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      Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain

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          Abstract

          Background

          Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain (LBP) and despite a prominent prevalence, present treatment options remain inadequate for a large portion of LBP patients. New developments in regenerative therapeutics offer potentially powerful medical tools to modify this pathology, with specific focus on (stem) cell transplantations. Multiple clinical trials have since reported overall beneficial outcomes favoring cell therapy. Nonetheless, the significance of these improvements is often not (clearly) discussed. As such, this narrative review aims to summarize the significance of the reported improvements from human clinical trials on IVD-targeted cell therapy.

          Methods

          Through a comprehensive narrative review we discuss the improvements in pain, disability, quality of life, and imaging modalities and reported adverse events following cell therapy for discogenic pain.

          Results

          Most clinical trials were able to report clear and significant improvements in pain and disability outcomes. Imaging and quality of life improvements however were not as clearly reported but did present some enhancements for a select number of patients. Finally, whether cell therapy can outperform placebo treatment remains intangible.

          Conclusions

          Our review highlights the clinical significance of observed trends in pain and disability improvement. Nevertheless, reporting quality was found unsatisfactory and large-scale randomized controlled studies remain small in number. Future studies and articles should put more emphasis on improvements in imaging modalities and compare outcomes to (placebo) control groups to fully elucidate the efficacy and safety of cellular therapeutics against LBP.

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          Most cited references100

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          Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.

          The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.
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            Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015

            Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17·2 billion, 95% uncertainty interval [UI] 15·4–19·2 billion) and diarrhoeal diseases (2·39 billion, 2·30–2·50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2·36 billion (2·35–2·37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20–30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Funding Bill & Melinda Gates Foundation.
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              The Oswestry Disability Index.

              The Oswestry Disability Index (ODI) has become one of the principal condition-specific outcome measures used in the management of spinal disorders. This review is based on publications using the ODI identified from the authors' personal databases, the Science Citation Index, and hand searches of Spine and current textbooks of spinal disorders. To review the versions of this instrument, document methods by which it has been validated, collate data from scores found in normal and back pain populations, provide curves for power calculations in studies using the ODI, and maintain the ODI as a gold standard outcome measure. It has now been 20 years since its original publication. More than 200 citations exist in the Science Citation Index. The authors have a large correspondence file relating to the ODI, that is cited in most of the large textbooks related to spinal disorders. All the published versions of the questionnaire were identified. A systematic review of this literature was made. The various reports of validation were collated and related to a version. Four versions of the ODI are available in English and nine in other languages. Some published versions contain misprints, and many omit the scoring system. At least 114 studies contain usable data. These data provide both validation and standards for other users and indicate the power of the instrument for detecting change in sample populations. The ODI remains a valid and vigorous measure and has been a worthwhile outcome measure. The process of using the ODI is reviewed and should be the subject of further research. The receiver operating characteristics should be explored in a population with higher self-report disabilities. The behavior of the instrument is incompletely understood, particularly in sensitivity to real change.
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                Author and article information

                Contributors
                Journal
                N Am Spine Soc J
                N Am Spine Soc J
                North American Spine Society Journal
                Elsevier
                2666-5484
                22 December 2022
                March 2023
                22 December 2022
                : 13
                : 100195
                Affiliations
                [0001]Tokai University School of Medicine, Department of Orthopedic Surgery, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
                Author notes
                [* ]Corresponding author. daisakai@ 123456is.icc.u-tokai.ac.jp
                Article
                S2666-5484(22)00098-1 100195
                10.1016/j.xnsj.2022.100195
                9841054
                36655116
                5137bb31-0027-4bc7-8f3a-1e1b7b0f06a4
                © 2022 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 1 November 2022
                : 24 November 2022
                : 15 December 2022
                Categories
                Advances in Spinal Regenerative Therapies

                cell therapy,low back pain,intervertebral disc,disc degeneration,regenerative medicine,mesenchymal stromal cells,stem cells,spine,disc herniation

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