Insulin resistance in the retina: possible implications for certain ocular diseases.

Insulin resistance (IR) is becoming a worldwide medical and public health challenge as an increasing prevalence of obesity and metabolic disorders. Accumulated evidence has demonstrated a strong relationship between IR and a higher incidence of several dramatically vision-threatening retinal diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. In this review, we provide a schematic overview of the associations between IR and certain ocular diseases and further explore the possible mechanisms. Although the exact causes explaining these associations have not been fully elucidated, underlying mechanisms of oxidative stress, chronic low-grade inflammation, endothelial dysfunction and vasoconstriction, and neurodegenerative impairments may be involved. Given that IR is a modifiable risk factor, it may be important to identify patients at a high IR level with prompt treatment, which may decrease the risk of developing certain ocular diseases. Additionally, improving IR through the activation of insulin signaling pathways could become a potential therapeutic target.

Identification of core genes in intervertebral disc degeneration using bioinformatics and machine learning algorithms.

Background: Intervertebral Disc Degeneration (IDD) is a major cause of lower back pain and a significant global health issue. However, the specific mechanisms of IDD remain unclear. This study aims to identify key genes and pathways associated with IDD using bioinformatics and machine learning algorithms. Methods: Gene expression profiles, including those from 35 LDH patients and 43 healthy volunteers, were downloaded from the GEO database (GSE124272, GSE150408, GSE23130, GSE153761). After merging four microarray datasets, differentially expressed genes (DEGs) were selected for GO and KEGG pathway enrichment analysis. Weighted Gene Co-expression Network Analysis (WGCNA) was then applied to the merged dataset to identify relevant modules and intersect with DEGs to discover candidate genes with diagnostic value. A LASSO model was established to select appropriate genes, and ROC curves were drawn to elucidate the diagnostic value of genetic markers. A Protein-Protein Interaction (PPI) network was constructed and visualized to determine central genes, followed by external validation using qRT-PCR. Results: Differential analysis of the preprocessed dataset identified 244 genes, including 183 upregulated and 61 downregulated genes. WGCNA analysis revealed the most relevant module intersecting with DEGs, yielding 9 candidate genes. The lasso-cox method was used for regression analysis, ultimately identifying 6 genes: ASPH, CDC42EP3, FOSL2, IL1R1, NFKBIZ, TCF7L2. A Protein-Protein Interaction (PPI) network created with GENEMANIA identified IL1R1 and TCF7L2 as central genes. Conclusion: Our study shows that IL1R1 and TCF7L2 are the core genes of IDD, offering new insights into the pathogenesis and therapeutic development of IDD.

Safety and Efficacy of Multiple Escalating Doses of RC28-E for Neovascular Age-Related Macular Degeneration: A Phase 1b Trial.

INTRODUCTION: To assess the safety and efficacy of repeated intravitreal injections of RC28-E, a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with neovascular age-related macular degeneration (AMD). This was a prospective, multicenter, open-label clinical trial; 37 patients with choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) letter scores between 73 and 34 were enrolled. METHODS: Treatment regimens consisted of a 3-month loading phase and a pro re nata (PRN) maintenance phase. This study included three treatment groups: the 0.5, 1.0, and 2.0 mg RC28-E groups, with escalating doses ranging from 0.5 to 2.0 mg. Patients were evaluated monthly for 48 weeks. Safety was assessed based on ocular and systemic adverse events (AEs), pharmacokinetic characteristics, and the presence of anti-RC28-E antibodies. Efficacy was assessed using the mean change in BCVA and central subfield thickness (CST) from baseline to week 48. RESULTS: Most AEs were mild or moderate. The most common AE was a minor injection-related subconjunctival hemorrhage (16.2%). The AEs did not increase with dose or repeated injections. At week 48, mean improvements in BCVA from baseline in the 0.5, 1.0, and 2.0 mg groups were 6.1 ± 8.3, 9.9 ± 10.7, and 7.6 ± 9.38 letters, respectively; mean reductions in CST in the three groups were 112.1 ± 160.5, 175.1 ± 212.4, and 128.7 ± 145.8 µm, respectively. The serum RC28-E concentrations in 95% of the patients were below the quantification limit of the assay. No significant change from baseline was observed in the mean plasma concentrations of VEGF or FGF over the 48 weeks of treatment. Pre-treatment antibodies to RC28-E were detected in 1 of the 37 patients. Antibodies to RC28-E were detected in two patients after dosing with RC28-E for 48 weeks. CONCLUSION: RC28-E was well tolerated and exhibited an overall favorable safety profile with evidence of improvements in BCVA and anatomical parameters.

Development of Vogt-Koyanagi-Harada disease-like uveitis during treatment by anti-programmed death-1 antibody: a case report.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) have been linked to the occurrence of Vogt-Koyanagi-Harada disease (VKHD)-like uveitis. Among the ICIs, there has been no report of immune-related adverse events (irAEs) caused by a new programmed death protein-1(PD-1) monoclonal antibody (Toripalimab). CASE PRESENTATION: This paper presents a case of VKHD-like uveitis that arose following Toripalimab therapy for urothelial cancer of the bladder, and the patient experienced symptoms 10 days after the final dosage of 20 months of medication treatment. This patient with bladder uroepithelial carcinoma had severe binocular acute panuveitis with exudative retinal detachment after receiving Toripalimab therapy. Binocular VKHD-like uveitis was suggested as a diagnosis. Both eyes recovered after discontinuing immune checkpoint inhibitors and local and systemic corticosteroid treatment. CONCLUSIONS: This report suggests that VKHD-like uveitis can also occur in patients receiving novel PD-1 antibodies and the importance of paying attention to eye complications in patients receiving treatment over a long period.

[Modified QuEChERS method combined with ultra performance liquid chromatography-tandem mass spectrometry for detection of cyclopiazonic acid in feeds].

Mycotoxins are toxic secondary metabolites produced by fungal species that can cause acute, subacute, and chronic toxicity in humans and animals. Thus, these toxins pose a significant threat to health and safety. Owing to the lack of effective antimold measures in the agricultural industry, feed ingredients such as corn, peanuts, wheat, barley, millet, nuts, oily feed, forage, and their byproducts are prone to mold and mycotoxin contamination, which can affect animal production, product quality, and safety. Cyclopiazonic acid (CPA), which is mainly biosynthesized from mevalonate, tryptophan, and diacetate units, is a myotoxic secondary metabolite produced by Penicillium and Aspergillus fungi. CPA is widely present as a copollutant with aflatoxins in various crops. Compared with some common mycotoxins such as aflatoxins, fumonisins, ochratoxins, zearalenones, and their metabolites, CPA has not been well investigated. In the United States, a survey showed that 51% of corn and 90% of peanut samples contained CPA, with a maximum level of 2.9 mg/kg. In Europe, CPA was found in Penicillium-contaminated cheeses as high as 4.0 mg/kg. Some studies have shown that CPA can cause irreversible damage to organs such as the liver and spleen in mice. Therefore, the establishment of a rapid and efficient analytical method for CPA is of great significance for the risk assessment of CPA in feeds, the development of standard limits, and the protection of feed product quality and safety. The QuEChERS method, a sample pretreatment method that is fast, simple, cheap, effective, and safe, is widely used in the analysis of pesticide residues in food. In this study, a modified QuEChERS method combined with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine CPA levels in feeds. The chromatographic separation and MS detection of CPA as well as the key factors affecting the extraction efficiency of CPA, including the type of extraction solvent, type of inorganic salt, and type and dosage of adsorbent, were optimized in detail. During the optimization of the chromatographic-separation step, the acid and salt concentrations of the mobile phase affected the separation and detection of CPA. During the optimization of the QuEChERS method, the addition of a certain amount of acetic acid improved the extraction efficiency of CPA because of its acidic nature; in addition, GCB and PSA significantly adsorbed CPA from the feed extract. Under optimal conditions, the CPA in the feed sample (1.0 g) was extracted with 2 mL of water and 4 mL of acetonitrile (ACN) containing 0.5% acetic acid. After salting out with 0.4 g of NaCl and 1.6 g of MgSO4, 1 mL of the ACN supernatant was purified by dispersive solid-phase extraction using 150 mg of MgSO4 and 50 mg of C18 and analyzed by UPLC-MS/MS. The sample was separated on a Waters HSS T3 column (100 mm×2.1 mm, 1.8 µm) using 2 mmol/L ammonium acetate aqueous solution with 0.5% formic acid and ACN as the mobile phases and then analyzed by positive electrospray ionization in multiple reaction monitoring mode. CPA exhibited good linearity in the range of 2-200 ng/mL, with a high correlation coefficient (r=0.9995). The limits of detection and quantification of CPA, which were calculated as 3 and 10 times the signal-to-noise ratio, respectively, were 0.6 and 2.0 µg/kg, respectively. The average recoveries in feed samples spiked with 10, 100, and 500 µg/kg CPA ranged from 70.1% to 78.5%, with an intra-day precision of less than 5.8% and an inter-day precision of less than 7.2%, indicating the good accuracy and precision of the proposed method. Finally, the modified QuEChERS-UPLC-MS/MS method was applied to the analysis of CPA in 10 feed samples obtained from Wuhan market. The analysis results indicated that the developed method has good applicability for CPA analysis in feed samples. In summary, an improved QuEChERS method was applied to the extraction and purification of CPA from feeds for the first time; this method provides a suitable analytical method for the risk monitoring, assessment, and standard-limit setting of CPA in feed samples.

Circulating Immune Landscape Profiling in Psoriasis Vulgaris and Psoriatic Arthritis by Mass Cytometry.

Background: Psoriasis, a systemic disorder mediated by the immune system, can appear on the skin, joints, or both. Individuals with cutaneous psoriasis (PsC) have an elevated risk of developing psoriatic arthritis (PsA) during their lifetime. Despite this known association, the cellular and molecular mechanisms underlying this progression remain unclear. Methods: We performed high-dimensional, in-depth immunophenotyping of peripheral blood mononuclear cells (PBMCs) in patients with PsA and psoriasis vulgaris (PsV) by mass cytometry. Blood samples were collected before and after therapy for a longitudinal study. Then three sets of comparisons were made here: active PsA vs. active PsV, untreated PsV vs. treated PsV, and untreated PsA vs. treated PsA. Results: Marked differences were observed in multiple lymphocyte subsets of PsA related to PsV, with expansion of CD4+ T cells, CD16- NK cells, and B cells. Notably, two critical markers, CD28 and CD127, specifically differentiated PsA from PsV. The expression levels of CD28 and CD127 on both Naïve T cells (TN) and central memory CD4+ T cells (TCM) were considerably higher in PsA than PsV. Meanwhile, after treatment, patients with PsV had higher levels of CD28hi CD127hi CD4+ TCM cells, CD28hi CD127hi CD4+ TN cells, and CD16- NK cells. Conclusion: In the circulation of PsA patients, the TN and CD4+ TCM are characterized with more abundant CD28 and CD127, which effectively distinguished PsA from PsV. This may indicate that individuals undergoing PsV could be stratified at high risk of developing PsA based on the circulating levels of CD28 and CD127 on specific cell subsets.

Finite element analysis of biomechanical effects of percutaneous cement discoplasty in scoliosis.

OBJECTIVE: To investigate the effect of bone cement on the vertebral body and biomechanical properties in percutaneous cement discoplasty (PCD) for degenerative lumbar disc disease. METHODS: Three-dimensional reconstruction of L2 ~ L3 vertebral bodies was performed in a healthy volunteer, and the corresponding finite element model of the spine was established. Biomechanical analysis was performed on the changes in stress distribution in different groups of models by applying quantitative loads. RESULTS: Models with percutaneous discoplasty (PCD) showed improved stability under various stress conditions, and intervertebral foraminal heights were superior to models without discoplasty. CONCLUSION: Cement discoplasty can improve the stability of the vertebral body to a certain extent and restore a certain height of the intervertebral foramen, which has a good development prospect and potential.

A hybrid forecasting approach for China's national carbon emission allowance prices with balanced accuracy and interpretability.

A significant milestone in China's carbon market was reached with the official launch and operation of the National Carbon Emission Trading Market. The accurate prediction of the carbon price in this market is crucial for the government to formulate scientific policies regarding the carbon market and for companies to participate effectively. Nevertheless, it remains challenging to accurately predict price fluctuations in the carbon market because of the volatility and instability caused by several complex factors. This paper proposes a new carbon price forecasting framework that considers the potential factors influencing national carbon prices, including data decomposition and reconstruction techniques, feature selection techniques, machine learning forecasting techniques for intelligent optimisation, and research on model interpretability. This comprehensive framework aims to improve the accuracy and understandability of carbon price projections to respond better to the complexity and uncertainty of carbon markets. The results indicate that (1) the hybrid forecasting framework is highly accurate in forecasting national carbon market prices and far superior to other comparative models; (2) the factors driving national carbon prices vary according to the time scale. High-frequency series are sensitive to short-term economic and energy market indicators. Medium- and low-frequency series are more susceptible to financial markets and long-term economic conditions than high-frequency series. This study provides insights into the factors affecting China's national carbon market price and serves as a reference for companies and governments to develop carbon price forecasting tools.

Deep learning-based estimation of axial length using macular optical coherence tomography images.

Background: This study aimed to develop deep learning models using macular optical coherence tomography (OCT) images to estimate axial lengths (ALs) in eyes without maculopathy. Methods: A total of 2,664 macular OCT images from 444 patients' eyes without maculopathy, who visited Beijing Hospital between March 2019 and October 2021, were included. The dataset was divided into training, validation, and testing sets with a ratio of 6:2:2. Three pre-trained models (ResNet 18, ResNet 50, and ViT) were developed for binary classification (AL ≥ 26 mm) and regression task. Ten-fold cross-validation was performed, and Grad-CAM analysis was employed to visualize AL-related macular features. Additionally, retinal thickness measurements were used to predict AL by linear and logistic regression models. Results: ResNet 50 achieved an accuracy of 0.872 (95% Confidence Interval [CI], 0.840-0.899), with high sensitivity of 0.804 (95% CI, 0.728-0.867) and specificity of 0.895 (95% CI, 0.861-0.923). The mean absolute error for AL prediction was 0.83 mm (95% CI, 0.72-0.95 mm). The best AUC, and accuracy of AL estimation using macular OCT images (0.929, 87.2%) was superior to using retinal thickness measurements alone (0.747, 77.8%). AL-related macular features were on the fovea and adjacent regions. Conclusion: OCT images can be effectively utilized for estimating AL with good performance via deep learning. The AL-related macular features exhibit a localized pattern in the macula, rather than continuous alterations throughout the entire region. These findings can lay the foundation for future research in the pathogenesis of AL-related maculopathy.

IL-31-dependent neurogenic inflammation restrains cutaneous type 2 immune response in allergic dermatitis.

Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting Il31 and its receptor Il31ra in a mouse model of house dust mite (HDM)-induced allergic dermatitis. Il31-deficient mice displayed a deficit in HDM dermatitis-associated scratching, consistent with its well-established role as a pruritogen. In contrast, Il31 deficiency increased the number and proportion of cutaneous type 2 cytokine-producing CD4+ T cells and serum IgE in response to HDM. Furthermore, Il4ra+ monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in Il31ra-deficient HDM dermatitis skin. Thus, IL-31 is not strictly a proinflammatory cytokine but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin. Our data support a model wherein IL-31 activation of IL31RA+ pruritoceptors triggers release of calcitonin gene-related protein (CGRP), which can mediate neurogenic inflammation, inhibit CD4+ T cell proliferation, and reduce T cell production of the type 2 cytokine IL-13. Together, these results illustrate a previously unrecognized neuroimmune pathway that constrains type 2 tissue inflammation in the setting of chronic cutaneous allergen exposure and may explain paradoxical dermatitis flares in atopic patients treated with anti-IL31RA therapy.

PREDICTIVE ROLES OF QUANTITATIVE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FEATURES IN PROGNOSIS OF MYOPIC CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To explore the predictive roles of the morphologic features of neovascularization in the prognosis of myopic choroidal neovascularization. METHODS: In this retrospective case series study, quantitative morphologic features of neovascularization were obtained from the optical coherence tomography angiography images. According to the number of anti-vascular endothelial growth factor injections administered within 1 year, the eyes were classified into a stable group (≤2 injections) or an unstable group (>2 injections). Best-corrected visual acuity was recorded before the treatment and at the 1-year follow-up. RESULTS: Overall, 50 eyes with treatment-naive myopic choroidal neovascularization were included; 26 in the stable group and 24 in the unstable group. Multivariate analysis showed that the eyes in the unstable group were associated with a larger lesion area (odds ratio = 2.596, P = 0.012), higher junction density (odds ratio = 1.611, P = 0.014), and higher end point density (odds ratio = 1.435, P = 0.023).The area under the receiver operating characteristic curve of the multivariate model was 0.865, with 91.7% sensitivity and 65.4% specificity. The final best-corrected visual acuity was significantly correlated with the lesion area (ß = 0.152, P = 0.032) after adjusted for age, sex, and baseline best-corrected visual acuity. CONCLUSION: Lesions with larger areas and higher end point and junction densities tended to have more frequent anti-vascular endothelial growth factor injections and worse visual outcomes in eyes with myopic choroidal neovascularization.

Finite element analysis of biomechanical effects of mineralized collagen modified bone cement on adjacent vertebral body after vertebroplasty.

Objective: To investigate whether mineralized collagen modified polymethyl methacrylate (MC-PMMA) bone cement impacts the implanted vertebral body and adjacent segments and the feasibility of biomechanical properties compared with common bone cement in the treatment of osteoporotic vertebral compression fractures (OVCF). Methods: A healthy volunteer was selected to perform a three-dimensional reconstruction of the T11-L1 vertebral body to establish the corresponding finite element model of the spine, and the changes in the stress distribution of different types of cement were biomechanically analyzed in groups by applying quantitative loads. Results: The stress distribution of the T11-L1 vertebral body was similar between the two bone types of cement under various stress conditions. Conclusion: Mineralized collagen modified bone cement had the advantages of promoting bone regeneration, good biocompatibility, good transformability, and coupling, and had support strength not inferior to common PMMA bone cement, indicating it has good development prospects and potential.

Characteristics of phenotypic antibiotic resistance of Helicobacter pylori and its correlation with genotypic antibiotic resistance: A retrospective study in Ningxia.

BACKGROUND: Geographic differences exist in the antibiotic resistance patterns of Helicobacter pylori. Personalized treatment regimens based on local or individual resistance data are essential. We evaluated the current status of H. pylori resistance in Ningxia, analyzed resistance-related factors, and assessed the concordance of phenotypic and genotypic resistance. METHODS: Strains were isolated from the gastric mucosa of patients infected with H. pylori in Ningxia and relevant clinical information was collected. Phenotypic antibiotic susceptibility assays (Kirby-Bauer disk diffusion) and antibiotic resistance gene detection (Sanger sequencing) were performed. RESULTS: We isolated 1955 H. pylori strains. The resistance rates of H. pylori to amoxicillin, levofloxacin, clarithromycin, and metronidazole were 0.9%, 42.4%, 40.4%, and 94.2%, respectively. Only five tetracycline-resistant and one furazolidone-resistant strain were identified. Overall, 3.3% of the strains were sensitive to all six antibiotics. Multidrug-resistant strains accounted for 22.9%, of which less than 20% were from Wuzhong. Strains isolated from women and patients with nonulcerative disease had higher rates of resistance to levofloxacin and clarithromycin. Higher rates of resistance to metronidazole, levofloxacin, and clarithromycin were observed in the older age group than in the younger age group. The kappa coefficients of phenotypic resistance and genotypic resistance for levofloxacin and clarithromycin were 0.830 and 0.809, respectively, whereas the remaining antibiotics showed poor agreement. CONCLUSION: H. pylori antibiotic resistance is severe in Ningxia. Therefore, furazolidone, amoxicillin, and tetracycline are better choices for the empirical therapy of H. pylori infection in this region. Host sex, age, and the presence of ulcerative diseases may affect antibiotic resistance of the bacteria. Personalized therapy based on genetic testing for levofloxacin and clarithromycin resistance may be a future direction for the eradication therapy of H. pylori infection in Ningxia.

Acute and subacute intraocular pressure and macular microvascular structure changes after intravitreal ranibizumab injection in eyes with branch retinal vein occlusion.

PURPOSE: To investigate early changes in the intraocular pressure (IOP) and macular microvascular structure in eyes with branch retinal vein occlusion (BRVO) treated with intravitreal Ranibizumab injection. METHODS: This study enrolled 30 patients (one eye per patient) who received intravitreal injections (IVI) of ranibizumab for macular edema secondary to BRVO. IOP were measured before, 30 min (min) and 1 month following IVI. Changes in macular microvascular structure were examined via assessment of foveal avascular zone (FAZ) parameters, vascular density (VD) of superficial vascular complex (SVC), and deep vascular complex (DVC) in whole macula, central fovea and parafovea area which were measured automatically by optical coherence tomography angiography (OCTA) on the same time as IOP examinations. Paired t test and Wilcoxon test were used to compare pre- and post-injection values. The correlation between IOP and OCTA findings was assessed. RESULTS: IOP Measurements at 30 min post-IVI (17.91 ± 3.36 mmHg) increased significantly from baseline (15.07 ± 2.58 mmHg, p < 0.001), then became similar with baseline after 1 month (15.00 ± 3.16 mmHg, p = 0.925). 30 min past the injection, the parameters of VD of the SCP significantly decreased in comparison to baseline, then became similar with baseline after one month, while there were no significant changes in other OCTA parameters, including parameters of VD of the DCP and the FAZ. At 1 month after IVI, in comparison to baseline, no significant changes were observed in all of the OCTA parameters (P > 0.05). There were no significant correlations between IOP and OCTA findings no matter 30 min or 1 month post-IVI (P > 0.05). CONCLUSIONS: Transient IOP elevation and decreased superficial macular capillary perfusion density were detected 30 min post-IVI, however, no potential continual macular microvascular damage was suspected.

Performances of artificial intelligence in detecting pathologic myopia: a systematic review and meta-analysis.

BACKGROUND/OBJECTIVE: Pathologic myopia (PM) is a major cause of severe visual impairment and blindness, and current applications of artificial intelligence (AI) have covered the diagnosis and classification of PM. This meta-analysis and systematic review aimed to evaluate the overall performance of AI-based models in detecting PM and related complications. METHODS: We searched PubMed, Scopus, Embase, Web of Science and IEEE Xplore for eligible studies before Dec 20, 2022. The methodological quality of included studies was evaluated using the Quality Assessment for Diagnostic Accuracy Studies (QUADAS-2). We calculated the pooled sensitivity (SEN), specificity (SPE) and the summary area under the curve (AUC) using a random effects model, to evaluate the performance of AI in the detection of PM based on fundus or optical coherence tomography (OCT) images. RESULTS: 22 studies were included in the systematic review, and 14 of them were included in the quantitative analysis. Of all included studies, SEN and SPE ranged from 80.0% to 98.7% and from 79.5% to 100.0% for PM detection, respectively. For the detection of PM, the summary AUC was 0.99 (95% confidence interval (CI) 0.97 to 0.99), and the pooled SEN and SPE were 0.95 (95% CI 0.92 to 0.96) and 0.97 (95% CI: 0.94 to 0.98), respectively. For the detection of PM-related choroid neovascularization (CNV), the summary AUC was 0.99 (95% CI: 0.97 to 0.99). CONCLUSION: Our review demonstrated the excellent performance of current AI algorithms in detecting PM and related complications based on fundus and OCT images.

A nomogram for predicting residual low back pain after percutaneous kyphoplasty in osteoporotic vertebral compression fractures.

To establish a risk prediction model for residual low back pain after percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures. We used retrospective data for model construction and evaluated the model using internal validation and temporal external validation and finally concluded that the model had good predictive performance. INTRODUCTION: The cause of residual low back pain in patients with osteoporotic vertebral compression fractures (OVCFs) after PKP remains highly controversial, and our goal was to investigate the most likely cause and to develop a novel nomogram for the prediction of residual low back pain and to evaluate the predictive performance of the model. METHODS: The clinical data of 281 patients with OVCFs who underwent PKP at our hospital from July 2019 to July 2020 were reviewed. The optimal logistic regression model was determined by lasso regression for multivariate analysis, thus constructing a nomogram. Bootstrap was used to perfomance the internal validation; receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to assess the predictive performance and clinical utility of the model, respectively. Temporal external validation of the model was also performed using retrospective data from 126 patients who underwent PKP at our hospital from January 2021 to October 2021. RESULTS: Lasso regression cross-validation showed that the variables with non-zero coefficients were the number of surgical vertebrae, preoperative bone mineral density (pre-BMD), smoking history, thoracolumbar fascia injury (TLFI), intraoperative facet joint injury (FJI), and postoperative incomplete cementing of the fracture line (ICFL). The above factors were included in the multivariate analysis and showed that the pre-BMD, smoking history, TLFI, FJI, and ICFL were independent risk factors for residual low back pain (P < 0.05). The ROC and calibration curve of the original model and temporal external validation indicated a good predictive power of the model. The DCA curve suggested that the model has good clinical practicability. CONCLUSION: The risk prediction model has good predictive performance and clinical practicability, which can provide a certain basis for clinical decision-making in patients with OVCFs.

ACVR1-activating mutation causes neuropathic pain and sensory neuron hyperexcitability in humans.

ABSTRACT: Altered bone morphogenetic protein (BMP) signaling is associated with many musculoskeletal diseases. However, it remains unknown whether BMP dysfunction has direct contribution to debilitating pain reported in many of these disorders. Here, we identified a novel neuropathic pain phenotype in patients with fibrodysplasia ossificans progressiva (FOP), a rare autosomal-dominant musculoskeletal disorder characterized by progressive heterotopic ossification. Ninety-seven percent of these patients carry an R206H gain-of-function point mutation in the BMP type I receptor ACVR1 (ACVR1 R206H ), which causes neofunction to Activin A and constitutively activates signaling through phosphorylated SMAD1/5/8. Although patients with FOP can harbor pathological lesions in the peripheral and central nervous system, their etiology and clinical impact are unclear. Quantitative sensory testing of patients with FOP revealed significant heat and mechanical pain hypersensitivity. Although there was no major effect of ACVR1 R206H on differentiation and maturation of nociceptive sensory neurons (iSNs) derived from FOP induced pluripotent stem cells, both intracellular and extracellular electrophysiology analyses of the ACVR1 R206H iSNs displayed ACVR1-dependent hyperexcitability, a hallmark of neuropathic pain. Consistent with this phenotype, we recorded enhanced responses of ACVR1 R206H iSNs to TRPV1 and TRPA1 agonists. Thus, activated ACVR1 signaling can modulate pain processing in humans and may represent a potential target for pain management in FOP and related BMP pathway diseases.

A Dynamic rRNA Ribomethylome Drives Stemness in Acute Myeloid Leukemia.

The development and regulation of malignant self-renewal remain unresolved issues. Here, we provide biochemical, genetic, and functional evidence that dynamics in ribosomal RNA (rRNA) 2'-O-methylation regulate leukemia stem cell (LSC) activity in vivo. A comprehensive analysis of the rRNA 2'-O-methylation landscape of 94 patients with acute myeloid leukemia (AML) revealed dynamic 2'-O-methylation specifically at exterior sites of ribosomes. The rRNA 2'-O-methylation pattern is closely associated with AML development stage and LSC gene expression signature. Forced expression of the 2'-O-methyltransferase fibrillarin (FBL) induced an AML stem cell phenotype and enabled engraftment of non-LSC leukemia cells in NSG mice. Enhanced 2'-O-methylation redirected the ribosome translation program toward amino acid transporter mRNAs enriched in optimal codons and subsequently increased intracellular amino acid levels. Methylation at the single site 18S-guanosine 1447 was instrumental for LSC activity. Collectively, our work demonstrates that dynamic 2'-O-methylation at specific sites on rRNAs shifts translational preferences and controls AML LSC self-renewal. SIGNIFICANCE: We establish the complete rRNA 2'-O-methylation landscape in human AML. Plasticity of rRNA 2'-O-methylation shifts protein translation toward an LSC phenotype. This dynamic process constitutes a novel concept of how cancers reprogram cell fate and function. This article is highlighted in the In This Issue feature, p. 247.

On-DNA Alkyne Iodination and Acetylenic Coupling as a Useful Tool for DEL Synthesis.

1-Iodoalkynes and 1,3-diynes are versatile chemical intermediates and pharmaceutically valuable ingredients. In this study, copper mediated on-DNA alkyne iodination and Cadiot-Chodkiewicz coupling are developed for the first time. This generates diverse, systematic, and unprecedented topographic structural features, which could be invaluable as molecular recognition agents for drug discovery in DEL screening.