Exploring the causal relationship between inflammatory cytokines and inflammatory arthritis: A Mendelian randomization study.

OBJECTIVES: Previous studies have reported an association between inflammatory cytokines and inflammatory arthritis, including Ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriatic arthritis (PsA). This study aims to explore the causal relationship between inflammatory cytokines and AS, RA, and PsA using Mendelian randomization (MR). METHODS: We conducted a bidirectional two-sample MR analysis using genetic summary data from a publicly available genome-wide association study (GWAS) that included 41 genetic variations of inflammatory cytokines, as well as genetic variant data for AS, RA, and PsA from the FinnGen consortium. The main analysis method used was Inverse variance weighted (IVW) to investigate the causal relationship between exposure and outcome. Additionally, other methods such as MR Egger, weighted median (WM), simple mode, and weighted mode were employed to strengthen the final results. Sensitivity analysis was also performed to ensure the reliability of the findings. RESULTS: The results showed that macrophage colony-stimulating factor (MCSF) was associated with an increased risk of AS (OR = 1.163, 95 % CI = 1.016-1.33, p = 0.028). Conversely, high levels of TRAIL and beta nerve growth factor (ß-NGF) were associated with a decreased risk of AS (OR = 0.892, 95 % CI = 0.81-0.982, p = 0.002; OR = 0.829, 95 % CI = 0.696-0.988, p = 0.036). Four inflammatory cytokines were found to be associated with an increased risk of PsA: vascular endothelial growth factor (VEGF) (OR = 1.161, 95 % CI = 1.057-1.275, p = 0.002); Interleukin 12p70 (IL12p70) (OR = 1.189, 95 % CI = 1.049-1.346, p = 0.007); IL10 (OR = 1.216, 95 % CI = 1.024-1.444, p = 0.026); IL13 (OR = 1.159, 95 % CI = 1.05-1.28, p = 0.004). Interleukin 1 receptor antagonist (IL-1rα) was associated with an increased risk of seropositive RA (OR = 1.181, 95 % CI = 1.044-1.336, p = 0.008). Similarly, genetic susceptibility to inflammatory arthritis was found to be causally associated with multiple inflammatory cytokines. Lastly, the sensitivity analysis supported the robustness of these findings. CONCLUSIONS: This study provides additional insights into the relationship between inflammatory cytokines and inflammatory arthritis, and may offer new clues for the etiology, diagnosis, and treatment of inflammatory arthritis.

Weaker photosynthetic acclimation to fluctuating than to corresponding steady UVB radiation treatments in grapevines.

The effects of transient increases in UVB radiation on plants are not well known; whether cumulative damage dominates or, alternately, an increase in photoprotection and recovery periods ameliorates any negative effects. We investigated photosynthetic capacity and metabolite accumulation of grapevines (Vitis vinifera Cabernet Sauvignon) in response to UVB fluctuations under four treatments: fluctuating UVB (FUV) and steady UVB radiation (SUV) at similar total biologically effective UVB dose (2.12 and 2.23 kJ m-2 day-1), and their two respective no UVB controls. We found a greater decrease in stomatal conductance under SUV than FUV. There was no decrease in maximum yield of photosystem II (Fv/Fm) or its operational efficiency (ɸPSII) under the two UVB treatments, and Fv/Fm was higher under SUV than FUV. Photosynthetic capacity was enhanced under FUV in the light-limited region of rapid light-response curves but enhanced by SUV in the light-saturated region. Flavonol content was similarly increased by both UVB treatments. We conclude that, while both FUV and SUV effectively stimulate acclimation to UVB radiation at realistic doses, FUV confers weaker acclimation than SUV. This implies that recovery periods between transient increases in UVB radiation reduce UVB acclimation, compared to an equivalent dose of UVB provided continuously. Thus, caution is needed in interpreting the findings of experiments using steady UVB radiation treatments to infer effects in natural environments, as the stimulatory effect of steady UVB is greater than that of the equivalent fluctuating UVB.

Development and validation of a machine learning-based nomogram for predicting HLA-B27 expression.

BACKGROUND: HLA-B27 positivity is normal in patients undergoing rheumatic diseases. The diagnosis of many diseases requires an HLA-B27 examination. METHODS: This study screened totally 1503 patients who underwent HLA-B27 examination, liver/kidney function tests, and complete blood routine examination in First Affiliated Hospital of Guangxi Medical University. The training cohort included 509 cases with HLA-B27 positivity whereas 611 with HLA-B27 negativity. In addition, validation cohort included 147 cases with HLA-B27 positivity whereas 236 with HLA-B27 negativity. In this study, 3 ML approaches, namely, LASSO, support vector machine (SVM) recursive feature elimination and random forest, were adopted for screening feature variables. Subsequently, to acquire the prediction model, the intersection was selected. Finally, differences among 148 cases with HLA-B27 positivity and negativity suffering from ankylosing spondylitis (AS) were investigated. RESULTS: Six factors, namely red blood cell count, human major compatibility complex, mean platelet volume, albumin/globulin ratio (ALB/GLB), prealbumin, and bicarbonate radical, were chosen with the aim of constructing the diagnostic nomogram using ML methods. For training queue, nomogram curve exhibited the value of area under the curve (AUC) of 0.8254496, and C-value of the model was 0.825. Moreover, nomogram C-value of the validation queue was 0.853, and the AUC value was 0.852675. Furthermore, a significant decrease in the ALB/GLB was noted among cases with HLA-B27 positivity and AS cases. CONCLUSION: To conclude, the proposed ML model can effectively predict HLA-B27 and help doctors in the diagnosis of various immune diseases.

Application of machine learning in prediction of bone cement leakage during single-level thoracolumbar percutaneous vertebroplasty.

BACKGROUND: In the elderly, osteoporotic vertebral compression fractures (OVCFs) of the thoracolumbar vertebra are common, and percutaneous vertebroplasty (PVP) is a common surgical method after fracture. Machine learning (ML) was used in this study to assist clinicians in preventing bone cement leakage during PVP surgery. METHODS: The clinical data of 374 patients with thoracolumbar OVCFs who underwent single-level PVP at The First People's Hospital of Chenzhou were chosen. It included 150 patients with bone cement leakage and 224 patients without it. We screened the feature variables using four ML methods and used the intersection to generate the prediction model. In addition, predictive models were used in the validation cohort. RESULTS: The ML method was used to select five factors to create a Nomogram diagnostic model. The nomogram model's AUC was 0.646667, and its C value was 0.647. The calibration curves revealed a consistent relationship between nomogram predictions and actual probabilities. In 91 randomized samples, the AUC of this nomogram model was 0.7555116. CONCLUSION: In this study, we invented a prediction model for bone cement leakage in single-segment PVP surgery, which can help doctors in performing better surgery with reduced risk.

Deficit irrigation and leaf removal modulate anthocyanin and proanthocyanidin repartitioning of Cabernet Sauvignon (Vitis vinifera L.) grape and resulting wine profile.

BACKGROUND: In monsoonal climates, grape anthocyanin and proanthocyanidin (PA) accumulations are unsatisfactory for producing optimal wine. Agronomical practices are often considered to be effective means for regulating fruit components. However, there is a lack of quantitative information on the effects of deficit irrigation (DI), basal leaf removal (LR) or their combination of deficit irrigation and leaf removal (DILR) on the characteristics of anthocyanin and PA compositions and their implications on the resulting wine quality. In this study, the dynamics of grape anthocyanin and PA accumulation were investigated in DI, LR and DILR during grape ripening, and the resulting wine profile was assessed. RESULTS: The contents of reducing sugar and total anthocyanins in Cabernet Sauvignon berries were significantly increased by DI, LR and DILR, while titratable acidity, total flavan-3-ols and tannins levels were generally decreased. Notably, the levels of 3'5'-substituted anthocyanins, such as malvidin and its derivatives significantly increased, and 3'-substituted anthocyanins decreased in both grape and wine under DI and DILR strategies. Skin PAs were sensitive to water deficits, whereas they were insensitive to LR. In resulting wine, PAs content and the proportion of 3'-hydroxylated PAs, such as (+)-catechin, (-)-epicatechin and (-)-epicatechin-3-O-gallate units were significantly decreased under DI and DILR, while molecular mass and the proportion of 3'5'-hydroxylated units of PAs were increased in response to DILR. CONCLUSION: The DILR was the most favorable for the repartitioning of anthocyanin and PA metabolites, and promoted the accumulation of tri-substituted forms contributing a higher color intensity, mouthfeel persistence, structure, and astringency of wine. This information provides an important strategy for modulating the anthocyanin and PA compositions by agricultural practices and achieving the desired quality of grapes and wines in monsoonal climates. © 2021 Society of Chemical Industry.

EspF is crucial for Citrobacter rodentium-induced tight junction disruption and lethality in immunocompromised animals.

Attaching/Effacing (A/E) bacteria include human pathogens enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC), and their murine equivalent Citrobacter rodentium (CR), of which EPEC and EHEC are important causative agents of foodborne diseases worldwide. While A/E pathogen infections cause mild symptoms in the immunocompetent hosts, an increasing number of studies show that they produce more severe morbidity and mortality in immunocompromised and/or immunodeficient hosts. However, the pathogenic mechanisms and crucial host-pathogen interactions during A/E pathogen infections under immunocompromised conditions remain elusive. We performed a functional screening by infecting interleukin-22 (IL-22) knockout (Il22-/-) mice with a library of randomly mutated CR strains. Our screen reveals that interruption of the espF gene, which encodes the Type III Secretion System effector EspF (E. coli secreted protein F) conserved among A/E pathogens, completely abolishes the high mortality rates in CR-infected Il22-/- mice. Chromosomal deletion of espF in CR recapitulates the avirulent phenotype without impacting colonization and proliferation of CR, and EspF complement in ΔespF strain fully restores the virulence in mice. Moreover, the expression levels of the espF gene are elevated during CR infection and CR induces disruption of the tight junction (TJ) strands in colonic epithelium in an EspF-dependent manner. Distinct from EspF, chromosomal deletion of other known TJ-damaging effector genes espG and map failed to impede CR virulence in Il22-/- mice. Hence our findings unveil a critical pathophysiological function for EspF during CR infection in the immunocompromised host and provide new insights into the complex pathogenic mechanisms of A/E pathogens.

Expression and localization of MrgprD in mouse intestinal tract.

MrgprD, a Mas-related G protein-coupled receptor, is initially identified in sensory neurons of mouse dorsal root ganglia (DRG) and has been suggested to participate in somatosensation. However, MrgprD has recently been found to be expressed outside the nervous system such as in aortic endothelia cells and neutrophils. In this study, we used immunohistochemistry to detect the expression and localization of MrgprD in mouse intestinal tract. The immunoreactivity (IR) of MrgprD was found in the smooth muscle layers of small intestine, colon and rectum. In addition, MrgprD IR was colocalized with F4/80-positive macrophages and CD3-positive T lymphocytes resident in the lamina propria of intestinal mucosa. MrgprD was also found to be expressed in primary peritoneal macrophages and splenic T lymphocytes. Furthermore, the presence of MrgprD mRNA and its protein was detected in murine macrophage-like RAW 264.7 and human T lymphocyte Jurkat cell lines. Our study shows, for the first time, the expression and localization of MrgprD in the intestinal tract and in macrophages and T lymphocytes, indicating the potential roles of MrgprD in intestinal mobility and immunity.

Decyanative Heteroarylations of Glycine Derivatives.

Amino acids and aromatic nitrogen heterocycles are widely used in pharmaceuticals. Herein, we present an effective visible-light-driven thiobenzoic acid (TBA)-catalyzed decyanative C(sp3)-H heteroarylation of glycine derivatives. This process occurs under mild and straightforward conditions, affording a range of valuable yet challenging-to-obtain α-heteroaryl amino acid derivatives. Moreover, this organocatalytic C(sp3)-C(sp2) bond formation reaction is applicable to the late-stage modification of various short peptides.

Construction of a predictive model for blood transfusion in patients undergoing total hip arthroplasty and identification of clinical heterogeneity.

A precise forecast of the need for blood transfusions (BT) in patients undergoing total hip arthroplasty (THA) is a crucial step toward the implementation of precision medicine. To achieve this goal, we utilized supervised machine learning (SML) techniques to establish a predictive model for BT requirements in THA patients. Additionally, we employed unsupervised machine learning (UML) approaches to identify clinical heterogeneity among these patients. In this study, we recruited 224 patients undergoing THA. To identify factors predictive of BT during the perioperative period of THA, we employed LASSO regression and the random forest (RF) algorithm as part of supervised machine learning (SML). Using logistic regression, we developed a predictive model for BT in THA patients. Furthermore, we utilized unsupervised machine learning (UML) techniques to cluster THA patients who required BT based on similar clinical features. The resulting clusters were subsequently visualized and validated. We constructed a predictive model for THA patients who required BT based on six predictive factors: Age, Body Mass Index (BMI), Hemoglobin (HGB), Platelet (PLT), Bleeding Volume, and Urine Volume. Before surgery, 1 h after surgery, 1 day after surgery, and 1 week after surgery, significant differences were observed in HGB and PLT levels between patients who received BT and those who did not. The predictive model achieved an AUC of 0.899. Employing UML, we identified two distinct clusters with significantly heterogeneous clinical characteristics. Age, BMI, PLT, HGB, bleeding volume, and urine volume were found to be independent predictors of BT requirement in THA patients. The predictive model incorporating these six predictors demonstrated excellent predictive performance. Furthermore, employing UML enabled us to classify a heterogeneous cohort of THA patients who received BT in a meaningful and interpretable manner.

Artificial intelligence-driven multiomics predictive model for abdominal aortic aneurysm subtypes to identify heterogeneous immune cell infiltration and predict disease progression.

BACKGROUND: Abdominal aortic aneurysm (AAA) poses a significant health risk and is influenced by various compositional features. This study aimed to develop an artificial intelligence-driven multiomics predictive model for AAA subtypes to identify heterogeneous immune cell infiltration and predict disease progression. Additionally, we investigated neutrophil heterogeneity in patients with different AAA subtypes to elucidate the relationship between the immune microenvironment and AAA pathogenesis. METHODS: This study enrolled 517 patients with AAA, who were clustered using k-means algorithm to identify AAA subtypes and stratify the risk. We utilized residual convolutional neural network 200 to annotate and extract contrast-enhanced computed tomography angiography images of AAA. A precise predictive model for AAA subtypes was established using clinical, imaging, and immunological data. We performed a comparative analysis of neutrophil levels in the different subgroups and immune cell infiltration analysis to explore the associations between neutrophil levels and AAA. Quantitative polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay were performed to elucidate the interplay between CXCL1, neutrophil activation, and the nuclear factor (NF)-κB pathway in AAA pathogenesis. Furthermore, the effect of CXCL1 silencing with small interfering RNA was investigated. RESULTS: Two distinct AAA subtypes were identified, one clinically more severe and more likely to require surgical intervention. The CNN effectively detected AAA-associated lesion regions on computed tomography angiography, and the predictive model demonstrated excellent ability to discriminate between patients with the two identified AAA subtypes (area under the curve, 0.927). Neutrophil activation, AAA pathology, CXCL1 expression, and the NF-κB pathway were significantly correlated. CXCL1, NF-κB, IL-1ß, and IL-8 were upregulated in AAA. CXCL1 silencing downregulated NF-κB, interleukin-1ß, and interleukin-8. CONCLUSION: The predictive model for AAA subtypes demonstrated accurate and reliable risk stratification and clinical management. CXCL1 overexpression activated neutrophils through the NF-κB pathway, contributing to AAA development. This pathway may, therefore, be a therapeutic target in AAA.

Prediction of additional hospital days in patients undergoing cervical spine surgery with machine learning methods.

BACKGROUND: Machine learning (ML), a subset of artificial intelligence (AI), uses algorithms to analyze data and predict outcomes without extensive human intervention. In healthcare, ML is gaining attention for enhancing patient outcomes. This study focuses on predicting additional hospital days (AHD) for patients with cervical spondylosis (CS), a condition affecting the cervical spine. The research aims to develop an ML-based nomogram model analyzing clinical and demographic factors to estimate hospital length of stay (LOS). Accurate AHD predictions enable efficient resource allocation, improved patient care, and potential cost reduction in healthcare. METHODS: The study selected CS patients undergoing cervical spine surgery and investigated their medical data. A total of 945 patients were recruited, with 570 males and 375 females. The mean number of LOS calculated for the total sample was 8.64 ± 3.7 days. A LOS equal to or <8.64 days was categorized as the AHD-negative group (n = 539), and a LOS > 8.64 days comprised the AHD-positive group (n = 406). The collected data was randomly divided into training and validation cohorts using a 7:3 ratio. The parameters included their general conditions, chronic diseases, preoperative clinical scores, and preoperative radiographic data including ossification of the anterior longitudinal ligament (OALL), ossification of the posterior longitudinal ligament (OPLL), cervical instability and magnetic resonance imaging T2-weighted imaging high signal (MRI T2WIHS), operative indicators and complications. ML-based models like Lasso regression, random forest (RF), and support vector machine (SVM) recursive feature elimination (SVM-RFE) were developed for predicting AHD-related risk factors. The intersections of the variables screened by the aforementioned algorithms were utilized to construct a nomogram model for predicting AHD in patients. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve and C-index were used to evaluate the performance of the nomogram. Calibration curve and decision curve analysis (DCA) were performed to test the calibration performance and clinical utility. RESULTS: For these participants, 25 statistically significant parameters were identified as risk factors for AHD. Among these, nine factors were obtained as the intersection factors of these three ML algorithms and were used to develop a nomogram model. These factors were gender, age, body mass index (BMI), American Spinal Injury Association (ASIA) scores, magnetic resonance imaging T2-weighted imaging high signal (MRI T2WIHS), operated segment, intraoperative bleeding volume, the volume of drainage, and diabetes. After model validation, the AUC was 0.753 in the training cohort and 0.777 in the validation cohort. The calibration curve exhibited a satisfactory agreement between the nomogram predictions and actual probabilities. The C-index was 0.788 (95% confidence interval: 0.73214-0.84386). On the decision curve analysis (DCA), the threshold probability of the nomogram ranged from 1 to 99% (training cohort) and 1 to 75% (validation cohort). CONCLUSION: We successfully developed an ML model for predicting AHD in patients undergoing cervical spine surgery, showcasing its potential to support clinicians in AHD identification and enhance perioperative treatment strategies.

Development and validation of a diagnostic model to differentiate spinal tuberculosis from pyogenic spondylitis by combining multiple machine learning algorithms.

This study focused on the development and validation of a diagnostic model to differentiate between spinal tuberculosis (STB) and pyogenic spondylitis (PS). We analyzed a total of 387 confirmed cases, out of which 241 were diagnosed with STB and 146 were diagnosed with PS. These cases were randomly divided into a training group (n = 271) and a validation group (n = 116). Within the training group, four machine learning (ML) algorithms (least absolute shrinkage and selection operator [LASSO], logistic regression analysis, random forest, and support vector machine recursive feature elimination [SVM-RFE]) were employed to identify distinctive variables. These specific variables were then utilized to construct a diagnostic model. The model's performance was subsequently assessed using the receiver operating characteristic (ROC) curves and the calibration curves. Finally, internal validation of the model was undertaken in the validation group. Our findings indicate that PS patients had an average platelet-to-neutrophil ratio (PNR) of 277.86, which was significantly higher than the STB patients' average of 69.88. The average age of PS patients was 54.71 years, older than the 48 years recorded for STB patients. Notably, the neutrophil-to-lymphocyte ratio (NLR) was higher in PS patients at 6.15, compared to the 3.46 NLR in STB patients. Additionally, the platelet volume distribution width (PDW) in PS patients was 0.2, compared to 0.15 in STB patients. Conversely, the mean platelet volume (MPV) was lower in PS patients at an average of 4.41, whereas STB patients averaged 8.31. Hemoglobin (HGB) levels were lower in PS patients at an average of 113.31 compared to STB patients' average of 121.64. Furthermore, the average red blood cell (RBC) count was 4.26 in PS patients, which was less than the 4.58 average observed in STB patients. After evaluation, seven key factors were identified using the four ML algorithms, forming the basis of our diagnostic model. The training and validation groups yielded area under the curve (AUC) values of 0.841 and 0.83, respectively. The calibration curves demonstrated a high alignment between the nomogram-predicted values and the actual measurements. The decision curve indicated optimal model performance with a threshold set between 2% and 88%. In conclusion, our model offers healthcare practitioners a reliable tool to efficiently and precisely differentiate between STB and PS, thereby facilitating swift and accurate diagnoses.

Prediction model for spinal cord injury in spinal tuberculosis patients using multiple machine learning algorithms: a multicentric study.

Spinal cord injury (SCI) is a prevalent and serious complication among patients with spinal tuberculosis (STB) that can lead to motor and sensory impairment and potentially paraplegia. This research aims to identify factors associated with SCI in STB patients and to develop a clinically significant predictive model. Clinical data from STB patients at a single hospital were collected and divided into training and validation sets. Univariate analysis was employed to screen clinical indicators in the training set. Multiple machine learning (ML) algorithms were utilized to establish predictive models. Model performance was evaluated and compared using receiver operating characteristic (ROC) curves, area under the curve (AUC), calibration curve analysis, decision curve analysis (DCA), and precision-recall (PR) curves. The optimal model was determined, and a prospective cohort from two other hospitals served as a testing set to assess its accuracy. Model interpretation and variable importance ranking were conducted using the DALEX R package. The model was deployed on the web by using the Shiny app. Ten clinical characteristics were utilized for the model. The random forest (RF) model emerged as the optimal choice based on the AUC, PRs, calibration curve analysis, and DCA, achieving a test set AUC of 0.816. Additionally, MONO was identified as the primary predictor of SCI in STB patients through variable importance ranking. The RF predictive model provides an efficient and swift approach for predicting SCI in STB patients.

Immune-dysregulated neutrophils characterized by upregulation of CXCL1 may be a potential factor in the pathogenesis of abdominal aortic aneurysm and systemic lupus erythematosus.

Background: The abdominal aortic aneurysm (AAA) incidence is closely related to systemic lupus erythematosus (SLE). However, the common mechanisms between AAA and SLE are still unknown. The purpose of this research was to examine the main molecules and pathways involved in the immunization process that lead to the co-occurrence of AAA and SLE through the utilization of quantitative bioinformatics analysis of publicly available RNA sequencing databases. Moreover, routine blood test information was gathered from 460 patients to validate the findings. Materials and methods: Datasets of both AAA (GSE57691 and GSE205071) and SLE (GSE50772 and GSE154851) were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were analyzed using bioinformatic tools. To determine the functions of the common differentially expressed genes (DEGs), Gene Ontology (GO) and Kyoto Encyclopedia analyses were conducted. Subsequently, the hub gene was identified through cytoHubba, and its validation was carried out in GSE47472 for AAA and GSE81622 for SLE. Immune cell infiltration analysis was performed to identify the key immune cells correlated with AAA and SLE, and to evaluate the correlation between key immune cells and the hub gene. Subsequently, the routine blood test data of 460 patients were collected, and the result of the immune cell infiltration analysis was further validated by univariate and multivariate logistic regression analysis. Results: A total of 25 common DEGs were obtained, and three genes were screened by cytoHubba algorithms. Upon validation of the datasets, CXCL1 emerged as the hub gene with strong predictive capabilities, as evidenced by an area under the curve (AUC) > 0.7 for both AAA and SLE. The infiltration of immune cells was also validated, revealing a significant upregulation of neutrophils in the AAA and SLE datasets, along with a correlation between neutrophil infiltration and CXCL1 upregulation. Clinical data analysis revealed a significant increase in neutrophils in both AAA and SLE patients (p < 0.05). Neutrophils were found to be an independent factor in the diagnosis of AAA and SLE, exhibiting good diagnostic accuracy with AUC >0.7. Conclusion: This study elucidates CXCL1 as a hub gene for the co-occurrence of AAA and SLE. Neutrophil infiltration plays a central role in the development of AAA and SLE and may serve to be a potential diagnostic and therapeutic target.

Photosensitized Anti-Markovnikov Hydroesterification of Unactivated Alkenes.

Hydrofunctionalization of alkenes represents a fundamental strategy in synthetic organic chemistry. Herein, we describe a visible-light-promoted approach for the anti-Markovnikov hydrooxygenation of unactivated alkenes. Our protocol features the utilization of a cost-effective, bench-stable, and easy-to-handle oxime ester as the reagent, enabled by energy-transfer catalysis. This methodology exhibits excellent functional group tolerance and mild reaction conditions, rendering it suitable for the hydroesterification of pharmaceutically relevant molecule-derived alkenes.

Network pharmacology combined with molecular docking and experimental validation to explore the potential mechanism of Cinnamomi ramulus against ankylosing spondylitis.

BACKGROUND: Cinnamomi ramulus (C. ramulus) is frequently employed in the treatment of ankylosing spondylitis (AS). However, the primary constituents, drug targets, and mechanisms of action remain unidentified. METHODS: In this study, various public databases and online tools were employed to gather information on the compounds of C. ramulus, drug targets, and disease targets associated with ankylosing spondylitis. The intersection of drug targets and disease targets was then determined to identify the common targets, which were subsequently used to construct a protein-protein interaction (PPI) network using the STRING database. Network analysis and the analysis of hub genes and major compounds were conducted using Cytoscape software. Furthermore, the Metascape platform was utilized for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Molecular docking studies and immunohistochemical experiments were performed to validate the core targets. RESULTS: The network analysis identified 2-Methoxycinnamaldehyde, cinnamaldehyde, and 2-Hydroxycinnamaldehyde as the major effective compounds present in C. ramulus. The PPI network analysis revealed PTGS2, MMP9, and TLR4 as the most highly correlated targets. GO and KEGG analyses indicated that C. ramulus exerts its therapeutic effects in ankylosing spondylitis through various biological processes, including the response to hormones and peptides, oxidative stress response, and inflammatory response. The main signaling pathways involved were IL-17, TNF, NF-kappa B, and Toll-like receptor pathways. Molecular docking analysis confirmed the strong affinity between the key compounds and the core targets. Additionally, immunohistochemical analysis demonstrated an up-regulation of PTGS2, MMP9, and TLR4 levels in ankylosing spondylitis. CONCLUSIONS: This study provides insights into the effective compounds, core targets, and potential mechanisms of action of C. ramulus in the treatment of ankylosing spondylitis. These findings establish a solid groundwork for future fundamental research in this field.

Identification of clinical heterogeneity and construction of a novel subtype predictive model in patients with ankylosing spondylitis: An unsupervised machine learning study.

BACKGROUND: Accurate classification of patients with ankylosing spondylitis (AS) is the premise of precision medicine so as to perform different medical interventions for different patient types. AS pathology is closely related to the changes in the immune microenvironment. In this study, we used unsupervised machine learning (UML) to classify patients with AS based on clinical characteristics. We then constructed a novel subtype predictive model for AS based on the clinical classification, after which we investigated the difference in the immune microenvironment to unravel the AS pathogenesis. METHODS: Overall, 196 patients with AS were enrolled. UML was used to cluster AS patients by similar clinical characteristics. Functional ability, disease status, and grading of radiologic features were assessed to verify the accuracy and heterogeneity of UML clustering. Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest algorithm were used to screen and identify predictive factors for the novel subtype of AS. Logistic regression was also performed to construct a predictive model of this novel subtype. Datasets were downloaded from the Gene Expression Omnibus database to assess immune cell infiltration, and the results were validated using data of routine blood tests from 3671 AS patients and 5720 non-AS patients. The differential expression of Fat Mass and Obesity-Associated Protein (FTO), an m6A regulator, between AS patients and healthy control subjects was confirmed using immunohistochemistry. RESULTS: UML clustering identified two clusters. The clinical characteristics of the two clusters were significantly heterogeneous. For the novel subtype of AS identified in UML clustering, a predictive model was built using three predictive factors, namely, C-reactive protein (CRP), absolute value of neutrophils (NEU), and absolute value of monocytes (MONO). The area under the curve of the predictive model was 0.983. Heterogeneity in the neutrophil and monocyte counts in AS was verified through immune cell infiltration analysis. Data from routine blood tests revealed that NEU and MONO were significantly higher in AS patients than in non-AS patients (p < 0.001). FTO expression was negatively correlated with both NEU and MONO. Immunohistochemistry analysis confirmed the downregulated expression of FTO. CONCLUSIONS: UML provides an explicable and remarkable classification of a heterogeneous cohort of AS patients. A novel subtype of AS was identified in UML clustering. CRP, NEU, and MONO were the independent predictive factors for the novel subtype of AS. FTO expression was correlated with immune cell infiltration in AS patients.

MMP9 and STAT1 are biomarkers of the change in immune infiltration after anti-tuberculosis therapy, and the immune status can identify patients with spinal tuberculosis.

BACKGROUND: Due to a lack of studies on immune-related pathogenesis and a clinical diagnostic model, the diagnosis of Spinal Tuberculosis (STB) remains uncertain. Our study aimed to investigate the possible pathogenesis of STB and to develop a clinical diagnostic model for STB based on immune cell infiltration. METHODS: Label-free quantification protein analysis of five pairs of specimens was used to determine the protein expression of the intervertebral disc in STB and non-STB. GO enrichment analysis, and KEGG pathway analysis were used to investigate the pathogenesis of STB. The Hub proteins were then eliminated. Four datasets were downloaded from the GEO database to analyze immune cell infiltration, and the results were validated using blood routine test data from 8535TB and 7337 non-TB patients. Following that, clinical data from 164 STB and 162 non-STB patients were collected. The Random-Forest algorithm was used to screen out clinical predictors of STB and build a diagnostic model. The differential expression of MMP9 and STAT1 in STB and controls was confirmed using immunohistochemistry. RESULTS: MMP9 and STAT1 were STB Hub proteins that were linked to disc destruction in STB. MMP9 and STAT1 were found to be associated with Monocytes, Neutrophils, and Lymphocytes in immune cell infiltration studies. Data from 15,872 blood routine tests revealed that the Monocytes ratio and Neutrophils ratio was significantly higher in TB patients than in non-TB patients (p < 0.001), while the Lymphocytes ratio was significantly lower in TB patients than in non-TB patients (p < 0.001). MMP9 and STAT1 expression were downregulated following the anti-TB therapy. For STB, a clinical diagnostic model was built using six clinical predictors: MR, NR, LR, ESR, BMI, and PLT. The model was evaluated using a ROC curve, which yielded an AUC of 0.816. CONCLUSIONS: MMP9 and STAT1, immune-related hub proteins, were correlated with immune cell infiltration in STB patients. MR, NR, LR ESR, BMI, and PLT were clinical predictors of STB. Thus, the immune cell Infiltration-related clinical diagnostic model can predict STB effectively.

Using Machine Learning to Predict Surgical Site Infection After Lumbar Spine Surgery.

Objective: The objective of this study was to utilize machine learning techniques to analyze perioperative factors and identify blood glucose levels that can predict the occurrence of surgical site infection following posterior lumbar spinal surgery. Methods: A total of 4019 patients receiving lumbar internal fixation surgery from an institute were enrolled between June 2012 and February 2021. First, the filtered data were randomized into the test and verification groups. Second, in the test group, specific variables were screened using logistic regression analysis, Lasso regression analysis, support vector machine, and random forest. Specific variables obtained using the four methods were intersected, and a dynamic model was constructed. ROC and calibration curves were constructed to assess model performance. Finally, internal model performance was verified in the verification group using ROC and calibration curves. Results: The data from 4019 patients were collected. In total, 1327 eligible cases were selected. By combining logistic regression analysis with three machine learning algorithms, this study identified four predictors associated with SSI, namely Modic changes, sebum thickness, hemoglobin, and glucose. Using this information, a prediction model was developed and visually represented. Then, we constructed ROC and calibration curves using the test group; the area under the ROC curve was 0.988. Further, calibration curve analysis revealed favorable consistency of nomogram-predicted values compared with real measurements. The C-index of our model was 0.986 (95% CI 0.981-0.994). Finally, we used the validation group to validate the model internally; the AUC was 0.987. Calibration curve analysis revealed favorable consistency of nomogram-predicted values compared with real measurements. The C-index was 0.982 (95% CI 0.974-0.999). Conclusion: Logistic regression analysis and machine learning were employed to select four risk factors: Modic changes, sebum thickness, hemoglobin, and glucose. Then, a dynamic prediction model was constructed to help clinicians simplify the monitoring and prevention of SSI.

Epidemiological characteristics of ankylosing spondylitis in Guangxi Province of China from 2014 to 2021.

Introduction: To explore the epidemiological characteristics of ankylosing spondylitis (AS) in Guangxi Province of China through a large sample survey of more than 50 million aboriginal aboriginal population. Material and methods: A systematic search was conducted using the International Classification of Diseases 10 (ICD-10) codes M45.x00(AS), M45.x03+(AS with iridocyclitis), and M40.101(AS with kyphosis) to search the database in the National Health Statistics Network Direct Reporting System (NHSNDRS). 14004 patients were eventually included in the study. The parameters analyzed included the number of patients, gender, marriage, blood type, occupation, age at diagnosis, and location of household registration data each year, and statistical analysis was performed. Results: AS incidence rates increased from 1.30 (95% CI: 1.20-1.40) per 100,000 person-years in 2014 to 5.71 (95% CI: 5.50-5.92) in 2020 in Guangxi Province, and decreased slightly in 2021. Males have a higher incidence than females; the ratio was 5.61 : 1. The mean age of diagnosis in male patients was 45.4 (95% CI: 45.1-45.7) years, in females 47.6 (95% CI: 46.8-48.4) years. The most frequent blood type was O, and the most frequent occupation was farmer. The AS incidence rate was disparate in different cities. Liuzhou city had the highest eight-year average AS incidence rates from 2014 to 2021, and Chongzuo city had the lowest (p < 0.05). There was no significant difference in the incidence between different ethnic groups (p > 0.05). Conclusions: The AS person-years incidence rate was increasing in Guangxi province of China from 2014 to 2020, which had obvious gender and regional differences, showing the characteristics of local area aggregation.