Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification.

Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various tumors, making it an important target for cancer treatment. Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Recently, a study showed that modification with dehydroalanine (Dha) can also lead to abnormal activation of MEK1, which has the potential to promote tumor development. In this study, we used molecular dynamics simulations and metadynamics to explore the mechanism of abnormal activation of MEK1 caused by the Dha modification and predicted the inhibitory effects of four FDA-approved MEK1 inhibitors on the Dha-modified MEK1. The results showed that the mechanism of abnormal activation of MEK1 caused by the Dha modification is due to the movement of the active segment, which opens the active pocket and exposes the catalytic site, leading to sustained abnormal activation of MEK1. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.

Bone-organ axes: bidirectional crosstalk.

In addition to its recognized role in providing structural support, bone plays a crucial role in maintaining the functionality and balance of various organs by secreting specific cytokines (also known as osteokines). This reciprocal influence extends to these organs modulating bone homeostasis and development, although this aspect has yet to be systematically reviewed. This review aims to elucidate this bidirectional crosstalk, with a particular focus on the role of osteokines. Additionally, it presents a unique compilation of evidence highlighting the critical function of extracellular vesicles (EVs) within bone-organ axes for the first time. Moreover, it explores the implications of this crosstalk for designing and implementing bone-on-chips and assembloids, underscoring the importance of comprehending these interactions for advancing physiologically relevant in vitro models. Consequently, this review establishes a robust theoretical foundation for preventing, diagnosing, and treating diseases related to the bone-organ axis from the perspective of cytokines, EVs, hormones, and metabolites.

Linking the relationship between dietary folic acid intake and risk of osteoporosis among middle-aged and older people: A nationwide population-based study.

Among middle-aged and older people, balanced and nutritious diets are the foundation for maintaining bone health and preventing osteoporosis. This study is aimed at investigating the link between dietary folic acid intake and the risk of osteoporosis among middle-aged and older people. A total of 20,686 people from the National Health and Nutritional Examination Survey (NHANES) 2007-2010 are screened and included, and 5312 people aged ≥45 years with integral data are ultimately enrolled in evaluation. Demographics and dietary intake-related data are gathered and analyzed, and the odds ratio (OR) and 95% confidence interval (CI) of each tertile category of dietary folic acid intake and each unit increase in folic acid are assessed via multivariate logistic regression models. On this basis, the receiver operating characteristic (ROC) curve is used to identify the optimal cutoff value of dietary folic acid intake for indicating the risk of osteoporosis. Of 5312 people with a mean age of 62.4 ± 11.0 years old, a total of 513 people with osteoporosis are screened, and the dietary folic acid intake amount of the osteoporosis group is significantly lower than that of the non-osteoporosis group (p < .001). The lowest tertile category is then used to act as a reference category, and a higher dietary folic acid intake amount is observed to be positively related to lower odds for risk of osteoporosis. This trend is also not changed in adjustments for combinations of different covariates (p all < .05). Based on this, a dietary folic acid intake of 475.5 µg/day is identified as an optimal cutoff value for revealing osteoporosis. Collectively, this nationwide population-based study reveals that a higher daily dietary folic acid intake has potential protective effects on osteoporosis in middle-aged and older people.

Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

BACKGROUND: Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. METHODS: We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. RESULTS: Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. CONCLUSIONS: Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.

Distance-decay equations of antibiotic resistance genes across freshwater reservoirs.

Distance-decay (DD) equations can discern the biogeographical pattern of organisms and genes in a better way with advanced statistical methods. Here, we developed a data Compilation, Arrangement, and Statistics framework to advance quantile regression (QR) into the generation of DD equations for antibiotic resistance genes (ARGs) across various spatial scales using freshwater reservoirs as an illustration. We found that QR is superior at explaining dissemination potential of ARGs to the traditionally used least squares regression (LSR). This is because our model is based on the 'law of limiting factors', which reduces influence of unmeasured factors that reduce the efficacy of the LSR method. DD equations generated from the 99th QR model for ARGs were 'Sall = 90.03e-0.01Dall' in water and 'Sall = 92.31e-0.011Dall' in sediment. The 99th QR model was less impacted by uneven sample sizes, resulting in a better quantification of ARGs dissemination. Within an individual reservoir, the 99th QR model demonstrated that there is no dispersal limitation of ARGs at this smaller spatial scale. The QR method not only allows for construction of robust DD equations that better display dissemination of organisms and genes across ecosystems, but also provides new insights into the biogeography exhibited by key parameters, as well as the interactions between organisms and environment.

Biosafety assessment of laying hens fed different treatments of black soldier flies (Hermetia illucens) under doxycycline stress.

The black soldier fly (BSF, Hermetia illucens) is a resource insect that can utilize livestock and poultry feces. However, BSFs may also increase the risk of transmission of antibiotic resistance genes (AGRs) that are widespread in livestock and poultry farm environments. Therefore, we aimed to evaluate the biosecurity risks of different BSF treatments in the laying chicken food chain using the "chicken manure-BSF-laying hens" model. Our results indicated that different BSF treatments significantly affected antibiotic residue, ARGs, MGEs, bacterial antibiotic resistance, and bacterial microbial community composition in the food chain of laying hens fed BSFs. These risks can be effectively reduced through starvation treatment and high-temperature grinding treatment. Comprehensive risk assessment analysis revealed that starvation combined with high-temperature milling (Group H) had the greatest effect.

Factors affecting meibomian gland area loss in symptomatic adults.

AIM: To characterize the distribution of meibomian gland (MG) area loss (MGL) and its relationship with demographic characteristics, mites, and symptoms. METHODS: This retrospective observational study included patients who visited the Dry Eye Clinic of Shenzhen Eye Hospital between June 2020 and August 2021. General patient characteristics, ocular symptoms, Demodex test results of the eyelid edges, and the results of a comprehensive ocular surface analysis were collected. MGL was analyzed using Image J software. RESULTS: This study enrolled 1204 outpatients aged 20-80 (40.70±13.44)y, including 357 males (29.65%) and 847 females (70.35%). The patients were classified into mild (n=155; 12.87%), moderate (n=795; 66.03%), severe (n=206; 17.11%), and extremely severe (n=48; 3.99%) MGL groups. MGL was significantly larger in female than in male (P=0.006). The degree of MGL also significantly differed in age (P<0.001) and the more numbers of mites with severity (P<0.001). Multivariate disordered multinomial logistic regression analysis identified that female sex, older age, secretory symptoms, and a large number of mites were risk factors for MGL (P<0.05). CONCLUSION: Patients with MGL are more likely to be older, female, more numbers of mites, and increased secretion.

Multiomics analysis of the effects of manure-borne doxycycline combined with oversized fiber microplastics on pak choi growth and the risk of antibiotic resistance gene transmission.

In this study, oversized microplastics (OMPs) were intentionally introduced into soil containing manure-borne doxycycline (DOX). This strategic approach was used to systematically examine the effects of combined OMP and DOX pollution on the growth of pak choi, analyze alterations in soil environmental metabolites, and explore the potential migration of antibiotic resistance genes (ARGs). The results revealed a more pronounced impact of DOX than of OMPs. Slender-fiber OMPs (SF OMPs) had a more substantial influence on the growth of pak choi than did coarse-fiber OMPs (CF OMPs). Conversely, CF OMPs had a more significant effect on the migration of ARGs within the system. When DOX was combined with OMPs, the negative effects of DOX on pak choi growth were mitigated through the synthesis of indole through the adjustment of carbon metabolism and amino acid metabolism in pak choi roots. In this process, Pseudohongiellaceae and Xanthomonadaceae were key bacteria. During the migration of ARGs, the potential host bacterium Limnobacter should be considered. Additionally, the majority of potential host bacteria in the pak choi endophytic environment were associated with tetG. This study provides insights into the intricate interplay among DOX, OMPs, ARGs, plant growth, soil metabolism, and the microbiome.

E-CLEAP: An ensemble learning model for efficient and accurate identification of antimicrobial peptides.

With the increasing problem of antimicrobial drug resistance, the search for new antimicrobial agents has become a crucial task in the field of medicine. Antimicrobial peptides, as a class of naturally occurring antimicrobial agents, possess broad-spectrum antimicrobial activity and lower risk of resistance development. However, traditional screening methods for antimicrobial peptides are inefficient, necessitating the development of an efficient screening model. In this study, we aimed to develop an ensemble learning model for the identification of antimicrobial peptides, named E-CLEAP, based on the Multilayer Perceptron Classifier (MLP Classifier). By considering multiple features, including amino acid composition (AAC) and pseudo amino acid composition (PseAAC) of antimicrobial peptides, we aimed to improve the accuracy and generalization ability of the identification process. To validate the superiority of our model, we employed five-fold cross-validation and compared it with other commonly used methods for antimicrobial peptide identification. In the experimental results on an independent test set, E-CLEAP achieved accuracies of 97.33% and 84% for the AAC and PseAAC features, respectively. The results demonstrated that our model outperformed other methods in all evaluation metrics. The findings of this study highlight the potential of the E-CLEAP model in enhancing the efficiency and accuracy of antimicrobial peptide screening, which holds significant implications for drug development, disease treatment, and biotechnology advancement. Future research can further optimize the model by incorporating additional features and information, as well as validating its reliability on larger datasets and in real-world environments. The source code and all datasets are publicly available at https://github.com/Wangsicheng52/E-CLEAP.

Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats.

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.

Yinhuang granule alleviates carbon tetrachloride-induced liver fibrosis in mice and its mechanism.

BACKGROUND: Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis. AIM: To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice. METHODS: To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected. RESULTS: The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1. CONCLUSION: YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.

A Rare Case Report of Intraosseous Spindle and Epithelioid Rhabdomyosarcoma With TFCP2 Rearrangement: A Pathological Diagnostic Conundrum and Literature Review.

Rhabdomyosarcoma is a highly malignant tumor with striated muscle differentiation, which is histologically classified as alveolar, embryonal, pleomorphic, and spindle cell/sclerosing histological subtype. Rhabdomyosarcoma with TFCP2 rearrangement, which usually occurs in the bone, is a newly identified rare spindle and epithelioid rhabdomyosarcoma with characteristic clinicopathological features and molecular alterations. We report a 39-year-old female patient who underwent local excision of the mandibular lesion. Microscopically, the intraosseous tumor was composed of spindle-shaped, epithelioid, and rhabdomyoblastic cells with atypical nuclei and atypical mitotic figures. In addition, TFCP2 rearrangement was revealed by the fluorescence in situ hybridization. The tumor was thus correctly diagnosed as rhabdomyosarcoma with TFCP2 rearrangement. The patient was scheduled to undergo radiotherapy, and triple-agent chemotherapy after surgery, and no tumor recurrence or metastasis was detected during the 3-month postoperative follow up. Since this tumor is relatively rare and newly recognized, it can be easily misdiagnosed or missed and might be a conundrum of pathological diagnosis. Familiarity with its clinicopathological features and molecular alterations is essential for its correct diagnosis. Therefore, we summarized the clinicopathological, immunohistochemical, and molecular alterations of 43 cases of this rare rhabdomyosarcoma variant in the English-language literature. In addition, the differential diagnosis of this lesion is crucial either.

Therapeutic role of neural stem cells in neurological diseases.

The failure of endogenous repair is the main feature of neurological diseases that cannot recover the damaged tissue and the resulting dysfunction. Currently, the range of treatment options for neurological diseases is limited, and the approved drugs are used to treat neurological diseases, but the therapeutic effect is still not ideal. In recent years, different studies have revealed that neural stem cells (NSCs) have made exciting achievements in the treatment of neurological diseases. NSCs have the potential of self-renewal and differentiation, which shows great foreground as the replacement therapy of endogenous cells in neurological diseases, which broadens a new way of cell therapy. The biological functions of NSCs in the repair of nerve injury include neuroprotection, promoting axonal regeneration and remyelination, secretion of neurotrophic factors, immune regulation, and improve the inflammatory microenvironment of nerve injury. All these reveal that NSCs play an important role in improving the progression of neurological diseases. Therefore, it is of great significance to better understand the functional role of NSCs in the treatment of neurological diseases. In view of this, we comprehensively discussed the application and value of NSCs in neurological diseases as well as the existing problems and challenges.

Evaluation of compost quality and the environmental effects of semipermeable membrane composting with poultry manure using sawdust or mushroom residue as the bulking agent.

Herein, the effects of different bulking agents (sawdust and mushroom residue), on compost quality and the environmental benefits of semipermeable film composting with poultry manure were investigated. The results show that composting with sawdust as the bulking agent resulted in greater efficiency and more cost benefits than composting with mushroom residue, and the cost of sawdust for treating an equal volume of manure was only 1/6 of that of mushroom residue. Additionally, lignin degradation and potential carbon emission reduction in the sawdust group were better than those in the mushroom residue group, and the lignin degradation efficiency of the bottom sample in the sawdust group was 48.57 %. Coupling between lignin degradation and potential carbon emission reduction was also closer in sawdust piles than in mushroom residue piles, and sawdust is more environmentally friendly. The abundance of key functional genes was higher at the bottom of each pile relative to the top and middle. Limnochordaceae, Lactobacillus and Enterococcus were the core microorganisms involved in coupling between lignin degradation and potential carbon emission reduction, and the coupled relationship was influenced by electric conductivity, ammonia nitrogen and total nitrogen in the compost piles. This study provides important data for supporting bulking agent selection in semipermeable film composting and for improving the composting process. The results have high value for compost production and process application.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Computational Assignment of Tantalum-related Strong Absorption Peaks in the Infrared Spectrum of Potassium Heptafluorotantalate.

Tantalum (Ta) is a valuable and rare metal that is extensively used in the production of implant materials and high-performance capacitors. However, a convenient and effective method for the separation of Ta from other compounds has yet to be developed. On the basis of first-principle density functional theory (DFT), we simulated the vibrational spectrum of potassium heptafluorotantalate (K2TaF7). By performing a dynamics analysis of vibrational modes, we assigned peaks in infrared (IR) absorption and Raman scattering spectra to their corresponding vibrations. We focused on the strong IR absorption peaks of Ta-related vibrational modes in K2TaF7 and concluded that three observed IR absorption peaks, at 285, 315, and 530 cm-1, are good candidates. Provided with high power radiation at these three frequencies (at about 8.55, 9.45, and 15.9 THz), the good efficiency of photon-phonon resonance absorption will facilitate Ta separation from a compound.

The role of olfactory ensheathing cells in the repair of nerve injury.

Cell transplantation has brought about a breakthrough in the treatment of nerve injuries, and the efficacy of cell transplantation compared to drug and surgical therapies is very exciting. In terms of transplantation targets, the classic cells include neural stem cells (NSCs) and Schwann cells, while a class of cells that can exist and renew throughout the life of the nervous system - olfactory ensheathing cells (OECs) - has recently been discovered in the olfactory system. OECs not only encircle the olfactory nerves but also act as macrophages and play an innate immune role. OECs can also undergo reprogramming to transform into neurons and survive and mature after transplantation. Currently, many studies have confirmed the repairing effect of OECs after transplantation into injured nerves, and safe and effective results have been obtained in clinical trials. However, the specific repair mechanism of OECs among them is not quite clear. For this purpose, we focus here on the repair mechanisms of OECs, which are summarized as follows: neuroprotection, secretion of bioactive factors, limitation of inflammation and immune regulation, promotion of myelin and axonal regeneration, and promotion of vascular proliferation. In addition, integrating the aspects of harvesting, purification, and prognosis, we found that OECs may be more suitable for transplantation than NSCs and Schwann cells, but this does not completely discard the value of these classical cells. Overall, OECs are considered to be one of the most promising transplantation targets for the treatment of nerve injury disorders.

Investigation of causal relationships between cortical structure and osteoporosis using two-sample Mendelian randomization.

The mutual interaction between bone characteristics and brain had been reported previously, yet whether the cortical structure has any relevance to osteoporosis is questionable. Therefore, we applied a two-sample bidirectional Mendelian randomization analysis to investigate this relationship. We utilized the bone mineral density measurements of femoral neck (n = 32,735) and lumbar spine (n = 28,498) and data on osteoporosis (7300 cases and 358,014 controls). The global surficial area and thickness and 34 specific functional regions of 51,665 patients were screened by magnetic resonance imaging. For the primary estimate, we utilized the inverse-variance weighted method. The Mendelian randomization-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis were conducted to assess heterogeneity and pleiotropy. We observed suggestive associations between decreased thickness in the precentral region (OR = 0.034, P = 0.003) and increased chance of having osteoporosis. The results also revealed suggestive causality of decreased bone mineral density in femoral neck to declined total cortical surface area (ß = 1400.230 mm2, P = 0.003), as well as the vulnerability to osteoporosis and reduced thickness in the Parstriangularis region (ß = -0.006 mm, P = 0.002). Our study supports that the brain and skeleton exhibit bidirectional crosstalk, indicating the presence of a mutual brain-bone interaction.

Intra-articular injection of tranexamic acid in patients with haemophilia arthritis: retrospective controlled study in total knee arthroplasty.

PURPOSE: Total knee arthroplasty is the main method for the treatment of advanced haemophilic knee arthritis. Due to the particularity of hemophilia, the blood management plan is the focus of the perioperative period for haemophilia patients. This study aimed to investigate the clinical effect and safety of intra-articular injection of tranexamic acid in patients with haemophilia. METHODS: This is a retrospective study. According to whether tranexamic acid is used or not, patients are divided into tranexamic acid group (n=30) and non-tranexamic acid group (n=29). Total blood loss, intraoperative blood loss, complete blood count, total amount of coagulation factor VIII (FVIII) usage, coagulation biomarkers, inflammatory biomarkers, knee range of motion, knee joint function, pain status, complication rate, and patient satisfaction were assessed and compared at a mean follow-up of 16 months. RESULTS: Injecting tranexamic acid into the knee joint cavity can effectively reduce the hidden blood loss and total blood loss (P<0.001), and reduce the patient's early postoperative inflammation biomarkers, pain status, and limb swelling. Therefore, the patient can obtain a better range of motion following total knee arthroplasty. In the long run, in terms of joint function and surgical satisfaction, there are no statistically significant differences. In addition, there are no statistically significant differences between the two groups of patients in terms of the total amount of FVIII usage, length of stay, and hospitalization expenses. CONCLUSION: In patients with haemophilia, intra-articular injection of tranexamic acid during total knee arthroplasty can effectively reduce postoperative blood loss, early postoperative inflammation levels, pain and limb swelling, and enable patients to receive higher-quality rehabilitation exercises to get better joint function. Previous studies on TKA in haemophilic patients have already demonstrated the efficacy of intra-articular injections of TXA in reducing postoperative blood loss. Our study confirms this efficacy.

Survival nomograms for simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy in patients with resectable colorectal liver metastasis.

Background: No well-performing nomogram has been developed specifically to predict individual-patient cancer-specific survival (CSS) and overall survival (OS) among patients with resectable colorectal liver metastasis (CRLM) who undergo simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy (NAC). We aim to investigate the prognosis of patients with resectable CRLM undergoing simultaneous resection of primary and hepatic lesions without NAC. Methods: Data of patients with CRLM in the Surveillance, Epidemiology and End Results Program (cohort, n = 225) were collected as the training set, and data of patients with CRLM treated at the National Cancer Center (cohort, n = 180) were collected as the validation set. The prognostic value of the clinicopathological parameters in the training cohort was assessed using Kaplan‒Meier curves and univariate and multivariate Cox proportional hazards models, and OS and CSS nomograms integrated with the prognostic variables were constructed. Calibration analyses, receiver operating characteristic (ROC) curves, and decision curve analyses (DCAs) were then performed to evaluate the performance of the nomograms. Results: There was no collinearity among the collected variables. Three factors were associated with OS and CSS: the pretreatment carcinoembryonic antigen (CEA) concentration, pathologic N (pN) stage, and adjuvant chemotherapy (each p < 0.05). OS and CSS nomograms were constructed using these three parameters. The calibration plots revealed favorable agreement between the predicted and observed outcomes. The areas under the ROC curves were approximately 0.7. The DCA plots revealed that both nomograms had satisfactory clinical benefits. The ROC curves and DCAs also confirmed that the nomogram surpassed the tumor, node, and metastasis staging system. Conclusion: The herein-described nomograms containing the pretreatment CEA concentration, pN stage, and adjuvant chemotherapy may be effective models for predicting postoperative survival in patients with CRLM.