estrogen response element-dependent pathway, which in turn elevated the m6A methylation and translational efficiency of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) mRNA, leading to increased PFKFB3 protein levels and enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Conversely, under hypoxia, E2 downregulated METTL3 transcription through a hypoxia response element-dependent mechanism, driven by elevated hypoxia-induced factor 1α (HIF-1α) levels, resulting in reduced PFKFB3 protein expression and diminished PASMCs proliferation and migration. Both METTL3 and PFKFB3 proteins are upregulated in the pulmonary arteries of patients with PAH. Collectively, these findings suggest that E2 exerts differential effects on PH progression via dual regulation of the METTL3/PFKFB3 protein under normoxic and hypoxic conditions, positioning the METTL3/PFKFB3 protein as a potential therapeutic target for PH treatment.

miR-145 inhibits aerobic glycolysis and cell proliferation of cervical cancer by acting on MYC.

Nearly half a million women are diagnosed with cervical cancer (CC) each year, with the incidence of CC stabilizing or rising in low-income and middle-income countries. Cancer cells use metabolic reprogramming to meet the needs of rapid proliferation, known as the Warburg effect, but the mechanism of the Warburg effect in CC remains unclear. microRNAs (miRNAs) have a wide range of effects on gene expression and diverse modes of action, and they regulate genes for metabolic reprogramming. Dysregulation of miRNA expression leads to metabolic abnormalities in tumor cells and promotes tumorigenesis and tumor progression. In this study, we found that miR-145 was negatively correlated with metabolic reprogramming-related genes and prevented the proliferation and metastasis of CC cell lines by impeding aerobic glycolysis. A dual-luciferase reporter assay showed that miR-145 can bind to the 3'-untranslated region (3'-UTR) of MYC. Chromatin Immunoprecipitation-quantitative real-time PCR indicated that MYC was involved in the regulation of glycolysis-related genes. In addition, miR-145 mimics significantly suppressed the growth of CC cell xenograft tumor, prolonged the survival time of mice, and dramatically silenced the expression of tumor proliferation marker Ki-67. Therefore, the results suggested that miR-145 affects aerobic glycolysis through MYC, which may be a potential target for the treatment of CC.

Glycolysis and de novo fatty acid synthesis cooperatively regulate pathological vascular smooth muscle cell phenotypic switching and neointimal hyperplasia.

Switching of vascular smooth muscle cells (VSMCs) from a contractile phenotype to a dedifferentiated (proliferative) phenotype contributes to neointima formation, which has been demonstrated to possess a tumor-like nature. Dysregulated glucose and lipid metabolism is recognized as a hallmark of tumors but has not thoroughly been elucidated in neointima formation. Here, we investigated the cooperative role of glycolysis and fatty acid synthesis in vascular injury-induced VSMC dedifferentiation and neointima formation. We found that the expression of hypoxia-inducible factor-1α (HIF-1α) and its target 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), a critical glycolytic enzyme, were induced in the neointimal VSMCs of human stenotic carotid arteries and wire-injured mouse carotid arteries. HIF-1α overexpression led to elevated glycolysis and resulted in a decreased contractile phenotype while promoting VSMC proliferation and activation of the mechanistic target of rapamycin complex 1 (mTORC1). Conversely, silencing Pfkfb3 had the opposite effects. Mechanistic studies demonstrated that glycolysis generates acetyl coenzyme A to fuel de novo fatty acid synthesis and mTORC1 activation. Whole-transcriptome sequencing analysis confirmed the increased expression of PFKFB3 and fatty acid synthetase (FASN) in dedifferentiated VSMCs. More importantly, FASN upregulation was observed in neointimal VSMCs of human stenotic carotid arteries. Finally, interfering with PFKFB3 or FASN suppressed vascular injury-induced mTORC1 activation, VSMC dedifferentiation, and neointima formation. Together, this study demonstrated that PFKFB3-mediated glycolytic reprogramming and FASN-mediated lipid metabolic reprogramming are distinctive features of VSMC phenotypic switching and could be potential therapeutic targets for treating vascular diseases with neointima formation. © 2023 The Pathological Society of Great Britain and Ireland.

Characterization of a small molecule inhibitor of the NLRP3 inflammasome and its potential use for acute lung injury.

Accumulating data support the key roles of the NLRP3 inflammasome, an essential component of the innate immune system, in human pathophysiology. As an emerging drug target and a potential biomarker for human diseases, small molecule inhibitors of the NLRP3 inflammasome have been actively pursued. Our recent studies identified a small molecule, MS-II-124, as a potent NLRP3 inhibitor and potential imaging probe. In this report, MS-II-124 was further characterized by an unbiased and comprehensive analysis through Eurofins BioMAP Diversity PLUS panel that contains 12 human primary cell-based systems. The analysis revealed promising activities of MS-II-124 on inflammation and immune functions, further supporting the roles of the NLRP3 inflammasome in these model systems. Further studies of MS-II-124 in mouse model of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and NLRP3 knockout mice demonstrated its target engagement, efficacy to suppress inflammatory cytokines and infiltration of immune cells in the lung tissues. In summary, the results support the therapeutic potential of MS-II-124 as a NLRP3 inhibitor and warrant future studies of this compound and its analogs to develop therapeutics for ALI/ARDS.

Structural basis for dual-mode inhibition of the ABC transporter MsbA.

The movement of core-lipopolysaccharide across the inner membrane of Gram-negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 Å resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family.

Par3L, a polarity protein, promotes M1 macrophage polarization and aggravates atherosclerosis in mice via p65 and ERK activation.

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

Neuroimaging prognostic factors for treatment response to motor imagery training after stroke.

The efficacy of motor imagery training for motor recovery is well acknowledged, but with substantial inter-individual variability in stroke patients. To help optimize motor imagery training therapy plans and screen suitable patients, this study aimed to explore neuroimaging biomarkers explaining variability in treatment response. Thirty-nine stroke patients were randomized to a motor imagery training group (n = 22, received a combination of conventional rehabilitation therapy and motor imagery training) and a control group (n = 17, received conventional rehabilitation therapy and health education) for 4 weeks of interventions. Their demography and clinical information, brain lesion from structural MRI, spontaneous brain activity and connectivity from rest fMRI, and sensorimotor brain activation from passive motor task fMRI were acquired to identify prognostic factors. We found that the variability of outcomes from sole conventional rehabilitation therapy could be explained by the reserved sensorimotor neural function, whereas the variability of outcomes from motor imagery training + conventional rehabilitation therapy was related to the spontaneous activity in the ipsilesional inferior parietal lobule and the local connectivity in the contralesional supplementary motor area. The results suggest that additional motor imagery training treatment is also efficient for severe patients with damaged sensorimotor neural function, but might be more effective for patients with impaired motor planning and reserved motor imagery.

PM10-bound trace elements in pan-European urban atmosphere.

Although many studies have discussed the impact of Europe's air quality, very limited research focused on the detailed phenomenology of ambient trace elements (TEs) in PM10 in urban atmosphere. This study compiled long-term (2013-2022) measurements of speciation of ambient urban PM10 from 55 sites of 7 countries (Switzerland, Spain, France, Greece, Italy, Portugal, UK), aiming to elucidate the phenomenology of 20 TEs in PM10 in urban Europe. The monitoring sites comprised urban background (UB, n = 26), traffic (TR, n = 10), industrial (IN, n = 5), suburban background (SUB, n = 7), and rural background (RB, n = 7) types. The sampling campaigns were conducted using standardized protocols to ensure data comparability. In each country, PM10 samples were collected over a fixed period using high-volume air samplers. The analysis encompassed the spatio-temporal distribution of TEs, and relationships between TEs at each site. Results indicated an annual average for the sum of 20 TEs of 90 ± 65 ng/m3, with TR and IN sites exhibiting the highest concentrations (130 ± 66 and 131 ± 80 ng/m3, respectively). Seasonal variability in TEs concentrations, influenced by emission sources and meteorology, revealed significant differences (p < 0.05) across all monitoring sites. Estimation of TE concentrations highlighted distinct ratios between non-carcinogenic and carcinogenic metals, with Zn (40 ± 49 ng/m3), Ti (21 ± 29 ng/m3), and Cu (23 ± 35 ng/m3) dominating non-carcinogenic TEs, while Cr (5 ± 7 ng/m3), and Ni (2 ± 6 ng/m3) were prominent among carcinogenic ones. Correlations between TEs across diverse locations and seasons varied, in agreement with differences in emission sources and meteorological conditions. This study provides valuable insights into TEs in pan-European urban atmosphere, contributing to a comprehensive dataset for future environmental protection policies.

Short-Term but Not Long-Term Knee Symptoms and Functional Improvements of Tissue Engineering Strategy for Meniscus Defects: A Systematic Review of Clinical Studies.

PURPOSE: To investigate the up-to-date clinical outcomes of tissue-engineered meniscus implants for meniscus defects. METHODS: A search was performed by 3 independent reviewers on PubMed, MEDLINE, EMBASE, and Cochrane from 2016 to June 18, 2023, with the term "meniscus" with all the following terms: "scaffolds," "constructs," "implant," and "tissue engineering." Inclusion criteria included "Clinical trials" and "English language articles" that involved isolated meniscus tissue engineering strategies for meniscus injuries. Only Level I to IV clinical studies were considered. The modified Coleman Methodology score was used for quality analysis of included clinical trials. The Methodological Index for Non-Randomized Studies was employed for analysis of the risk of study bias and methodological quality. RESULTS: The search identified 2,280 articles, and finally 19 original clinical trials meeting the inclusion criteria were included. Three types of tissue-engineered meniscus implants (CMI-Menaflex, Actifit, and NUsurface) have been clinically evaluated for meniscus reconstruction. Lack of standardized outcome measures and imaging protocols limits comparison between studies. CONCLUSIONS: Tissue-engineered meniscus implants can provide short-term knee symptom and function improvements, but no implants have been shown to propose significant long-term benefits for meniscus defects. LEVEL OF EVIDENCE: Level IV, systematic review of Level I to IV studies.

Research on Convex Fiber Grating Tactile Sliding Sensor Based on Mechanical Fingers.

In order to solve the problem of flexible sliding tactile composite sensing in the actual grasp of intelligent robot fingers, this paper proposes a research on a convex fiber grating tactile sliding sensor based on mechanical fingers. Based on the sensing principle of fiber Bragg grating, 3D printing technology was used to encapsulate the FBG sensor array with elastic 50 A resin, a double-layer "hemispherical cuboid" distributed sensing unit was designed, and the FBG slippery tactile sensor was actually pasted on the surface of the mechanical finger for static and dynamic experiments. The experimental results show that the slippery tactile sensor designed in this paper has a good linear relationship with temperature and strain. The temperature sensitivities of the polymer-packaged FBGs are KT1 = 13.04 pm/°C and KT2 = 12.91 pm/°C, and they have a pressure sensitivity of 40.4 pm/N and 31.2 pm/N, respectively. The FBG sliding tactile sensor not only realizes the identification of the sliding signal generation point and the end point but also completes the classification and identification of sandpaper, cardboard, and polypropylene plastic, and it has a high degree of fit with the robot finger, which has certain application value for the intelligent robot sliding tactile signal perception.

Research on FBG Tactile Sensing Shape Recognition Based on Convolutional Neural Network.

Shape recognition plays a significant role in the field of robot perception. In view of the low efficiency and few types of shape recognition of the fiber tactile sensor applied to flexible skin, a convolutional-neural-network-based FBG tactile sensing array shape recognition method was proposed. Firstly, a sensing array was fabricated using flexible resin and 3D printing technology. Secondly, a shape recognition system based on the tactile sensing array was constructed to collect shape data. Finally, shape classification recognition was performed using convolutional neural network, random forest, support vector machine, and k-nearest neighbor. The results indicate that the tactile sensing array exhibits good sensitivity and perception capability. The shape recognition accuracy of convolutional neural network is 96.58%, which is 6.11%, 9.44%, and 12.01% higher than that of random forest, k-nearest neighbor, and support vector machine. Its F1 is 96.95%, which is 6.3%, 8.73%, and 11.94% higher than random forest, k-nearest neighbor, and support vector machine. The research of FBG shape sensing array based on convolutional neural network provides an experimental basis for shape perception of flexible tactile sensing.

The impact of COVID-19 on hip and knee arthroplasty surgical volume in China.

PURPOSE: The reduction of hip and knee arthroplasty surgical volume has been reported in many countries during the COVID-19 pandemic. In China, there is no national joint registry system and the impact of COVID-19 towards surgical volume remains unclear. The aim of this study was to investigate the hip and knee arthroplasty surgical volume in China during the pandemic and evaluate its change trends. METHODS: Annual sale numbers of prostheses used in total knee arthroplasty (TKA), total hip arthroplasty (THA), and femoral head replacement (FHR) from 2011 to 2021 was collected from providers registered in National Medical Products Administration (NMPA). Annual surgical volume of TKA, THA, FHR, unicompartmental knee arthroplasty (UKA), and revision of hip/knee arthroplasty (RJA) was collected from member hospitals of Beijing Joint Society (BJS). We used linear regression to estimate the loss of surgical volume. Annual surgical volume obtained from Britain and Australian joint registries were used to make comparison. RESULTS: In China, the surgical volume of THA/FHR, TKA, and UKA in 2020 all decreased compared to the predicted value, with a reduction of 82,525 cases (13.46%), 165,178 cases (33.50%), and 151 cases (0.65%), respectively. All the three procedures showed significant recovery in 2021. The surgical volumes of THA/FHR and UKA were 68,813 and 9402 cases higher than predicted levels, respectively, while TKA volume remained slightly below the predicted level. The regional statistics in Beijing showed similar change mode. In 2020, the surgical volume of THA/FHR, TKA, FHR, and UKA all decreased compared to the predicted value, with a reduction of 5031 cases (43.37%), 5290 cases (40.69%), 620 cases (29.18%), and 925 cases (39.11%), respectively. In 2021, with the exception of FHR, the number of these procedures increased compared to 2020, but remained below the predicted value. Compared with the data from Britain and Australia, China experienced less reduction and faster recovery in the proportions of elderly people (> 65 years old) who undergo hip and knee arthroplasty during the COVID-19 pandemic. CONCLUSION: During the COVID-19 pandemic, although hip and knee arthroplasty surgical volume in China showed a similar "restoration-recovery" change pattern with other countries, China took fewer losses in this field.

Clinical outcome and survival rate of condylar constrained knee prosthesis in revision total knee arthroplasty: an average nine point six year follow-up.

PURPOSE: Condylar constrained knee prostheses (CCK) are increasingly used in revision total knee arthroplasty (rTKA), but the clinical effectiveness and long-term survival remain a debate. The purpose of this study is to report the long-term clinical and radiographic outcome, implant survival rate, and surgical safety of revision total knee arthroplasty with condylar constrained knee prosthesis. METHODS: A retrospective cohort study was performed on patients undergoing rTKA with CCK. The cases who received rTKA with CCK from January 2005 to January 2022 were selected. The duration of operation, the estimated perioperative blood loss, and the intraoperative blood transfusion rate were recorded to evaluate surgical safety. The pain visual analog scale (VAS), range of motion (ROM), the Hospital for Special Surgery (HSS) score, the Knee Society Score (KSS), the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and the Oxford knee score (OKS) was recorded to assess clinical outcome. Standard anteroposterior, lateral, skyline and long-standing AP radiographs of the lower limbs were conducted to assess radiographic outcome. Implant survival was analyzed by Kaplan-Meier survival estimates. RESULTS: Fifty-five cases were followed up for an average of 9.6 years (1-18 years), including 16 males and 38 females, with an average age of 66 and an average BMI of 26.9 kg/m2. The  main reasons for revision were periprosthetic infection (32 knees, 58.2%) and aseptic loosening (13 knees, 23.6%). The duration of operation was 149 ± 56.2 min. The perioperative blood loss was 973.6 ± 421.6 ml. At the last follow-up, VAS (8.0 ± 1.1 to 1.3 ± 1.4), ROM (82.7° ± 26.1° to 108.4° ± 11.8°), HSS (45.0 ± 10.4 to 85.3 ± 8.6), KSKS (38.4 ± 12.1 to 88.5 ± 12.0), KSFS (19.6 ± 12.9 to 68.8 ± 15.1), WOMAC (67.9 ± 12.5 to 14.4 ± 9.5), and OKS (9.9 ± 4.2 to 41.6 ± 7.7) were significantly improved (P < 0.001). A total of five complications were observed, all of which were periprosthetic infection. Non-progressive radiolucent lines were observed in 26 knees (47.3%). The 10-year survival rate for no operation was 96.0%. The ten year survival rate for no revision was 98.0%. CONCLUSION: The use of CCK prosthesis for rTKA can achieve good long-term efficacy and prosthesis survival.

Safety and effectiveness of intraosseous regional prophylactic antibiotics in total knee arthroplasty: a systematic review and meta-analysis.

BACKGROUND: Intraosseous regional administration (IORA) as a widely applicable and clinically valuable route of administration has gained significant attention in the context of total knee arthroplasty (TKA) for the prophylactic administration of antibiotics. However, there is still controversy regarding its effectiveness and safety. The latest meta-analysis reports that the use of IORA for antibiotics in TKA is as safe and effective as IV administration in preventing prosthetic joint infection (PJI), but they did not separate the statistics for primary TKA and revision TKA, which may be inappropriate. There is currently a lack of evidence specifically comparing the outcomes of prophylactic antibiotic administration via IORA or IV route in primary/revision TKA, respectively, and new research evidence has emerged. PURPOSES: In this study, we conducted a systematic review and meta-analysis with the primary objective of comparing the local drug tissue concentration and the incidence of PJI between preoperative IORA and intravenous (IV) administration of prophylactic antibiotics in TKA. Additionally, the occurrence of complications between the two administration routes was also compared. PATIENTS AND METHODS: This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA) guidelines. Retrospective cohort studies and prospective randomized controlled trials that utilized intraosseous local drug delivery for prophylactic antibiotics in knee arthroplasty were included. English literature from PubMed, Embase, and Cochrane Library databases was searched from the inception of each database until December 2023. Two researchers independently screened the literature, assessed the quality, and extracted data according to the inclusion criteria. The primary outcomes were local antibiotic tissue concentration and postoperative PJI incidence, while the secondary outcome was the occurrence of postoperative complications. Statistical analysis was performed using Review Manager 5.3 software. RESULTS: This study included 7 prospective randomized controlled trials and 5 retrospective cohort studies. A total of 4091 patients participated in the 12 included studies, with 1,801 cases receiving IORA and 2,290 cases in the control group. In terms of local drug tissue concentration, intraosseous infusion (IO) 500 mg vancomycin significantly increased the drug concentration in the periarticular adipose tissue (SMD: 1.36; 95% CI: 0.87-1.84; P < 0.001; I2 = 0%) and bone tissue (SMD: 0.94; 95% CI: 0.49-1.40; P < 0.001; I2 = 0%) compared to IV 1 g vancomycin. Regarding the incidence of postoperative PJI after primary TKA, IO 500 mg vancomycin was more effective in reducing the occurrence of PJI compared to IV 1 g vancomycin (OR: 0.19; 95% CI: 0.06-0.59; P < 0.001; I2 = 36%). Finally, no significant differences were found between the two groups in terms of postoperative pulmonary embolism (PE) (OR: 1.72; 95% CI: 0.22-13.69; P = 0.59; I2 = 0%) and vancomycin-related complications (OR: 0.54; 95% CI: 0.25-1.19; P = 0.44; I2 = 0%). CONCLUSIONS: Preoperative prophylactic antibiotic administration via IORA in TKA significantly increases local drug tissue concentration without significantly increasing systemic drug-related complications compared to traditional IV administration. In primary TKA, low-dose vancomycin via IORA is more effective in reducing the incidence of PJI compared to traditional IV regimens. However, its effectiveness remains controversial in high-risk populations for PJI, such as obese, diabetic, and renal insufficiency patients, as well as in revision TKA.

Strain-modulated Ru-O Covalency in Ru-Sn Oxide Enabling Efficient and Stable Water Oxidation in Acidic Solution.

RuO2 is one of the benchmark electrocatalysts used as the anode material in proton exchange membrane water electrolyser. However, its long-term stability is compromised due to the participation of lattice oxygen and metal dissolution during oxygen evolution reaction (OER). In this work, weakened covalency of Ru-O bond was tailored by introducing tensile strain to RuO6 octahedrons in a binary Ru-Sn oxide matrix, prohibiting the participation of lattice oxygen and the dissolution of Ru, thereby significantly improving the long-term stability. Moreover, the tensile strain also optimized the adsorption energy of intermediates and boosted the OER activity. Remarkably, the RuSnOx electrocatalyst exhibited excellent OER activity in 0.1 M HClO4 and required merely 184 mV overpotential at a current density of 10 mA cm-2 . Moreover, it delivered a current density of 10 mA cm-2 for at least 150 h with negligible potential increase. This work exemplifies an effective strategy for engineering Ru-based catalysts with extraordinary performance toward water splitting.