Prediction model of deep vein thrombosis risk after lower extremity orthopedic surgery.

Purpose: This investigation was conceived to engineer and appraise a pioneering clinical nomogram, crafted to bridge the extant chasm in literature regarding the postoperative risk stratification for deep vein thrombosis (DVT) in the aftermath of lower extremity orthopedic procedures. This novel tool offers a sophisticated and discerning algorithm for risk prediction, heretofore unmet by existing methodologies. Methods: In this retrospective observational study, clinical records of hospitalized patients who underwent lower extremity orthopedic surgery were collected at the Wuxi TCM Hospital Affiliated to the Nanjing University of Chinese Medicine between Jan 2017 and Oct 2019. The univariate and multivariate analysis with the backward stepwise method was applied to select features for the predictive nomogram. The performance of the nomogram was evaluated with respect to its discriminant capability, calibration ability, and clinical utility. Result: A total of 5773 in-hospital patients were eligible for the study, with the incidence of deep vein thrombosis being approximately 1 % in this population. Among 31 variables included, 5 of them were identified to be the predictive features in the nomogram, including age, mean corpuscular hemoglobin concentration (MCHC), D-dimer, platelet distribution width (PDW), and thrombin time (TT). The area under the receiver operating characteristic (ROC) curve in the training and validation cohort was 85.9 % (95%CI: 79.96 %-90.04 %) and 85.7 % (95%CI: 78.96 %-90.69 %), respectively. Both the calibration curves and decision curve analysis demonstrated the overall satisfactory performance of the model. Conclusion: Our groundbreaking nomogram is distinguished by its unparalleled accuracy in discriminative and calibrating functions, complemented by its tangible clinical applicability. This innovative instrument is set to empower clinicians with a robust framework for the accurate forecasting of postoperative DVT, thus facilitating the crafting of bespoke and prompt therapeutic strategies, aligning with the rigorous standards upheld by the most esteemed biomedical journals.

The non-linear associations between blood manganese level and sarcopenia in patients undergoing maintenance hemodialysis: A multicenter cross-sectional study.

BACKGROUND AND AIMS: Manganese (Mn), a vital element in energy metabolism, is predominantly stored in skeletal muscles and plays a crucial role in muscle function and strength. Patients on maintenance hemodialysis (MHD) often experience muscle wasting due to metabolic disruption and inflammation. This study aimed to explore the relationship between blood Mn levels and sarcopenia in a patient population. METHODS: In this multicenter cross-sectional study, conducted from March 2021 to March 2022, 386 patients on MHD from three medical centers were included. Blood Mn levels were measured using inductively coupled plasma mass spectrometry, and body composition was assessed post-dialysis using bioelectrical impedance analysis. Grip strength was measured using a digital dynamometer. The patients were categorized into groups with and without sarcopenia. Using a generalized additive model to fit a smooth curve, we employed a generalized linear model to identify the optimal inflection point and explore the threshold effect after discovering a segmented relationship. Subsequently, a binary logistic regression analysis was conducted to investigate the relationship between blood manganese levels and the risk of sarcopenia, with adjustments made for potential confounding factors. RESULTS: A negative correlation was observed between blood Mn levels and sarcopenia-related parameters (Appendicular Skeletal Muscle Mass Index and grip strength) in Spearman's correlation analysis (both P < 0.05). After adjusting for confounding factors, a nonlinear association was identified. When blood Mn was ≤ 10.6 µg/L, the increase in sarcopenia was not statistically significant (P > 0.05). Conversely, when blood Mn exceeded 10.6 µg/L, each 1 µg/L increase raised the risk of sarcopenia by 0.1 times. Considering confounders, multivariate binary logistic regression confirmed an independent association between elevated blood Mn levels and sarcopenia. CONCLUSION: This study revealed an independent association between elevated blood Mn levels (> 10.6 µg/L) and sarcopenia in patients undergoing MHD. These findings emphasize the importance of understanding the Mn metabolism in the context of muscle health in this patient population. Further research is warranted to explore the underlying mechanisms and potential interventions for mitigating sarcopenia in patients with elevated blood Mn levels undergoing MHD.

Grape seed-derived procyanidins decreases neuropathic pain and nerve regeneration by suppression of toll-like receptor 4-myeloid differentiation factor-88 signaling.

Background: Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Methods: Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Result: Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Conclusion: Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.

Functional Property and Regulatory Mechanism of Macrophages in Complementary and Alternative Medicine: From Bench to Clinic.

Complementary and alternative medicine (CAM) includes a wide range of treatments that are gaining acceptance among the public. It is increasingly being recognized as a viable option for treating various diseases with minimal side effects. Common avenues of this therapy include herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy, and homeopathy etc. Macrophages are highly heterogeneous cells that play multiple regulatory roles. Practices such as herbal medicine, acupuncture, physical exercise, aromatherapy and dietary therapy exert curative effects by modulating the polarization status and the secretory phenotype of macrophages directly. Furthermore, herbal medicine, acupuncture, and physical exercise influence the crosstalk between macrophages and other types of cells, including cancer cells and T cells. Mechanistically, herbal medicine and acupuncture produce curative effects in diverse diseases, including inflammatory diseases and tumors, mainly by influencing the phosphorylation of signaling proteins in macrophages. Therefore, targeting macrophages offers theoretical support for advancing the scientific understanding of this therapy and aids in identifying potential therapeutic options. Hence, in this review, we systematically summarize the different regulations of macrophages in herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy and homeopathy, and further highlight the therapeutic potential of targeting macrophages in complementary and alternative medicine.

DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma.

BACKGROUND: The faithful maintenance of DNA methylation homeostasis indispensably requires DNA methyltransferase 1 (DNMT1) in cancer progression. We previously identified DNMT1 as a potential candidate target for oral squamous cell carcinoma (OSCC). However, how the DNMT1- associated global DNA methylation is exploited to regulate OSCC remains unclear. METHODS: The shRNA-specific DNMT1 knockdown was employed to target DNMT1 on oral cancer cells in vitro, as was the use of DNMT1 inhibitors. A xenografted OSCC mouse model was established to determine the effect on tumor suppression. High-throughput microarrays of DNA methylation, bulk and single-cell RNA sequencing analysis, multiplex immunohistochemistry, functional sphere formation and protein immunoblotting were utilized to explore the molecular mechanism involved. Analysis of human samples revealed associations between DNMT1 expression, global DNA methylation and collaborative molecular signaling with oral malignant transformation. RESULTS: We investigated DNMT1 expression boosted steadily during oral malignant transformation in human samples, and its inhibition considerably minimized the tumorigenicity in vitro and in a xenografted OSCC model. DNMT1 overexpression was accompanied by the accumulation of cancer-specific DNA hypomethylation during oral carcinogenesis; conversely, DNMT1 knockdown caused atypically extensive genome-wide DNA hypomethylation in cancer cells and xenografted tumors. This novel DNMT1-remodeled DNA hypomethylation pattern hampered the dual activation of PI3K-AKT and CDK2-Rb and inactivated GSK3ß collaboratively. When treating OSCC mice, targeting DNMT1 achieved greater anticancer efficacy than the PI3K inhibitor, and reduced the toxicity of blood glucose changes caused by the PI3K inhibitor or combination of PI3K and CDK inhibitors as well as adverse insulin feedback. CONCLUSIONS: Targeting DNMT1 remodels a novel global DNA hypomethylation pattern to facilitate anticancer efficacy and minimize potential toxic effects via balanced signaling synergia. Our study suggests DNMT1 is a crucial gatekeeper regarding OSCC destiny and treatment outcome.

Advancing pain management for extremity trauma: the evolution of ultrasound-guided nerve blocks for patients in the supine position in trauma centers.

PURPOSE: Trauma, particularly extremity trauma, poses a considerable challenge in healthcare, especially among young adults. Given the severity of patient pain and the risks associated with excessive opioid use, managing acute pain in trauma centers is inherently complex. This study aims to investigate the application and benefits of ultrasound-guided nerve blocks for early pain management in patients with extremity trauma positioned supine. METHODS: A comprehensive literature review was conducted to assess the effectiveness and advantages of ultrasound-guided peripheral nerve blocks in the acute pain management of extremity trauma patients in the supine position. Special emphasis was placed on evaluating the selection criteria, indications, contraindications, adverse reactions, and potential complications associated with these nerve block techniques. RESULTS: Ultrasound-guided nerve blocks represent a safer and more precise option for managing pain in extremity trauma patients placed in the supine position. These techniques offer significant advantages in terms of reducing healthcare expenses, diminishing reliance on opioid medications, and mitigating opioid-related complications. Nonetheless, challenges may arise due to the necessity for patient cooperation during specific nerve block procedures. CONCLUSION: Ultrasound-guided nerve blocks present a promising avenue for early pain management in extremity trauma patients positioned supinely. Their implementation can lead to improved patient outcomes by alleviating pain severity, reducing opioid consumption, and cutting down healthcare costs. Further research and clinical integration of these techniques is imperative to enhance pain management protocols in trauma centers.

Knowledge, attitudes, and practice toward postoperative cognitive dysfunction among anesthesiologists in China: a cross-sectional study.

BACKGROUND: To investigate the knowledge, attitudes, and practice (KAP) toward postoperative cognitive dysfunction (POCD) among anesthesiologists in China. METHODS: This cross-sectional study was conducted nationwide among Chinese anesthesiologists between December 2022 and January 2023. The demographic information and KAP scores of the respondents were collected using a web-based questionnaire. The mean KAP dimension scores ≥ 60% were considered good. RESULTS: This study enrolled 1032 anesthesiologists (51.2% male). The mean total scores of knowledge, positive attitude, and positive practice were 9.3 ± 1.2 (max 12), 34.8 ± 3.3 (max 40), and 30.6 ± 6.7 (max 40), respectively. The knowledge items with correctness scores < 60% were "the anesthetic drugs that tend to cause POCD" (23.3%) and "Treatment of POCD" (40.3%). Multivariable analysis showed that ≥ 40 years old, master's degree or above, intermediate professional title (i.e., attending physician), senior professional title (i.e., chief physician), and working in tertiary hospitals were independently associated with adequate knowledge. Multivariable analysis showed that the attitude scores, middle professional title, and ≥ 16 years of experience were independently associated with good practice. CONCLUSIONS: These results suggest that Chinese anesthesiologists have good knowledge, favorable attitudes, and good practice toward POCD. Still, some points remain to be improved (e.g., the drugs causing POCD and managing POCD) and should be emphasized in training and continuing education. TRIAL REGISTRATION: ChiCTR2200066749.

Corrigendum: Time to clinical improvement: an appropriate surrogate endpoint for pulmonary arterial hypertension medication trials.

[This corrects the article DOI: 10.3389/fcvm.2023.1142721.].

Disulfidptosis and its Role in Peripheral Blood Immune Cells after a Stroke: A New Frontier in Stroke Pathogenesis.

BACKGROUND: Stroke-Induced Immunodepression (SIID) is characterized by apoptosis in blood immune populations, such as T cells, B cells, NK cells, and monocytes, leading to the clinical presentation of lymphopenia. Disulfidptosis is a novel form of programmed cell death characterized by accumulating disulfide bonds in the cytoplasm, resulting in cellular dysfunction and eventual cell death. OBJECTIVE: In this study, we investigated the association between disulfidptosis and stroke by analyzing gene sequencing data from peripheral blood samples of stroke patients. METHODS: Differential gene expression analysis identified a set of disulfidptosis-related genes (DRGs) significantly associated with stroke. Initial exploration identified 32 DRGs and their interactions. Our study encompassed several analyses to understand the molecular mechanisms of DRGs in stroke. Weighted Gene Co-Expression Network Analysis (WGCNA) uncovered modules of co-expressed genes in stroke samples, and differentially expressed gene (DEG) analysis highlighted 1643 key genes. RESULTS: These analyses converged on four hub genes of DRGs (SLC2A3, SLC2A14, SLC7A11, NCKAP1) associated with stroke. Immune cell composition analysis indicated positive correlations between hub genes and macrophages M1, M2, and neutrophils and negative associations with CD4+ and CD8+ T cells, B cells, and NK cells. Sub-cluster analysis revealed two distinct clusters with different immune cell expression profiles. Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of apoptosis-related pathways, neurotrophin signaling, and actin cytoskeleton regulation. Associations between hub genes and apoptosis, necroptosis, ferroptosis, and cuproptosis, were also identified. CONCLUSION: These results suggest that the DRG hub genes are interconnected with various cell death pathways and immune processes, potentially contributing to stroke pathological development.

Stellate ganglion block in the treatment of SAPHO syndrome: a case report.

Synovitis, acne, palmoplantar pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare and refractory autoinflammatory disease, and there is no consensus on its treatment. Stellate ganglion block (SGB) blocks sympathetic nerves, ameliorates immune dysfunction, and alleviates stress response, which has been used to treat various chronic pain syndromes, arrhythmias, and post-traumatic stress disorder (PTSD). Also, the SGB has been reported to be successfully used to treat certain skin diseases, autoinflammatory diseases, and menopausal symptoms. In this study, over 3 years of follow-up, we found that SGB successfully intervened the symptoms of SAPHO syndrome, including sternoclavicular joint arthritis and palmoplantar pustulosis.

Lichen planus pemphigoides induced by anti-PD-1 antibody: A case only involved in oral mucosa with excellent topical treatment efficiency.

Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal disease that can occur in patients receiving immune checkpoint inhibitors. Its clinical manifestations are combined with the characteristics of lichen planus with bullous pemphigoid that can occur on either skin or oral mucosa. It should be noted that oral LPP is very rare. Here, we report a novel case of oral LPP induced by an anti-PD-1 agent. The patient presented with typical clinical features in oral mucosa, and the diagnosis was based on histopathology and immunological studies. Given that the patient was receiving an anti-PD-1 agent, topical therapy was chosen, and a nice therapeutic effect was obtained. No significant recurrence was observed after a 2-year follow-up. A good and stable therapeutic effect achieved by rapid and local symptomatic medication suggests that accurate and sensitive diagnosis is necessary.

Remimazolam Dosing for Gastroscopy: A Randomized Noninferiority Trial.

BACKGROUND: Remimazolam, an ultra-short-acting benzodiazepine, may provide adequate sedation for endoscopy while causing less cardiovascular or respiratory disturbance than propofol. Although fixed-dose administration is suggested, body weight affects the volume of the central chamber and thus affects the sedation depth that can be achieved by the first dose. This study aimed to compare the efficacy and safety of different doses of remimazolam and propofol by body weight for sedation during gastroscopy. METHODS: This multicenter, randomized, single-blind, parallel-controlled noninferiority trial recruited patients from five centers between March 2021 and July 2022. A total of 1,883 patients scheduled to undergo gastroscopy were randomized to groups receiving 0.15 mg/kg remimazolam, 0.2 mg/kg remimazolam, or 1.5 mg/kg propofol. The noninferiority margin was set to 5%. The primary outcome was the success rate of sedation. Adverse events were recorded to evaluate safety. RESULTS: The sedation success rate of the 0.2 mg/kg remimazolam group was not inferior to that of the 1.5 mg/kg propofol group (98.7% vs. 99.4%; risk difference, -0.64%; 97.5% CI, -2.2 to 0.7%, meeting criteria for noninferiority). However, the sedation success rate of the 0.15 mg/kg remimazolam group was 88.5%, and that of the 1.5 mg/kg propofol group was 99.4% (risk difference, -10.8%; 97.5% CI, -14.0% to -8.0%), demonstrating inferiority. Simultaneously, the overall adverse events rate of remimazolam was lower than that of propofol, and the incidence of bradycardia, hypotension, subclinical respiratory depression, and hypoxia in the remimazolam groups was significantly lower than that in the propofol group. CONCLUSIONS: This trial established the noninferior sedation success rate of remimazolam (0.2 mg/kg but not 0.15 mg/kg) compared with propofol (1.5 mg/kg), with a superior safety profile.

Anesthesia/surgery-induced learning and memory dysfunction by inhibiting mitophagy-mediated NLRP3 inflammasome inactivation in aged mice.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication, not only affects the quality of life of the elderly and increases the mortality rate, but also brings a greater burden to the family and society. Previous studies demonstrated that Nod-like receptor protein 3 (NLRP3) inflammasome participates in various inflammatory and neurodegenerative diseases. However, possible mitophagy mechanism in anesthesia/surgery-elicited NLRP3 inflammasome activation remains to be elucidated. Hence, this study clarified whether mitophagy dysfunction is related to anesthesia/surgery-elicited NLRP3 inflammasome activation. POCD model was established in aged C57BL/6 J mice by tibial fracture fixation under isoflurane anesthesia. Morris Water Maze (MWM) was used to evaluate learning and memory abilities. We found that in vitro experiments, lipopolysaccharide (LPS) significantly facilitated NLRP3 inflammasome activation and mitophagy inhibition in BV2 cells. Rapamycin restored mitophagy and improved mitochondrial function, and inhibited NLRP3 inflammasome activation induced by LPS. In vivo experiments, anesthesia and surgery caused upregulation of hippocampal NLRP3, caspase recruitment domain (ASC) and interleukin-1ß (IL-1 ß), and downregulation of microtubule-associated protein light chain 3II (LC3II) and Beclin1 in aged mice. Olaparib inhibited anesthesia/surgery-induced NLRP3, ASC, and IL-1ß over-expression in the hippocampus, while upregulated the expression of LC3II and Beclin1. Furthermore, Olaparib improved cognitive impairment in older mice. These results revealed that mitophagy was involved in NLRP3 inflammasome-mediated anesthesia/surgery-induced cognitive deficits in aged mice. Overall, our results suggested that mitophagy was related in NLRP3 inflammasome-induced cognitive deficits after anesthesia and surgery in aged mice. Activating mitophagy may have clinical benefits in the prevention of cognitive impairment induced by anesthesia and surgery in elderly patients.

Identifying multi-target drugs for prostate cancer using machine learning-assisted transcriptomic analysis.

Prostate cancer is a leading cause of cancer death in men, and the development of effective treatments is of great importance. This study explored to identify the candidate drugs for prostate cancer by transcriptomic data and CMap database analysis. After integrating the results of omics analysis, bisoprolol is confirmed as a promising drug. Moreover, cell experiment reveals its potential inhibitory effect on the proliferation of prostate cancer cells. Importantly, machine learning methods are employed to predict the targets of bisoprolol, and the dual-target ADRB3 and hERG are explored by dynamic simulation. The findings of this study demonstrate the potential of bisoprolol as a multi-target drug for prostate cancer treatment and the feasibility of using beta-adrenergic receptor inhibitors in prostate cancer treatment. In addition, the proposed research approach is promising for discovering potential drugs for cancer treatment by leveraging the concept of drug side effects leading to anticancer effects. Further research is necessary to investigate the pharmacological action, potential toxicity, and underlying mechanisms of bisoprolol in treating prostate cancer with ADRB3.Communicated by Ramaswamy H. Sarma.

Identification of drug-side effect association via correntropy-loss based matrix factorization with neural tangent kernel.

Adverse drug reactions include side effects, allergic reactions, and secondary infections. Severe adverse reactions can cause cancer, deformity, or mutation. The monitoring of drug side effects is an important support for post marketing safety supervision of drugs, and an important basis for revising drug instructions. Its purpose is to timely detect and control drug safety risks. Traditional methods are time-consuming. To accelerate the discovery of side effects, we propose a machine learning based method, called correntropy-loss based matrix factorization with neural tangent kernel (CLMF-NTK), to solve the prediction of drug side effects. Our method and other computational methods are tested on three benchmark datasets, and the results show that our method achieves the best predictive performance.

IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.

AIM: Postoperative cognitive dysfunction (POCD) is a common postoperative complication, especially in elderly patients. It extends hospital stay, increases the mortality rate and are heavy burdens to the family and society. Accumulating research has indicated that overactivation of pyrin domain-containing protein 3 (NLRP3) inflammasomes is related to POCD andplays a critical role in activating pro-inflammatory cytokines. According to existing studies, indoleamine 2,3-dioxygenase (IDO) is potently up-regulated by inflammatory factors, tryptophan in brain is mainly catalyzed by IDO to kynurenine (KYN), KYN metabolism may contribute to the development of depressive disorder and memory deficits. Hence, this study elucidated whether IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice. MATERIAL AND METHODS: POCD model was established in aged C57BL/6J mice by exploratory laparotomy under isoflurane anesthesia. Learning and memory were determined using Morris water maze. RESULTS: The data showed that IDO and kynurenine aminotransferase-II (KAT-II) mRNA in hippocampus was up-regulated, and NLRP3, caspase recruitment domain (ASC), interleukin-1b (IL-1b) and IDO overexpressed, KYN levels increased after anesthesia and surgery. NLRP3 inflammasome inhibitor (MCC950) reversed NLRP3, ASC, IL-1b and IDO overexpression, and the elevation of KYN levels. To clarify the role of IDO-Kynurenine pathway in postoperative cognitive impairment, IDO inhibitor (1-methyl-Ltryptophan 1-MT) reduced the elevation of KYN and kynurenic acid (KYNA) levels, reduction of tryptophan (TRP), as well as improved learning and memory abilities. Finally, KAT-II inhibitor (PF-04859989) reduced brain KYNA levels and restored the cognitive impairment. CONCLUSION: These results reveal that IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment.

Severe hypoxemia after extubation secondary to myxedema coma: a case report.

Myxedema coma is a rare and life-threatening endocrine emergency characterized by abnormalities in multiple organ systems. A 32-year-old woman with prolonged undiagnosed severe hypothyroidism was referred to our hospital owing to lower abdominal pain and menopause for more than 3 months. She underwent exploratory laparotomy and induced abortion under general anesthesia, and developed severe hypoxemia after extubation. She was diagnosed with myxedema coma, and was subsequently discharged with a good prognosis following treatment. This case suggests that myxedema coma should be considered a potential etiology of peri-operative hypoxemia. The findings in this case emphasize the importance of anesthesiologists' comprehensive understanding of myxedema coma. Prompt diagnosis followed by treatment is essential to reduce the mortality rate associated with this condition.