Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors.

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging.

The transition from ordered to noisy is a significant epigenetic signature of aging and age-related disease. As a paradigm of healthy human aging and longevity, long-lived individuals (LLI, >90 years old) may possess characteristic strategies in coping with the disordered epigenetic regulation. In this study, we constructed high-resolution blood epigenetic noise landscapes for this cohort by a methylation entropy (ME) method using whole genome bisulfite sequencing (WGBS). Although a universal increase in global ME occurred with chronological age in general control samples, this trend was suppressed in LLIs. Importantly, we identified 38,923 genomic regions with LLI-specific lower ME (LLI-specific lower entropy regions, for short, LLI-specific LERs). These regions were overrepresented in promoters, which likely function in transcriptional noise suppression. Genes associated with LLI-specific LERs have a considerable impact on SNP-based heritability of some aging-related disorders (e.g., asthma and stroke). Furthermore, neutrophil was identified as the primary cell type sustaining LLI-specific LERs. Our results highlight the stability of epigenetic order in promoters of genes involved with aging and age-related disorders within LLI epigenomes. This unique epigenetic feature reveals a previously unknown role of epigenetic order maintenance in specific genomic regions of LLIs, which helps open a new avenue on the epigenetic regulation mechanism in human healthy aging and longevity.

Quality of life in young patients with acute type a aortic dissection in China: comparison with Marfan syndrome and non-Marfan syndrome.

BACKGROUND: There is a paucity of Chinese studies evaluating the quality of life (QoL) in young acute type A aortic dissection (AAAD) patients with Marfan syndrome. METHODS: Young adult AAAD patients (younger than 45 years old) underwent surgical treatment at our institution from January 2017 to December 2020 were consecutive enrolled. The hospital survivors completed 1 year of follow up. Patients were divided into two groups according to the presence or absence of Marfan syndrome (MFS). A 1:1 propensity score matching (PSM) with a caliper 0.2 was conducted to balance potential bias in baseline. The follow-up data were analyzed primarily for change in quality of life and anxiety status. RESULTS: After PSM, 32 comparable pairs were matched. The baseline data were comparable and postoperative complications were similar between groups. In terms of SF-36 scale, the role physical, bodily pain, role emotional and mental health subscales were no significantly improved in MFS patients over time. At 1 year after discharged, the subscale of mental health and bodily pain were significantly lower in the MFS group than in the non-MFS group. In terms of HADS assessments, the level of anxiety in MFS patients was significantly higher than in non-MFS patients at 1 year after discharged. CONCLUSIONS: The QoL in young AAAD patients with MFS is lower than those without MFS after surgery. This may be associated with the uncontrollable persistent chronic pain and the uncertainty and concerns for the disease's progression.

Left ventricular recovery after total arterial coronary artery bypass grafting versus conventional coronary artery bypass grafting in patients with multivessel coronary artery disease and reduced left ventricular ejection fraction.

BACKGROUND: We compared total arterial revascularization (TAR) versus conventional revascularization (CR) in terms of left ventricular function recovery in patients with multivessel coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). METHODS: We conducted a retrospective cohort study of 162 consecutive patients with multivessel CAD and reduced LVEF who underwent isolated coronary artery bypass grafting at our institution between January 2013 and July 2022. We assessed left ventricular function by transthoracic echocardiography at admission, before discharge, and at follow-up of 3, 6, and 12 months, using LVEF, global longitudinal peak strain, end-diastolic volume index, and end-systolic volume index. We also evaluated mitral valve regurgitation and graft patency rate at 1 year. RESULTS: The TAR group had a significantly higher increase in LVEF and global longitudinal peak strain, and a significantly lower decrease in end-diastolic volume index and end-systolic volume index than the CR group at 6 and 12 months after surgery. The TAR group also had a significantly lower degree of mitral valve regurgitation than the CR group at all-time points within 12 months after surgery. The TAR group had a significantly higher graft patency rate than the CR group at 12 months. There was no significant difference in hospital mortality or repeat revascularization between the groups. CONCLUSIONS: TAR was associated with better recovery of left ventricular function than CR in patients with multivessel CAD and reduced LVEF. Further studies are needed to confirm these findings in this high-risk population.

Mid-term outcomes of total neointima implantation in surgical repair of acute type A aortic dissection.

Total neointima implantation (patch neointima technique + triple-branched stent graft placement) has been performed in proximal aortic repair for acute type A aortic dissection (ATAAD) for more than 10 years at a center. However, there is no report on the mid-term outcomes with a control group of the surgical procedure. Consequently, the authors aimed to evaluate the safety and efficacy of this technique in this study. Patients who underwent the total neointima implantation were classified as Group A, and those who underwent the conventional aortic root reconstruction with the "sandwich" technique and the total aortic arch replacement were classified as Group B. Furthermore, the authors described the preoperative characteristics, operative data, and patient outcomes. Group A patients experienced a shorter surgery duration, lower volumes of perioperative bleeding, and fewer red blood cell transfusions. The incidence of neurological complications was significantly reduced in Group A. All patients maintained a normal range of proximal aortic sizes after surgery. Kaplan-Meier analysis revealed no significant differences between the patients in the two groups regarding cumulative mortality and the incidence of moderate-to-severe aortic insufficiency. In well-selected patients, total neointima implantation is an alternative procedure for the surgical repair of ATAAD.

Electronanofiltration Membranes with a Bilayer Charged Structure Enable High Li+/Mg2+ Selectivity.

Achieving separation of lithium and magnesium with similar radii is crucial for the current lithium extraction technology from salt lakes, which usually possess a high lithium-to-magnesium ratio. Herein, we proposed the facile sequential interfacial polymerization (SIP) approach to construct electronanofiltration membranes (ENFMs) with a bilayer charged structure consisting of a high positively charged surface and a negatively charged sublayer. The trimesoyl chloride (TMC) concentration was adjusted to enhance the -COOH content and negative charge of the polyamide sublayer to promote Li+ migration, and then the quaternized polyethylenimine was introduced to the membrane surface by the SIP process to increase the positive charge density on the surface of the ENFMs, which would block the migration of Mg2+ and enhance the Li+/Mg2+ selectivity of the ENFMs. The optimal quaternary-modified ENFMs achieved outstanding selectivity for Li+/Mg2+ (49.85) and high Li+ flux (4.10 × 10-8 mol cm-2 s-1) at a current density of 10 mA cm-2. Moreover, in simulated brines with low lithium concentration and high Mg2+/Li+ ratio, the optimal ENFMs also displayed elevated Li+/Mg2+ selectivity (>45), highlighting the substantial promise of the membranes for practical applications.

Multi-Omics Characteristics of Ferroptosis Associated with Colon Adenocarcinoma Typing and Survival.

BACKGROUND: Ferroptosis, an iron-dependent form of cell death, plays a crucial role in the progression of various cancers, including colon adenocarcinoma (COAD). However, the multi-omics signatures relevant to ferroptosis regulation in COAD diagnosis remain to be elucidated. METHODS: The transcriptomic, miRNAomic, and methylomic profiles of COAD patients were acquired from the Cancer Genome Atlas (TCGA). Ferroptosis activity in these patients was determined, represented by a ferroptosis score (FS), using single-sample gene set enrichment analysis (ssGSEA) based on the expression of ferroptosis-related genes. RESULTS: Results showed that the COAD patients with high-FS displayed favorable survival outcomes and heightened drug sensitivity. They also exhibited an up-regulation of genes involved in immune-related pathways (e.g., tumor necrosis factor signaling pathway), suggesting a correlation between immunity and ferroptosis in COAD progression. Furthermore, three survival prediction models were established based on 10 CpGs, 12 long non-coding RNAs (lncRNAs), and 14 microRNAs (miRNAs), respectively. These models demonstrated high accuracy in predicting COAD survival, achieving areas under the curve (AUC) >0.7. The variables used in the three models also showed strong correlations at different omics levels and were effective at discriminating between high-FS and low-FS COAD patients (AUC >0.7). CONCLUSIONS: This study identified different DNA methylation (DNAm), lncRNA, and miRNA characteristics between COAD patients with high and low ferroptosis activity. Furthermore, ferroptosis-related multi-omics signatures were established for COAD prognosis and classification. These insights present new opportunities for improving the efficacy of COAD therapy.

Expansion and contraction of lake basin shape the genetic structure of Sinocyclocheilus (Osteichthyes: Cypriniformes: Cyprinidae) populations in Central Yunnan, China.

Geological events can strongly affect the genetic structures and differentiation of fish populations. Especially, as an endemic fish of the genus Sinocyclocheilus in the Yunnan-Guizhou Plateau, the effects of key geological events on the distributions and genetic structures remain poorly understood. Examining the phylogeographic patterns of Sinocyclocheilus fishes can be useful for elucidating the spatio-temporal dynamics of their population size, dispersal history and extent of geographical isolation, thereby providing a theoretical basis for their protection. Here, we used single nucleotide polymorphisms (SNP) method to investigate the phylogeographic patterns of Sinocyclocheilus fishes. Our analysis supports the endemicity of Sinocyclocheilus, but the samples of different regions of Sinocyclocheilus contain multiple ancestral components, which displayed more admixed and diversified genetic components, this may be due to the polymorphism of the ancestors themselves, or gene infiltration caused by hybridization between adjacent species of Sinocyclocheilus. We estimate that the most recent common ancestor (MRCA) of Sinocyclocheilus fish in the Central Yunnan Basin at approximately 3.75~3.11 Ma, and infer that the evolution of Sinocyclocheilus in the central Yunnan Basin is closely related to the formation of plateau lakes (around 4.0~0.02 Ma), and identifies the formation of Dianchi Lake and Fuxian Lake as key geological events shaping Sinocyclocheilus population structure. It is also the first time to prove that the altitude change has a great influence on the genetic variation among the populations of Sinocyclocheilus.

Application of ensemble learning for predicting GABAA receptor agonists.

BACKGROUND: Over the past few decades, agonists binding to the benzodiazepine site of the GABAA receptor have been successfully developed as clinical drugs. Different modulators (agonist, antagonist, and reverse agonist) bound to benzodiazepine sites exhibit different or even opposite pharmacological effects, however, their structures are so similar that it is difficult to distinguish them based solely on molecular skeleton. This study aims to develop classification models for predicting the agonists. METHODS: 306 agonists or non-agonists were collected from literature. Six machine learning algorithms including RF, XGBoost, AdaBoost, GBoost, SVM, and ANN algorithms were employed for model development. Using six descriptors including 1D/2D Descriptors, ECFP4, 2D-Pharmacophore, MACCS, PubChem, and Estate fingerprint to characterize chemical structures. The model interpretability was explored by SHAP method. RESULTS: The best model demonstrated an AUC value of 0.905 and an MCC value of 0.808 for the test set. The PubMac-based model (PubMac-GB) achieved best AUC values of 0.935 for test set. The SHAP analysis results emphasized that MaccsFP62, ECFP_624, ECFP_724, and PubchemFP213 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. The PubMac-GB model was applied to virtual screening for potential GABAA agonists and the top 100 compounds were given. CONCLUSION: Overall, our ensemble learning-based model (PubMac-GB) achieved comparable performance and would be helpful in effectively identifying agonists of GABAA receptors.

Scrutiny of genome-wide somatic mutation profiles in centenarians identifies the key genomic regions for human longevity.

Somatic mutations accumulate with age and are associated closely with human health, their characterization in longevity cohorts remains largely unknown. Here, by analyzing whole genome somatic mutation profiles in 73 centenarians and 51 younger controls in China, we found that centenarian genomes are characterized by a markedly skewed distribution of somatic mutations, with many genomic regions being specifically conserved but displaying a high function potential. This, together with the observed more efficient DNA repair ability in the long-lived individuals, supports the existence of key genomic regions for human survival during aging, with their integrity being of essential to human longevity.

RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment.

BACKGROUND: Regulator of G protein signaling 5 (RGS5), as a negative regulator of G protein-coupled receptor (GPCR) signaling, is highly expressed in arterial VSMCs and pericytes, which is involved in VSMC phenotypic heterogeneity and vascular remodeling in tumors. However, its role in normal and tumor vascular remodeling is controversial. METHODS: RGS5 knockout (Rgs5-KO) mice and RGS5 overexpression or knockdown in VSMCs in vivo by adeno-associated virus type 9 (AAV) carrying RGS5 cDNA or small hairpin RNA (shRNA) targeting RGS5 were used to determine the functional significance of RGS5 in vascular inflammation. RGS5 expression in the triple-negative (TNBCs) and non-triple-negative breast cancers (Non-TNBCs) was determined by immunofluorescent and immunohistochemical staining. The effect of breast cancer cell-conditioned media (BC-CM) on the pro-inflammatory phenotype of VSMCs was measured by phagocytic activity assays, adhesion assay and Western blot. RESULTS: We identified that knockout and VSMC-specific knockdown of RGS5 exacerbated accumulation and pyroptosis of pro-inflammatory VSMCs, resulting in vascular remodeling, which was negated by VSMC-specific RGS5 overexpression. In contrast, in the context of breast cancer tissues, the role of RGS5 was completely disrupted. RGS5 expression was increased in the triple-negative breast cancer (TNBC) tissues and in the tumor blood vessels, accompanied with an extensive vascular network. VSMCs treated with BC-CM displayed enhanced pro-inflammatory phenotype and higher adherent with macrophages. Furthermore, tumor-derived RGS5 could be transferred into VSMCs. CONCLUSIONS: These findings suggest that tumor microenvironment shifts the function of RGS5 from anti-inflammation to pro-inflammation and induces the pro-inflammatory phenotype of VSMCs that is favorable for tumor metastasis.

Naringenin improves muscle endurance via activation of the Sp1-ERRγ transcriptional axis.

Skeletal muscle function declines in the aging process or disease; however, until now, skeletal muscle has remained one of the organs most undertreated with medication. In this study, naringenin (NAR) was found to build muscle endurance in wild-type mice of different ages by increasing oxidative myofiber numbers and aerobic metabolism, and it ameliorates muscle dysfunction in mdx mice. The transcription factor Sp1 was identified as a direct target of NAR and was shown to mediate the function of NAR on muscle. Moreover, the binding site of NAR on Sp1 was further validated as GLN-110. NAR enhances the binding of Sp1 to the CCCTGCCCTC sequence of the Esrrg promoter by promoting Sp1 phosphorylation, thus upregulating Esrrg expression. The identification of the Sp1-ERRγ transcriptional axis is of great significance in basic muscle research, and this function of NAR has potential implications for the improvement of muscle function and the prevention of muscle atrophy.

LogD7.4 prediction enhanced by transferring knowledge from chromatographic retention time, microscopic pKa and logP.

Lipophilicity is a fundamental physical property that significantly affects various aspects of drug behavior, including solubility, permeability, metabolism, distribution, protein binding, and toxicity. Accurate prediction of lipophilicity, measured by the logD7.4 value (the distribution coefficient between n-octanol and buffer at physiological pH 7.4), is crucial for successful drug discovery and design. However, the limited availability of data for logD modeling poses a significant challenge to achieving satisfactory generalization capability. To address this challenge, we have developed a novel logD7.4 prediction model called RTlogD, which leverages knowledge from multiple sources. RTlogD combines pre-training on a chromatographic retention time (RT) dataset since the RT is influenced by lipophilicity. Additionally, microscopic pKa values are incorporated as atomic features, providing valuable insights into ionizable sites and ionization capacity. Furthermore, logP is integrated as an auxiliary task within a multitask learning framework. We conducted ablation studies and presented a detailed analysis, showcasing the effectiveness and interpretability of RT, pKa, and logP in the RTlogD model. Notably, our RTlogD model demonstrated superior performance compared to commonly used algorithms and prediction tools. These results underscore the potential of the RTlogD model to improve the accuracy and generalization of logD prediction in drug discovery and design. In summary, the RTlogD model addresses the challenge of limited data availability in logD modeling by leveraging knowledge from RT, microscopic pKa, and logP. Incorporating these factors enhances the predictive capabilities of our model, and it holds promise for real-world applications in drug discovery and design scenarios.

Metastatic spinal cord compression as the first manifestation of malignancy: A retrospective study of surgical outcome from single institution.

BACKGROUND: Given the limited studies addressing the issue about the effect of different surgical modalities for metastatic spinal cord compression (MSCC) as the first malignancy manifestation, we conducted a retrospective case-control study to evaluate the surgical outcome of MSCC as the first malignancy manifestation. METHODS: A total of 128 patients who were suspected of having metastatic spinal cord compression and underwent surgery from 2008 to 2021 were enrolled in the study. All patients were categorized into either 'debulking group' or 'palliative group'. RESULTS: The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), Frankel scale, and Karnofsky scores. All the outcomes were analyzed with a data cutoff of December 31, 2021. There was a significant difference between groups in progression-free survival (PFS) (p = 0.0094). However, there was no significant difference between groups in the overall survival (OS) (p = 0.0746). Age of onset, gender, duration of symptoms, and location of spinal metastasis, initial Frankel, initial Tomita scores, and initial Karnofsky performance scale showed no significant differences between groups. CONCLUSION: In conclusion, debulking surgery was shown to provide better neurological recoveries and could be considered first in patients with metastatic spinal cord compression as the first malignancy manifestation.

Incorporation of Selenium Derived from Nanoparticles into Plant Proteins in Vivo.

Diets comprising selenium-deficient crops have been linked to immune disorders and cardiomyopathy. Selenium nanoparticles (SeNPs) have emerged as a promising nanoplatform for selenium-biofortified agriculture. However, SeNPs fail to reach field-scale applications due to a poor understanding of the fundamental principles of its behavior. Here, we describe the transport, transformation, and bioavailability of SeNPs through a combination of in vivo and in vitro experiments. We show synthesized amorphous SeNPs, when sprayed onto the leaves of Arabidopsis thaliana, are rapidly biotransformed into selenium(IV), nonspecifically incorporated as selenomethionine (SeMet), and specifically incorporated into two selenium-binding proteins (SBPs). The SBPs identified were linked to stress and reactive oxygen species (mainly H2O2 and O2-) reduction, processes that enhance plant growth and primary root elongation. Selenium is transported both upwards and downwards in the plant when SeNPs are sprayed onto the leaves. With the application of Silwet L-77 (a common agrochemical surfactant), selenium distributed throughout the whole plant including the roots, where pristine SeNPs cannot reach. Our results demonstrate that foliar application of SeNPs promotes plant growth without causing nanomaterial accumulation, offering an efficient way to obtain selenium-fortified agriculture.

Two-incision totally thoracoscopic mitral valve repair combined with radiofrequency atrial fibrillation ablation in rheumatic mitral valve disease: Early results of a case series of 43 consecutive patients.

BACKGROUND: Few studies have reported the outcomes of two-incision total thoracoscopic mitral valve repair (MVr) and concomitant radiofrequency atrial fibrillation ablation (RAFA) in patients with rheumatic mitral valve disease and atrial fibrillation (AF). METHODS: We retrospectively analyzed 43 consecutive patients who underwent MVr and RAFA through two-incision total thoracoscopic technique from October 2018 to June 2022. We collected data on baseline characteristics, perioperative outcomes, and early-term results. RESULTS: The mean age was 55.67 ± 7.64 years and 29 (67.4%) patients had New York Heart Association (NYHA) class III or IV. The mean cardiopulmonary bypass (CPB) time was 115.56 ± 8.53 min and aortic clamping time was 81.42 ± 7.54 min. There were no in-hospital deaths or strokes. The mean preoperative mitral valve orifice area (MVOA) was 0.95 (0.84-1.16) cm2 and increased to 2.56 (2.41-2.87) cm2 at discharge and 2.54 (2.44-2.76) cm2 at 3 months after surgery (P < .001). At discharge, 32 (74.4%) patients were in sinus rhythm, 7 (20.9%) were in junctional or atrial flutter rhythm, and 4 (9.3%) remained in AF. At 6 months, 35 (81.4%) patients were in sinus rhythm, 5 (11.63%) were in junctional or atrial flutter rhythm, and 3 (4.7%) were in AF. CONCLUSIONS: Two-incision total thoracoscopic MVr and RAFA is a safe and effective procedure that can improve the MVOA and promote conversion of AF to sinus rhythm in patients with rheumatic mitral valve disease and AF. Further studies with larger sample size and longer follow-up are needed to confirm the long-term benefits of this approach.

Predicting the retention time of Synthetic Cannabinoids using a combinatorial QSAR approach.

Background: Abuse of Synthetic Cannabinoids (SCs) has become a serious threat to public health. Due to the various structural and chemical group modified by criminals, their detection is a major challenge in forensic toxicological identification. Therefore, rapid and efficient identification of SCs is important for forensic toxicology and drug bans. The prediction of an analyte's retention time in liquid chromatography is an important index for the qualitative analysis of compounds and can provide informatics solutions for the interpretation of chromatographic data. Methods: In this study, experimental data from high-resolution mass spectrometry (HRMS) are used to construct a regression model for predicting the retention time of SCs using machine learning methods. The prediction ability of the model is improved by adopting a strategy that combines different descriptors in different independent machine-learning methods. Results: The best model was obtained with a method that combined Substructure Fingerprint Count and Finger printer features and the support vector regression (SVR) method, as it exhibited an R2 value of 0.81 for the validation set and 0.83 for the test set. In addition, 4 new SCs were predicted by the optimized model, with a prediction error within 3%. Conclusions: Our study provides a model that can predict the retention time of compounds and it can be used as a filter to reduce false-positive candidates when used in combination with LC-HRMS, especially in the absence of reference standards. This can improve the confidence of identification in non-targeted analysis and the reliability of identifying unknown substances.

Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia.

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis in vitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease.

Does the Presence of Missing Data Affect the Performance of the SORG Machine-learning Algorithm for Patients With Spinal Metastasis? Development of an Internet Application Algorithm.

BACKGROUND: The Skeletal Oncology Research Group machine-learning algorithm (SORG-MLA) was developed to predict the survival of patients with spinal metastasis. The algorithm was successfully tested in five international institutions using 1101 patients from different continents. The incorporation of 18 prognostic factors strengthens its predictive ability but limits its clinical utility because some prognostic factors might not be clinically available when a clinician wishes to make a prediction. QUESTIONS/PURPOSES: We performed this study to (1) evaluate the SORG-MLA's performance with data and (2) develop an internet-based application to impute the missing data. METHODS: A total of 2768 patients were included in this study. The data of 617 patients who were treated surgically were intentionally erased, and the data of the other 2151 patients who were treated with radiotherapy and medical treatment were used to impute the artificially missing data. Compared with those who were treated nonsurgically, patients undergoing surgery were younger (median 59 years [IQR 51 to 67 years] versus median 62 years [IQR 53 to 71 years]) and had a higher proportion of patients with at least three spinal metastatic levels (77% [474 of 617] versus 72% [1547 of 2151]), more neurologic deficit (normal American Spinal Injury Association [E] 68% [301 of 443] versus 79% [1227 of 1561]), higher BMI (23 kg/m2 [IQR 20 to 25 kg/m2] versus 22 kg/m2 [IQR 20 to 25 kg/m2]), higher platelet count (240 × 103/µL [IQR 173 to 327 × 103/µL] versus 227 × 103/µL [IQR 165 to 302 × 103/µL], higher lymphocyte count (15 × 103/µL [IQR 9 to 21× 103/µL] versus 14 × 103/µL [IQR 8 to 21 × 103/µL]), lower serum creatinine level (0.7 mg/dL [IQR 0.6 to 0.9 mg/dL] versus 0.8 mg/dL [IQR 0.6 to 1.0 mg/dL]), less previous systemic therapy (19% [115 of 617] versus 24% [526 of 2151]), fewer Charlson comorbidities other than cancer (28% [170 of 617] versus 36% [770 of 2151]), and longer median survival. The two patient groups did not differ in other regards. These findings aligned with our institutional philosophy of selecting patients for surgical intervention based on their level of favorable prognostic factors such as BMI or lymphocyte counts and lower levels of unfavorable prognostic factors such as white blood cell counts or serum creatinine level, as well as the degree of spinal instability and severity of neurologic deficits. This approach aims to identify patients with better survival outcomes and prioritize their surgical intervention accordingly. Seven factors (serum albumin and alkaline phosphatase levels, international normalized ratio, lymphocyte and neutrophil counts, and the presence of visceral or brain metastases) were considered possible missing items based on five previous validation studies and clinical experience. Artificially missing data were imputed using the missForest imputation technique, which was previously applied and successfully tested to fit the SORG-MLA in validation studies. Discrimination, calibration, overall performance, and decision curve analysis were applied to evaluate the SORG-MLA's performance. The discrimination ability was measured with an area under the receiver operating characteristic curve. It ranges from 0.5 to 1.0, with 0.5 indicating the worst discrimination and 1.0 indicating perfect discrimination. An area under the curve of 0.7 is considered clinically acceptable discrimination. Calibration refers to the agreement between the predicted outcomes and actual outcomes. An ideal calibration model will yield predicted survival rates that are congruent with the observed survival rates. The Brier score measures the squared difference between the actual outcome and predicted probability, which captures calibration and discrimination ability simultaneously. A Brier score of 0 indicates perfect prediction, whereas a Brier score of 1 indicates the poorest prediction. A decision curve analysis was performed for the 6-week, 90-day, and 1-year prediction models to evaluate their net benefit across different threshold probabilities. Using the results from our analysis, we developed an internet-based application that facilitates real-time data imputation for clinical decision-making at the point of care. This tool allows healthcare professionals to efficiently and effectively address missing data, ensuring that patient care remains optimal at all times. RESULTS: Generally, the SORG-MLA demonstrated good discriminatory ability, with areas under the curve greater than 0.7 in most cases, and good overall performance, with up to 25% improvement in Brier scores in the presence of one to three missing items. The only exceptions were albumin level and lymphocyte count, because the SORG-MLA's performance was reduced when these two items were missing, indicating that the SORG-MLA might be unreliable without these values. The model tended to underestimate the patient survival rate. As the number of missing items increased, the model's discriminatory ability was progressively impaired, and a marked underestimation of patient survival rates was observed. Specifically, when three items were missing, the number of actual survivors was up to 1.3 times greater than the number of expected survivors, while only 10% discrepancy was observed when only one item was missing. When either two or three items were omitted, the decision curves exhibited substantial overlap, indicating a lack of consistent disparities in performance. This finding suggests that the SORG-MLA consistently generates accurate predictions, regardless of the two or three items that are omitted. We developed an internet application (https://sorg-spine-mets-missing-data-imputation.azurewebsites.net/) that allows the use of SORG-MLA with up to three missing items. CONCLUSION: The SORG-MLA generally performed well in the presence of one to three missing items, except for serum albumin level and lymphocyte count (which are essential for adequate predictions, even using our modified version of the SORG-MLA). We recommend that future studies should develop prediction models that allow for their use when there are missing data, or provide a means to impute those missing data, because some data are not available at the time a clinical decision must be made. CLINICAL RELEVANCE: The results suggested the algorithm could be helpful when a radiologic evaluation owing to a lengthy waiting period cannot be performed in time, especially in situations when an early operation could be beneficial. It could help orthopaedic surgeons to decide whether to intervene palliatively or extensively, even when the surgical indication is clear.