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This is a prospective study to establish prediction models that map the refined Scoliosis Research Society 22-item (SRS-22r) onto EuroQoL-5 dimension 5-level (EQ-5D-5L) utility scores in adolescent idiopathic scoliosis (AIS) patients. Comparison of treatment outcomes in AIS can be determined by cost-utility analysis. However, the mainstay spine-specific health-related quality of life outcome measure, the SRS-22r questionnaire does not provide utility assessment. In this study, AIS patients were prospectively recruited to complete both the EQ-5D-5L and SRS-22r questionnaires by trained interviewers. Ordinary least squares regression was undertaken to develop mapping models, which the validity and robustness were assessed by using the 10-fold cross-validation procedure. EQ-5D-5L utility scores were regressed on demographics, Cobb angle, curve types, treatment modalities, and five domains of the SRS-22r questionnaire. Three models were developed using stepwise selection method. EQ-5D-5L scores were regressed on 1) main effects of SRS-22r subscale scores, 2) as per 1 plus squared and interaction terms, and 3) as per 2 plus demographic and clinical characteristics. Model goodness-of-fit was assessed using R-square, adjusted R-square, and information criteria; whereas the predictive performance was evaluated using root mean square error (RMSE), mean absolute error (MAE), and the proportion of absolute error within the threshold of 0.05 and 0.10. A total of 227 AIS patients with mean age of 15.6 years were recruited. The EQ-5D-5L scores were predicted by four domains of SRS-22r (main effects of 'Function', 'Pain', 'Appearance' and 'Mental Health', and squared term of 'Function' and 'Pain'), and Cobb angle in Model 3 with the best goodness-of-fit (R-square/adjusted R-square: 62.1%/60.9%). Three models demonstrated an acceptance predictive performance in error analysis applying 10-fold cross-validation to three models where RMSE and MAE were between 0.063-0.065 and between 0.039-0.044, respectively. Model 3 was therefore recommended out of three mapping models established in this paper. To our knowledge, this is the first study to map a spine-specific health-related quality of life measure onto EQ-5D-5L for AIS patients. With the consideration and incorporation of demographic and clinical characteristics, over 60% variance explained by mapping model 3 enabled the satisfactory prediction of EQ-5D-5L utility scores from existing SRS-22r data for health economic appraisal of different treatment options.

Ultrasonic osteotomy devices (UODs) have emerged as precise bone-cutting instruments with soft tissue-sparing benefits; yet their impact on bone healing and adjacent neural tissue remains underexplored. This study aimed to investigate the effects of UODs versus conventional rotary high-speed burr (HSB) on bone healing and central nervous functions using mouse split calvarial bone defect models. Bilateral parietal bone defects were created in the skulls of mice using UOD (right) and HSB (left). Intraoperative heat generation was recorded using a thermal camera. Bone healing progress was assessed via longitudinal micro-CT over 8 weeks, supplemented by histological (H&E staining) and neurofunctional (cylinder test) analyses at 2-, 4-, 6-, and 8-week intervals. All 24 mice completed the 8-week follow-up without complications. Micro-CT revealed comparable bone defect closure rates between groups (p > 0.05). Despite irrigation, UOD generated transient temperature spikes exceeding 60 °C. Histologically, UOD-treated bone adjacent to defects displayed loosened, wave-like multilayered structures. UOD sides also showed brain tissue hyalinization and structural defects, correlating with transient parietal lobe dysfunction in cylinder tests. UOD induced transient thermal spikes, altered bone morphology, and subtle neurofunctional changes. Caution is advised when deploying UODs near neural tissues or delicate bone regions.

Current clinical evidence suggests that a well-planned physiotherapeutic scoliosis specific exercise (PSSE) program is effective for scoliosis regression. We investigated the effect of curve patterns on Cobb angles with PSSE. This was a non-randomized prospective clinical trial that recruited participants with adolescent idiopathic scoliosis between January and June 2017. Participants were grouped by curve pattern into major thoracic and major lumbar groups. An outpatient-based PSSE program was conducted with the following schedule of intensive exercise: ≥ 1 session of supervised PSSE per month and > 30min of home exercise 5 days/week in the first 6 months, after which exercise frequency was reduced to 1 session of supervised PSSE every three months and > 30min of home exercise 5 days/week until 2 years after study initiation. Radiographic Cobb angle progressions were identified at the 1, 1.5 and 2-year follow-ups. A mixed model analysis of variance (ANOVA) was performed to examine the differences in Cobb angles between groups at four testing time points. The two-tailed significance level was set to 0.05. In total, 40 participants were recruited, including 22 with major thoracic curves (5 males and 17 females; mean age 13.5±1.8 years; Cobb angle 18-45 degrees) and 18 with major lumbar curves (7 males and 11 females; mean age 12.7±1.7 years; Cobb angle 15-48 degrees). Curve regressions, namely the reduction of Cobb angles between 7 to 10 degrees were noted in 9.1% of participants in the major thoracic group; reductions of 6 to 13 degrees were noted in 33.3% of participants in the major lumbar group at the 2-year follow-up. Repeated measurements revealed a significant time effect (F2.2,79.8 = 4.1, p = 0.02), but no group (F2.2,79.8 = 2.3, p = 0.1) or time × group (F1,37 = 0.97, p = 0.3) effects in reducing Cobb angles after 2 years of PSSE. A logistic regression analysis revealed that no correlation was observed between curve pattern and curve regression or stabilization (OR: 0.2, 95% CI: 0.31-1.1, p = 0.068) at the 2-year follow-up. This was the first study to investigate the long-term effects of PSSE in reducing Cobb angles on the basis of major curve location. No significant differences in correction were observed between major thoracic and major lumbar curves. A regression effect and no curve deterioration were noted in both groups at the 2-year follow-up. ChiCTR1900028073.

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg 2+ ), the diverse roles of Mg 2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg 2+ in bone repair. During the early inflammation phase, Mg 2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg 2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg 2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg 2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg 2+ . Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg 2+ in bone healing. Supplementation of magnesium (Mg2+) or its inclusion in biomaterials has beneficial effects for bone formation, but it has also been reported that it can have detrimental effects. Here, the authors analyse dose- and time-dependent effects of Mg2+ on bone regeneration and show that it can stimulate monocyte-macrophage lineage cells to support bone formation in the early phases of repair, but inhibit bone repair and mineralization in later stages by promoting a pro-inflammatory environment.

Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans. A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990-2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines. Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat), COL11A1 (rs1676486), GDF5 (rs143383), SKT (rs16924573), THBS2 (rs9406328) and MMP9 (rs17576). Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.

Bone formation induced by divalent metal cations has been widely reported; however, the underlying mechanism is unclear. Here we report that these cations stimulate skeleton interoception by promoting prostaglandin E2 secretion from macrophages. This immune response is accompanied by the sprouting and arborization of calcitonin gene-related polypeptide-α + nerve fibers, which sense the inflammatory cue with PGE 2 receptor 4 and convey the interoceptive signals to the central nervous system. Activating skeleton interoception downregulates sympathetic tone for new bone formation. Moreover, either macrophage depletion or knockout of cyclooxygenase-2 in the macrophage abolishes divalent cation-induced skeleton interoception. Furthermore, sensory denervation or knockout of EP4 in the sensory nerves eliminates the osteogenic effects of divalent cations. Thus, our study reveals that divalent cations promote bone formation through the skeleton interoceptive circuit, a finding which could prompt the development of novel biomaterials to elicit the therapeutic power of these divalent cations. Mechanisms underlying bone formation induced by divalent metal cations remain largely unknown. Here the authors show that these cations can activate the skeleton interoceptive circuit through the immune-neural axis to initiate new bone formation.

Reactive oxygen species (ROS) are a promising alternative bactericide. However, it is questioned that bacteria can potentially develop resistance to ROS, similar to their resistance against antibiotics and silver. Herein, it is reported that Gram‐negative bacteria, including Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae, develop resistance to ROS after six repeated exposures. Notably, ROS minimum inhibitory concentration of Pseudomonas aeruginosa significantly increases to 256‐fold after ten passages. The resistance mechanism predominantly originates from the intensified biosynthesis of the highly reductive hydrogen sulfide (H2S) and pyoverdine (PVD) siderophores, effectively neutralizing ROS. Simultaneously, PVD transports Fe3+ from the extracellular space into the bacteria, releasing H2S bound to Fe3+ and enhancing ROS scavenging. Additionally, the enhanced outer membrane (OM) biogenesis establishes a robust OM barrier, impeding ROS penetration. The acquired resistance to ROS can be significantly reduced by incorporating additional Fe3+ into the culture medium or disrupting the H2S biosynthetic gene. These observations suggest that careful consideration is required when utilizing ROS against Gram‐negative bacteria. It is anticipated that understanding this resistance mechanism can inform the development of future antimicrobial agents, particularly for Gram‐negative bacteria. Discover how Gram‐negative bacteria develop resistance to reactive oxygen species, and how scientists aim to overcome this challenge.

Selecting fusion levels based on the Luk et al criteria for operative management of thoracic adolescent idiopathic scoliosis (AIS) with hook and hybrid systems yields acceptable curve correction and balance parameters; however, it is unknown whether utilizing a purely pedicle screw strategy is effective. Utilizing the fulcrum bending radiographic (FBR) to assess curve flexibility to select fusion levels, the following study assessed the efficacy of pedicle screw fixation with alternate level screw strategy (ALSS) for thoracic AIS. A retrospective study with prospective radiographic data collection/analyses (preoperative, postoperative 1-week and minimum 2-year follow-up) of 28 operative thoracic AIS patients undergoing ALSS was performed. Standing coronal/sagittal and FBR Cobb angles, FBR flexibility, fulcrum bending correction index (FBCI), trunkal shift, radiographic shoulder height (RSH), and list were assessed on x-rays. Fusion level selection was based on the Luk et al criteria and compared to conventional techniques. In the primary curve, the mean preoperative and postoperative 1 week and last follow-up standing coronal Cobb angles were 59.9, 17.2 and 20.0 degrees, respectively. Eighteen patients (64.3%) had distal levels saved (mean: 1.6 levels) in comparison to conventional techniques. Mean immediate and last follow-up FBCIs were 122.6% and 115.0%, respectively. Sagittal alignment did not statistically differ between any assessment intervals (p>0.05). A decrease in trunkal shift was noted from preoperative to last follow-up (p = 0.003). No statistically significant difference from preoperative to last follow-up was noted in RSH and list (p>0.05). No \"add-on\" of other vertebra or decompensation was noted and all patients achieved fusion. This is the first report to note that using the FBR for decision-making in selecting fusion levels in thoracic AIS patients undergoing management with pedicle screw constructs (e.g. ALSS) is a cost-effective strategy that can achieve clinically-relevant deformity correction that is maintained and without compromising fusion levels.

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Low back pain (LBP), as a leading cause of disability, is a common musculoskeletal disorder that results in major social and economic burdens. Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration, a significant contributor to LBP. Inflammatory mediators also play an indispensable role in discogenic LBP. The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies. Here, an overview of the advances in inflammation-related pain in disc degeneration is provided, with a discussion on the role of inflammation in IVD degeneration and pain induction. Puncture models, mechanical models, and spontaneous models as the main animal models to study painful disc degeneration are discussed, and the underlying signaling pathways are summarized. Furthermore, potential drug candidates, either under laboratory investigation or undergoing clinical trials, to suppress discogenic LBP by eliminating inflammation are explored. We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.