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Diverse internal and external pathologic stimuli can trigger cellular stress response pathways (CSRPs) that are usually counteracted by intrinsic homeostatic machinery, which responds to stress by initiating complex signaling mechanisms to eliminate either the stressor or the damaged cells. There is growing evidence that CSRPs can have context-dependent homeostatic or pathologic functions that may result in tissue fibrosis under persistence of stress. CSRPs can drive intercellular communications through exosomes (trafficking and secretory pathway determinants) secreted in response to stress-induced proteostasis rebalancing. The injured tissue environment upon sensing the stress turns on a precisely orchestrated network of immune responses by regulating cytokine-chemokine production, recruitment of immune cells, and modulating fibrogenic niche and extracellular matrix (ECM) cross-talk during fibrotic pathologies like cardiac fibrosis, liver fibrosis, laryngotracheal stenosis, systemic scleroderma, interstitial lung disease and inflammatory bowel disease. Immunostimulatory RNAs (like double stranded RNAs) generated through deregulated RNA processing pathways along with RNA binding proteins (RBPs) of RNA helicase (RNA sensors) family are emerging as important components of immune response pathways during sterile inflammation. The paradigm-shift in RNA metabolism associated interactome has begun to offer new therapeutic windows by unravelling the novel RBPs and splicing factors in context of developmental and fibrotic pathways. We would like to review emerging regulatory nodes and their interaction with CSRPs, and tissue remodeling with major focus on cardiac fibrosis, and inflammatory responses underlying upper airway fibrosis.

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Letter to the editor concerning ''The Rate of Heterotic Ossification Following Cervical Disc Arthroplasty: A Systematic Review and Comparison of Data'' by Dowell et al W ith great interest, we have read the article by Dowell et al 1 published in Spine.The author pooled heterotic ossification rates and annum rates after cervical total disc replacement. We highly appreciate their contributions to this important topic. However, there is a point that may mislead readers, and some supplementary explanations would be of benefit.In this article, severe heterotic ossification may not be able to protect adjacent segments and may lead to degeneration. However, natural process plays an important role in the occurrence of adjacent segment degeneration (ASD). ASD is indeed a common phenomenon, but it may reflect the natural history of cervical spondylosis 2 . Matsumoto et al 3 found more than 60% of 201 asymptomatic volunteers had cervical degeneration within 10 years, and degeneration rate was comparable between surgical group and control group at C5-6. Park et al 4 found 85% of patients with ASD had degenerative changes in the adjacent segments before surgery, which indicate that preoperative degeneration contributes to the increasing risk of ASD in patients receiving anterior cervical spine surgery. Therefore, natural degeneration should not be ignored when analyzing the causes of ASD. If possible, a subgroup analysis of ASD in this article can give us more clues to reach more comprehensive and rigorous conclusions.Once again, we thank the authors for their contribution in this field and hope readers can benefit from it.

We read and discussed the article ''Surgery for degenerative cervical myelopathy: What really counts?" by Gembruch et al 1 with great interest and inquisitiveness. Given the present controversy surrounding the treatment of degenerative cervical myelopathy, when and whom to operate, we found this article to be valuable regarding pointing of factors affecting outcome and timing of surgery.In this study, symptoms duration was not found to be an independent predictor contrary to previous studies and systematic review. 2 Tetreault et al 3 concluded that predictors achieving a minimum clinically important difference on the modified Japanese Orthopedic Association score were younger age, shorter duration of symptoms, nonsmokers, and lack of significant gait impairment. What could be the reason for contradictory results in this study compared to previous studies or is it due to some other variables? Is there any way to help in earlier diagnosis and differentiating degenerative cervical myelopathy in the elderly in presence of comorbidities for prompt treatment to ensure a better outcome?

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