The mechanical properties measurement could be affected by forceps: a technical note on sampling human annulus fibrosus.

PURPOSE: To compare the mechanical properties of human annulus fibrosus obtained by forceps versus bistoury and observe whether the measurement could be affected by forceps sampling method. METHODS: In this study, the mechanical properties of the the extracellular matrix (ECM) of human annulus fibrosus, including elastic modulus and stiffness, were investigated using atomic force microscope (AFM). Tissue was obtained from patients during operation using a bistoury or nucleus pulposus forceps. Tissues obtained with the nucleus pulposus forceps were considered as the forceps group and those obtained with a bistoury were considered as the bistoury group. RESULTS: There was no significant difference observed between the forceps and bistoury group according to histological staining. The elastic modulus of the forceps group was 0.41 ± 0.08 MPa, and that of bistoury group was 0.53 ± 0.13 MPa, and the difference between the two groups was statistically significant (p < 0.05). The stiffness of the forceps group was 0.024 ± 0.003 N/m, and that of the bistoury group was 0.037 ± 0.003 N/m, and the difference between the two groups was statistically significant (p < 0.05). CONCLUSION: The results indicate that the forceps sampling method has a substantial negative effect on the micromechanical properties of the ECM of the annulus fibrosus. Bistoury sampling method is recommended as the experimental subject for exploring the micromechanics mechanisms of cervical degenerative disease.

Causal impact of DNA methylation on refracture in elderly individuals with osteoporosis - a prospective cohort study.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCF) in the elderly increase refracture risk post-surgery, leading to higher mortality rates. Genome-wide association studies (GWAS) have identified susceptibility genes for osteoporosis, but the phenotypic variance explained by these genes has been limited, indicating the need to explore additional causal factors. Epigenetic modifications, such as DNA methylation, may influence osteoporosis and refracture risk. However, prospective cohorts for assessing epigenetic alterations in Chinese elderly patients are lacking. Here, we propose to conduct a prospective cohort study to investigate the causal network of DNA polymorphisms, DNA methylation, and environmental factors on the development of osteoporosis and the risk of refracture. METHODS: We will collect vertebral and peripheral blood from 500 elderly OVCF patients undergoing surgery, extract DNA, and generate whole genome genotype data and DNA methylation data. Observation indicators will be collected and combined with one-year follow-up data. A healthy control group will be selected from a natural population cohort. Epigenome-wide association studies (EWAS) of osteoporosis and bone mineral density will be conducted. Differential methylation analysis will compare candidate gene methylation patterns in patients with and without refracture. Multi-omics prediction models using genetic variants and DNA methylation sites will be built to predict OVCF risk. DISCUSSION: This study will be the first large-scale population-based study of osteoporosis and bone mineral density phenotypes based on genome-wide data, multi-time point methylation data, and phenotype data. By analyzing methylation changes related to osteoporosis and bone mineral density in OVCF patients, the study will explore the feasibility of DNA methylation in evaluating postoperative osteoporosis intervention effects. The findings may identify new molecular markers for effective anti-osteoporosis treatment and inform individualized prevention and treatment strategies. TRIAL REGISTRATION: chictr.org.cn ChiCTR2200065316, 02/11/2022.

Compositional and functional aberrance of the gut microbiota in treatment-naïve patients with primary Sjögren's syndrome.

OBJECTIVES: To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE). METHODS: Stool samples from 78 treatment-naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment-naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment. RESULTS: The gut microbiota of treatment-naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to healthy controls. CONCLUSIONS: The gut microbiota in treatment-naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

Phenotypic and genotypic characterization of Chinese adult patients with NLRP3­associated autoinflammatory disease with hearing loss.

OBJECTIVES: Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant systemic autoinflammatory disease. We aimed to summarize the phenotypic and genotypic features of Chinese adult NLRP3-AID patients with hearing loss. METHODS: A retrospective cohort study of twenty-one adult patients with NLRP3-AID was conducted in Peking Union Medical College Hospital between July 2015 and March 2023. All patients underwent whole exome sequencing and otorhinolaryngologic assessments. Clinical features and therapeutic data were collected and analyzed. RESULTS: We found that 13/21 (61.90%) of patients had hearing loss with high-frequency impairment in the majority, and most patients presented with vestibular dysfunction as a new finding. The NLRP3-AID patients with early-onset, cold or stress triggered episodes, red eyes, fatigue, hypopsia and mutations located in the NACHT domain of the NLRP3 protein were more likely to suffer from hearing loss, especially sensorineural hearing loss, perhaps as a result of pathogenic variants of high penetrance. By a series of audiological evaluations, tumor necrosis factor (TNF)-α inhibitors were confirmed to improve or reverse hearing loss. CONCLUSIONS: We reported the first cohort of Chinese adult NLRP3-AID patients with hearing loss and characterized vestibular dysfunction, highlighted the necessity for attention to high-frequency hearing, and provided potential alternative treatment.

Compositional and functional aberrance of the gut microbiota in treatment naïve patients with primary Sjögren's syndrome.

OBJECTIVES: To investigate the compositional and functional characteristics of the gut microbiota in primary Sjögren's syndrome (pSS) and compare them with those in systemic lupus erythematosus (SLE). METHODS: Stool samples from 78 treatment naïve pSS patients and 78 matched healthy controls were detected by shotgun metagenomic sequencing and compared with those from 49 treatment naïve SLE patients. The virulence loads and mimotopes of the gut microbiota were also assessed by sequence alignment. RESULTS: The gut microbiota of treatment naïve pSS patients had lower richness and evenness and showed a different community distribution than that of healthy controls. The microbial species enriched in the pSS-associated gut microbiota included Lactobacillus salivarius, Bacteroides fragilis, Ruminococcus gnavus, Clostridium bartlettii, Clostridium bolteae, Veillonella parvula, and Streptococcus parasanguinis. Lactobacillus salivarius was the most discriminating species in the pSS patients, especially in those with interstitial lung disease (ILD). Among the differentiating microbial pathways, the superpathway of l-phenylalanine biosynthesis was also further enriched in pSS complicated with ILD. There were more virulence genes carried by the gut microbiota in pSS patients, most of which encoded peritrichous flagella, fimbriae, or curli fimbriae, three types of bacterial surface organelles involved in bacterial colonization and invasion. Five microbial peptides with the potential to mimic pSS-related autoepitopes were also enriched in the pSS gut. SLE and pSS shared significant gut microbial traits, including the community distribution, altered microbial taxonomy and pathways, and enriched virulence genes. However, Ruminococcus torques was depleted in pSS patients but enriched in SLE patients compared to that in healthy controls. CONCLUSIONS: The gut microbiota in treatment naïve pSS patients was disturbed and shared significant similarity with that in SLE patients.

Topotecan plus Platinum-Based Chemotherapy versus Etoposide plus Platinum-Based Chemotherapy for Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Whether topotecan plus platinum-based chemotherapy (TP) can achieve better results than etoposide plus platinum-based chemotherapy (EP) for small-cell lung cancer (SCLC) treatment is still controversial in clinical applications. We compared the effectiveness and toxicity of TP versus EP in this meta-analysis. METHODS: We searched PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for completeness one by one to find articles that met the conditions. Overall survival (OS) and progression-free survival (PFS) were analyzed as primary endpoints, and the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed as secondary endpoints. RESULTS: In total, 2,480 articles were retrieved, and 6 randomized controlled trials (RCTs) contained results based on 1,924 patients. EP suggested conspicuously better OS (hazard ratio [HR]: 1.24 [1.02, 1.50], p = 0.03) and PFS (HR: 1.39 [1.17, 1.64], p = 0.0001) in SCLC treatment than TP, and ORR (54.1% vs. 60.2%, risk ratio [RR]: 0.77 [0.57, 1.06], p = 0.11), and DCR (74.9% vs. 84.4%, RR: 0.89 [0.79, 1.00], p = 0.06) tended to favor EP. Subgroup analysis of subsistence showed that EP had prominent benefit in the following subgroups: Asian, median age > 60, first-line treatment, ECOG 0-2, intravenous topotecan, and cisplatin. AEs illustrated that EP had conspicuously more anemia and alopecia than TP. CONCLUSIONS: Compared with TP, EP was noticeably better in OS and PFS, but EP was toxic in terms of anemia and alopecia. More multicenter, better planned RCTs are needed.

Clinical impact of 3-level anterior cervical decompression and fusion (ACDF) on the occipito-atlantoaxial complex: a retrospective study of patients who received a zero-profile anchored spacer versus cage-plate construct.

PURPOSE: To evaluate changes in the sagittal parameters of the occipito-atlantoaxial complex after three-level anterior cervical decompression and fusion (ACDF) and identify the influential factors by comparing ACDF with a zero-profile anchored spacer (ACDF-Z) versus a cage-plate construct (ACDF-P). METHODS: The cohort comprised 106 patients who underwent three-level contiguous ACDF-Z or ACDF-P for cervical radiculopathy and/or myelopathy. Standing, flexion, and extension radiographs of cervical spine were obtained preoperatively, and 3 and 12 months postoperatively. The assessed cervical sagittal parameters were the platform angle of the axis, Cobb angle, and range of motion (ROM) of C2⁃7, C0⁃1, and C1⁃2. RESULTS: In both the ACDF-Z and ACDF-P groups, the Cobb angle of the upper cervical spine decreased and the C0-1 ROM increased from preoperatively to 3 and 12 months postoperatively (P < 0.01). The alignment restoration was lost at 12 months compared with 3 months in the ACDF-Z group, but not in the ACDF-P group (P < 0.01). The ACDF-P group showed more loss of C2-7 ROM and more compensatory changes in C0-2 ROM than the ACDF-Z group (P < 0.05). CONCLUSION: The Cobb angle decreased and ROM increased significantly as compensatory changes of the atlantooccipital or atlantoaxial joint after both types of ACDF, which may accelerate degeneration. The zero-profile anchored spacer had less impact on the occipito-atlantoaxial complex but was worse at maintaining the alignment restoration, which were contrary to the cage-plate construct. Surgeons should be aware of the impact of multi-level ACDFs on the occipito-atlantoaxial complex.

The association between cervical focal kyphosis and myelopathy severity in patients with cervical spondylotic myelopathy before surgery.

PURPOSE: Cervical focal kyphosis could often be observed in patients with cervical spondylotic myelopathy (CSM). However, the association between it and myelopathy severity remains unclear. This study aims to elucidate the association between cervical focal kyphosis and myelopathy severity before surgery. METHODS: A retrospective review of 191 consecutive patients treated for CSM from 2017 to 2019 was surveyed. Seven MRI and five radiographic parameters were measured, clinical parameters were included. Patients were divided into two sagittal focal angle groups (lordosis/kyphosis) and two disc herniation severity groups (severe/non-severe). The potential risk factors of myelopathy symptoms were analysed. RESULTS: Significant correlations between cervical sagittal focal angles, several other imaging findings and myelopathy severity were found in both total patients (R2 = 0.51, P < 0.001) and non-severe disc herniation patients (R2 = 0.73, P < 0.001) in multivariate regression models. Compression ratio of spinal cord exhibited the strongest correlation with JOA scores (r = - 0.567, P < 0.001). Cervical focal angles on MRI exhibited a stronger negative correlation with JOA scores (r = - 0.429, P < 0.001) than did angles on the other three postures on radiographs. Dramatic differences in JOA scores could be found in patients with non-severe cervical disc herniation, when a subgroup analysis was performed between cervical lordosis group and more than 4° kyphosis group (14.2 ± 1.7 vs. 11.1 ± 1.7, P < 0.001). CONCLUSION: Cervical focal kyphosis associates with severe myelopathy symptoms in patients with CSM, especially without severe disc herniation. This association may indicate an optimal cervical focal angle in surgical plan. It appeared feasible to assess both the cervical focal angles and spinal cord compression on supine MRI.

An Unrecognized Ligament and its Ossification in the Craniocervical Junction: Prevalence, Patient Characteristics, and Anatomic Evidence.

BACKGROUND: In the craniocervical junction, the ligaments between the anterior foramen magnum and the anterior arch of the atlas are not well defined, and ossification of the ligaments in this region has rarely been reported. Characterizing the anatomy and ossification of these ligaments may help in the diagnosis and treatment of disorders in this region. QUESTIONS/PURPOSES: (1) What is the prevalence of an unrecognized ossification at the craniocervical junction in patients with cervical spine disorders, and what are the patient characteristics associated with this ossification? (2) Do patients with this ossification have a greater risk of ossification of other structures at the craniocervical junction or cervical spine? (3) Is there an unreported ligament at this ossified site? METHODS: We conducted a retrospective study of 578 hospitalized patients who underwent CT for cervical spine disorders between January 2016 and July 2020. Based on the inclusion criteria, 11% (66 of 578) were excluded because of a cervical or craniocervical tumor, deformity, infection, fracture or dislocation, or prior surgery, leaving 89% (512 of 578) for analysis. These 512 patients had diagnoses of cervical radiculopathy, cervical myelopathy, cervical spondylotic amyotrophy, cervical spinal cord injury without a radiographic abnormality, or axial neck pain. Their mean age was 57 years (range 22-90 years), and 60% of the patients were men. Patient characteristics including age, gender, and diagnosis were retrieved from a longitudinally maintained institutional database. CT images were used to assess the presence of a previously unrecognized ossification and ossification of other structures in the craniocervical junction and cervical spine, including the posterior longitudinal ligament, anterior longitudinal ligament, nuchal ligament, ligamentum flavum, transverse ligament, and apical ligament, as well as diffuse idiopathic skeletal hyperostosis (DISH). The association between these structures was also assessed. This unreported ossification was called the capped dens sign. It was defined and graded from 1 to 3. Grade 3 was defined as the typical capped dens sign. Cervical spine MRI was used to assess whether there was an unreported structure in the same region as where the capped dens sign was detected on CT images. In the database of a recent study, there were 33 patients younger than 41 years. Nine percent (three of 33) were excluded because they did not have cervical spine MRI. MRIs of the remaining 30 patients were assessed. Their mean age was 35 years (range 22-40 years), and 58% were men. All cervical spine CT images and MRIs were reviewed by one senior spine surgeon and one junior spine surgeon twice with a 2-week interval. Blinding was accomplished by removing identifying information from the radiographs and randomly assigning them to each examiner. Any discrepancy with respect to the grade of the capped dens sign was adjudicated by a third blinded senior spine surgeon. Intrarater and interrater reliabilities were assessed by calculating weighted kappa statistics. No ligament or membrane was reported at this site. MRI is not sensitive to identify thin tissue in this region, especially when severe degeneration has occurred. A cadaveric study was conducted to discover a potential ligament between the inferior margin of the foramen magnum and the anterior arch of the atlas, as prompted by the newly discovered ossification in the clinical analysis of this study. Six embalmed human cadaveric craniocervical regions (three male and three female cadavers; median age 56 years, range 45-78 years) were dissected by a senior anatomist and a senior anatomy technician. A mid-sagittal section of the craniocervical junction was created, allowing us to explore the interval between the anterior foramen magnum and anterior arch of the atlas. A histologic analysis was conducted in two of the six cadavers (a male cadaver, 45 years; and a female cadaver, 51 years). Slides were made with 4-µm sections and stained with hematoxylin and eosin. RESULTS: A novel capped dens sign was detected in 39% (198 of 512) of the patients and the most typical capped dens sign was detected in 19% (96 of 512) of patients. The prevalence of this sign was the highest in patients with cervical spondylotic amyotrophy (12 of 25 patients). The prevalence of ossification of the anterior longitudinal ligament, ligamentum nuchae, and apical ligament, as well as DISH, was higher in patients with a capped dens sign than in those without (p = 0.04, p < 0.001, p < 0.001, and p = 0.001, respectively). The capped dens sign was identified in 69% (18 of 26) of the patients with DISH. A thin and short band-like structure or osteophyte was detected on MRI in 87% (26 of 30), in the same region as the capped dens sign. In the cadaveric study, an unreported, distinct ligamentous structure was identified at this ossified site. It originated from the posterosuperior rim of the anterior arch of the atlas to the inferior margin of the foramen magnum, which we called the inter-atlanto-occipital ligament. It was found in all six dissected craniocervical junctions. The histologic analysis revealed dense connective tissue. CONCLUSION: More than one-third of the patients in this series demonstrated CT evidence of a previously unrecognized ossification in the craniocervical junction, which we called the capped dens sign. Anatomic evidence of this sign, which was a previously unidentified ligament, was also newly discovered in this region. This study was conducted among Asian patients and specimens. Further studies among diverse ethnic groups may be needed to generalize the results. An additional well-designed prospective study will be needed to provide further evidence regarding the potential pathophysiology and clinical relevance of the capped dens sign. Furthermore, the cadaveric analysis in this study was only a preliminary report of the ligament; further biomechanical research is needed to investigate its function. CLINICAL RELEVANCE: Knowledge of this novel ligament may improve the diagnosis and treatment of craniocervical stability and dislocation. Ossification of this ligament is correlated with age, cervical spondylotic amyotrophy, and DISH. We wonder whether patients with cervical degenerative disorders who also have a capped dens sign may be at risk for the formation of osteophytes of an uncovertebral joint, which may result in palsy of the upper limb muscles. The capped dens sign may be the craniocervical manifestation of DISH. This possible association between the capped dens sign and DISH should be considered when performing surgery on patients with the capped dens sign.

Adjacent segment motion following multi-level ACDF: a kinematic and clinical study in patients with zero-profile anchored spacer or plate.

PURPOSE: To investigate the adjacent segment kinematics, including the instantaneous axis of rotation (IAR) and range of motion (ROM), after anterior cervical discectomy and fusion (ACDF), and to compare between ACDF with zero-profile anchored spacer (ACDF-Z) and ACDF with plate (ACDF-P). METHODS: Eighty-seven patients (ACDF-Z = 63; ACDF-P = 24) were included. Flexion, extension and neutral cervical radiographs were obtained before operation and at 1-year follow-up. C2-C7 ROM, adjacent segment ROMs, and IARs were measured. Clinical evaluation was based on the Visual Analogue Scale, Neck Disability Index, and Japanese Orthopaedic Association score. RESULTS: After ACDF-Z, location of the superior IAR-AP reduced 1.60 mm, which represents 8% of the vertebral body (P < 0.001), and location of the inferior IAR-SI reduced 2.19 mm, 17% of the vertebral body (P = 0.02). After ACDF-P, location of the superior IAR-AP increased 0.8 mm, which means 6% of the vertebral body (P = 0.008), location of the inferior IAR-AP increased 3.34 mm, 22% of the vertebral body (P = 0.03), and location of the inferior IAR-SI reduced 3.14 mm, 25% of the vertebral body (P = 0.002). C2-C7 ROM significantly decreased after both ACDF-Z and ACDF-P (P < 0.001). Neither ACDF-Z nor ACDF-P significantly affected the adjacent segment ROMs (P > 0.05). CONCLUSIONS: Both ACDF-Z and ACDF-P significantly impacted cervical kinematics, although both procedures obtained satisfactory clinical results in the treatment of cervical spondylosis. After both ACDF-Z and ACDF-P, C2-C7 ROM decreased significantly, while adjacent segment ROMs were preserved. ACDF-Z and ACDF-P impact the location of adjacent segment IAR-SI in similar way, while impact the location of adjacent segment IAR-AP in diverse ways. These slides can be retrieved under Electronic Supplementary Material.

Comparison of hybrid constructs with 2-level artificial disc replacement and 2-level anterior cervical discectomy and fusion for surgical reconstruction of the cervical spine: a kinematic study in whole cadavers.

BACKGROUND: Multi-level cervical degeneration of the spine is a common clinical pathology that is often repaired by anterior cervical discectomy and fusion (ACDF). The aim of this study was to investigate the kinematics of the cervical spine after hybrid surgery compared with 2-level ACDF. MATERIAL AND METHODS: Five freshly frozen, unembalmed whole human cadavers were used including 3 males and 2 females with a mean age of 51 ± 8 years. After evaluating the intact spine for range of motion (ROM), sagittal alignment and instantaneous center of rotation (ICR), each cadaver underwent 4 consecutive surgeries: 2-level artificial disc replacement (ADR) from C4 to C6 (ADR surgery); 2-level ACDF from C4 to C6 (ACDF surgery); hybrid C4-5 ACDF and C5-6 ADR (ACDF+ADR surgery); and hybrid C4-5 ADR and C5-6 ACDF (ADR+ACDF surgery). The ROM and ICR of adjacent intact segments (C3-4; C6-7), and whole sagittal alignment were revaluated. RESULTS: Two-level ACDF resulted in increased ROM at C3-4 and C6-7 compared with intact spine. ROM was significantly different to intact spine using ACDF surgery at C3-C4 and C6-C7 and ROM was increased with ACDF+ADR surgery at C6-C7 (all P<0.05). No improvement in sagittal alignment was observed with any approach. The localization of the ICR shifted upwards and anteriorly at C3-C4 after reconstruction. ICR changes at C3-C4 were greatest for ADR+ACDF surgery and were significantly different to ACDF surgery (P<0.05), but not between ADR surgery and ACDF+ADR surgery. At C6-C7, the ICR was more posterior and superior than in the intact condition. The greatest change in ICR was observed in ACDF surgery at the C6-C7 level, significantly different from the other groups (P<0.05). CONCLUSIONS: For 2-level reconstruction, hybrid surgery and ADR did not alter ROM and minimally changed ICR at the adjacent-level. The type of surgery had a significant impact on the ICR location. This suggests that hybrid surgery may be a viable option for 2-level cervical surgery.

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO.

Background: Manifestations of thyroid-associated ophthalmopathy (TAO) vary greatly. Few tools and indicators are available to assess TAO, restricting personalized diagnosis and treatment. Aim: To identify an aptamer targeting thyroid-stimulating hormone receptor (TSHR) and utilize this aptamer to evaluate clinical activity in patients with TAO. Methods: An aptamer targeting TSHR was developed by exponential enrichment and systematic evaluation of TSHR ligands. After truncation and optimization, the affinity, equilibrium dissociation constant, and serum stability of this aptamer were evaluated. The affinity of the TSHR-targeting aptamer to isolated fibrocytes was assessed, as was aptamer internalization by fibrocytes. The mechanism of binding was determined by molecular docking. The correlation between disease manifestations and the percentage of TSHR-positive cells was assessed by correlation analysis. Results: The aptamer TSHR-21-42 was developed to bind to TSHR, with the equilibrium dissociation constant being 71.46 Kd. Isolated fibrocytes were shown to bind TSHR-21-42 through TSHR, with its affinity maintained at various temperatures and ion concentrations. TSHR-21-42 could compete with anti-TSHR antibody, both for binding site to TSHR and uptake by cells after binding. In addition, TSHR-21-42 could bind to leukocytes in peripheral blood, with this binding differing in patients with TAO and healthy control subjects. The percentage of TSHR-positive monocytes, as determined by binding of TSHR-21-42, correlated positively with clinical activity score in patients with TAO, indicating that TSHR-21-42 binding could assess the severity of TAO. Conclusion: This aptamer targeting TSHR may be used to objectively assess disease activity in patients with TAO, by evaluating the percentages of TSHR positive cells in peripheral blood.

The symbiont Wolbachia alleviates pesticide susceptibility in the two-spotted spider mite Tetranychus urticae through enhanced host detoxification pathways.

The two-spotted spider mite (Tetranychus urticae) is one of the most well-known pesticide-resistant agricultural pests, with resistance often attributed to changes such as target-site mutations and detoxification activation. Recent studies show that pesticide resistance can also be influenced by symbionts, but their involvement in this process in spider mites remains uncertain. Here, we found that infection with Wolbachia, a well-known bacterial reproductive manipulator, significantly increased mite survival after exposure to the insecticides abamectin, cyflumetofen, and pyridaben. Wolbachia-infected (WI) mites showed higher expression of detoxification genes such as P450, glutathione-S-transferase (GST), ABC transporters, and carboxyl/cholinesterases. RNA interference experiments confirmed the role of the two above-mentioned detoxification genes, TuCYP392D2 and TuGSTd05, in pesticide resistance. Increased GST activities were also observed in abamectin-treated WI mites. In addition, when wild populations were treated with abamectin, WI mites generally showed better survival than uninfected mites. However, genetically homogeneous mites with different Wolbachia strains showed similar survival. Finally, abamectin treatment increased Wolbachia abundance without altering the mite's bacterial community. This finding highlights the role of Wolbachia in orchestrating pesticide resistance by modulating host detoxification. By unraveling the intricate interplay between symbionts and pesticide resistance, our study lays the groundwork for pioneering strategies to combat agricultural pests.

Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome.

BACKGROUND AND OBJECTIVES: The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. METHODS: RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines. RESULTS: Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1ß and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement. CONCLUSION: Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.

Influence of Blood Pressure on Acute Cervical Spinal Cord Injury Without Fracture and Dislocation: Results From a Retrospective Analysis.

OBJECTIVE: The objective of this study was to investigate the influence of blood pressure on the severity and functional recovery of patients with acute cervical spinal cord injury (SCI) without fracture and dislocation. METHODS: A retrospective case control study analyzed the data of 40 patients admitted to our orthopedics department (Beijing Tiantan Hospital, Capital Medical University) from January 2013 to February 2021. They were diagnosed as acute cervical SCI without fracture and dislocation. Gender, age, height, weight, history of hypertension, postinjury American Spinal Injury Association grade, postinjury modified Japanese Orthopaedic Association (mJOA) score, postoperative mJOA score, 1-year follow-up mJOA score, preoperative mean arterial pressure (MAP), intramedullary T2 hyperintensity, and hyponatremia were collected. The patients were divided into groups and subgroups based on their history of hypertension and preoperative MAP. The effects of history of hypertension and preoperative MAP on the incidence of T2 hyperintensity, hyponatremia, the improvement rate of the postoperative mJOA and 1-year follow-up mJOA scores were analyzed. RESULTS: Patients with history of hypertension had a lower incidence of intramedullary T2 hyperintensity than patients without history of hypertension (P < 0.05). Patients with history of hypertension and patients with a higher preoperative MAP had better neurological recovery at 1 year of follow-up (P < 0.05). CONCLUSIONS: Blood pressure has great influence on acute cervical SCI without fracture and dislocation. Maintaining a higher preoperative MAP is advantageous for better recovery after SCI. Attention should be paid to the dynamic management of blood pressure to avoid the adverse effects of hypotension after SCI.

Lomitapide repurposing for treatment of malignancies: A promising direction.

The development of novel drugs from basic science to clinical practice requires several years, much effort, and cost. Drug repurposing can promote the utilization of clinical drugs in cancer therapy. Recent studies have shown the potential effects of lomitapide on treating malignancies, which is currently used for the treatment of familial hypercholesterolemia. We systematically review possible functions and mechanisms of lomitapide as an anti-tumor compound, regarding the aspects of apoptosis, autophagy, and metabolism of tumor cells, to support repurposing lomitapide for the clinical treatment of tumors.

Case Report: Missing zinc finger domains: hemophagocytic lymphohistiocytosis in a GATA2 deficiency patient triggered by non-tuberculous mycobacteriosis.

Haploinsufficiency of GATA2, also known as GATA2 deficiency, leads to a wide spectrum of clinical manifestations. Here we described another 28-year-old man with a GATA2 variant who also suffered from hemophagocytic lymphohistiocytosis(HLH), who was finally diagnosed with HLH triggered by Mycobacterium avium bloodstream infection due to primary immunodeficiency. We reviewed GATA2 deficiency patients with HLH and found that GATA2 variants causing loss of zinc finger domains were associated with HLH, and erythema nodosa might be an accompanying symptom.

Downhole parameter prediction method based on multi-layer water injection model and historical data-based model parameter identification.

Wireless communication has become a preferred direction for the development of layered water injection tools due to its low cost and high reliability. However, the wireless system relies on the underground battery for power supply，and each communication will consume a significant amount of energy. In order to save energy consumption, the wireless system adopts the intermittent sleep communication mode, with intervals of usually more than one month. During the idle time of communication, the downhole parameters such as pressure and flowrate will change as the pressure and flowrate at the wellhead. Therefore, it is crucial to predict downhole parameters based on the wellhead pressure and flowrate. In this study, a downhole parameter prediction method based on multi-layer water injection model is proposed. A multilayer injection prediction model was established based on the hydraulic analysis of the tubing string, and the model parameters were identified and updated using the historical data uploaded each time. The pressure and flow rate measured at the wellhead were used as inputs to the model, and the recursive relationship between layers in the multilayer model was utilized to predict downhole parameters for each layer. A model parameter optimization method based on time-weighting is proposed in order to address the gradual changes in model parameters during water injection. This method assigns greater weight to more recent historical data, resulting in optimized model parameters. Experimental results show that the proposed method can effectively predict the flowrate and pressure of each layer, with a prediction deviation of less than 5% F.S., which provides technical support for the application and popularization of the wireless layered water injection system.

New retinal findings in NLRP3-associated autoinflammatory disease.

PURPOSE: To determine whether the rare NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) is associated with retinal changes and to assess the ocular involvement. METHODS: A retrospective cohort study of 20 patients(40 eyes) diagnosed with rare NLRP3-AID at Peking Union Medical College Hospital, from April 2015 to August 2022. Patients underwent a comprehensive ophthalmological examination, including visual acuity, intraocular pressure examination, slit-lamp examination, fundus photography, optical coherence tomography(OCT), and fluorescence angiography (FA). Some patients also underwent optical coherence tomography angiography (OCTA). RESULTS: This study analyzed 40 eyes of 20 patients (11 [55.0%] male; median age, 25.0 years [range, 12-52 years]) and 13 patients (26 eyes, 65%) demonstrated ocular involvement. The most common ophthalmologic manifestation was conjunctivitis (22 eyes, 84.6%), followed by papilledema (14 eyes, 53.8%), retinopathy (10 eyes, 38.5%), optic atrophy (6 eyes, 23.1%), uveitis (4 eyes, 15.4%), reduced pupil light reflex (3 eyes, 11.5%) and cataracts (2 eyes, 7.7%). Ocular involvement was bilateral in 11 patients (55.0%). Five kinds of retinal lesions were seen in 5 patients (10 eyes, 25%) with NLRP3-AID, including peripheral retinal vascular leakage, microaneurysms, macular ischemia, macular epiretinal membrane formation and drusen. CONCLUSIONS: Peripheral retinal vascular leakage, macular ischemia, microaneurysms and drusen are newly identified retinal findings in patients with NLRP3-AID, which suggests the importance of detailed retinal examination in these patients.

Immune responses of six-transmembrane epithelial antigen of the prostate 4 functions as a novel biomarker in gastric cancer.

BACKGROUND: Immune cells play an important role in regulating the behavior of tumor cells. According to emerging evidence, six-transmembrane epithelial antigen of the prostate 4 (STEAP4) performs a crucial part in tumor microenvironmental immune response and tumorigenesis, and serves as the potential target for cellular and antibody immunotherapy. However, the immunotherapeutic role of STEAP4 in gastric cancer (GC) remains unclear. AIM: To investigate the expression of STEAP4 in GC and its relationship with immune infiltrating cells, and explore the potential value of STEAP4 as an immune prognostic indicator in GC. METHODS: The expression level of STEAP4 was characterized by immunohistochemistry in tumors and adjacent non-cancerous samples in 96 GC patients. Tumor Immune Estimation Resource was used to study the correlation between STEAP4 and tumor immune infiltration level and immune infiltration gene signature. R package was used to analyze the relationship between STEAP4 expression and immune and stromal scores in GC (GSE62254) by the ESTIMATE algorithm, and Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis were applied to analyze the effect of STEAP4 on clinical prognosis. RESULTS: Immunohistochemistry analysis showed that STEAP4 expression was higher in GC tissues than in adjacent tissues, and STEAP4 expression was positively correlated with the clinical stage of GC. In GC, the expression of STEAP4 was positively correlated with the infiltration levels of B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. The expression level of STEAP4 was strongly correlated with most of the immune markers. In addition, STEAP4 expression was inversely correlated with tumor purity, but correlated with stromal score (r = 0.43, P < 0.001), immune score (r = 0.29, P < 0.001) and estimate score (r = 0.39, P < 0.001). Moreover, stromal, immune, and estimate scores were higher in the STEAP4 high expression group, whereas tumor purity was higher in the STEAP4 Low expression group. The relationship between STEAP4 expression and prognosis of patients with GC was further investigated, and the results showed that high STEAP4 expression was associated with poor overall survival and disease-free survival. In addition, Kaplan-Meier Plotter showed that high expression of STEAP4 was significantly correlated with poor survival of patients with GC. CONCLUSION: The current findings suggest an oncogenic role for STEAP4 in GC, with significantly high levels being associated with poor prognosis. Investigation of the GC tumor microenvironment suggests the potential function of STEAP4 is connected with the infiltration of diverse immune cells, which may contribute to the regulation of the tumor microenvironment. In conclusion, STEAP4 may serve as a potential therapeutic target for GC to improve the immune infiltration, as well as serve as a prognostic biomarker for judging the prognosis and immune infiltration status of GC.