Generic placeholder image

Current Rheumatology Reviews

Editor-in-Chief

ISSN (Print): 1573-3971
ISSN (Online): 1875-6360

Review Article

Emerging and New Treatment Options for Knee Osteoarthritis

Author(s): Md. Abu Bakar Siddiq*, Danny Clegg, Tim L. Jansen and Johannes J. Rasker

Volume 18, Issue 1, 2022

Published on: 10 December, 2021

Page: [20 - 32] Pages: 13

DOI: 10.2174/1573397117666211116111738

Price: $65

Abstract

Osteoarthritis (OA) is the most prevalent type of arthritis worldwide, resulting in pain and often chronic disability and a significant burden on healthcare systems globally. Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, intra-articular corticosteroid injections are of little value in the long term, and opioids may have ominous consequences. Radiotherapy of knee OA has no added value. Physical therapy, exercises, weight loss, and lifestyle modifications may give pain relief, improve physical functioning and quality of life. However, none of them has articular cartilage regenerating potential. Due to a better understanding of osteoarthritis, innovative new treatment options have been developed. In this narrative review, we focus on emerging OA knee treatments, relieving symptoms, and regenerating damaged articular cartilage that includes intra-articular human serum albumin, conventional disease-modifying anti-rheumatic drugs (DMARDs), metformin, lipid-lowering agents (statin), nerve growth factors antagonists, bone morphogenetic protein, fibroblast growth factors, Platelet-Rich Plasma (PRP), Mesenchymal Stem Cells (MSC), exosomes, interleukin-1 blockers, gene-based therapy, and bisphosphonate.

Keywords: Anti-inflammatory agents, analgesics, cartilage, knee, nerve growth factors, osteoarthritis, pain, platelet-rich plasma.

[1]
Berenbaum F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 2013; 21(1): 16-21.
[http://dx.doi.org/10.1016/j.joca.2012.11.012] [PMID: 23194896]
[2]
Favero M, Ramonda R, Goldring MB, Goldring SR, Punzi L. Early knee osteoarthritis. RMD Open 2015; 1: e000062.
[http://dx.doi.org/10.1136/rmdopen-2015-000062] [PMID: 26557380]
[3]
Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med 2010; 26(3): 355-69.
[http://dx.doi.org/10.1016/j.cger.2010.03.001] [PMID: 20699159]
[4]
Chua JR, Jamal S, Riad M, et al. Disease burden in Osteoarthritis (OA) is similar to Rheumatoid Arthritis (RA) at initial rheumatology visit and significantly greater six months later. Arthritis Rheumatol 2019; 71(8): 1276-84.
[http://dx.doi.org/10.1002/art.40869] [PMID: 30891933]
[5]
Luyten FP, Bierma-Zeinstra S, Dell’Accio F, et al. Toward classification criteria for early osteoarthritis of the knee. Semin Arthritis Rheum 2018; 47(4): 457-63.
[http://dx.doi.org/10.1016/j.semarthrit.2017.08.006] [PMID: 28917712]
[6]
Klement MR, Sharkey PF. The significance of osteoarthritis-associated bone marrow lesions in the knee. J Am Acad Orthop Surg 2019; 27(20): 752-9.
[http://dx.doi.org/10.5435/JAAOS-D-18-00267] [PMID: 30964755]
[7]
Sadatsuki R, Ishijima M, Kaneko H, et al. Bone marrow lesion is associated with disability for activities of daily living in patients with early stage knee osteoarthritis. J Bone Miner Metab 2019; 37(3): 529-36.
[http://dx.doi.org/10.1007/s00774-018-0950-z] [PMID: 30187274]
[8]
Chu CR, Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treatment of pre-osteoarthritis. Arthritis Res Ther 2012; 14(3): 212-22.
[http://dx.doi.org/10.1186/ar3845] [PMID: 22682469]
[9]
King LK, Marshall DA, Faris P, et al. BEST-Knee Research Team. Use of recommended non-surgical knee osteoarthritis management in patients prior to total knee arthroplasty: A cross-sectional study. J Rheumatol 2020; 47(8): 1253-60.
[http://dx.doi.org/10.3899/jrheum.190467] [PMID: 31732554]
[10]
Hochberg M, Altman RD, April KT, et al. American College of Rheumatology. American College of Rheumatology 2012 Recommendations for the use of non-pharmacological and pharmacological therapies in osteoarthritis of the hand, hip and knee. Arthritis Care Res (Hoboken) 2012; 64(4): 465-74.
[http://dx.doi.org/10.1002/acr.21596] [PMID: 22563589]
[11]
Zhang W, Ouyang H, Dass CR, Xu J. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res 2016; 4: 15040.
[http://dx.doi.org/10.1038/boneres.2015.40] [PMID: 26962464]
[12]
Dieppe P, Goldingay S, Greville-Harris M. The power and value of placebo and nocebo in painful osteoarthritis. Osteoarthritis Cartilage 2016; 24(11): 1850-7.
[http://dx.doi.org/10.1016/j.joca.2016.06.007] [PMID: 27338671]
[13]
Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: Meta-analysis of randomised controlled trials. Ann Rheum Dis 2008; 67(12): 1716-23.
[http://dx.doi.org/10.1136/ard.2008.092015] [PMID: 18541604]
[14]
CASP checklists. Available from: https://casp-uk.net/casp-tools-checklists/
[15]
Frederick ED, Hausburg MA, Thomas GW, Rael LT, Brody E, Bar-Or D. The low molecular weight fraction of human serum albumin upregulates COX2, prostaglandin E2, and prostaglandin D2 under inflammatory conditions in osteoarthritic knee synovial fibroblasts. Biochem Biophys Rep 2016; 8: 68-74.
[http://dx.doi.org/10.1016/j.bbrep.2016.08.015] [PMID: 28955943]
[16]
Bar-Or D, Salottolo KM, Loose H, et al. A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee. PLoS One 2014; 9(2): e87910.
[http://dx.doi.org/10.1371/journal.pone.0087910] [PMID: 24498399]
[17]
Schwappach J, Dryden SM, Salottolo KM. Preliminary trial of intra-articular LMWF-5A for osteoarthritis of the knee. Orthopedics 2017; 40(1): e49-53.
[http://dx.doi.org/10.3928/01477447-20160926-02] [PMID: 27684085]
[18]
Salottolo K, Cole B, Bar-Or D. Intra-articular injection of the anti-inflammatory compound LMWF-5A in adults with severe osteoarthritis: A double-blind prospective randomized controlled multi-center safety and efficacy trial. Patient Saf Surg 2018; 12: 11.
[19]
Schwappach J, Schultz J, Salottolo K, Bar-Or D. Incidence of total knee replacement subsequent to intra-articular injection of the anti-inflammatory compound LMWF-5A versus saline: A long-term follow-up study to a randomized controlled trial. Patient Saf Surg 2018; 12: 14.
[http://dx.doi.org/10.1186/s13037-018-0162-4] [PMID: 29881459]
[20]
Persson MSM, Sarmanova A, Doherty M, Zhang W. Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: A meta-analysis of randomized controlled trials. Rheumatology (Oxford) 2018; 57(10): 1830-7.
[http://dx.doi.org/10.1093/rheumatology/key131] [PMID: 29917100]
[21]
Wenham CY, Grainger AJ, Hensor EM, Caperon AR, Ash ZR, Conaghan PG. Methotrexate for pain relief in knee osteoarthritis: An open-label study. Rheumatology (Oxford) 2013; 52(5): 888-92.
[http://dx.doi.org/10.1093/rheumatology/kes386] [PMID: 23300331]
[22]
Enteshari-Moghaddam A, Isazadehfar K, Habibzadeh A, Hemmati M. Efficacy of methotrexate on pain severity reduction and improvement of quality of life in patients with moderate to severe knee osteoarthritis. Anesth Pain Med 2019; 9(3): e89990.
[http://dx.doi.org/10.5812/aapm.89990] [PMID: 31497519]
[23]
Kingsbury SR, Tharmanathan P, Keding A, et al. Significant pain reduction with oral methotrexate in knee osteoarthritis; results from a randomised controlled phase III trial of treatment effectiveness. Arthritis Rheumatol 2019; 27(S1): S84-5.
[24]
Tamura T, Higuchi Y, Kitamura H, et al. Novel hyaluronic acid-methotrexate conjugate suppresses joint inflammation in the rat knee: efficacy and safety evaluation in two rat arthritis models. Arthritis Res Ther 2016; 18: 79.
[http://dx.doi.org/10.1186/s13075-016-0971-8] [PMID: 27039182]
[25]
Jokar M, Mirfeizi Z, Keyvanpajouh K. The effect of hydroxychloroquine on symptoms of knee osteoarthritis: A double-blind randomized controlled clinical trial. Iran J Med Sci 2013; 38(3): 221-6.
[PMID: 24174692]
[26]
ClinicalTrials.gov Identifier: Genovese, M. Hydroxychloroquine/Atorvastatin in the Treatment of Osteoarthritis (OA) of the Knee. National Library of Medicine (US) NCT01645176, 2017.
[27]
Lu CH, Chung CH, Lee CH, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan. PLoS One 2018; 13(1): e0191242.
[http://dx.doi.org/10.1371/journal.pone.0191242] [PMID: 29385156]
[28]
Wang Y, Hussain SM, Wluka AE, et al. Association between metformin use and disease progression in obese people with knee osteoarthritis: Data from the osteoarthritis initiative-a prospective cohort study. Arthritis Res Ther 2019; 21(1): 127.
[http://dx.doi.org/10.1186/s13075-019-1915-x] [PMID: 31126352]
[29]
Yu SM, Han Y, Kim SJ. Simvastatin induces differentiation in rabbit articular chondrocytes via Wnt/β-catenin pathway. Eur J Pharmacol 2019; 863: 172672. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0014299919306247?via%3Dihub
[http://dx.doi.org/10.1016/j.ejphar.2019.172672] [PMID: 31542485]
[30]
Simopoulou T, Malizos KN, Poultsides L, Tsezou A. Protective effect of atorvastatin in cultured osteoarthritic chondrocytes. J Orthop Res 2010; 28(1): 110-5.
[PMID: 19623662]
[31]
Clockaerts S, Van Osch GJ, Bastiaansen-Jenniskens YM, et al. Statin use is associated with reduced incidence and progression of knee osteoarthritis in the Rotterdam study. Ann Rheum Dis 2012; 71(5): 642-7.
[http://dx.doi.org/10.1136/annrheumdis-2011-200092] [PMID: 21989540]
[32]
Eymard F, Parsons C, Edwards MH, et al. Statin use and knee osteoarthritis progression: Results from a post-hoc analysis of the SEKOIA trial. Joint Bone Spine 2018; 85(5): 609-14.
[http://dx.doi.org/10.1016/j.jbspin.2017.09.014] [PMID: 29037516]
[33]
Michaëlsson K, Lohmander LS, Turkiewicz A, Wolk A, Nilsson P, Englund M. Association between statin use and consultation or surgery for osteoarthritis of the hip or knee: A pooled analysis of four cohort studies. Osteoarthritis Cartilage 2017; 25(11): 1804-13.
[http://dx.doi.org/10.1016/j.joca.2017.07.013] [PMID: 28756279]
[34]
Li J, Zhang B, Liu WX, et al. Metformin limits osteoarthritis development and progression through activation of AMPK signalling. Ann Rheum Dis 2020; 79(5): 635-45.
[http://dx.doi.org/10.1136/annrheumdis-2019-216713] [PMID: 32156705]
[35]
Park MJ, Moon SJ, Baek JA, et al. Metformin augments anti-inflammatory and chondroprotective properties of mesenchymal stem cells in experimental osteoarthritis. J Immunol 2019; 203(1): 127-36.
[http://dx.doi.org/10.4049/jimmunol.1800006] [PMID: 31142603]
[36]
Shang X, Wang Z, Tao H. Mechanism and therapeutic effectiveness of nerve growth factor in osteoarthritis pain. Ther Clin Risk Manag 2017; 13: 951-6.
[http://dx.doi.org/10.2147/TCRM.S139814] [PMID: 28814877]
[37]
Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010; 363(16): 1521-31.
[http://dx.doi.org/10.1056/NEJMoa0901510] [PMID: 20942668]
[38]
Brown MT, Murphy FT, Radin DM, Davignon I, Smith MD, West CR. Tanezumab reduces osteoarthritic hip pain: results of a randomized, double-blind, placebo-controlled phase III trial. Arthritis Rheum 2013; 65(7): 1795-803.
[http://dx.doi.org/10.1002/art.37950] [PMID: 23553790]
[39]
Miyagi M, Ishikawa T, Kamoda H, et al. Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice. BMC Musculoskelet Disord 2017; 18(1): 428.
[http://dx.doi.org/10.1186/s12891-017-1792-x] [PMID: 29100502]
[40]
von Loga IS, El-Turabi A, Jostins L, et al. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Ann Rheum Dis 2019; 78(5): 672-5.
[http://dx.doi.org/10.1136/annrheumdis-2018-214489] [PMID: 30862648]
[41]
Miller RE, Malfait AM, Block JA. Current status of nerve growth factor antibodies for the treatment of osteoarthritis pain. Clin Exp Rheumatol 2017; 107(5): 85-7.
[42]
Berenbaum F, Blanco FJ, Guermazi A, et al. Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period. Ann Rheum Dis 2020; 79(6): 800-10.
[http://dx.doi.org/10.1136/annrheumdis-2019-216296] [PMID: 32234715]
[43]
Dakin P, DiMartino SJ, Gao H, et al. The efficacy, tolerability, and joint safety of fasinumab in osteoarthritis pain: A phase IIb/III double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheumatol 2019; 71(11): 1824-34.
[http://dx.doi.org/10.1002/art.41012] [PMID: 31207169]
[44]
Chen J, Li J, Li R, et al. Efficacy and safety of tanezumab on osteoarthritis knee and hip pains: A meta-analysis of randomized controlled trials. Pain Med 2017; 18(2): 374-85.
[PMID: 28034979]
[45]
Schmelz M, Mantyh P, Malfait AM, et al. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain 2019; 160(10): 2210-20.
[http://dx.doi.org/10.1097/j.pain.0000000000001625] [PMID: 31145219]
[46]
Deng ZH, Li YS, Gao X, Lei GH, Huard J. Bone morphogenetic proteins for articular cartilage regeneration. Osteoarthritis Cartilage 2018; 26(9): 1153-61.
[http://dx.doi.org/10.1016/j.joca.2018.03.007] [PMID: 29580979]
[47]
Liu Y, Hou R, Yin R, Yin W. Correlation of bone morphogenetic protein-2 levels in serum and synovial fluid with disease severity of knee osteoarthritis. Med Sci Monit 2015; 21: 363-70.
[http://dx.doi.org/10.12659/MSM.892160] [PMID: 25644704]
[48]
Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Musculoskelet Disord 2010; 11: 232.
[http://dx.doi.org/10.1186/1471-2474-11-232] [PMID: 20932341]
[49]
Badlani N, Inoue A, Healey R, Coutts R, Amiel D. The protective effect of OP-1 on articular cartilage in the development of osteoarthritis. Osteoarthritis Cartilage 2008; 16(5): 600-6.
[http://dx.doi.org/10.1016/j.joca.2007.09.009] [PMID: 17977753]
[50]
Hicks JJ, Rocha JL, Li H, Huard J, Wang Y, Hogan MV. Sustained release of bone morphogenetic protein 2 via coacervate improves muscle derived stem cell mediated cartilage regeneration in MIA-induced osteoarthritis. Orthop J Sports Med 2016; 4: 7.
[http://dx.doi.org/10.1177/2325967116S00152]
[51]
BMP-2 bone morphogenetic protein 2 2018. Available from: https://www.ncbi.nlm.nih.gov/gene/650 Accessed on 04/02/2018.
[52]
Sharma AC, Srivastava RN, Srivastava SR, Agrahari A, Singh A, Parmar D. Evaluation of the association between a single-nucleotide polymorphism of bone morphogenetic proteins 5 gene and risk of knee osteoarthritis. J Postgrad Med 2017; 63: 151-156.
[http://dx.doi.org/10.1177/2040622319825567] [PMID: 30815245]
[53]
Gato-Calvo L, Magalhaes J, Ruiz-Romero C, Blanco FJ, Burguera EF. Platelet-rich plasma in osteoarthritis treatment: review of current evidence. Ther Adv Chronic Dis 2019; 10: 2040622319825567.
[http://dx.doi.org/10.1177/2040622319825567] [PMID: 30815245]
[54]
Petrera M, De Croos JN, Iu J, Hurtig M, Kandel RA, Theodoropoulos JS. Supplementation with platelet-rich plasma improves the in vitro formation of tissue-engineered cartilage with enhanced mechanical properties. Arthroscopy 2013; 29(10): 1685-92.
[http://dx.doi.org/10.1016/j.arthro.2013.07.259] [PMID: 24075614]
[55]
van Buul GM, Koevoet WL, Kops N, et al. Platelet-rich plasma releasate inhibits inflammatory processes in osteoarthritic chondrocytes. Am J Sports Med 2011; 39(11): 2362-70.
[http://dx.doi.org/10.1177/0363546511419278] [PMID: 21856929]
[56]
Burchard R, Huflage H, Soost C, Richter O, Bouillon B, Graw JA. Efficiency of platelet-rich plasma therapy in knee osteoarthritis does not depend on level of cartilage damage. J Orthop Surg Res 2019; 14(1): 153.
[http://dx.doi.org/10.1186/s13018-019-1203-0] [PMID: 31126348]
[57]
Raeissadat SA, Ghorbani E, Sanei Taheri M, et al. MRI changes after platelet rich plasma injection in knee osteoarthritis (randomized clinical trial). J Pain Res 2020; 13(1): 65-73.
[http://dx.doi.org/10.2147/JPR.S204788] [PMID: 32021396]
[58]
Halpern B, Chaudhury S, Rodeo SA, et al. Clinical and MRI outcomes after platelet-rich plasma treatment for knee osteoarthritis. Clin J Sport Med 2013; 23(3): 238-9.
[http://dx.doi.org/10.1097/JSM.0b013e31827c3846] [PMID: 23238250]
[59]
Raeissadat SA, Hosseini GP, Bahrami MH, et al. The Comparison effects of intra-articular injection of Platelet-Rich Plasma (PRP), Plasma Rich in Growth Factor (PRGF), Hyaluronic Acid (HA), and ozone in knee osteoarthritis; A one year randomized clinical trial. Ann Rheum Dis 2020; 79(S1): 1744-5.
[60]
Di Martino A, Di Matteo B, Papio T, et al. Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: Results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med 2019; 47(2): 347-54.
[http://dx.doi.org/10.1177/0363546518814532] [PMID: 30545242]
[61]
Karasavvidis T, Totlis T, Gilat R, Cole BJ. Platelet-rich plasma combined with hyaluronic acid improves pain and function compared with hyaluronic acid alone in knee osteoarthritis: A systematic review and meta-analysis. Arthroscopy 2021; 37(4): 1277-1287.e1.
[http://dx.doi.org/10.1016/j.arthro.2020.11.052] [PMID: 33278533]
[62]
Altamura SA, Di Martino A, Andriolo L, et al. Platelet-rich plasma for sport-active patients with knee osteoarthritis: Limited return to sport. BioMed Res Int 2020; 2020: 8243865. Available from: https://www.hindawi.com/journals/bmri/2020/8243865/
[http://dx.doi.org/10.1155/2020/8243865] [PMID: 32076616]
[63]
Su K, Bai Y, Wang J, Zhang H, Liu H, Ma S. Comparison of hyaluronic acid and PRP intra-articular injection with combined intra-articular and intraosseous PRP injections to treat patients with knee osteoarthritis. Clin Rheumatol 2018; 37(5): 1341-50.
[http://dx.doi.org/10.1007/s10067-018-3985-6] [PMID: 29388085]
[64]
Lin KY, Yang CC, Hsu CJ, Yeh ML, Renn JH. Intra-articular injection of platelet-rich plasma is superior to hyaluronic acid or saline solution in the treatment of mild to moderate knee osteoarthritis: A randomized, double-blind, triple-parallel, placebo-controlled clinical trial. Arthroscopy 2019; 35(1): 106-17.
[http://dx.doi.org/10.1016/j.arthro.2018.06.035] [PMID: 30611335]
[65]
Rai SK, Raman VP, Rohit V, Wani SS. Combined intra-articular injections (Hyaluronic acid, platelet-rich plasma, and corticosteroid) for osteoarthritis knee, an effective alternative treatment. J Orthop Trauma Rehabil 2018; 10(1): 57-60.
[http://dx.doi.org/10.4103/jotr.jotr_7_17]
[66]
Dhillon MS, Patel S, Bansal T. Improvising PRP for use in osteoarthritis knee- upcoming trends and futuristic view. J Clin Orthop Trauma 2019; 10(1): 32-5.
[http://dx.doi.org/10.1016/j.jcot.2018.10.005] [PMID: 30705528]
[67]
Mohiuddin AKM, Lewis P, Choudhury KN, Sadiq BU. Clinical outcome of photoactivated platelet-rich plasma in the treatment of knee osteoarthritis. Rheumatol Orthop Med 2018; 4(1): 1-4.
[68]
Badr ME, Hafez EA, Atif EG, El-Sayed Heba M. Intra-articular injection of platelet-rich plasma and therapeutic exercise in knee osteoarthritis. Egypt Rheumatol Rehabil 2019; 46(1): 1-10.
[http://dx.doi.org/10.4103/err.err_22_18]
[69]
O’Connell B, Wragg NM, Wilson SL. The use of PRP injections in the management of knee osteoarthritis. Cell Tissue Res 2019; 376(2): 143-52.
[http://dx.doi.org/10.1007/s00441-019-02996-x] [PMID: 30758709]
[70]
Platelet-rich plasma injections for osteoarthritis of the knee, Inc. Available from: https://www.nice.org.uk/guidance/IPG637
[71]
Robinson K. EULAR Issues Recommendations for Knee OA Platelet-Rich Plasma Injections. 2020. Available from: https://www.rheumatologynetwork.com/view/eular-issues-recommendations-knee-oa-platelet-rich-plasma-injections Accessed on 29 June, published on 11 June, 2020.
[72]
Shahid M, Kundra R. Platelet-Rich Plasma (PRP) for knee disorders. EFORT Open Rev 2017; 2(1): 28-34.
[http://dx.doi.org/10.1302/2058-5241.2.160004] [PMID: 28607768]
[73]
Manchikanti L, Centeno CJ, Atluri S, et al. Bone Marrow Concentrate (BMC) therapy in musculoskeletal disorders: evidence-based policy position Statement of American Society of Interventional Pain Physicians (ASIPP). Pain Physician 2020; 23(2): E85-E131.
[PMID: 32214287]
[74]
Gong J, Fairley J, Cicuttini FM, et al. Effect of stem cell injections on osteoarthritis-related structural outcomes-a systematic review. J Rheumatol 2021; 48(4): 585-97.
[http://dx.doi.org/10.3899/jrheum.200021] [PMID: 33004537]
[75]
Chahal J, Gómez-Aristizábal A, Shestopaloff K, et al. Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med 2019; 8(8): 746-57.
[PMID: 30964245]
[76]
Freitag J, Bates D, Wickham J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: A randomized controlled trial. Regen Med 2019; 14(3): 213-30.
[http://dx.doi.org/10.2217/rme-2018-0161] [PMID: 30762487]
[77]
Gobbi A, Whyte GP. Long-term clinical outcomes of one-stage cartilage repair in the knee with hyaluronic acid-based scaffold embedded with mesenchymal stem cells sourced from bone marrow aspirate concentrate. Am J Sports Med 2019; 47(7): 1621-8.
[http://dx.doi.org/10.1177/0363546519845362] [PMID: 31095402]
[78]
Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: A proof-of-concept clinical trial. Stem cell 2014; 32(5): 1254-66.
[http://dx.doi.org/10.1002/stem.1634]
[79]
Hernigou P, Delambre J, Quiennec S, Poignard A. Human bone marrow mesenchymal stem cell injection in subchondral lesions of knee osteoarthritis: A prospective randomized study versus contralateral arthroplasty at a mean fifteen year follow-up. Int Orthop 2021; 45(2): 365-73.
[http://dx.doi.org/10.1007/s00264-020-04571-4] [PMID: 32322943]
[80]
Song JS, Hong KT, Kim NM, et al. Cartilage regeneration in osteoarthritic knees treated with distal femoral osteotomy and intra-lesional implantation of allogenic human umbilical cord blood-derived mesenchymal stem cells: A report of two cases. Knee 2019; 26(6): 1445-50.
[http://dx.doi.org/10.1016/j.knee.2019.07.017] [PMID: 31443940]
[81]
Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived Mesenchymal Stromal Cells (MSCs) for knee osteoarthritis: Repeated MSC dosing is superior to a Single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med 2019; 8(3): 215-24.
[http://dx.doi.org/10.1002/sctm.18-0053] [PMID: 30592390]
[82]
Xing D, Wu J, Wang B, et al. Intra-articular delivery of umbilical cord-derived mesenchymal stem cells temporarily retard the progression of osteoarthritis in a rat model. Int J Rheum Dis 2020; 23(6): 778-87.
[http://dx.doi.org/10.1111/1756-185X.13834] [PMID: 32319197]
[83]
Geng Y, Chen J, Alahdal M, et al. Intra-articular injection of hUC-MSCs expressing miR-140-5p induces cartilage self-repairing in the rat osteoarthritis. J Bone Miner Metab 2020; 38(3): 277-88.
[http://dx.doi.org/10.1007/s00774-019-01055-3] [PMID: 31760502]
[84]
Zhu Y, Wang Y, Zhao B, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther 2017; 8(1): 64.
[http://dx.doi.org/10.1186/s13287-017-0510-9] [PMID: 28279188]
[85]
Hsu CC, Cheng JH, Wang CJ, Ko JY, Hsu SL, Hsu TC. Shockwave therapy combined with autologous adipose-derived mesenchymal stem cells is better than with human umbilical cord Wharton’s jelly-derived mesenchymal stem cells on knee osteoarthritis. Int J Mol Sci 2020; 21(4): 1217.
[http://dx.doi.org/10.3390/ijms21041217] [PMID: 32059379]
[86]
Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and stem cell therapy in humans: A systematic review. Osteoarthritis Cartilage 2018; 26(6): 711-29.
[http://dx.doi.org/10.1016/j.joca.2018.02.906] [PMID: 29544858]
[87]
Songa Y, Zhanga J, Xua H, et al. Mesenchymal stem cells in knee osteoarthritis treatment: A systematic review and meta-analysis. J orthop Transl 2020; 24: 121-30.
[88]
Ni Z, Zhou S, Li S, et al. Exosomes: Roles and therapeutic potential in osteoarthritis. Bone Res 2020; 8: 25.
[http://dx.doi.org/10.1038/s41413-020-0100-9]
[89]
Ni Z, Kuang L, Chen H, et al. The exosome-like vesicles from osteoarthritic chondrocyte enhanced mature IL-1β production of macrophages and aggravated synovitis in osteoarthritis. Cell Death Dis 2019; 10(7): 522.
[http://dx.doi.org/10.1038/s41419-019-1739-2] [PMID: 31285423]
[90]
Zhou Q, Cai Y, Jiang Y, Lin X. Exosomes in osteoarthritis and cartilage injury: Advanced development and potential therapeutic strategies. Int J Biol Sci 2020; 16(11): 1811-20.
[http://dx.doi.org/10.7150/ijbs.41637] [PMID: 32398951]
[91]
Nummenmaa E, Hamalainen M, Moilanen T, Vuolteenaho K, Moilanen E. Effects of fibroblast growth factor-2 and its receptor antagonists in osteoarthritis. Osteoarthr cartel 2015; 23(S2): A269.
[http://dx.doi.org/10.1016/j.joca.2015.02.490]
[92]
Li R, Wang B, He CQ, et al. Upregulation of fibroblast growth factor 1 in the synovial membranes of patients with late stage osteoarthritis. Genet Mol Res 2015; 14(3): 11191-9.
[http://dx.doi.org/10.4238/2015.September.22.13] [PMID: 26400350]
[93]
Honsawek S, Yuktanandana P, Tanavalee A, Saetan N, Anomasiri W, Parkpian V. Correlation between plasma and synovial fluid basic fibroblast growth factor with radiographic severity in primary knee osteoarthritis. Int Orthop 2012; 36(5): 981-5.
[http://dx.doi.org/10.1007/s00264-011-1435-z] [PMID: 22173563]
[94]
Li ZC, Xiao J, Wang G, et al. Fibroblast growth factor-21 concentration in serum and synovial fluid is associated with radiographic bone loss of knee osteoarthritis. Scand J Clin Lab Invest 2015; 75(2): 121-5.
[http://dx.doi.org/10.3109/00365513.2014.992942] [PMID: 25549692]
[95]
Zhu L, Weng Z, Shen P, et al. S100B regulates inflammatory response during osteoarthritis via fibroblast growth factor receptor 1 signaling. Mol Med Rep 2018; 18(6): 4855-64.
[http://dx.doi.org/10.3892/mmr.2018.9523] [PMID: 30280200]
[96]
Lohmander LS, Hellot S, Dreher D, et al. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: A randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 2014; 66(7): 1820-31.
[http://dx.doi.org/10.1002/art.38614] [PMID: 24740822]
[97]
Hochberg MC, Guermazi A, Guehring H, et al. Effect of intra-articular sprifermin vs. placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: The FORWARD randomized clinical Trial. JAMA 2019; 322(14): 1360-70.
[http://dx.doi.org/10.1001/jama.2019.14735] [PMID: 31593273]
[98]
Zeng N, Chen XY, Yan ZP, Li JT, Liao T, Ni GX. Efficacy and safety of sprifermin injection for knee osteoarthritis treatment: A meta-analysis. Arthritis Res Ther 2021; 23(1): 107.
[http://dx.doi.org/10.1186/s13075-021-02488-w] [PMID: 33836824]
[99]
Joosten LA, Helsen MMA, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 1999; 163(9): 5049-55.
[PMID: 10528210]
[100]
Ismail HM, Miotla-Zarebska J, Troeberg L, et al. JNK-2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. Arthritis Rheumatol 2016; 68(5): 1165-71.
[PMID: 26663140]
[101]
Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000; 43(5): 1001-9.
[http://dx.doi.org/10.1002/1529-0131(200005)43:5<1001::AID-ANR7>3.0.CO;2-P] [PMID: 10817552]
[102]
Fraenkel L, Roubenoff R, LaValley M, et al. The association of peripheral monocyte derived interleukin 1beta (IL-1beta), IL-1 receptor antagonist, and tumor necrosis factor-alpha with osteoarthritis in the elderly. J Rheumatol 1998; 25(9): 1820-6.
[PMID: 9733466]
[103]
Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther 2011; 13(4): R125.
[http://dx.doi.org/10.1186/ar3430] [PMID: 21801403]
[104]
Lacy SE, Wu C, Ambrosi DJ, et al. Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1α and IL-1β. MAbs 2015; 7(3): 605-19.
[http://dx.doi.org/10.1080/19420862.2015.1026501] [PMID: 25764208]
[105]
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377(12): 1119-31.
[http://dx.doi.org/10.1056/NEJMoa1707914] [PMID: 28845751]
[106]
Schieker M, Conaghan PG, Mindeholm L, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: Exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2020; 173(7): 509-15.
[http://dx.doi.org/10.7326/M20-0527] [PMID: 32744862]
[107]
Marchetti C, Swartzwelter B, Gamboni F, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci USA 2018; 115(7): E1530-9.
[http://dx.doi.org/10.1073/pnas.1716095115] [PMID: 29378952]
[108]
Vincent TL. IL-1 in osteoarthritis: time for a critical review of the literature. F1000 Res 2019; 8: F1000 Faculty Rev-934.
[http://dx.doi.org/10.12688/f1000research.18831.1] [PMID: 31249675]
[109]
Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy approved in Korea. J Am Acad Orthop Surg 2018; 26(2): e36-8.
[http://dx.doi.org/10.5435/JAAOS-D-17-00695] [PMID: 29303924]
[110]
Kim MK, Ha CW, In Y, et al. A multicenter, double-blind, phase III clinical trial to evaluate the efficacy and safety of a cell and gene therapy in knee osteoarthritis patients. Hum Gene Ther Clin Dev 2018; 29(1): 48-59.
[http://dx.doi.org/10.1089/humc.2017.249] [PMID: 29641281]
[111]
Lee B. INVOSSA, a first-in-class of cell and gene therapy for osteoarthritis treatment: the phase III trial. Osteoarthritis Cartilage 2018; 26(7): S43-4.
[http://dx.doi.org/10.1016/j.joca.2018.02.103]
[112]
Saviola G, Ferrari P, Niccolò E, et al. Use of clodronate for painful knee prosthesis in osteoarthritis patients: A 6-month pilot study. Minerva Med 2020; 111(6): 551-9.
[http://dx.doi.org/10.23736/S0026-4806.20.06706-3] [PMID: 32573517]
[113]
Hayes KN, Giannakeas V, Wong AKO. Bisphosphonate use is protective of radiographic knee osteoarthritis progression among those with low disease severity and being non-overweight: Data from the osteoarthritis initiative. J Bone Miner Res 2020; 35(12): 2318-26.
[http://dx.doi.org/10.1002/jbmr.4133] [PMID: 32662919]
[114]
Xing RL, Zhao LR, Wang PM. Bisphosphonates therapy for osteoarthritis: A meta-analysis of randomized controlled trials. Springerplus 2016; 5(1): 1704.
[http://dx.doi.org/10.1186/s40064-016-3359-y] [PMID: 27757376]
[115]
Vaysbrot EE, Osani MC, Musetti MC, McAlindon TE, Bannuru RR. Are bisphosphonates efficacious in knee osteoarthritis? A meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2018; 26(2): 154-64.
[http://dx.doi.org/10.1016/j.joca.2017.11.013] [PMID: 29222056]
[116]
Cai G, Aitken D, Laslett LL, et al. Effect of intravenous zoledronic acid on tibiofemoral cartilage volume among patients with knee osteoarthritis with bone marrow lesions: A randomized clinical trial. JAMA 2020; 323(15): 1456-66.
[http://dx.doi.org/10.1001/jama.2020.2938] [PMID: 32315057]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy
Request history8.2.27PHP Version376msRequest Duration28MBMemory UsageGET article/{article_id}/{param?}Route
  • warninglog[13:33:33] LOG.warning: Optional parameter $article_id declared before required parameter $request i...
  • warninglog[13:33:33] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • warninglog[13:33:33] LOG.warning: trim(): Passing null to parameter #1 ($string) of type string is deprecated ...
  • warninglog[13:33:33] LOG.warning: strip_tags(): Passing null to parameter #1 ($string) of type string is depre...
  • warninglog[13:33:33] LOG.warning: strip_tags(): Passing null to parameter #1 ($string) of type string is depre...
  • warninglog[13:33:33] LOG.warning: Function strftime() is deprecated in /home/alphaeurekaselec/public_html/stor...
  • Booting (123ms)time
  • Application (252ms)time
  • 1 x Application (67.14%)
    252ms
    1 x Booting (32.86%)
    123ms
    14 templates were rendered
    • articlearticle.blade.php#?blade
    • includes.article_top_bannerarticle_top_banner.blade.php#?blade
    • includes.article_referencearticle_reference.blade.php#?blade
    • export_citation_formexport_citation_form.blade.php#?blade
    • includes.article_bottom_bannerarticle_bottom_banner.blade.php#?blade
    • includes.inc_related_journalsinc_related_journals.blade.php#?blade
    • includes.inc_related_ebooksinc_related_ebooks.blade.php#?blade
    • includes.journal_rightmenujournal_rightmenu.blade.php#?blade
    • includes.journal_right_bannerjournal_right_banner.blade.php#?blade
    • layouts.appapp.blade.php#?blade
    • layouts._login_access_login_access.blade.php#?blade
    • layouts._header_header.blade.php#?blade
    • layouts._main_menu_main_menu.blade.php#?blade
    • layouts._footer_menu_footer_menu.blade.php#?blade
    uri
    GET article/{article_id}/{param?}
    middleware
    web, check_user_access
    controller
    App\Http\Controllers\ArticleController@GetArticleDetails
    namespace
    App\Http\Controllers
    where
    as
    article
    file
    app/Http/Controllers/ArticleController.php:1974-2510
    36 statements were executed, 4 of which were duplicates, 32 unique. Show only duplicated157ms
    • Connection Establishedalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 9. middleware::check_user_access:24
      • 10. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 11. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address (ip_address,visitor_agent,visitor_count, created_on,updated_on) VALUES ('59599081','',1,1739972013,1739972013) ON DUPLICATE KEY UPDATE visitor_count=visitor_count + 1, updated_on=1739972013
      1.21msalphaeurekaselec_live_10_06_2022UserAccessCheck.php#24
      Backtrace
      • 11. middleware::check_user_access:24
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • INSERT INTO visitor_ip_address_detail (ip_address,visitor_url,visitor_count, created_on,updated_on) VALUES ('59599081','/article/118858',1,1739972013,1739972013)
      240μsalphaeurekaselec_live_10_06_2022UserAccessCheck.php#27
      Backtrace
      • 11. middleware::check_user_access:27
      • 12. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 14. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 15. vendor/laravel/framework/src/Illuminate/Foundation/Http/Middleware/VerifyCsrfToken.php:88
    • (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_trail WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_journal_volume_token WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_trail WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_ebook_volume_token WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_trail WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_issue_token WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_trail WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_article_token WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_trail WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_chapter_token WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) union (select `user_id`, `to_ip`, `from_ip` from (select user_id, to_ip, from_ip FROM user_access_disease_corporate WHERE to_ip >= 59599081 ORDER BY to_ip ASC LIMIT 1) as `tjv` where `from_ip` <= 59599081) limit 1
      19.63msalphaeurekaselec_live_10_06_2022UserAccess.php#784
      Bindings
      • 0: 59599081
      • 1: 59599081
      • 2: 59599081
      • 3: 59599081
      • 4: 59599081
      • 5: 59599081
      • 6: 59599081
      • 7: 59599081
      • 8: 59599081
      • 9: 59599081
      • 10: 59599081
      • 11: 59599081
      • 12: 59599081
      • 13: 59599081
      • 14: 59599081
      • 15: 59599081
      Backtrace
      • 14. app/Models/UserAccess/UserAccess.php:784
      • 15. middleware::check_user_access:114
      • 16. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Middleware/SubstituteBindings.php:50
      • 18. vendor/laravel/framework/src/Illuminate/Pipeline/Pipeline.php:183
    • SELECT at.type_name, p.copyright, p.publisher_location,m.month,y.year, a.publish_on, a.nid article_nid,a.article_id, a.pmid, a.issue_id, a.title, a.abstract,a.podcast,a.altmetric_score,a.altmetric_url,a.kudos_url, a.page_count, a.first_page, a.elocator, a.last_page, i.publication_date, a.file_name, a.file_path, a.doi, a.is_epub,a.epub_type, a.volume_id, a.is_uploaded, a.editor_choice, a.is_epub, j.image_file_name, a.article_no, a.art_type AS article_type, a.supplementary_filename,a.html_filename,a.prc_filename,a.epub_filename, a.graph_abs_lg_filename, a.graph_abs_sm_filename, a.oa_image_lg_filename, a.oa_image_sm_filename, j.journal_banner,a.animated_abstract,a.erratum_in,a.erratum_for, (CASE WHEN a.issue_id =0 THEN j.epub_price ELSE j.price END) AS sell_price, j.epub_price, j.nid AS jour_nid, j.title AS journal_title, j.issn, j.eissn,j.journal_id, j.subtitle AS jour_subtitle, v.volume_id,v.volume_name AS volume, v.year_id, i.title AS issue, i.month_id ,i.type issue_type, j.subtitle,j.formerly_title, ac.subtitle AS epub_title,a.crossmark_enabled,a.text_mining_urls,a.license_urls,a.created, a.receivedate, a.revisedate, a.acceptdate,js.js_title FROM article a LEFT JOIN article_section ac ON a.is_epub = ac.art_sec_id LEFT JOIN journal_section js ON a.js_id = js.js_id LEFT JOIN article_type at ON a.art_type = at.art_type_id LEFT JOIN issue i ON a.issue_id = i.issue_id LEFT JOIN month m ON m.id = i.month_id LEFT JOIN volume v ON v.volume_id = a.volume_id INNER JOIN year y ON y.id = v.year_id INNER JOIN journal j ON j.journal_id = a.journal_id INNER JOIN publisher p ON p.publisher_id = j.publisher_id WHERE a.article_id=118858
      1.09msalphaeurekaselec_live_10_06_2022Article.php#408
      Backtrace
      • 11. app/Models/Article.php:408
      • 12. app/Http/Controllers/ArticleController.php:2515
      • 13. app/Http/Controllers/ArticleController.php:2035
      • 14. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 15. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `journal` where `journal_id` = 52 limit 1
      1.13msalphaeurekaselec_live_10_06_2022Journal.php#64
      Bindings
      • 0: 52
      Backtrace
      • 14. app/Models/Journal.php:64
      • 15. app/Http/Controllers/ArticleController.php:2516
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select j.nid as journal_nid,j.flyer_link,j.title ,j.issn,j.eissn,j.keyword, j.journal_id as journal_id, j.subtitle, j.image_file_name,j.description,j.journal_insight_url,j.doi from `subject_journal` as `sj` inner join `journal` as `j` on `j`.`journal_id` = `sj`.`journal_id` where j.journal_status=1 and subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=52) and sj.journal_id!=52 group by `j`.`nid`) as `aggregate_table`
      650μsalphaeurekaselec_live_10_06_2022Subject.php#200
      Backtrace
      • 16. app/Models/Subject.php:200
      • 17. app/Http/Controllers/ArticleController.php:2517
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select count(*) as aggregate from (select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=52) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid`) as `aggregate_table`
      950μsalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 16. app/Models/Subject.php:220
      • 17. app/Http/Controllers/ArticleController.php:2518
      • 18. app/Http/Controllers/ArticleController.php:2035
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 20. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select v.nid as volume_id,e.nid,e.title,v.issn,v.eissn,v.isbn,v.eisbn,e.ebook_id, v.image_file_name,v.file_path,v.flyer_link,v.ebook_volume_id, v.volume_name,v.doi,v.year_id,v.introduction from `subject_ebook` as `se` inner join `ebook` as `e` on `e`.`ebook_id` = `se`.`ebook_id` inner join `ebook_volume` as `v` on `v`.`ebook_id` = `se`.`ebook_id` inner join `year` as `y` on `y`.`id` = `v`.`year_id` where subject_id IN (SELECT subject_id FROM subject_journal WHERE journal_id=52) and v.ebook_status='1' and y.year > 2020 group by `v`.`nid` order by `v`.`ebook_volume_id` desc limit 10 offset 0
      830μsalphaeurekaselec_live_10_06_2022Subject.php#220
      Backtrace
      • 14. app/Models/Subject.php:220
      • 15. app/Http/Controllers/ArticleController.php:2518
      • 16. app/Http/Controllers/ArticleController.php:2035
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `keywords` where `article_id` = '118858'
      1.58msalphaeurekaselec_live_10_06_2022Keywords.php#43
      Bindings
      • 0: 118858
      Backtrace
      • 13. app/Models/Keywords.php:43
      • 14. app/Http/Controllers/ArticleController.php:2519
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select * from `article_citation` where `article_id` = '118858'
      4.55msalphaeurekaselec_live_10_06_2022Article.php#1570
      Bindings
      • 0: 118858
      Backtrace
      • 13. app/Models/Article.php:1570
      • 14. app/Http/Controllers/ArticleController.php:2520
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select CONCAT_WS(' ',au.first_name, ' ', ifnull(au.initials,''), ' ', au.last_name) as authors, CONCAT(au.last_name, IFNULL(CONCAT(' ', au.initials), ''), ' ', au.first_name) AS authorsRIS, CONCAT_WS(' ',au.last_name, ' ', ifnull(au.initials,''), ' ', au.first_name) as authorsCiteAs, CONCAT_WS(' ',au.first_name, IFNULL(CONCAT(' ', au.initials), ''), IFNULL(CONCAT(' ', au.last_name), '')) as authorsmodal , `au`.*, `af`.`ror_id`, `af`.`institution`, `af`.`department`, `af`.`country`, `af`.`city`, `af`.`address`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.institution,','),''), ifnull(concat(af.department,','),''), ifnull(concat(af.address,','),''), ifnull(concat(af.city,','),''), ifnull(concat(af.country,','),''), ifnull(concat(af.postal_code,','),''), ifnull(concat(af.phone,','),''), ifnull(concat(af.fax,','),''))) SEPARATOR '|')) as `author_affiliation`, (GROUP_CONCAT(TRIM(BOTH ', ' FROM CONCAT(ifnull(concat(af.web_view,','),''))) SEPARATOR '|')) as `web_view` from `author` as `au` left join `author_affiliation` as `af` on `au`.`author_id` = `af`.`author_id` where `au`.`article_id` = '118858' group by `au`.`author_id` order by `au`.`article_id` asc, `au`.`sequence` asc
      2.63msalphaeurekaselec_live_10_06_2022Author.php#86
      Bindings
      • 0: 118858
      Backtrace
      • 13. app/Models/Author.php:86
      • 14. app/Http/Controllers/ArticleController.php:2533
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      400μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2535
      • 15. app/Http/Controllers/ArticleController.php:2035
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
    • select `subtitle` from `journal` where `continues_publication_journal` = 1
      700μsalphaeurekaselec_live_10_06_2022Article.php#1960
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/Article.php:1960
      • 14. app/Http/Controllers/ArticleController.php:2062
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • Select j.subtitle, v.volume_id as volume_id,v.year_id,y.year as year,v.volume_name, v.total_no_of_issues, i.issue_id as issue_id,i.title as issue, i.publication_date as issue_pub_date from journal j join volume v on j.journal_id = v.journal_id join issue i on v.volume_id = i.volume_id join article a on a.issue_id = i.issue_id join year y on v.year_id = y.id where j.journal_id = 52 and i.is_uploaded = 1 order by v.volume_name+0 desc, i.title+0 desc limit 1
      41.68msalphaeurekaselec_live_10_06_2022Issue.php#298
      Backtrace
      • 11. app/Models/Issue.php:298
      • 12. app/Http/Controllers/ArticleController.php:2068
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 1 and a.journal_id = 52 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      8.41msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2070
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid,a.publish_on, a.pmid,a.article_id,a.doi,j.journal_id,j.subtitle,v.volume_name,a.volume_id as volume_id, a.issue_id,a.title,first_page, last_page, page_count,abstract,ifnull(is_abstract,"y"),asec.title as article_section,at.type_name as article_type_name, a.article_id as ArticleID ,is_epub,epub_price,epub_type,a.created, y.year from `article` as `a` left join `article_section` as `asec` on `asec`.`art_sec_id` = `a`.`is_epub` left join `article_type` as `at` on `at`.`art_type_id` = `a`.`art_type` left join `journal` as `j` on `j`.`journal_id` = `a`.`journal_id` inner join `volume` as `v` on `a`.`volume_id` = `v`.`volume_id` inner join `year` as `y` on `v`.`year_id` = `y`.`id` where a.article_status != "W" and a.is_epub = 4 and a.journal_id = 52 and a.is_uploaded = 1 group by `a`.`article_id` order by `a`.`publish_on` desc
      6.13msalphaeurekaselec_live_10_06_2022Article.php#528
      Backtrace
      • 13. app/Models/Article.php:528
      • 14. app/Http/Controllers/ArticleController.php:2071
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select pdf, html, epub, prc from `article_metrics` where `article_id` = 118858 limit 1
      300μsalphaeurekaselec_live_10_06_2022Article.php#744
      Bindings
      • 0: 118858
      Backtrace
      • 14. app/Models/Article.php:744
      • 15. app/Http/Controllers/ArticleController.php:2091
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from content_by_diseases where content_id = 118858 and content_type = 'article' order by status desc limit 1
      4.79msalphaeurekaselec_live_10_06_2022Article.php#751
      Backtrace
      • 11. app/Models/Article.php:751
      • 12. app/Http/Controllers/ArticleController.php:2094
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select a.nid article_nid,a.title article_title,j.title journal_title from content_by_diseases cd inner join article a on a.article_id=cd.content_id inner join journal j on j.journal_id=a.journal_id where cd.pid = 258 and cd.sub_disease_id = 394 and content_id!=118858 and cd.content_type = 'article' order by rand() limit 20
      41.15msalphaeurekaselec_live_10_06_2022Article.php#769
      Backtrace
      • 11. app/Models/Article.php:769
      • 12. app/Http/Controllers/ArticleController.php:2098
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `node_meta` where `nid` = 197957 limit 1
      380μsalphaeurekaselec_live_10_06_2022Meta.php#30
      Bindings
      • 0: 197957
      Backtrace
      • 14. app/Models/Meta.php:30
      • 15. app/Http/Controllers/ArticleController.php:2101
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `bo`.* from `bundle_offer` as `bo` where `bo`.`bundle_status` = 'A' order by `bo`.`bundle_id` desc
      320μsalphaeurekaselec_live_10_06_2022BundleOffer.php#57
      Bindings
      • 0: A
      Backtrace
      • 13. app/Models/BundleOffer.php:57
      • 14. app/Http/Controllers/ArticleController.php:2108
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `tbl_ht_submission` as `h` where `h`.`subtitle` = 'CRR' and (h.proposal_closing_date = 0 OR TO_DAYS(FROM_UNIXTIME(h.proposal_closing_date)) >= TO_DAYS(NOW())) order by `h`.`manuscript` asc
      320μsalphaeurekaselec_live_10_06_2022Article.php#2025
      Bindings
      • 0: CRR
      Backtrace
      • 13. app/Models/Article.php:2025
      • 14. app/Http/Controllers/ArticleController.php:2112
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '118858' and content_type = 'a' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      410μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2186
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '11306' and content_type = 'i' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      350μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2207
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select count(*) as total_count, content_type_access_id as access_type from journal_access where content_type_id = '3211' and content_type = 'v' and ( (from_date <= CURDATE() and to_date >= CURDATE() and perpetual= 0) or (from_date is null and to_date is null and perpetual= 1) )
      430μsalphaeurekaselec_live_10_06_2022ContentAccess.php#647
      Backtrace
      • 11. app/Models/ContentAccess.php:647
      • 12. app/Http/Controllers/ArticleController.php:2231
      • 13. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 14. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3211) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3211) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"volume" as access_level,"" as issue_id,"" as article_id from `user_access_journal_volume_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.volume_id = 3211)
      8.18msalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2272
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11306) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11306) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"issue" as access_level,j.issue_id,"" as article_id from `user_access_issue_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.issue_id = 11306)
      690μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2297
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 118858) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 118858) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"article" as access_level, j.issue_id, j.article_id from `user_access_article_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59599081 and j.to_ip >=59599081 )) and ((j.from_date <= 1739972013 and j.to_date >= 1739972013 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.article_id = 118858)
      640μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ArticleController.php:2329
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `first_page` < '20' and is_uploaded = 1 and issue_id = 11306 order by cast(first_page as SIGNED) desc limit 1
      580μsalphaeurekaselec_live_10_06_2022Article.php#1819
      Bindings
      • 0: 20
      Backtrace
      • 14. app/Models/Article.php:1819
      • 15. app/Http/Controllers/ArticleController.php:2470
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select * from `article` where `last_page` > '32' and is_uploaded = 1 and issue_id = 11306 order by cast(first_page as SIGNED) asc limit 1
      500μsalphaeurekaselec_live_10_06_2022Article.php#1831
      Bindings
      • 0: 32
      Backtrace
      • 14. app/Models/Article.php:1831
      • 15. app/Http/Controllers/ArticleController.php:2472
      • 16. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 17. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `language_id` from `multilanguage` where `short_code` = 'en'
      230μsalphaeurekaselec_live_10_06_2022ArticleController.php#2497
      Bindings
      • 0: en
      Backtrace
      • 14. app/Http/Controllers/ArticleController.php:2497
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 18. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select `source_lang_label`, `target_lang_label` from `multilanguage_labels` where `target_lang_id` = 1
      230μsalphaeurekaselec_live_10_06_2022MultiLanguage.php#23
      Bindings
      • 0: 1
      Backtrace
      • 13. app/Models/MultiLanguage.php:23
      • 14. app/Http/Controllers/ArticleController.php:2498
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select `id` from `multilanguage_article` where `article_id` = 118858 limit 1
      2.56msalphaeurekaselec_live_10_06_2022ArticleController.php#2506
      Bindings
      • 0: 118858
      Backtrace
      • 16. app/Http/Controllers/ArticleController.php:2506
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 18. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 19. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
      • 20. vendor/laravel/framework/src/Illuminate/Routing/Route.php:206
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 52 and `b`.`banner_from_date` <= 1739972013 and `b`.`banner_to_date` >= 1739972013 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.24msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 52
      • 3: 1739972013
      • 4: 1739972013
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` inner join `journal` as `j` on `j`.`journal_id` = `bd`.`content_id` where `b`.`banner_journal` = 1 and `bd`.`content_type` = 'J' and `bd`.`content_id` = 52 and `b`.`banner_from_date` <= 1739972013 and `b`.`banner_to_date` >= 1739972013 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.21msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: J
      • 2: 52
      • 3: 1739972013
      • 4: 1739972013
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='4f5e7a483faad0d399eea6f19c222c00'
      240μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\MultiLanguage
    1MultiLanguage.php#?
        _token
        rjgItwWUBX9OquB2z8Kjo5pNY3aNfORfWlnP63Wl
        uc_cart_id
        4f5e7a483faad0d399eea6f19c222c00
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/article/118858" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /article/118858
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
        array:9 [ "cookie" => array:1 [ 0 => "wayfindertarget=eyJpdiI6InJEYTJ0RkpCVVlaNW9ma1lSRFFFQ2c9PSIsInZhbHVlIjoiMjFoYXQyaTZLaTF2SFczaXVQQStzSW1xSkltSnRPNHdEV2dsUnBCL0syTU44N2ZKNExFdG85WjFLZDJtdUE0SW1QLzloM0pMVkpuME81bml5anF0NUE9PSIsIm1hYyI6IjVjYjhkYTA1YmM1YzI0YWJjNjNhNzU4NDhlZDMxMjJjMmY4YWNjNzc4MTU3ODFiOTdmNWI4MDI4YWNlNTY5MmQiLCJ0YWciOiIifQ%3D%3Dwayfindertarget=eyJpdiI6InJEYTJ0RkpCVVlaNW9ma1lSRFFFQ2c9PSIsInZhbHVlIjoiMjFoYXQyaTZLaTF2SFczaXVQQStzSW1xSkltSnRPNHdEV2dsUnBCL0syTU44N2ZKNExFdG85WjFLZDJtdUE0SW1Q" ] "accept-encoding" => array:1 [ 0 => "gzip, deflate" ] "accept" => array:1 [ 0 => "text/html,application/xhtml+xml,application/xml;q=0.9,image/avif,image/webp,image/apng,*/*;q=0.8,application/signed-exchange;v=b3;q=0.7" ] "user-agent" => array:1 [ 0 => "Mozilla/5.0 AppleWebKit/537.36 (KHTML, like Gecko; compatible; ClaudeBot/1.0; +claudebot@anthropic.com)" ] "upgrade-insecure-requests" => array:1 [ 0 => "1" ] "cache-control" => array:1 [ 0 => "no-cache" ] "pragma" => array:1 [ 0 => "no-cache" ] "connection" => array:1 [ 0 => "keep-alive" ] "host" => array:1 [ 0 => "alpha.eurekaselect.com" ] ]
        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Wed, 19 Feb 2025 13:33:33 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ilo2Y0UwY2RuTlo5WlhzcXBGRnBodHc9PSIsInZhbHVlIjoiaFFoaEsvakJBUGFxVzJUZWNzSnNuK012K2t4dFdpZVBEVlc5TnlxeVN1a0ZnMkxzMi95TFJuNXAvcVFiVVVQTWpMVXpNSFBEbmJ0aCtaZ0tsK1U5RHYwUHVyemJxS1crRkdNbVhxdnc0eG1XRTMyeTBSVTN3Tkg4ZStNVkd4M1EiLCJtYWMiOiI5MDhhZjdhNzYwNjY2NGNkZTE0N2EyNGY0ZjI3OTdmNGY2MTg2NGEzNjRiMWMwOGI0ZDdmNmVhNGU5NTQ0MGQ3IiwidGFnIjoiIn0%3D; expires=Sat, 22 Feb 2025 01:33:33 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6Ilo2Y0UwY2RuTlo5WlhzcXBGRnBodHc9PSIsInZhbHVlIjoiaFFoaEsvakJBUGFxVzJUZWNzSnNuK012K2t4dFdpZVBEVlc5TnlxeVN1a0ZnMkxzMi95TFJuNXAvcVFiVVVQTWpMVXpNS" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik1uUlRIa3Y0TGQyd3l5L0Vlbms1RkE9PSIsInZhbHVlIjoic20vbXg4RmlMektUTHgraE1rNTMwb2gxd1hZbDF6RHJPWm9jZW1xRnU3ejJuNkZCalBSK1c3MGh1ejYrVWZYendDZnprRUpoTkc4dDc3NlRuRGFjOC8yUnZNVnV3SjdyVWdScFpaRnB6d2RFNW9WR2VPK3BTS05SREtFT014R3QiLCJtYWMiOiI5NjdkNGU4NzdkNzRhMWNjOThhZDA4ZTAwMTMzMDg2YjIzNzBhNjI2M2I4MWVjYmQyOWQ0MjRmYWRiYTk5ZGIyIiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6Ik1uUlRIa3Y0TGQyd3l5L0Vlbms1RkE9PSIsInZhbHVlIjoic20vbXg4RmlMektUTHgraE1rNTMwb2gxd1hZbDF6RHJPWm9jZW1xRnU3ejJuNkZCalBSK1c3MGh" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6Ilo2Y0UwY2RuTlo5WlhzcXBGRnBodHc9PSIsInZhbHVlIjoiaFFoaEsvakJBUGFxVzJUZWNzSnNuK012K2t4dFdpZVBEVlc5TnlxeVN1a0ZnMkxzMi95TFJuNXAvcVFiVVVQTWpMVXpNSFBEbmJ0aCtaZ0tsK1U5RHYwUHVyemJxS1crRkdNbVhxdnc0eG1XRTMyeTBSVTN3Tkg4ZStNVkd4M1EiLCJtYWMiOiI5MDhhZjdhNzYwNjY2NGNkZTE0N2EyNGY0ZjI3OTdmNGY2MTg2NGEzNjRiMWMwOGI0ZDdmNmVhNGU5NTQ0MGQ3IiwidGFnIjoiIn0%3D; expires=Sat, 22-Feb-2025 01:33:33 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6Ilo2Y0UwY2RuTlo5WlhzcXBGRnBodHc9PSIsInZhbHVlIjoiaFFoaEsvakJBUGFxVzJUZWNzSnNuK012K2t4dFdpZVBEVlc5TnlxeVN1a0ZnMkxzMi95TFJuNXAvcVFiVVVQTWpMVXpNS" 1 => "alphaeurekaselectnet_session=eyJpdiI6Ik1uUlRIa3Y0TGQyd3l5L0Vlbms1RkE9PSIsInZhbHVlIjoic20vbXg4RmlMektUTHgraE1rNTMwb2gxd1hZbDF6RHJPWm9jZW1xRnU3ejJuNkZCalBSK1c3MGh1ejYrVWZYendDZnprRUpoTkc4dDc3NlRuRGFjOC8yUnZNVnV3SjdyVWdScFpaRnB6d2RFNW9WR2VPK3BTS05SREtFT014R3QiLCJtYWMiOiI5NjdkNGU4NzdkNzRhMWNjOThhZDA4ZTAwMTMzMDg2YjIzNzBhNjI2M2I4MWVjYmQyOWQ0MjRmYWRiYTk5ZGIyIiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6Ik1uUlRIa3Y0TGQyd3l5L0Vlbms1RkE9PSIsInZhbHVlIjoic20vbXg4RmlMektUTHgraE1rNTMwb2gxd1hZbDF6RHJPWm9jZW1xRnU3ejJuNkZCalBSK1c3MGh" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "rjgItwWUBX9OquB2z8Kjo5pNY3aNfORfWlnP63Wl" "uc_cart_id" => "4f5e7a483faad0d399eea6f19c222c00" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/article/118858" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-19 13:33:33GET/article/118858614361