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The efficacy and safety of oral antibiotic treatment in patients with chronic low back pain and Modic changes: A systematic review and meta-analysis 口服抗生素治疗慢性腰背痛和 Modic 病变患者的有效性和安全性：系统回顾与荟萃分析
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-09-19 DOI: 10.1002/jsp2.1281
Arnold Y. L. Wong, G. Michael Mallow, Sabina M. Pinto, Alexander L. Hornung, Samuel S. Rudisill, Khaled Aboushaala, Peter M. Udby, Howard S. An, Dino Samartzis

Background

This systematic review and meta-analysis aimed to summarize evidence regarding the effectiveness and safety of oral antibiotic intervention for chronic low back pain (CLBP) patients with/without type-1 Modic changes (MC1).

Methods

AMED, CINAHL, Cochrane Library, Embase, and Medline were searched from inception to March 3, 2023. Randomized controlled trials (RCTs) or non-RCTs that investigated the effectiveness or safety of oral antibiotics in treating CLBP patients were eligible for inclusion. Two independent reviewers screened abstracts, full-text articles, and extracted data. The methodological quality of each included article were evaluated by RoB2 and NIH quality assessment tools. The quality of evidence was appraised by GRADE. Meta-analyses were performed, where applicable. A subgroup analysis was conducted to evaluate the RCTs and case series separately, and to evaluate the effect of removing a low-quality RCT.

Results

Three RCTs and four case series were included. All Amoxicillin-clavulanate/Amoxicillin treatments lasted for approximately 3 months. Moderate- and low-quality evidence suggested that antibiotic was significantly better than placebo in improving disability and quality of life in CLBP patients with MC1 at 12-month follow-up, respectively. Low-quality evidence from meta-analyses of RCTs showed that oral antibiotic was significantly better than placebo in improving pain and disability in CLBP patients with MC1 immediately post-treatment. Very low-quality evidence from the case series suggested that oral Amoxicillin-clavulanate significantly improved LBP/leg pain, and LBP-related disability. Conversely, low-quality evidence found that oral Amoxicillin alone was not significantly better than placebo in improving global perceived health in patients with CLBP at the 12-month follow-up. Additionally, oral antibiotic users had significantly more adverse effects than placebo users.

Conclusions

Although oral antibiotics were statistically superior to placebo in reducing LBP-related disability in patients with CLBP and concomitant MC1, its clinical significance remains uncertain. Future large-scale high-quality RCTs are warranted to validate the effectiveness of antibiotics in individuals with CLBP.

背景 本系统综述和荟萃分析旨在总结有关口服抗生素干预患有/未患有 1 型莫迪病（MC1）的慢性腰背痛（CLBP）患者的有效性和安全性的证据。 方法 检索从开始到 2023 年 3 月 3 日的 AMED、CINAHL、Cochrane Library、Embase 和 Medline。研究口服抗生素治疗 CLBP 患者的有效性或安全性的随机对照试验 (RCT) 或非 RCT 均符合纳入条件。两名独立审稿人筛选摘要、全文并提取数据。每篇纳入文章的方法学质量均由 RoB2 和 NIH 质量评估工具进行评估。证据质量采用 GRADE 进行评估。在适用的情况下进行了元分析。进行了亚组分析，分别评估了研究性试验和病例系列，并评估了剔除一项低质量研究性试验的效果。 结果 共纳入了 3 项研究性试验和 4 个病例系列。所有阿莫西林-克拉维酸/阿莫西林的疗程均为 3 个月左右。中度和低质量证据表明，在随访 12 个月时，抗生素在改善 MC1 CLBP 患者的残疾和生活质量方面分别明显优于安慰剂。对研究性试验进行荟萃分析后得出的低质量证据表明，口服抗生素在改善MC1慢性膀胱炎患者治疗后即刻的疼痛和残疾状况方面明显优于安慰剂。来自病例系列的极低质量证据表明，口服阿莫西林-克拉维酸能明显改善枸橼酸盐/腿痛以及与枸橼酸盐相关的残疾。相反，低质量的证据表明，在 12 个月的随访中，单用口服阿莫西林在改善慢性阻塞性肺病患者的总体健康感知方面并没有明显优于安慰剂。此外，口服抗生素使用者的不良反应明显多于安慰剂使用者。 结论 虽然口服抗生素在减少CLBP和并发MC1患者的LBP相关残疾方面在统计学上优于安慰剂，但其临床意义仍不确定。今后有必要进行大规模、高质量的 RCT 研究，以验证抗生素对 CLBP 患者的有效性。
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引用次数: 0
Impact of autophagy inhibition on intervertebral disc cells and extracellular matrix 抑制自噬对椎间盘细胞和细胞外基质的影响
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-09-13 DOI: 10.1002/jsp2.1286
Rebecca Kritschil, Vivian Li, Dong Wang, Qing Dong, Prashanta Silwal, Toren Finkel, Joon Lee, Gwendolyn Sowa, Nam Vo

Background

Intervertebral disc degeneration (IDD) is a leading contributor to low back pain (LBP). Autophagy, strongly activated by hypoxia and nutrient starvation, is a vital intracellular quality control process that removes damaged proteins and organelles to recycle them for cellular biosynthesis and energy production. While well-established as a major driver of many age-related diseases, autophagy dysregulation or deficiency has yet been confirmed to cause IDD.

Methods

In vitro, rat nucleus pulposus (NP) cells treated with bafilomycin A1 to inhibit autophagy were assessed for glycosaminoglycan (GAG) content, proteoglycan synthesis, and cell viability. In vivo, a transgenic strain (Col2a1-Cre; Atg7fl/fl) mice were successfully generated to inhibit autophagy primarily in NP tissues. Col2a1-Cre; Atg7fl/fl mouse intervertebral discs (IVDs) were evaluated for biomarkers for apoptosis and cellular senescence, aggrecan content, and histological changes up to 12 months of age.

Results

Here, we demonstrated inhibition of autophagy by bafilomycin produced IDD features in the rat NP cells, including increased apoptosis and cellular senescence (p21CIP1) and decreased expression of disc matrix genes Col2a1 and Acan. H&E histologic staining showed significant but modest degenerative changes in NP tissue of Col2a1-Cre; Atg7fl/fl mice compared to controls at 6 and 12 months of age. Intriguingly, 12-month-old Col2a1-Cre; Atg7fl/fl mice did not display increased loss of NP proteoglycan. Moreover, markers of apoptosis (cleaved caspase-3, TUNEL), and cellular senescence (p53, p16INK4a, IL-1β, TNF-α) were not affected in 12-month-old Col2a1-Cre; Atg7fl/fl mice compared to controls. However, p21CIP1and Mmp13 gene expression were upregulated in NP tissue of 12-month-old Col2a1-Cre; Atg7fl/fl mice compared to controls, suggesting p21CIP1-mediated cellular senescence resulted from NP-targeted Atg7 knockout might contribute to the observed histological changes.

Conclusion

The absence of overt IDD features from disrupting Atg7-mediated macroautophagy in NP tissue implicates other compensatory mechanisms, highlighting additiona

背景 椎间盘退变（IDD）是导致腰背痛（LBP）的主要原因。自噬是一种重要的细胞内质量控制过程，可清除受损蛋白质和细胞器，使其循环用于细胞生物合成和能量生产。自噬是许多与年龄有关的疾病的主要驱动因素，但自噬失调或缺乏尚未被证实会导致 IDD。 方法 在体外，用巴佛洛霉素 A1 处理大鼠髓核（NP）细胞以抑制自噬，评估糖胺聚糖（GAG）含量、蛋白多糖合成和细胞活力。在体内，成功培育出了转基因品系（Col2a1-Cre; Atg7fl/fl）小鼠，主要在NP组织中抑制自噬。我们对 Col2a1-Cre; Atg7fl/fl 小鼠椎间盘（IVD）进行了评估，检测其细胞凋亡和细胞衰老的生物标记物、骨胶原含量以及 12 个月大的组织学变化。 结果 在这里，我们证实了巴佛洛霉素抑制自噬作用会在大鼠 NP 细胞中产生 IDD 特征，包括细胞凋亡和细胞衰老（p21CIP1）增加以及椎间盘基质基因 Col2a1 和 Acan 表达减少。H&E组织学染色显示，与对照组相比，6个月和12个月大的Col2a1-Cre; Atg7fl/fl小鼠的NP组织发生了显著但温和的退行性变化。耐人寻味的是，12 个月大的 Col2a1-Cre; Atg7fl/fl 小鼠并没有表现出 NP 蛋白多糖丢失增加。此外，与对照组相比，12月龄的Col2a1-Cre; Atg7fl/fl小鼠的细胞凋亡标志物（裂解的caspase-3、TUNEL）和细胞衰老标志物（p53、p16INK4a、IL-1β、TNF-α）均未受到影响。然而，与对照组相比，12月龄 Col2a1-Cre; Atg7fl/fl 小鼠的 NP 组织中 p21CIP1 和 Mmp13 基因表达上调，这表明 NP 靶向 Atg7 基因敲除导致的 p21CIP1 介导的细胞衰老可能是观察到的组织学变化的原因之一。 结论 在NP组织中破坏Atg7介导的大自噬作用并没有导致明显的IDD特征，这意味着还存在其他代偿机制，突出表明还需要进行更多的研究来阐明自噬在调节年龄依赖性IDD方面的复杂生物学作用。
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引用次数: 0
Development of normalized quantitative measures of lumbar disc degeneration 腰椎间盘退变标准化定量测量方法的发展。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-09-12 DOI: 10.1002/jsp2.1278
Samuel King, John Magnussen, James Elliott, Mark Jonathan Hancock

Background

Lumbar disc degeneration (DD) is widely regarded as a likely contributor to low back pain (LBP), but the association between DD and LBP is relatively weak. No known studies have normalized quantitative measures of DD severity relative to multiple variables such as age, height, and disc level. This study developed normalized quantitative measures (z-scores) of disc signal intensity (DSI) and disc height (DH) to rate relative severity of DD.

Methods

Raw (unnormalized) quantitative measures of DSI and DH alongside potential normalization variables were acquired from MRI scans and clinical data of 76 patients. The associations between the raw quantitative measures and potential normalization variables were investigated to develop the normalized quantitative measures (z-scores) of DSI and DH. Construct validity was assessed by comparing the normalized measures to an experienced radiologist's subjective measures of relative severity of DSI and DH loss.

Results

CSF signal intensity, age, and disc level were significantly associated with raw DSI (R2 = 0.06, 0.25, and 0.09, respectively). Lumbar height and disc level were significantly associated with raw DH (R2 = 0.13 and 0.31). Normalizing DSI and DH by these variables resulted in stronger relationships (R2 = 0.39 and 0.37) than raw DSI and DH (R2 = 0.24 and 0.31) with the radiologist's subjective measures. Normalized DSI and DH were both normally distributed (p = 0.32 and 0.12).

Conclusions

Construct validity and the distributions suggested that normalized quantitative measures of DSI and DH are better than existing measures of DSI and DH at rating relative DD severity. Determining whether normalized quantitative measures are more predictive of clinical outcomes is important future research.

背景：腰椎间盘退变（DD）被广泛认为可能是导致腰痛（LBP）的原因，但DD与LBP之间的相关性相对较弱。没有已知的研究将DD严重程度相对于年龄、身高和椎间盘水平等多个变量的定量测量标准化。本研究开发了椎间盘信号强度（DSI）和椎间盘高度（DH）的归一化定量测量（z评分），以评定DD的相对严重程度。方法：从76名患者的MRI扫描和临床数据中获得DSI和DH的原始（未归一化）定量测量值以及潜在的归一化变量。研究了原始定量测量和潜在归一化变量之间的关联，以开发DSI和DH的归一化定量测量（z分数）。通过将标准化测量与经验丰富的放射科医生对DSI和DH损失相对严重程度的主观测量进行比较来评估结构有效性。结果：CSF信号强度、年龄和椎间盘水平与原始DSI显著相关（R2 = 分别为0.06、0.25和0.09）。腰椎高度和椎间盘水平与原始DH显著相关（R2 = 0.13和0.31）。通过这些变量归一化DSI和DH导致更强的关系（R2 = 0.39和0.37）比原始DSI和DH（R2 = 0.24和0.31）。归一化DSI和DH均呈正态分布（p = 0.32和0.12）。结论：结构有效性和分布表明，DSI和DH的标准化定量测量在评定相对DD严重程度方面优于DSI和DH现有的测量。确定标准化的定量测量是否更能预测临床结果是未来重要的研究。
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引用次数: 0
Preclinical to clinical translation for intervertebral disc repair: Effects of species-specific scale, metabolism, and matrix synthesis rates on cell-based regeneration 椎间盘修复的临床前转化：物种特异性规模、代谢和基质合成率对细胞再生的影响。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-09-07 DOI: 10.1002/jsp2.1279
Emily E. McDonnell, Niamh Wilson, Marcos N. Barcellona, Tara Ní Néill, Jessica Bagnall, Pieter A. J. Brama, Gráinne M. Cunniffe, Stacey L. Darwish, Joseph S. Butler, Conor T. Buckley

Background

A significant hurdle for potential cell-based therapies is the subsequent survival and regenerative capacity of implanted cells. While many exciting developments have demonstrated promise preclinically, cell-based therapies for intervertebral disc (IVD) degeneration fail to translate equivalent clinical efficacy.

Aims

This work aims to ascertain the clinical relevance of both a small and large animal model by experimentally investigating and comparing these animal models to human from the perspective of anatomical scale and their cellular metabolic and regenerative potential.

Materials and Methods

First, this work experimentally investigated species-specific geometrical scale, native cell density, nutrient metabolism, and matrix synthesis rates for rat, goat, and human disc cells in a 3D microspheroid configuration. Second, these parameters were employed in silico to elucidate species-specific nutrient microenvironments and predict differences in temporal regeneration between animal models.

Results

This work presents in silico models which correlate favorably to preclinical literature in terms of the capabilities of animal regeneration and predict that compromised nutrition is not a significant challenge in small animal discs. On the contrary, it highlights a very fine clinical balance between an adequate cell dose for sufficient repair, through de novo matrix deposition, without exacerbating the human microenvironmental niche.

Discussion

Overall, this work aims to provide a path towards understanding the effect of cell injection number on the nutrient microenvironment and the “time to regeneration” between preclinical animal models and the large human IVD. While these findings help to explain failed translation of promising preclinical data and the limited results emerging from clinical trials at present, they also enable the research field and clinicians to manage expectations on cell-based regeneration.

Conclusion

Ultimately, this work provides a platform to inform the design of clinical trials, and as computing power and software capabilities increase in the future, it is conceivable that generation of patient-specific

背景：潜在的细胞治疗的一个重要障碍是植入细胞的后续存活和再生能力。尽管许多令人兴奋的进展已经在临床前证明了前景，但基于细胞的椎间盘退变治疗未能转化为同等的临床疗效。目的：这项工作旨在从解剖规模及其细胞代谢和再生潜力的角度，通过实验研究和比较小型和大型动物模型与人类的临床相关性。材料和方法：首先，这项工作实验研究了大鼠、山羊和人类椎间盘细胞在三维微信息素配置中的物种特异性几何尺度、天然细胞密度、营养代谢和基质合成率。其次，这些参数在计算机中用于阐明物种特异性营养微环境，并预测动物模型之间时间再生的差异。结果：这项工作提出了在动物再生能力方面与临床前文献有良好相关性的计算机模型，并预测营养受损在小动物椎间盘中不是一个重大挑战。相反，它强调了在不加剧人类微环境生态位的情况下，通过从头开始的基质沉积进行足够修复的足够细胞剂量之间的非常好的临床平衡。讨论：总的来说，这项工作旨在为理解细胞注射次数对营养微环境的影响以及临床前动物模型和大型人类IVD之间的“再生时间”提供一条途径。虽然这些发现有助于解释有希望的临床前数据的翻译失败以及目前临床试验产生的有限结果，但它们也使研究领域和临床医生能够管理对基于细胞再生的期望。结论：最终，这项工作为临床试验的设计提供了一个平台，随着未来计算能力和软件能力的提高，可以想象，生成特定于患者的模型可以用于患者评估以及术前和术中规划。
{"title":"Preclinical to clinical translation for intervertebral disc repair: Effects of species-specific scale, metabolism, and matrix synthesis rates on cell-based regeneration","authors":"Emily E. McDonnell,&nbsp;Niamh Wilson,&nbsp;Marcos N. Barcellona,&nbsp;Tara Ní Néill,&nbsp;Jessica Bagnall,&nbsp;Pieter A. J. Brama,&nbsp;Gráinne M. Cunniffe,&nbsp;Stacey L. Darwish,&nbsp;Joseph S. Butler,&nbsp;Conor T. Buckley","doi":"10.1002/jsp2.1279","DOIUrl":"10.1002/jsp2.1279","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A significant hurdle for potential cell-based therapies is the subsequent survival and regenerative capacity of implanted cells. While many exciting developments have demonstrated promise preclinically, cell-based therapies for intervertebral disc (IVD) degeneration fail to translate equivalent clinical efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>This work aims to ascertain the clinical relevance of both a small and large animal model by experimentally investigating and comparing these animal models to human from the perspective of anatomical scale and their cellular metabolic and regenerative potential.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and Methods</h3>\u0000 \u0000 <p>First, this work experimentally investigated species-specific geometrical scale, native cell density, nutrient metabolism, and matrix synthesis rates for rat, goat, and human disc cells in a 3D microspheroid configuration. Second, these parameters were employed in silico to elucidate species-specific nutrient microenvironments and predict differences in temporal regeneration between animal models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>This work presents in silico models which correlate favorably to preclinical literature in terms of the capabilities of animal regeneration and predict that compromised nutrition is not a significant challenge in small animal discs. On the contrary, it highlights a very fine clinical balance between an adequate cell dose for sufficient repair, through de novo matrix deposition, without exacerbating the human microenvironmental niche.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>Overall, this work aims to provide a path towards understanding the effect of cell injection number on the nutrient microenvironment and the “time to regeneration” between preclinical animal models and the large human IVD. While these findings help to explain failed translation of promising preclinical data and the limited results emerging from clinical trials at present, they also enable the research field and clinicians to manage expectations on cell-based regeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Ultimately, this work provides a platform to inform the design of clinical trials, and as computing power and software capabilities increase in the future, it is conceivable that generation of patient-specific","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jsp2.1279","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41129726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
The influence of ligament biomechanics on proximal junctional kyphosis and failure in patients with adult spinal deformity 韧带生物力学对成人脊柱畸形患者近端连接后凸和失败的影响。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-08-25 DOI: 10.1002/jsp2.1277
Micah Blais, Bahar Shahidi, Brad Anderson, Eli O'Brien, Courtney Moltzen, Tina Iannacone, Robert K. Eastlack, Gregory M. Mundis Jr

Purpose

It is unknown whether the biomechanics of the posterior ligamentous complex (PLC) are impaired in individuals undergoing surgery for adult spinal deformity (ASD). Characterizing these properties may improve our understanding of proximal junctional kyphosis (PJK; defined as proximal junctional angle [PJA] of >10 deg from UIV-1 to UIV + 2), as well as proximal junctional failure (PJF; symptomatic PJK requiring revision). The purpose of this prospective observational study is to compare biomechanical properties of the PLC in individuals with ASD who do, and do not develop PJK or PJF within 1 year of spinal fusion surgery.

Methods

Intraoperative biopsies of PLC were obtained from 32 consecutive patients undergoing spinal fusions for ASD (>4 levels). Ligament peak force, tensile stress, tensile strain, and elastic modulus (EM) were measured with a materials testing system. Biomechanical properties and tissue dimensions were correlated with age, gender, BMI, vitamin D level, osteoporosis, sagittal alignment, PJA and change in PJA preoperatively, within 3 months, and at 1 year postoperatively.

Results

Longer ligaments were associated with greater PJA change at 3 months (p = 0.04), and thinner ligaments were associated with greater PJA change at 1 year (r = 0.57, p = 0.01). Greater EM was associated with greater PJA at both 3 months and 1 year (p = 0.03). Five participants had a change in PJA of >10 1 year postoperatively, and three participants demonstrated PJF. EM was significantly higher in individuals who required revision surgery (p = 0.003), and ligament length was greater (p = 0.03). Preoperative sagittal alignment was not related to incidence of revision surgery (p > 0.10).

Conclusions

The biomechanical properties of the PLC may be associated with higher risk for proximal failure. Ligaments that are longer, thinner, and less elastic are associated with higher postoperative PJA. Furthermore stiffer EM of the ligament is associated with the need for revision surgery.

目的：尚不清楚接受成人脊柱畸形（ASD）手术的患者后韧带复合体（PLC）的生物力学是否受损。描述这些特性可以提高我们对近端交界后凸的理解（PJK；定义为>10的近端交界角[PJA] 从UIV-1到UIV的度数 + 2） ，以及近端连接衰竭（PJF；症状性PJK需要翻修）。这项前瞻性观察性研究的目的是比较患有和未在1 脊柱融合手术年。方法：对32例因ASD（>4级）接受脊柱融合术的连续患者进行术中PLC活检。使用材料测试系统测量韧带峰值力、拉伸应力、拉伸应变和弹性模量（EM）。生物力学特性和组织尺寸与年龄、性别、BMI、维生素D水平、骨质疏松症、矢状位对齐、PJA和术前PJA的变化相关 月，在1 术后一年。结果：韧带越长，PJA变化越大 月（p = 0.04），并且较薄的韧带与1 年（r = 0.57，p = 0.01）。EM越大，PJA越大 月和1 年（p = 0.03）。五名参与者的PJA变化>10 1 术后一年，三名参与者表现出PJF。EM在需要翻修手术的个体中显著较高（p = 0.003），韧带长度更大（p = 术前矢状位对齐与翻修手术的发生率无关（p > 0.10）。结论：PLC的生物力学特性可能与更高的近端衰竭风险有关。较长、较薄、弹性较低的韧带与术后PJA较高有关。此外，韧带的EM变硬与翻修手术的需要有关。
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引用次数: 0
Construction of circ_0071922-miR-15a-5p-mRNA network in intervertebral disc degeneration by RNA-sequencing 通过RNA测序构建椎间盘退变中circ_0071922-miR-15a-5p-mRNA网络
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-08-24 DOI: 10.1002/jsp2.1275
Yongjin Li, Baobao Wang, Wenzhi Sun, Chao Kong, Junzhe Ding, Feng Hu, Jianhua Li, Xiaolong Chen, Shibao Lu

Background

Low back pain (LBP) is the main factor of global disease burden. Intervertebral disc degeneration (IVDD) has long been known as the leading reason of LBP. Increasing studies have verified that circular RNAs (circRNAs)-microRNAs (miRNAs)-mRNAs network is widely involved in the pathological processes of IVDD. However, no study was made to demonstrate the circRNAs-mediated ferroptosis, oxidative stress, extracellular matrix metabolism, and immune response in IVDD.

Methods

We collected 3 normal and 3 degenerative nucleus pulposus tissues to conduct RNA-sequencing to identify the key circRNAs and miRNAs in IVDD. Bioinformatics analysis was then conducted to construct circRNAs-miRNAs-mRNAs interaction network associated with ferroptosis, oxidative stress, extracellular matrix metabolism, and immune response. We also performed animal experiments to validate the therapeutic effects of key circRNAs in IVDD.

Results

We found that circ_0015435 was most obviously upregulated and circ_0071922 was most obviously downregulated in IVDD using RNA-sequencing. Then we observed that hsa-miR-15a-5p was the key downstream of circ_0071922, and hsa-miR-15a-5p was the top upregulated miRNA in IVDD. Bioinformatics analysis was conducted to predict that 56 immunity-related genes, 29 ferroptosis-related genes, 23 oxidative stress-related genes and 8 ECM-related genes are the targets mRNAs of hsa-miR-15a-5p. Then we constructed a ceRNA network encompassing 24 circRNAs, 6 miRNAs, and 101 mRNAs. Additionally, we demonstrated that overexpression of circ_0071922 can alleviate IVDD progression in a rat model.

Conclusions

The findings of this study suggested that circ_0071922-miR-15a-5p-mRNA signaling network might affect IVDD by modulating the nucleus pulposus cells ferroptosis, oxidative stress, ECM metabolism, and immune response, which is an effective therapeutic targets of IVDD.

腰痛（LBP）是造成全球疾病负担的主要因素。椎间盘退变（IVDD）一直被认为是LBP的主要原因。越来越多的研究证实，环状RNA（circRNAs）-微小RNA（miRNAs）-mRNA网络广泛参与IVDD的病理过程。然而，没有研究证明circRNAs介导的IVDD中的脱铁性贫血、氧化应激、细胞外基质代谢和免疫反应。我们收集了3个正常和3个退行性髓核组织，进行RNA测序，以鉴定IVDD中的关键circRNA和miRNA。然后进行生物信息学分析，构建与脱铁性贫血、氧化应激、细胞外基质代谢和免疫反应相关的circRNAs-miRNAs-mRNAs相互作用网络。我们还进行了动物实验，以验证关键circRNA在IVDD中的治疗效果。使用RNA测序，我们发现circ_0015435在IVDD中最明显上调，circ_0071922最明显下调。然后我们观察到，hsa‐miR‐15a‐5p是circ_0071922的关键下游，而hsa‐miR‐15a-5p是IVDD中上调最多的miRNA。进行生物信息学分析，预测56个免疫相关基因、29个脱铁相关基因、23个氧化应激相关基因和8个ECM相关基因是hsa‐miR‐15a‐5p的靶mRNA。然后我们构建了一个包含24个circRNA、6个miRNA和101个mRNA的ceRNA网络。此外，我们证明circ_0071922的过表达可以减轻大鼠模型中IVDD的进展。本研究结果表明，circ_0071922‐miR‐15a‐5p‐mRNA信号网络可能通过调节髓核细胞脱铁、氧化应激、ECM代谢和免疫反应来影响IVDD，这是IVDD的有效治疗靶点。
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引用次数: 0
Deep learning-based detection and classification of lumbar disc herniation on magnetic resonance images 基于深度学习的磁共振图像腰椎间盘突出症的检测和分类。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-08-14 DOI: 10.1002/jsp2.1276
Weicong Zhang, Ziyang Chen, Zhihai Su, Zhengyan Wang, Jinjin Hai, Chengjie Huang, Yuhan Wang, Bin Yan, Hai Lu

Background

The severity assessment of lumbar disc herniation (LDH) on MR images is crucial for selecting suitable surgical candidates. However, the interpretation of MR images is time-consuming and requires repetitive work. This study aims to develop and evaluate a deep learning-based diagnostic model for automated LDH detection and classification on lumbar axial T2-weighted MR images.

Methods

A total of 1115 patients were analyzed in this retrospective study; both a development dataset (1015 patients, 15 249 images) and an external test dataset (100 patients, 1273 images) were utilized. According to the Michigan State University (MSU) classification criterion, experts labeled all images with consensus, and the final labeled results were regarded as the reference standard. The automated diagnostic model comprised Faster R-CNN and ResNeXt101 as the detection and classification network, respectively. The deep learning-based diagnostic performance was evaluated by calculating mean intersection over union (IoU), accuracy, precision, sensitivity, specificity, F1 score, the area under the receiver operating characteristics curve (AUC), and intraclass correlation coefficient (ICC) with 95% confidence intervals (CIs).

Results

High detection consistency was obtained in the internal test dataset (mean IoU = 0.82, precision = 98.4%, sensitivity = 99.4%) and external test dataset (mean IoU = 0.70, precision = 96.3%, sensitivity = 97.8%). Overall accuracy for LDH classification was 87.70% (95% CI: 86.59%–88.86%) and 74.23% (95% CI: 71.83%–76.75%) in the internal and external test datasets, respectively. For internal testing, the proposed model achieved a high agreement in classification (ICC = 0.87, 95% CI: 0.86–0.88, P < 0.001), which was higher than that of external testing (ICC = 0.79, 95% CI: 0.76–0.81, P < 0.001). The AUC for model classification was 0.965 (95% CI: 0.962–0.968) and 0.916 (95% CI: 0.908–0.925) in the internal and external test datasets, respectively.

Conclusions

The automated diagnostic model achieved high performance in detecting and classifying LDH and exhibited considerable consistency with experts' classification.

背景：在MR图像上评估腰椎间盘突出症（LDH）的严重程度对于选择合适的手术候选者至关重要。然而，MR图像的解释是耗时的并且需要重复的工作。本研究旨在开发和评估一种基于深度学习的诊断模型，用于腰椎轴T2加权MR图像的LDH自动检测和分类。方法：对1115例患者进行回顾性分析；两个开发数据集（1015名患者，15名 249张图像）和外部测试数据集（100名患者、1273张图像）。根据密歇根州立大学（MSU）的分类标准，专家对所有图像进行了一致标记，最终标记结果作为参考标准。自动诊断模型包括分别作为检测和分类网络的Faster R-CNN和ResNeXt101。基于深度学习的诊断性能通过计算联合平均交叉点（IoU）、准确性、精密度、敏感性、特异性、F1评分、受试者工作特征曲线下面积（AUC）、，组内相关系数（ICC）和95%置信区间（CI）。结果：内部测试数据集中获得了较高的检测一致性（平均IoU = 0.82，精度 = 98.4%，灵敏度 = 99.4%）和外部测试数据集（平均IoU = 0.70，精度 = 96.3%，灵敏度 = 在内部和外部测试数据集中，LDH分类的总体准确率分别为87.70%（95%CI:86.59%-88.86%）和74.23%（95%CI:71.83%-76.75%）。对于内部测试，所提出的模型在分类上达成了高度一致（ICC = 0.87,95%置信区间：0.86-0.88，P P 结论：该自动诊断模型在LDH的检测和分类方面取得了较高的性能，并与专家的分类表现出相当的一致性。
{"title":"Deep learning-based detection and classification of lumbar disc herniation on magnetic resonance images","authors":"Weicong Zhang,&nbsp;Ziyang Chen,&nbsp;Zhihai Su,&nbsp;Zhengyan Wang,&nbsp;Jinjin Hai,&nbsp;Chengjie Huang,&nbsp;Yuhan Wang,&nbsp;Bin Yan,&nbsp;Hai Lu","doi":"10.1002/jsp2.1276","DOIUrl":"10.1002/jsp2.1276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The severity assessment of lumbar disc herniation (LDH) on MR images is crucial for selecting suitable surgical candidates. However, the interpretation of MR images is time-consuming and requires repetitive work. This study aims to develop and evaluate a deep learning-based diagnostic model for automated LDH detection and classification on lumbar axial T2-weighted MR images.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A total of 1115 patients were analyzed in this retrospective study; both a development dataset (1015 patients, 15 249 images) and an external test dataset (100 patients, 1273 images) were utilized. According to the Michigan State University (MSU) classification criterion, experts labeled all images with consensus, and the final labeled results were regarded as the reference standard. The automated diagnostic model comprised Faster R-CNN and ResNeXt101 as the detection and classification network, respectively. The deep learning-based diagnostic performance was evaluated by calculating mean intersection over union (IoU), accuracy, precision, sensitivity, specificity, F1 score, the area under the receiver operating characteristics curve (AUC), and intraclass correlation coefficient (ICC) with 95% confidence intervals (CIs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>High detection consistency was obtained in the internal test dataset (mean IoU = 0.82, precision = 98.4%, sensitivity = 99.4%) and external test dataset (mean IoU = 0.70, precision = 96.3%, sensitivity = 97.8%). Overall accuracy for LDH classification was 87.70% (95% CI: 86.59%–88.86%) and 74.23% (95% CI: 71.83%–76.75%) in the internal and external test datasets, respectively. For internal testing, the proposed model achieved a high agreement in classification (ICC = 0.87, 95% CI: 0.86–0.88, <i>P</i> &lt; 0.001), which was higher than that of external testing (ICC = 0.79, 95% CI: 0.76–0.81, <i>P</i> &lt; 0.001). The AUC for model classification was 0.965 (95% CI: 0.962–0.968) and 0.916 (95% CI: 0.908–0.925) in the internal and external test datasets, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The automated diagnostic model achieved high performance in detecting and classifying LDH and exhibited considerable consistency with experts' classification.</p>\u0000 </section>\u0000 </div>","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e6/2d/JSP2-6-e1276.PMC10540823.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41114623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Epidemiology of Modic changes in dogs: Prevalence, possible risk factors, and association with spinal phenotypes 犬Modic变化的流行病学：患病率、可能的危险因素以及与脊柱表型的关系。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-07-21 DOI: 10.1002/jsp2.1273
Martijn Beukers, Guy C. M. Grinwis, Johannes C. M. Vernooij, Lisanne van der Hoek, Anna R. Tellegen, Björn P. Meij, Stefanie Veraa, Dino Samartzis, Marianna A. Tryfonidou, Frances C. Bach

Background

Chronic low back pain, a leading contributor to disease burden worldwide, is often caused by intervertebral disc (IVD) degeneration. Modic changes (MCs) are MRI signal intensity changes due to lesions in vertebral bone marrow adjacent to degenerated IVDs. Only a few studies described the histopathological changes associated with MC to date. MC type 1 is suggested to be associated with bone marrow infiltration of fibrovascular tissue, type 2 with fatty infiltration, and type 3 with bone sclerosis in humans.

Methods

This study investigated whether the dog can be a valuable animal model to research MCs, by examining the prevalence, imaging, and histological characteristics of lumbar MCs in dogs (340 dogs, 2496 spinal segments).

Results

Logistic regression analysis indicated that the presence of lumbosacral MCs was associated with age and disc herniation (annulus fibrosis protrusion and/or nucleus pulposus extrusion). According to MRI analysis, MCs were mostly detected at the lumbosacral junction in dogs. Most signal intensity changes represented MC type 3, while previous spinal surgery seemed to predispose for the development of MC type 1 and 2. Histological analysis (16 dogs, 39 spinal segments) indicated that IVDs with MCs showed more histopathological abnormalities in the endplate and vertebral bone marrow than IVDs without MCs. Mostly chondroid proliferation in the bone marrow was encountered, while the histologic anomalies described in humans associated with MCs, such as fibrovascular or fatty infiltration, were scarcely detected.

Conclusions

Dogs spontaneously develop MCs, but may exhibit other pathological processes or more chronic bone marrow pathologies than humans with MCs. Therefore, more research is needed to determine the translatability of the MCs encountered in dog low-back-pain patients.

背景：慢性腰痛是世界范围内疾病负担的主要原因，通常是由椎间盘（IVD）变性引起的。Modic changes（MCs）是指由于退变IVD附近的脊椎骨髓病变引起的MRI信号强度变化。迄今为止，只有少数研究描述了与MC相关的组织病理学变化。MC 1型被认为与骨髓纤维血管组织浸润有关，2型与脂肪浸润有关，3型与人类骨硬化有关。方法：本研究通过检测MCs的患病率、影像学、，结果：Logistic回归分析表明，腰骶部MCs的存在与年龄和椎间盘突出（纤维环突出和/或髓核挤压）有关。根据MRI分析，MCs主要出现在狗的腰骶交界处。大多数信号强度变化表现为MC 3型，而以前的脊柱手术似乎容易发展为MC 1型和2型。组织学分析（16只狗，39个脊椎节段）表明，与没有MC的IVD相比，有MC的IVDs在终板和脊椎骨髓中显示出更多的组织病理学异常。骨髓中大多出现软骨样增生，而在人类中描述的与MCs相关的组织学异常，如纤维血管或脂肪浸润，几乎没有检测到。结论：狗会自发发展为MCs，但可能表现出其他病理过程或比患有MCs的人更慢性的骨髓病变。因此，需要更多的研究来确定在狗腰痛患者中遇到的MCs的可翻译性。
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引用次数: 1
The effect of fatty infiltration, revision surgery, and sex on lumbar multifidus passive mechanical properties 脂肪浸润、翻修手术和性别对腰椎多裂肌被动力学性能的影响。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-07-17 DOI: 10.1002/jsp2.1266
Bahar Shahidi, Jennifer A. Padwal, Jeannie J. Su, Gilad Regev, Vinko Zlomislic, R. Todd Allen, Steven R. Garfin, Choll Kim, Richard L. Lieber, Samuel R. Ward

Purpose

Previous research has demonstrated increased stiffness in the multifidus muscle compared to other paraspinal muscles at the fiber bundle level. We aimed to compare single fiber and fiber bundle passive mechanical properties of multifidus muscle: (1) in 40 patients undergoing primary versus revision surgery and (2) in muscle with mild versus severe fatty infiltration.

Methods

The degree of muscle fatty infiltration was graded using the patients' spine magnetic resonance images. Average single fiber and fiber bundle passive mechanical properties across three tests were compared between primary (N = 30) and revision (N = 10) surgery status, between mild and severe fatty infiltration levels, between sexes, and with age from passive stress–strain tests of excised multifidus muscle intraoperative biopsies.

Results

At the single fiber level, elastic modulus was unaffected by degree of fatty infiltration or surgery status. Female sex (p = 0.001) and younger age (p = 0.04) were associated with lower multifidus fiber elastic modulus. At the fiber bundle level, which includes connective tissue around fibers, severe fatty infiltration (p = 0.01) and younger age (p = 0.06) were associated with lower elastic modulus. Primary surgery also demonstrated a moderate, but non-significant effect for lower elastic modulus (p = 0.10).

Conclusions

Our results demonstrate that female sex is the primary driver for reduced single fiber elastic modulus of the multifidus, while severity of fatty infiltration is the primary driver for reduced elastic modulus at the level of the fiber bundle in individuals with lumbar spine pathology.

目的：先前的研究表明，与其他棘旁肌相比，多裂肌在纤维束水平上的硬度增加。我们的目的是比较多裂肌的单纤维和纤维束被动力学特性：（1）在40名接受初次和翻修手术的患者中，以及（2）在轻度和重度脂肪浸润的肌肉中。方法：利用患者脊柱磁共振图像对肌肉脂肪浸润程度进行分级。比较了三次试验中初级（N = 30）和修订（N = 10） 手术状态，轻度和重度脂肪浸润水平之间，性别之间，以及随着年龄的变化，来自切除的多裂肌术中活检的被动应力-应变测试。结果：在单纤维水平上，弹性模量不受脂肪浸润程度或手术状态的影响。女性（p = 0.001）和年龄较小（p = 0.04）与较低的多裂纤维弹性模量相关。在纤维束水平，包括纤维周围的结缔组织，严重的脂肪浸润（p = 0.01）和年龄较小（p = 0.06）与较低的弹性模量相关。初次手术对较低的弹性模量也有中等但不显著的影响（p = 0.10）。结论：我们的研究结果表明，女性是导致多裂肌单纤维弹性模量降低的主要驱动因素，而脂肪浸润的严重程度是导致腰椎病变患者纤维束弹性模量下降的主要驱动原因。
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引用次数: 1
Recommendations for intervertebral disc notochordal cell investigation: From isolation to characterization 椎间盘脊索细胞研究的建议：从分离到表征。
IF 3.7 3区 医学 Q1 Medicine
JOR Spine
Pub Date : 2023-07-09 DOI: 10.1002/jsp2.1272
Rebecca J. Williams, Lisanne T. Laagland, Frances C. Bach, Lizzy Ward, Wilson Chan, Vivian Tam, Adel Medzikovic, Shaghayegh Basatvat, Lily Paillat, Nicolas Vedrenne, Joseph W. Snuggs, Deepani W. Poramba-Liyanage, Judith A. Hoyland, Danny Chan, Anne Camus, Stephen M. Richardson, Marianna A. Tryfonidou, Christine L. Le Maitre

Background

Lineage-tracing experiments have established that the central region of the mature intervertebral disc, the nucleus pulposus (NP), develops from the embryonic structure called “the notochord”. However, changes in the cells derived from the notochord which form the NP (i.e., notochordal cells [NCs]), in terms of their phenotype and functional identity from early developmental stages to skeletal maturation are less understood. These key issues require further investigation to better comprehend the role of NCs in homeostasis and degeneration as well as their potential for regeneration. Progress in utilizing NCs is currently hampered due to poor consistency and lack of consensus methodology for in vitro NC extraction, manipulation, and characterization.

Methods

Here, an international group has come together to provide key recommendations and methodologies for NC isolation within key species, numeration, in vitro manipulation and culture, and characterization.

Results

Recommeded protocols are provided for isolation and culture of NCs. Experimental testing provided recommended methodology for numeration of NCs. The issues of cryopreservation are demonstrated, and a pannel of immunohistochemical markers are provided to inform NC characterization.

Conclusions

Together we hope this article provides a road map for in vitro studies of NCs to support advances in research into NC physiology and their potential in regenerative therapies.

背景：谱系追踪实验已经证实，成熟椎间盘的中心区域，髓核（NP），是由称为“脊索”的胚胎结构发育而来的。然而，从早期发育阶段到骨骼成熟，形成NP的脊索衍生细胞（即脊索细胞[NCs]）在表型和功能特性方面的变化尚不清楚。这些关键问题需要进一步研究，以更好地理解NCs在稳态和变性中的作用及其再生潜力。由于一致性差以及缺乏一致的体外NC提取、操作和表征方法，目前阻碍了利用NC的进展。方法：在这里，一个国际小组聚集在一起，为关键物种内的NC分离、计数、体外操作和培养以及表征提供了关键建议和方法。结果：为NCs的分离和培养提供了推荐的方案。实验测试提供了计算NCs的推荐方法。证明了冷冻保存的问题，并提供了一系列免疫组织化学标记物来告知NC的特征。结论：我们共同希望这篇文章为NCs的体外研究提供一个路线图，以支持NC生理学及其在再生治疗中的潜力的研究进展。
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引用次数: 0
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