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World J Orthop. Jul 18, 2013; 4(3): 103-106
Published online Jul 18, 2013. doi: 10.5312/wjo.v4.i3.103
Mechanical solution for a mechanical problem: Tennis elbow
Bruce Rothschild, Department of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272, United States
Bruce Rothschild, Biodiversity Institute, University of Kansas, Lawrence, KS 66045, United States
Author contributions: Rothschild B solely contributed to this paper.
Correspondence to: Bruce Rothschild, Professor, Department of Medicine, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH 44272, United States. bmr@ku.edu
Telephone: +1-785-6151523 Fax: +1-785-5942691
Received: February 17, 2013
Revised: March 19, 2013
Accepted: April 10, 2013
Published online: July 18, 2013
Processing time: 151 Days and 0.3 Hours

Abstract

Lateral epicondylitis is a relatively common clinical problem, easily recognized on palpation of the lateral protuberance on the elbow. Despite the “itis” suffix, it is not an inflammatory process. Therapeutic approaches with topical non-steroidal anti-inflammatory drugs, corticosteroids and anesthetics have limited benefit, as would be expected if inflammation is not involved. Other approaches have included provision of healing cytokines from blood products or stem cells, based on the recognition that this repetitive effort-derived disorder represents injury. Noting calcification/ossification of tendon attachments to the lateral epicondyle (enthesitis), dry needling, radiofrequency, shock wave treatments and surgical approaches have also been pursued. Physiologic approaches, including manipulation, therapeutic ultrasound, phonophoresis, iontophoresis, acupuncture and exposure of the area to low level laser light, has also had limited success. This contrasts with the benefit of a simple mechanical intervention, reducing the stress on the attachment area. This is based on displacement of the stress by use of a thin (3/4-1 inch) band applied just distal to the epicondyle. Thin bands are required, as thick bands (e.g., 2-3 inch wide) simply reduce muscle strength, without significantly reducing stress. This approach appears to be associated with a failure rate less than 1%, assuming the afflicted individual modifies the activity that repeatedly stresses the epicondylar attachments.

Key Words: Epicondylitis; Tennis elbow; Adaptive equipment; Mechanical overload; Elbow; Inflammation

Core tip: Lateral epicondylitis is a mechanical problem with a mechanical solution. While there have been many approaches, some quite exotic, to this phenomenon, there is a very effective non-invasive treatment: application of a 3/4-1 inch forearm band just below the elbow, of course associated with modification of the activity that is stressing the epicondylar attachments.



CHARACTER OF LATERAL EPICONDYLITIS

Popularly referred to as tennis elbow, lateral epicondylitis is a relatively common clinical problem[1,2] that has apparently confounded many attempts at its resolution. Easily recognized on induced pain/replication of symptoms by palpation of the lateral protuberance on the elbow, the term lateral epicondylitis identifies a disorder localized to that lateral epicondyle. The “itis” suffix in the term epicondylitis is misleading. Histological evaluation does not support categorizing it as an inflammatory process[3-5]. Microscopic examination actually reveals angiofibroblastic and mucoid degeneration, attributed to mechanical overloading[3]. Indeed, ultrasound evaluation reveals mechanical damage to tendons[6-9].

ANALGESIC AND ANTI-INFLAMMATORY INTERVENTION

The multitude of approaches to management of a clinical problem suggests either that it is quite responsive to intervention or that the optimal approaches have yet to be identified. Many of the approaches to treatment of lateral epicondylitis seem to be predicated on the subsequently falsified hypothesis that the epicondylitis represented an inflammatory process[3-9]. These attempts have included use of oral or topical non-steroidal anti-inflammatory drugs[10-12], injections[13] of corticosteroids[10,13-20], anesthetics (e.g., bupivacaine)[21] or even botulinum toxin[22] injection, none of which have had documented long-term clinical benefit[3]. Simply treating the pain symptom with analgesics has also provided inadequate relief[10,11,21,23].

INJURY-PREDICATED INTERVENTION

Based on recognition that epicondylitis represents an injury, another approach has been to inject autologous blood[24-27] or platelet-rich plasma[3,18,21,24,28,29]. This is predicated on the hypothesis that these injections provide growth factors, which stimulate healing. Similarly, skin-derived stem cells have been injected with this goal[30]. The enthesitis (irritation of tendon insertions) occasionally leads to calcification/ossification of those attachments. Speculation that the ossification/calcification process is the source of pain, radiofrequency[31] and shock wave[32,33] treatments have also been pursued. Surgical approaches have included percutaneous tenotomy and arthroscopic approaches[23,26,34-39].

PHYSIOLOGIC APPROACHES

More physiologic approaches have included physiatric/physical therapy techniques including manipulation, therapeutic ultrasound, phonophoresis, iontophoresis, acupuncture and exposure of the area to low-level laser[11,19,38,40-43]. An intriguing approach has been dry needling[25,34]. This is especially remarkable, as the lateral epicondyle has been listed[44], I believe erroneously[45], as a fibromyalgia trigger point and needling has been utilized as an approach to treatment of fibromyalgia[46]. The efficacy of all these approaches has been limited[3,13-16,25,28,29,38,47]. The study by Creaney et al[25] showed statistically significant clinical improvement in 60%-72%, but not complete relief. This is a greater response than with other approaches, but none identify complete resolution.

MECHANICAL INTERVENTION

The efficacy of these variably invasive approaches contrasts with a simple mechanical intervention. The irritation that appears to be the source of the pain derives from stresses produced by the muscles which attach to the lateral epicondyle[48]. Reducing the stress on the attachment area seems a reasonable approach. Logically, a band applied to the forearm, just distal to the elbow, would be expected to reduce stress on muscle attachment to the epicondyle, and it does. Early attempts to utilize this approach, however, were only marginally effective, because commercially available bands have an unintended effect. Those several inch wide bands only reduced effective muscle strength. The reduced available muscle power did reduce stress on the epicondyle, but did so inadequately and use of such armbands was less effective than immobilization of the elbow[12]. The latter, of course, results in muscle atrophy and loss of strength.

My personal approach has been to utilize Velcro bands of 0.75 to 1 inch in width and to assure their application 1 inch below the epicondyle. That position is critical. Such placement has no effect on muscle strength, but displaces the stresses on the epicondyle, such that it was now at the site of the band and thus distal to the epicondyle. Pain was immediately reduced and eliminated within several weeks. Patients were advised to wear the bands continually, except when sleeping, and to continue their use for two weeks beyond their perception of any residual elbow pain. Recurrences have responded equally well, once the activity responsible for the epicondyle stress is modified. I have had only 5 patients who have not responded (with complete resolution of elbow symptoms) in the three decades that I have utilized this approach. That represents less than 1% failure rate, and that was in individuals who would or could not modify the activity[2,42,49,50] that was repeatedly stressing the epicondylar attachments.

Footnotes

P- Reviewer Nader ND S- Editor Gou SX L- Editor A E- Editor Zhang DN

References
1.  Hamilton PG. The prevalence of humeral epicondylitis: a survey in general practice. J R Coll Gen Pract. 1986;36:464-465.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Shiri R, Viikari-Juntura E, Varonen H, Heliövaara M. Prevalence and determinants of lateral and medial epicondylitis: a population study. Am J Epidemiol. 2006;164:1065-1074.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 433]  [Cited by in F6Publishing: 395]  [Article Influence: 21.9]  [Reference Citation Analysis (0)]
3.  Chaudhury S, de La Lama M, Adler RS, Gulotta LV, Skonieczki B, Chang A, Moley P, Cordasco F, Hannafin J, Fealy S. Platelet-rich plasma for the treatment of lateral epicondylitis: sonographic assessment of tendon morphology and vascularity (pilot study). Skeletal Radiol. 2013;42:91-97.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 34]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
4.  Walz DM, Newman JS, Konin GP, Ross G. Epicondylitis: pathogenesis, imaging, and treatment. Radiographics. 2010;30:167-184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 151]  [Cited by in F6Publishing: 128]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
5.  Chard MD, Cawston TE, Riley GP, Gresham GA, Hazleman BL. Rotator cuff degeneration and lateral epicondylitis: a comparative histological study. Ann Rheum Dis. 1994;53:30-34.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 158]  [Cited by in F6Publishing: 171]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
6.  Regan W, Wold LE, Coonrad R, Morrey BF. Microscopic histopathology of chronic refractory lateral epicondylitis. Am J Sports Med. 1992;20:746-749.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 265]  [Cited by in F6Publishing: 207]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
7.  Connell D, Burke F, Coombes P, McNealy S, Freeman D, Pryde D, Hoy G. Sonographic examination of lateral epicondylitis. AJR Am J Roentgenol. 2001;176:777-782.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Levin D, Nazarian LN, Miller TT, O’Kane PL, Feld RI, Parker L, McShane JM. Lateral epicondylitis of the elbow: US findings. Radiology. 2005;237:230-234.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Nirschl RP, Pettrone FA. Tennis elbow. The surgical treatment of lateral epicondylitis. J Bone Joint Surg Am. 1979;61:832-839.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Hay EM, Paterson SM, Lewis M, Hosie G, Croft P. Pragmatic randomised controlled trial of local corticosteroid injection and naproxen for treatment of lateral epicondylitis of elbow in primary care. BMJ. 1999;319:964-968.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 167]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
11.  Trudel D, Duley J, Zastrow I, Kerr EW, Davidson R, MacDermid JC. Rehabilitation for patients with lateral epicondylitis: a systematic review. J Hand Ther. 2004;17:243-266.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Labelle H, Guibert R. Efficacy of diclofenac in lateral epicondylitis of the elbow also treated with immobilization. The University of Montreal Orthopaedic Research Group. Arch Fam Med. 1997;6:257-262.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Altay T, Günal I, Oztürk H. Local injection treatment for lateral epicondylitis. Clin Orthop Relat Res. 2002;127-130.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Coombes BK, Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injections and other injections for management of tendinopathy: a systematic review of randomised controlled trials. Lancet. 2010;376:1751-1767.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 555]  [Cited by in F6Publishing: 501]  [Article Influence: 35.8]  [Reference Citation Analysis (0)]
15.  Orchard J. Corticosteroid injection for lateral epicondylalgia is helpful in the short term, but harmful in the longer term; data for non-corticosteroid injections and other tendinopathies are limited. Evid Based Med. 2011;16:116-117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 10]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
16.  Stefanou A, Marshall N, Holdan W, Siddiqui A. A randomized study comparing corticosteroid injection to corticosteroid iontophoresis for lateral epicondylitis. J Hand Surg Am. 2012;37:104-109.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 37]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
17.  Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med. 2010;38:255-262.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 513]  [Cited by in F6Publishing: 431]  [Article Influence: 30.8]  [Reference Citation Analysis (0)]
18.  Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39:1200-1208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 385]  [Cited by in F6Publishing: 337]  [Article Influence: 25.9]  [Reference Citation Analysis (0)]
19.  Smidt N, van der Windt DA, Assendelft WJ, Devillé WL, Korthals-de Bos IB, Bouter LM. Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial. Lancet. 2002;359:657-662.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  Assendelft WJ, Hay EM, Adshead R, Bouter LM. Corticosteroid injections for lateral epicondylitis: a systematic overview. Br J Gen Pract. 1996;46:209-216.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med. 2006;34:1774-1778.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Wong SM, Hui AC, Tong PY, Poon DW, Yu E, Wong LK. Treatment of lateral epicondylitis with botulinum toxin: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2005;143:793-797.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Baumgard SH, Schwartz DR. Percutaneous release of the epicondylar muscles for humeral epicondylitis. Am J Sports Med. 1982;10:233-236.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 112]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
24.  Thanasas C, Papadimitriou G, Charalambidis C, Paraskevopoulos I, Papanikolaou A. Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. Am J Sports Med. 2011;39:2130-2134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 230]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
25.  Creaney L, Wallace A, Curtis M, Connell D. Growth factor-based therapies provide additional benefit beyond physical therapy in resistant elbow tendinopathy: a prospective, single-blind, randomised trial of autologous blood injections versus platelet-rich plasma injections. Br J Sports Med. 2011;45:966-971.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 203]  [Cited by in F6Publishing: 174]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
26.  Connell DA, Ali KE, Ahmad M, Lambert S, Corbett S, Curtis M. Ultrasound-guided autologous blood injection for tennis elbow. Skeletal Radiol. 2006;35:371-377.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Edwards SG, Calandruccio JH. Autologous blood injections for refractory lateral epicondylitis. J Hand Surg Am. 2003;28:272-278.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Mishra A, Gosens T. Clinical indications and techniques for the use of platelet-rich plasma in the elbow. Oper Tech Sports Med. 2011;19:170-176.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Wolf JM, Ozer K, Scott F, Gordon MJ, Williams AE. Comparison of autologous blood, corticosteroid, and saline injection in the treatment of lateral epicondylitis: a prospective, randomized, controlled multicenter study. J Hand Surg Am. 2011;36:1269-1272.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 93]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
30.  Connell D, Datir A, Alyas F, Curtis M. Treatment of lateral epicondylitis using skin-derived tenocyte-like cells. Br J Sports Med. 2009;43:293-298.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 98]  [Cited by in F6Publishing: 93]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
31.  Lin CL, Lee JS, Su WR, Kuo LC, Tai TW, Jou IM. Clinical and ultrasonographic results of ultrasonographically guided percutaneous radiofrequency lesioning in the treatment of recalcitrant lateral epicondylitis. Am J Sports Med. 2011;39:2429-2435.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 27]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
32.  Wang CJ, Chen HS. Shock wave therapy for patients with lateral epicondylitis of the elbow: a one- to two-year follow-up study. Am J Sports Med. 2002;30:422-425.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Speed CA, Nichols D, Richards C, Humphreys H, Wies JT, Burnet S, Hazleman BL. Extracorporeal shock wave therapy for lateral epicondylitis-a double blind randomized controlled trial. J Orthop Res. 2002;2:895-898.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 129]  [Cited by in F6Publishing: 112]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
34.  McShane JM, Shah VN, Nazarian LN. Sonographically guided percutaneous needle tenotomy for treatment of common extensor tendinosis in the elbow: is a corticosteroid necessary. J Ultrasound Med. 2008;27:1137-1144.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Schipper ON, Dunn JH, Ochiai DH, Donovan JS, Nirschl RP. Nirschl surgical technique for concomitant lateral and medial elbow tendinosis: a retrospective review of 53 elbows with a mean follow-up of 11.7 years. Am J Sports Med. 2011;39:972-976.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 20]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
36.  Cummins CA. Lateral epicondylitis: in vivo assessment of arthroscopic debridement and correlation with patient outcomes. Am J Sports Med. 2006;34:1486-1491.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 39]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
37.  Owens BD, Murphy KP, Kuklo TR. Arthroscopic release for lateral epicondylitis. Arthroscopy. 2001;17:582-587.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Jobe FW, Ciccotti MG. Lateral and Medial Epicondylitis of the Elbow. J Am Acad Orthop Surg. 1994;2:1-8.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Vangsness CT, Jobe FW. Surgical treatment of medial epicondylitis. Results in 35 elbows. J Bone Joint Surg Br. 1991;73:409-411.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Smidt N, Assendelft WJ, Arola H, Malmivaara A, Greens S, Buchbinder R, van der Windt DA, Bouter LM. Effectiveness of physiotherapy for lateral epicondylitis: a systematic review. Ann Med. 2003;35:51-62.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 115]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
41.  Simunovic Z, Trobonjaca T, Trobonjaca Z. Treatment of medial and lateral epicondylitis--tennis and golfer’s elbow--with low level laser therapy: a multicenter double blind, placebo-controlled clinical study on 324 patients. J Clin Laser Med Surg. 1998;16:145-151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 68]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
42.  Nirschl RP, Rodin DM, Ochiai DH, Maartmann-Moe C. Iontophoretic administration of dexamethasone sodium phosphate for acute epicondylitis. A randomized, double-blinded, placebo-controlled study. Am J Sports Med. 2003;31:189-195.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33:160-172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5950]  [Cited by in F6Publishing: 5631]  [Article Influence: 165.6]  [Reference Citation Analysis (0)]
44.  Binder AI, Hazleman BL. Lateral humeral epicondylitis--a study of natural history and the effect of conservative therapy. Br J Rheumatol. 1983;22:73-76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 111]  [Cited by in F6Publishing: 80]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
45.  Siceloff E, Blasko G, Rothschild BM. Variability of fibromyalgia-like symptoms among individuals with silicone breast implants according to cosmetic and reconstructive indications: Contrast with a non-implant fibromyalgia control group. Comp Ther. 1999;25:479-491.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Mayhew E, Ernst E. Acupuncture for fibromyalgia--a systematic review of randomized clinical trials. Rheumatology (Oxford). 2007;46:801-804.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 94]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
47.  Labelle H, Guibert R, Joncas J, Newman N, Fallaha M, Rivard CH. Lack of scientific evidence for the treatment of lateral epicondylitis of the elbow. An attempted meta-analysis. J Bone Joint Surg Br. 1992;74:646-651.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Ljung BO, Lieber RL, Fridén J. Wrist extensor muscle pathology in lateral epicondylitis. J Hand Surg Br. 1999;24:177-183.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 86]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
49.  Kurppa K, Viikari-Juntura E, Kuosma E, Huuskonen M, Kivi P. Incidence of tenosynovitis or peritendinitis and epicondylitis in a meat-processing factory. Scand J Work Environ Health. 1991;17:32-37.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Dimberg L. The prevalence and causation of tennis elbow (lateral humeral epicondylitis) in a population of workers in an engineering industry. Ergonomics. 1987;30:573-579.  [PubMed]  [DOI]  [Cited in This Article: ]