KMTLabeler: An Interactive Knowledge-Assisted Labeling Tool for Medical Text Classification.

The process of labeling medical text plays a crucial role in medical research. Nonetheless, creating accurately labeled medical texts of high quality is often a time-consuming task that requires specialized domain knowledge. Traditional methods for generating labeled data typically rely on rigid rule-based approaches, which may not adapt well to new tasks. While recent machine learning (ML) methodologies have mitigated the manual labeling efforts, configuring models to align with specific research requirements can be challenging for labelers without technical expertise. Moreover, automated labeling techniques, such as transfer learning, face difficulties in in directly incorporating expert input, whereas semi-automated methods, like data programming, allow knowledge integration through rules or knowledge bases but may lack continuous result refinement throughout the entire labeling process. In this study, we present a collaborative human-ML teaming workflow that seamlessly integrates visual cluster analysis and active learning to assist domain experts in labeling medical text with high efficiency. Additionally, we introduce an innovative neural network model called the embedding network, which incorporates expert insights to generate task-specific embeddings for medical texts. We integrate the workflow and embedding network into a visual analytics tool named KMTLabeler, equipped with coordinated multi-level views and interactions. Two illustrative case studies, along with a controlled user study, provide substantial evidence of the effectiveness of KMTLabeler in creating an efficient labeling environment for medical text classification.

Leveraging Historical Medical Records as a Proxy via Multimodal Modeling and Visualization to Enrich Medical Diagnostic Learning.

Simulation-based Medical Education (SBME) has been developed as a cost-effective means of enhancing the diagnostic skills of novice physicians and interns, thereby mitigating the need for resource-intensive mentor-apprentice training. However, feedback provided in most SBME is often directed towards improving the operational proficiency of learners, rather than providing summative medical diagnoses that result from experience and time. Additionally, the multimodal nature of medical data during diagnosis poses significant challenges for interns and novice physicians, including the tendency to overlook or over-rely on data from certain modalities, and difficulties in comprehending potential associations between modalities. To address these challenges, we present DiagnosisAssistant, a visual analytics system that leverages historical medical records as a proxy for multimodal modeling and visualization to enhance the learning experience of interns and novice physicians. The system employs elaborately designed visualizations to explore different modality data, offer diagnostic interpretive hints based on the constructed model, and enable comparative analyses of specific patients. Our approach is validated through two case studies and expert interviews, demonstrating its effectiveness in enhancing medical training.

Decreased programmed cell death ligand 2-positive monocytic myeloid-derived suppressor cells and programmed cell death protein 1-positive T-regulatory cells in patients with type 2 diabetes: implications for immunopathogenesis.

Objectives: The activation of immune cells plays a significant role in the progression of type 2 diabetes. This study aimed to investigate the potential role of myeloid-derived suppressor cells (MDSCs) and T-regulatory cells (Tregs) in type 2 diabetes. Methods: A total of 61 patients diagnosed with type 2 diabetes were recruited. Clinical characteristics were reviewed and peripheral blood samples were collected. We calculated the percentage of different cells. Frequencies of MDSC subsets refered to the percentage of G-MDSCs (CD15+CD33+CD11b+CD14-HLA-DR-/low) in CD45 positive cells and the percentage of M-MDSCs (CD14+CD15-CD11b+CD33+HLA-DR-/low) in lymphocytes plus monocytes. Results: Frequencies of programmed cell death ligand 1-positive granulocytic MDSCs (PD-L1+ G-MDSCs), programmed cell death ligand 2-positive monocytic MDSCs (PD-L2+ M-MDSCs), PD-L2+ G-MDSC, and programmed cell death protein 1-positive Tregs (PD-1+Tregs) were decreased in patients with type 2 diabetes. The frequency of PD-1+ Tregs was positively related to PD-L2+ M-MDSCs (r= 0.357, P = 0.009) and negatively related to HbA1c (r = -0.265, P = 0.042), fasting insulin level (r = -0.260, P = 0.047), and waist circumference (r = -0.373, P = 0.005). Conclusions: Decreased PD-L2+ M-MDSCs and PD-1+ Tregs may promote effector T cell activation, leading to chronic low-grade inflammation in type 2 diabetes. These findings highlight the contribution of MDSCs and Tregs to the immunopathogenesis of type 2 diabetes and suggest their potential as targets for new therapeutic approaches.

Characteristics of cervical intervertebral disc signal intensity: an analysis of T2-weighted magnetic resonance imaging in 5843 asymptomatic Chinese subjects.

PURPOSE: The study aimed to observe cervical intervertebral discs (IVDs) in asymptomatic subjects and to explore the factors associated with cervical intervertebral disc degeneration (IVDD). METHODS: Cervical spine MRI of 5843 subjects was retrospectively analyzed. On the sagittal T2-weighted MR images, the mean signal intensities of the nucleus pulposus were obtained. Standard signal intensity (SSI) of intervertebral discs was defined as the ratio of mean disc signal intensity to mean CSF signal intensity. RESULTS: In subjects under 70 years old, the SSI of IVD was lowest at the C5/6 level. In those over 70, the SSI of IVD was similar among the disc levels from C2/3 to C7/T1. The disc SSI decreased significantly with age in both genders. In subjects under 70 years old, the SSI of the discs at each level was higher in females than in males. In those over 70 years old, no difference was found in disc SSI between two genders at most disc levels. Logistic regression analysis showed that kyphotic and straight cervical spine, obesity and older age were associated with higher risk of having lower disc SSI. CONCLUSION: To our knowledge, this is the largest cross-sectional study using MRI-based quantitative assessment to characterize cervical IVDD in asymptomatic subjects. Cervical IVDD was shown to progress with age and significantly correlated with gender, BMI and cervical alignment. Early intervention of related factors may help delay cervical IVDD and prevent future neck and shoulder pain.

IL-1ß contributes to the secretion of sclerostin by osteocytes and targeting sclerostin promotes spinal fusion at early stages.

BACKGROUND: Despite extensive research, there is still a need for safe and effective agents to promote spinal fusion. Interleukin (IL)-1ß is an important factor which influences the bone repair and remodelling. The purpose of our study was to determine the effect of IL-1ß on sclerostin in osteocytes and to explore whether inhibiting the secretion of sclerostin from osteocytes can promote spinal fusion at early stages. METHODS: Small-interfering RNA was used to suppress the secretion of sclerostin in Ocy454 cells. MC3T3-E1 cells were cocultured with Ocy454 cells. Osteogenic differentiation and mineralisation of MC3T3-E1 cells were evaluated in vitro. SOST knock-out rat generated using the CRISPR-Cas9 system and rat spinal fusion model was used in vivo. The degree of spinal fusion was assessed by manual palpation, radiographic analysis and histological analysis at 2 and 4 weeks. RESULTS: We found that IL-1ß level had a positive association with sclerostin level in vivo. IL-1ß promoted the expression and secretion of sclerostin in Ocy454 cells in vitro. Inhibition of IL-1ß-induced secretion of sclerostin from Ocy454 cells could promote the osteogenic differentiation and mineralisation of cocultured MC3T3-E1 cells in vitro. The extent of spinal graft fusion was greater in SOST-knockout rats than in wild-type rats at 2 and 4 weeks. CONCLUSIONS: The results demonstrate that IL-1ß contributes to a rise in the level of sclerostin at early stages of bone healing. Suppressing sclerostin may be an important therapeutic target capable of promoting spinal fusion at early stages.

Predictive Classification System for Low Back Pain Based on Unsupervised Clustering.

STUDY DESIGN: Retrospective study. OBJECTIVE: Lumbar magnetic resonance imaging (MRI) findings are believed to be associated with low back pain (LBP). This study sought to develop a new predictive classification system for low back pain. METHOD: Normal subjects with repeated lumbar MRI scans were retrospectively enrolled. A new classification system, based on the radiological features on MRI, was developed using an unsupervised clustering method. RESULTS: One hundred and fifty-nine subjects were included. Three distinguishable clusters were identified with unsupervised clustering that were significantly correlated with LBP (P = .017). The incidence of LBP was highest in cluster 3 (57.14%), nearly twice the incidence in cluster 1 (30.11%). There were obvious differences in the sagittal parameters among the 3 clusters. Cluster 3 had the smallest intervertebral height. Based on follow-up findings, 27% of subjects changed clusters. More subjects changed from cluster 1 to clusters 2 or 3 (14.5%) than changed from cluster 2 or cluster 3 to cluster 1 (5%). Participation in sport was more frequent in subjects who changed from cluster 3 to cluster 1. CONCLUSION: Using an unsupervised clustering method, we developed a new classification system comprising 3 clusters, which were significantly correlated with LBP. The prediction of LBP is independent of age and better than that based on individual sagittal parameters derived from MRI. A change in cluster during follow-up may partially predict lumbar degeneration. This study provides a new system for the prediction of LBP that should be useful for its diagnosis and treatment.

Effect of hyaluronic acid on cytokines and immune cells change in patients of knee osteoarthritis.

PURPOSE: To evaluate the changes of cytokines and immune cells after Intra-articular hyaluronic acid(IAHA)injections in patients with knee osteoarthritis (KOA). PATIENTS AND METHODS: Sixteen patients were included in the study, with a total of 65 IAHA injections. The Numeric Rating Scale (NRS) and Lysholm scores were evaluated at each visit. The immune cells and 14 cytokines of synovial fluid were analyzed at each visit. The association between immune cells and cytokines were examined. RESULTS: IL-6 and IL-8 were the most common cytokines in the synovial fluid of KOA patients. The synovial fluid was orchestrated by macrophages (69%) and Lymphocytes (18%). Neutrophils were less to count of the total cell population (< 2%). The cytokines decreased significantly after the first injection and then tended to be stable. Lymphocytes increased a lot, while Macrophages decreased in the early stage, then increased after multiple injections. The proposition of M1 decreased in the early stage, then increased after multiple injections, while M2 increased consistently. M1 and M2 were positively associated with IL-6 and IL-8. CONCLUSION: The synovial fluid of KOA patients was orchestrated by macrophages (69%) and Lymphocytes (18%) and cytokines like IL-6 and IL-8. IAHA may play an anti-inflammatory functional role through the decreased production of IL-6 and IL-8 by macrophages through polarization. The results from this study partially revealed the effect of IAHA on cytokines and immune cells change in KOA patients, and therapies targeting pathogenic cytokines and immune cells might be used to attenuate the knee joint inflammation and release pain. TRIAL REGISTRATION: ChiCTR2100050133; date registered 17 August 2021.

[Research progress on regulation of mitophagy by traditional Chinese medicine in prevention and treatment of chronic kidney diseases].

The prevalence of chronic kidney disease(CKD) increases year by year and has become a highly prevalent disease, seriously affecting the quality of life of patients and bringing heavy family burden. There are many diseases causing CKD, including va-rious primary and secondary glomerulonephritis, renal tubular injury, and renal vascular lesions. Although routine medical treatment for CKD can alleviate the clinical symptoms to a certain extent, it is sometimes difficult to prevent the progression of CKD. Traditional Chinese medicine(TCM) is advantageous in high safety, few adverse reactions, and definite clinical efficacy in the treatment of CKD. The active components contained can play a synergistic effect through multiple pathways and multiple targets to delay disease progression, but its mechanism of action has not been fully elucidated. As revealed by the literature in this field in China and abroad, abnormal mitophagy is a common feature of the pathogenesis of CKD of different types. In recent years, a large number of studies have proved that the regulation of mitophagy through the PINK1/Parkin signaling pathway and mitophagy receptor pathway could delay the progression of CKD and protect renal function. Therefore, the regulation of mitophagy by TCM in the prevention and treatment of CKD through related pathways has become a potential therapeutic target in recent years. This paper reviewed the research articles on the definite efficacy of TCM in preventing and treating CKD by regulating mitophagy through relevant pathways to provide new targets and stra-tegies for preventing and treating CKD and delaying their entry into end-stage renal diseases.

In vitro and in vivo effects of hyperglycemia and diabetes mellitus on nucleus pulposus cell senescence.

Diabetes mellitus contributes to intervertebral disc degeneration. Nucleus pulposus cell senescence plays an important role in intervertebral disc degeneration. However, the effects of hyperglycemia on human nucleus pulposus cells and the underlying process remains poorly understood. In the current study, we evaluated the effects of high glucose levels on human nucleus pulposus cell senescence in vitro and the effects of hyperglycemia on rat nucleus pulposus aging in vivo. Human nucleus pulposus cells were cultured in high-glucose medium (200 mM glucose) for 48 h. Senescence-associated ß-galactosidase staining, western blot analysis, and enzyme-linked immunosorbent assays were performed to evaluate human nucleus pulposus cell senescence. Flow cytometry and enzyme-linked immunosorbent assays were used to evaluate reactive oxygen species and advanced glycation end-product levels. Transcriptome sequencing followed by bioinformatics analysis was used to understand the abnormal biological processes of nucleus pulposus cells cultured in high-glucose medium. Diabetes mellitus rat models were established and histopathological and immunohistochemical analysis was conducted to examine nucleus pulposus tissue senescence in vivo. Exposure to a high glucose concentration promoted human nucleus pulposus cell senescence and increased the senescence-related secretion phenotype in human nucleus pulposus cells in vitro and in rat nucleus pulposus tissue in vivo. Bioinformatics analysis showed that hub genes were involved in nucleus pulposus cell cycle activities and cell senescence. The results suggest that appropriate blood glucose control may be key to preventing intervertebral disc degeneration in diabetic patients.

Design, Synthesis, and Structure-Activity Relationship Optimization of Pyrazolopyrimidine Amide Inhibitors of Phosphoinositide 3-Kinase γ (PI3Kγ).

Phosphoinositide-3-kinase γ (PI3Kγ) is highly expressed in immune cells and promotes the production and migration of inflammatory mediators. The inhibition of PI3Kγ has been shown to repolarize the tumor immune microenvironment to a more inflammatory phenotype, thereby controlling immune suppression in cancer. Herein, we report the structure-based optimization of an early lead series of pyrazolopyrimidine isoindolinones, which culminated in the discovery of highly potent and isoform-selective PI3Kγ inhibitors with favorable drug-like properties. X-ray cocrystal structure analysis, molecular docking studies, and detailed structure-activity relationship investigations resulted in the identification of the optimal amide and isoindolinone substituents to achieve a desirable combination of potency, selectivity, and metabolic stability. Preliminary in vitro studies indicate that inhibition of PI3Kγ with compound 56 results in a significant immune response by increasing pro-inflammatory cytokine gene expression in M1 macrophages.

The feasibility and efficacy of a community-based multifactorial intervention to improve the cardiovascular risk factor control among patients with type 2 diabetes: A 2-year cluster randomized trial.

TRIAL DESIGN: Our study is to investigate the feasibility and effectiveness of multiple cardiovascular factors intervention (MFI) in type 2 diabetes patients in China's primary care setting. METHODS: We performed a cluster randomized trial to compare the proportion of patients achieved the targets between usual care group (control, 9 sites, n = 868) and MFI group (8 sites, n = 739) among patients with type 2 diabetes in primary care setting. Logistic regression model with random effects was used to estimate the association of the effect of intervention and the proportion achieved the targets. RESULTS: At baseline, the end of 1 year, and 2 years follow-up, the proportion of patients achieved all 3 target goals (HbA1c < 7.0%, blood pressure < 130/80 mm Hg and low-density lipoprotein cholesterol < 2.6 mmol/L) were 5.7%, 5.9%, 5.7% in the control group and 5.9%, 10.6%, 12.3% in the MFI group. After adjusting sex, age, diabetes duration, body mass index, HbA1c, blood pressure, and low-density lipoprotein cholesterol at baseline, there was no difference between the 2 groups (OR (95% CI): 1.27 (0.38-4.27) and 1.86 (0.79-4.38) for the first year and second year, respectively). When stratified by payment method, the patients with medical insurance or public expenses had a higher proportion achieved target goals (6.9% vs 16.4%, OR (95% CI): 2.30 (1.04-5.08)) in the second year. CONCLUSIONS: The controlling of cardiovascular risk factor targets remains suboptimal among patients with type 2 diabetes in primary care setting. MFI in type 2 diabetes improved cardiovascular disease risk profile, especially in the patients with medical insurance.

Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.

Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.

Beyond the Intention: Individual-Level Determinants and Intergenerational Differences of Floating Populations' Actual Settlement Choices in Dongguan, China.

The migration process and patterns of floating populations have received continuing attention from scholars and policymakers. In China, however, studies have been focused on the settlement intention of floating populations based on sampling surveys and yielded inconsistent findings. Drawing upon 18,178,167 authentic individual samples of floating populations in Dongguan city, this study contributes to the literature by examining the effect of individual characteristics on the actual resident actions of floating populations, and revealing both the heterogeneity and continuity of their urban residence among four generations (i.e., during the 1960s, 1970s, 1980s, and 1990s). The results show that the proportion of actual resident actions is lower than that reported by previous studies on settlement intentions, and that male, married, middle-aged, more educated, and long-residing members are more likely to choose to stay in Dongguan. Compared to their predecessors, the 1990 cohort reveals significant heterogeneities in their actual settlement choices. The study draws broad implications from the analysis, calling for the equalization of public welfare in Chinese cities and the encouragement of floating populations to sustain long-term residence in the destination cities.

Discovery of Potent and Selective 7-Azaindole Isoindolinone-Based PI3Kγ Inhibitors.

The successful application of immunotherapy in the treatment of cancer relies on effective engagement of immune cells in the tumor microenvironment. Phosphoinositide 3-kinase γ (PI3Kγ) is highly expressed in tumor-associated macrophages, and its expression levels are associated with tumor immunosuppression and growth. Selective inhibition of PI3Kγ offers a promising strategy in immuno-oncology, which has led to the development of numerous potent PI3Kγ inhibitors with variable selectivity profiles. To facilitate further investigation of the therapeutic potential of PI3Kγ inhibition, we required a potent and PI3Kγ-selective tool compound with sufficient metabolic stability for use in future in vivo studies. Herein, we describe some of our efforts to realize this goal through the systematic study of SARs within a series of 7-azaindole-based PI3Kγ inhibitors. The large volume of data generated from this study helped guide our subsequent lead optimization efforts and will inform further development of PI3Kγ-selective inhibitors for use in immunomodulation.

Integrated Bioinformatics Analysis of Hub Genes and Pathways Associated with a Compression Model of Spinal Cord Injury in Rats.

BACKGROUND Spinal cord injury (SCI) is a serious nervous system condition that can cause lifelong disability. The aim of this study was to identify potential molecular mechanisms and therapeutic targets for SCI. MATERIAL AND METHODS We constructed a weighted gene coexpression network and predicted which hub genes are involved in SCI. A compression model of SCI was established in 45 Sprague-Dawley rats, which were divided into 5 groups (n=9 per group): a sham operation group, and 1, 3, 5, and 7 days post-SCI groups. The spinal cord tissue on the injured site was harvested on 1, 3, 5, and 7 days after SCI and 3 days after surgery in the sham operation group. High-throughput sequencing was applied to investigate the expression profile of the mRNA in all samples. Differentially expressed genes were screened and included in weighted gene coexpression network analysis (WGCNA). Co-expressed modules and hub genes were identified by WGCNA. The biological functions of each module were investigated using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. RESULTS According to the RNA-seq data, a total of 1965 differentially expressed genes were screened, and WGCNA identified 10 coexpression modules and 5 hub genes. Module function analysis revealed that SCI was associated with immune response, cell division, neuron projection development, and collagen fibril organization. CONCLUSIONS Our study revealed dynamic changes in a variety of biological processes following SCI and identified 5 hub genes via WGCNA. These results provide insights into the molecular mechanisms and therapeutic targets of SCI.

Discovery of Potent and Selective PI3Kγ Inhibitors.

The selective inhibition of the lipid signaling enzyme PI3Kγ constitutes an opportunity to mediate immunosuppression and inflammation within the tumor microenvironment but is difficult to achieve due to the high sequence homology across the class I PI3K isoforms. Here, we describe the design of a novel series of potent PI3Kγ inhibitors that attain high isoform selectivity through the divergent projection of substituents into both the "selectivity" and "alkyl-induced" pockets within the adenosine triphosphate (ATP) binding site of PI3Kγ. These efforts have culminated in the discovery of 5-[2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl]-2-[(1S)-1-cyclopropylethyl]-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (4, IC50 = 0.064 µM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.

A finite element analysis on comparing the stability of different posterior fixation methods for thoracic total en bloc spondylectomy.

OBJECTIVE: To compare the spinal stability with different fixation methods after thoracic TES using finite element analysis METHODS: The spinal finite element model was established from a healthy volunteer, and the validity was verified. The models of T8 thoracic total en bloc spondylectomy (TES) with and without artificial vertebral body were established combination with different fixation methods: the first was long segment fixation with fixed segments T5-7, T9-11; the second was short segment fixation with fixed segments T6-7, T9-10; the third was modified short segment with a pair of vertebral body screws on T7 and T9 added on the basis of short segment fixation. The motions of each model in standing state were simulated in software. The range of motion (ROM) and internal fixation stress changes were analyzed. RESULTS: When anterior support was effective, the three fixation methods could effectively maintain the stability of the spine. However, when anterior support failed, the ROM of the long segment fixation group and the short segment fixation group in the flexion-extension directions was significantly higher than that of when the anterior support existed, while the modified short segment fixation group had no significant changes. Meanwhile, the stress of internal fixation in the long segment fixation group and the short segment fixation group were greatly increased. However, there were no significant changes in modified short segment fixation group. CONCLUSION: After TES, the presence of the thoracic cage gives partial anterior stabilization. When the anterior support failed, the modified short segment fixation method can provide better stability.

Discovery of AB680: A Potent and Selective Inhibitor of CD73.

Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.

Discovery of Potent and Selective Non-Nucleotide Small Molecule Inhibitors of CD73.

CD73 is an extracellular mediator of purinergic signaling. When upregulated in the tumor microenvironment, CD73 has been implicated in the inhibition of immune function through overproduction of adenosine. Traditional efforts to inhibit CD73 have involved antibody therapy or the development of small molecules, the most potent of which mimic the acidic and ionizable structure of the enzyme's natural substrate, adenosine 5'-monophosphate (AMP). Here, we report the systematic discovery of a novel class of non-nucleotide CD73 inhibitors that are more potent than all other nonphosphonate inhibitor classes reported to date. These efforts have culminated in the discovery of 4-({5-[4-fluoro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (73, IC50 = 12 nM) and 4-({5-[4-chloro-1-(2H-indazol-6-yl)-1H-1,2,3-benzotriazol-6-yl]-1H-pyrazol-1-yl}methyl)benzonitrile (74, IC50 = 19 nM). Cocrystallization of 74 with human CD73 demonstrates a competitive binding mode. These compounds show promise for the improvement of drug-like character via the attenuation of the acidity and low membrane permeability inherent to known nucleoside inhibitors of CD73.

Cage migration after unilateral instrumented transforaminal lumbar interbody fusion and associated risk factors: a modified measurement method.

OBJECTIVE: In this retrospective study, a modified measurement method was used to analyze cage migration during follow-up after unilateral instrumented transforaminal lumbar interbody fusion (TLIF) and identify associated factors. METHODS: We retrospectively evaluated 75 patients who had been treated with unilateral instrumented TLIF. Cage migration was quantitatively defined as anterior-posterior or lateral displacement of the cage. RESULTS: Five patients had significant cage migration (6.7%), but none developed severe neural symptoms during follow-up or underwent reoperation. The cages tended to migrate posteriorly or toward the side of surgery. The initial cage position and patient age were strongly associated with migration. Migration was less frequent when the cages were initially placed closer to the side of surgery. Patients of advanced age were more likely to develop anterior-posterior migration than were young patients. CONCLUSION: Cage migration is related to the initial position of the cage. Particular attention is required when performing unilateral instrumented TLIF in patients of advanced age because they are most likely to develop cage migration. Quantification of cage migration is an effective method of exploring the associated factors.