Conservative treatment of acute appendicitis

Federico Coccolini, Paola Fugazzola, Massimo Sartelli, Enrico Cicuttin, Maria Grazia Sibilla, Gioacchino Leandro, Gian Luigi De' Angelis, Federica Gaiani, Francesco Di Mario, Matteo Tomasoni, Fausto Catena, Luca Ansaloni, Federico Coccolini, Paola Fugazzola, Massimo Sartelli, Enrico Cicuttin, Maria Grazia Sibilla, Gioacchino Leandro, Gian Luigi De' Angelis, Federica Gaiani, Francesco Di Mario, Matteo Tomasoni, Fausto Catena, Luca Ansaloni

Abstract

Acute appendicitis has been considered by surgeons a progressive disease leading to perforation for more than 100 years. In the last decades the theories about this concept gained attention, especially in adults. However, appendectomy for acute appendicitis remains the most common urgent/emergent surgical procedure. At present, accumulating evidences are showing the changing in clinical practice towards the non-operative management of several cases of acute appendicitis either non-complicated or complicated. The present review aims to show the literature results regarding the non-operative management of acute appendicitis in non-complicated and in complicated cases.

References

    1. Amyand C. Of an inguinal rupture, with a pin in the appendix cecal, incrusted with stone; and some observations on wounds in the guts. Philos Trans R Soc Lond. 1736;39:329–336.
    1. Hutchinson R. Amyand’s hernia. J R Soc Med. 1993;86(2):104–105.
    1. Geddes CR, McAlister VC. A surgical review of the priority claims attributed to Abraham Groves (1847-1935) Can J Surg. 2009;52(5):E126–E20.
    1. McBurney C. Experience with early operative interference in cases of disease of the vermiform appendix. N YMed J. 1889;50:676–684.
    1. McBurney C. The incision made in the abdominal wall in cases of appendicitis, with a description of a new method of operating. Ann Surg. 1894;20(1):38–43.
    1. Morgenstern L. Charles McBurney (1845-1913). Afield from the appendix. Surg Endosc. 1996;10(4):385–386.
    1. Semm K. Endoscopic intraabdominal surgery in gynecology. Wien Klin Wochenschr. 1983;95(11):353–367.
    1. Ure BM, Spangenberger W, Hebebrand D, Eypasch EP, Troidl H. Laparoscopic surgery in children and adolescents with suspectedappendicitis: results of medical technology assessment. Eur J Pediatr Surg. 1992;2(6):336–340.
    1. Aufderheide AC. Cambridge, UK: Cambridge University Press; 2003. The Scientific Study of Mummies.
    1. Bailey H. The Ochsner-Sherren (delayed) treatment of acute appendicitis: indications and technique. BMJ. 1930;1(3603):140–143.
    1. Coldrey E. Five years of conservative treatment of acute appendicitis. J Int Coll Surg. 1959;32:255–261.
    1. Anonymous. Combined traditional Chinese andwesternmedicine in acute appendicitis. Chin Med J (Engl) 1977;3(4):266–269.
    1. Adams ML. The medical management of acute appendicitis in a nonsurgical environment: a retrospective case review. Mil Med. 1990;155(8):345–347.
    1. Gurin NN, Slobodchuk IuS, Gavrilov IuF. The efficacy of the conservative treatment of patients with acute appendicitis on board ships at sea. Vestn Khir Im I I Grek. 1992;148(5):144–150.
    1. Tingstedt B, Johansson J, Nehez L, Andersson R. Late abdominal complaints after appendectomy – readmissions during long-term follow-up. Dig Surg. 2004;21:23–27.
    1. De Coppi P, Pozzobon M, Piccoli M, et al. Isolation of mesenchymal stem cells from human vermiform appendix. J Surg Res. 2006;135(1):85–91.
    1. Randal Bollinger R, Barbas AS, Bush EL, Lin SS, Parker W. Biofilms in the large bowel suggest an apparent function of the human vermiform appendix. J Theor Biol. 2007;249(4):826–831.
    1. Blomqvist PG, Andersson RE, Granath F, Lambe MP, Ekbom AR. Mortality after appendectomy in Sweden, 1987-1996. Ann Surg. 2001;233(4):455–460.
    1. Flum DR, Koepsell T. The clinical and economic correlates of misdiagnosed appendicitis: nationwide analysis. Arch Surg. 2002;137(7):799–804. discussion 804.
    1. Andersson RE. Small bowel obstruction after appendicectomy. Br J Surg. 2001;88(10):1387–1391.
    1. Duron JJ, Hay JM, Msika S, et al. French Association for Surgical Research. Prevalence and mechanisms of small intestinal obstruction following laparoscopic abdominal surgery: a retrospective multicenter study. Arch Surg. 2000;135(2):208–212.
    1. Zbar RI, Crede WB, McKhann CF, Jekel JF. The postoperative incidence of small bowel obstruction following standard, open appendectomy and cholecystectomy: a six-year retrospective cohort study at Yale-New Haven Hospital. Conn Med. 1993;57(3):123–127.
    1. Leung TT, Dixon E, Gill M, et al. Bowel obstruction following appendectomy: what is the true incidence? Ann Surg. 2009;250(1):51–53.
    1. Svensson JF, Hall NJ, Eaton S, Pierro A, Wester T. A Review of Conservative Treatment of Acute Appendicitis. Eur J Pediatr Surg. 2012;22:185–194.
    1. Eriksson S, Granström L. Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis. Br J Surg. 1995;82(2):166–169.
    1. Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic treatment in acute appendicitis. a prospective multicenter randomized controlled trial. World J Surg. 2006;30(6):1033–1037.
    1. Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg. 2009;96(5):473–481.
    1. Vons C, Barry C, Maitre S, et al. Amoxicillin plus clavulanic acid versus appendicectomy for treatment of acute uncomplicated appendicitis: an open-label, non-inferiority, randomized controlled trial. Lancet. 2011;377(9777):1573–1579.
    1. Malik AA, Bari SU. Conservative management of acute appendicitis. J Gastrointest Surg. 2009;13(5):966–970.
    1. Horton MD, Counter SF, Florence MG, Hart MJ. A prospective trial of computed tomography and ultrasonography for diagnosing appendicitis in the atypical patient. Am J Surg. 2000;179(5):379–381.
    1. Retraction note to: Conservative management of acute appendicitis. J Gastrointest Surg. 2011;15(12):2302.
    1. Varadhan KK, Humes DJ, Neal KR, Lobo DN. Antibiotic therapy versus appendectomy for acute appendicitis: a meta-analysis. World J Surg. 2010;34(2):199–209.
    1. Ansaloni L, Catena F, Coccolini F, et al. Surgery versus conservative antibiotic treatment in acute appendicitis: a systematic review and meta-analysis of randomized controlled trials. Dig Surg. 2011;28(3):210–221.
    1. Cobben LP, de Van Otterloo AM, Puylaert JB. Spontaneously resolving appendicitis: frequency and natural history in 60 patients. Radiology. 2000;215:349–52.
    1. Liu K, Fogg L. Use of antibiotics alone for treatment of uncomplicated acute appendicitis: a systematic review and meta-analysis. Surgery. 2011;150(4):673–683.
    1. Wilms IM, de Hoog DE, de Visser DC, Janzing HM. Appendectomy versus antibiotic treatment for acute appendicitis. Cochrane Database Syst Rev. 2011;(11):CD008359.
    1. Fitzmaurice GJ, McWilliams B, Hurreiz H, Epanomeritakis E. Antibiotics versus appendectomy in the management of acute appendicitis: a review of the current evidence. Can J Surg. 2011;54(5):307–314.
    1. Farahnak M, Talaei-Khoei M, Gorouhi F, Jalali A, Gorouhi F. The Alvarado score and antibiotics therapy as a corporate protocol versus conventional clinical management: randomized controlled pilot study of approach to acute appendicitis. Am J Emerg Med. 2007;25(7):850–852.
    1. Mason RJ, Moazzez A, Sohn H, Katkhouda N. Meta-analysis of randomized trials comparing antibiotic therapy with appendectomy for acute uncomplicated (no abscess or phlegmon) appendicitis. Surg Infect (Larchmt) 2012;13(2):74–84.
    1. Mason RJ. Surgery for appendicitis: is it necessary? Surg Infect (Larchmt) 2008;9(4):481–48841.
    1. Varadhan KK, Neal KR, Lobo DN. Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials. BMJ. 2012;344:e2156.
    1. Heller MB, Skolnick ML. Ultrasound documentation of spontaneously resolving appendicitis. Am J Emerg Med. 1993;11:51–3.
    1. Hawes AS, Whalen GF. Recurrent and chronic appendicitis: the other inflammatory conditions of the appendix. Am Surg. 1994;60:217–9.
    1. Migraine S, Atri M, Bret PM, Lough JO, Hinchey JE. Spontaneously resolving acute appendicitis: clinical and sonographic documentation. Radiology. 1997;205:55–8.
    1. Pieper R, Kager L, Nasman P. Clinical significance of mucosal inflammation of the vermiform appendix. Ann Surg. 1983;197:368–74.
    1. Puylaert JB, Rutgers PH, Lalisang RI, et al. A prospective study of ultrasonography in the diagnosis of appendicitis. N Engl J Med. 1987;317:666–9.
    1. Jeffrey RB, Jr, Laing FC, Townsend RR. Acute appendicitis: sonographic criteria based on 250 cases. Radiology. 1988;167:327–9.
    1. Ooms HW, Koumans RK, Ho Kang You PJ, Puylaert JB. Ultrasonography in the diagnosis of acute appendicitis. Br J Surg. 1991;78:315–8.
    1. Rioux M. Sonographic detection of the normal and abnormal appendix. AJR Am J Roentgenol. 1992;158:773–8.
    1. Barber MD, McLaren J, Rainey JB. Recurrent appendicitis. Br J Surg. 1997;84:110–2.
    1. Kirshenbaum M, Mishra V, Kuo D, Kaplan G. Resolving appendicitis: role of CT. Abdom Imaging. 2003;28:276–9.
    1. Carr NJ. The pathology of acute appendicitis. Ann Diagn Pathol. 2000;4:46–58.
    1. Livingston EH, Woodward WA, Sarosi GA, Haley RW. Disconnect between incidence of nonperforated and perforated appendicitis: implications for pathophysiology and management. Ann Surg. 2007;245:886–92.
    1. Andersson RE. The natural history and traditional management of appendicitis revisited: spontaneous resolution and predominance of prehospital perforations imply that a correct diagnosis is more important than an early diagnosis. World J Surg. 2007;31:86–92.
    1. Petrosyan M, Estrada J, Chan S, et al. CT scan in patients with suspected appendicitis: clinical implications for the acute care surgeon. Eur Surg Res. 2008;40:211–9.
    1. Paajanen H, Grönroos JM, Rautio T, Nordström P, Aarnio M, Rantanen T, Hurme S, Dean K, Jartti A, Mecklin JP, Sand J, Salminen P. A prospective randomized controlled multicenter trial comparing antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis (APPAC trial) BMC Surgery. 2013;13:3.
    1. Simillis C, Symeonides P, Shorthouse AJ, Tekkis PP. A meta-analysis comparing conservative treatment versus acute appendectomy for complicated appendicitis (abscess or phlegmon) Surgery. 2010;147:818–29.
    1. Brown CV, Abrishami M, Muller M, Velmahos GC. Appendiceal abscess: immediate operation or percutaneous drainage? Am Surg. 2003;69:829–32.
    1. Bufo AJ, Shah RS, Li MH, Cyr NA, Hollabaugh RS, Hixson SD, et al. Interval appendectomy for perforated appendicitis in children. J Laparoendosc Adv Surg Tech A. 1998;8:209–14.
    1. Erdogan D, Karaman I, Narci A, Karaman A, Cavusoglu YH, Aslan MK, et al. Comparison of two methods for the management of appendicular mass in children. Pediatr Surg Int. 2005;21:81–3.
    1. Foran B, Berne TV, Rosoff L. Management of the appendiceal mass. Arch Surg. 1978;113:1144–5.
    1. Gahukamble DB, Khamage AS, Gahukamble LD. Management of appendicular mass in children. Ann Trop Paediatr. 1993;13:365–7.
    1. Gastrin U, Josephson S. Appendiceal abscess-acute appendectomy or conservative treatment. Acta Chir Scand. 1969;135:539–42.
    1. Gomez-Lorenzo E, Dominguez Sanchez J, Octavio de Toledo JM, Alvarez C, Bernardez J, Sierra JA, et al. Appendiceal plastron: comparative study of emergency appendectomy with conservative treatment (195 cases) Rev Esp Enferm Apar Dig. 1987;71:151–5.
    1. Handa N, Muramori K, Taguchi S. Early appendectomy versus an interval appendectomy for appendiceal abscess in children. Fukuoka Igaku Zasshi. 1997;88:389–94.
    1. Henry MC, Gollin G, Islam S, Sylvester K, Walker A, Silverman BL, et al. Matched analysis of nonoperative management vs immediate appendectomy for perforated appendicitis. J Pediatr Surg. 2007;42:19–24.
    1. Ho CM, Chen Y, Lai HS, Lin WH, Hsu WM, Chen WJ. Comparison of critical conservative treatment versus emergency operation in children with ruptured appendicitis with tumor formation. J Formos Med Assoc. 2004;103:359–63.
    1. Hoffmann J, Rolff M, Lomborg V, Franzmann M. Ultraconservative management of appendiceal abscess. J R Coll Surg. 1991;36:18–20.
    1. Hurme T, Nylamo E. Conservative versus operative treatment of appendicular abscess. Experience of 147 consecutive patients. Ann Chir Gynaecol. 1995;84:33–6.
    1. Lewin J, Fenyo G, Engstrom L. Treatment of appendiceal abscess. Acta Chir Scand. 1988;154:123–5.
    1. Oliak D, Yamini D, Udani VM, Lewis RJ, Arnell T, Vargas H, et al. Initial nonoperative management for periappendiceal abscess. Dis Colon Rectum. 2001;44:936–41.
    1. Roach JP, Partrick DA, Bruny JL, Allshouse MJ, Karrer FM, Ziegler MM. Complicated appendicitis in children: a clear role for drainage and delayed appendectomy. Am J Surg. 2007;194:769–73.
    1. Samuel M, Hosie G, Holmes K. Prospective evaluation of nonsurgical versus surgical management of appendiceal mass. J Pediatr Surg. 2002;37:882–6.
    1. Tingstedt B, Bexe-Lindskog E, Ekelund M, Andersson R. Management of appendiceal masses. Eur J Surg. 2002;168:579–82.
    1. Wiegering VA, Kellenberger CJ, Bodmer N, et al. Conservative management of acute appendicitis in children with hematologic malignancies during chemotherapy-induced neutropenia. J Pediatr Hematol Oncol. 2008;30(6):464–467.
    1. Abeş M, Petik B, Kazil S. Nonoperative treatment of acute appendicitis in children. J Pediatr Surg. 2007;42(8):1439–1442.
    1. Chen C, Botelho C, Cooper A, et al. Current practice patterns in the treatment of perforated appendicitis in children. J Am Coll Surg. 2003;196:212–1.
    1. Weber TR, Keller MA, Bower RJ, Spinner G, Vierling K. Is delayed operative treatment worth the trouble with perforated appendicitis is children? Am J Surg. 2003;186(6):685–688. discussion 688-689.
    1. Vane DW, Fernandez N. Role of interval appendectomy in the management of complicated appendicitis in children. World J Surg. 2006;30(1):51–54.
    1. Erdogan D, Karaman I, Narci A, et al. Comparison of two methods for the management of appendicular mass in children. Pediatr Surg Int. 2005;21:81–3.
    1. Bufo AJ, Shah RS, Li MH, et al. Interval appendectomy for perforated appendicitis in children. J Laparoendosc Adv Surg Tech A. 1998;8(4):209–214.
    1. Gillick J, Velayudham M, Puri P. Conservative management of appendix mass in children. Br J Surg. 2001;88:1539–42.
    1. Kogut KA, Blakely ML, Schropp KP, et al. The association of elevated percent bands on admission with failure and complications of interval appendectomy. J Pediatr Surg. 2001;36(1):165–168.
    1. Weiner DJ, Katz A, Hirschl RB, Drongowski R, Coran AG. Interval appendectomy in perforated appendicitis. Pediatr Surg Int. 1995;10:82–85.
    1. Surana R, Puri P. Appendiceal mass in children. Pediatr Surg Int. 1995;10:79–81.
    1. Nadler EP, Reblock KK, Vaughan KG, Meza MP, Ford HR, Gaines BA. Predictors of outcome for children with perforated appendicitis initially treated with non-operative management. Surg Infect (Larchmt) 2004;5(4):349–356.
    1. Alexander F, Magnuson D, DiFiore J, et al. Specialty versus generalist care of children with appendicitis: an outcome comparison. J Pediatr Surg. 2001;36:1510–3.
    1. Bratton SL, Haberkern CM, Waldhausen JHT. Acute appendicitis risks of complications: age and Medicaid insurance. Pediatrics. 2000;106:75–8.
    1. Henry MC, Gollin G, Islam S, et al. Matched analysis of nonoperative management vs immediate appendectomy for perforated appendicitis. J Pediatr Surg. 2007;42(1):19–23. discussion 23-24.
    1. Aprahamian CJ, Barnhart DC, Bledsoe SE, Vaid Y, Harmon CM. Failure in the nonoperative management of pediatric ruptured appendicitis: predictors and consequences. J Pediatr Surg. 2007;42(6):934–938. discussion 938.
    1. Whyte C, Levin T, Harris BH. Early decisions in perforated appendicitis in children: lessons from a study of nonoperative management. J Pediatr Surg. 2008;43(8):1459–1463.
    1. Blakely ML, Williams R, Dassinger MS, et al. Early vs interval appendectomy for children with perforated appendicitis. Arch Surg. 2011;146(6):660–665.
    1. Myers AL, Williams RF, Giles K, et al. Hospital cost analysis of a prospective, randomized trial of early vs interval appendectomy for perforated appendicitis in children. J Am Coll Surg. 2012;214(4):427–434. discussion 434-435.
    1. Di Saverio S, Sibilio A, Giorgini E, Biscardi A, Villani S, Coccolini F, Smerieri N, Pisano M, Ansaloni L, Sartelli M, Catena F, Tugnoli G. The NOTA Study (Non Operative Treatment for Acute Appendicitis). Prospective Study on the Efficacy and Safety of Antibiotics (Amoxicillin and Clavulanic Acid) for Treating Patients With Right Lower Quarter Abdominal Pain and Long-term Follow-up of Conservatively Treated Suspected Appendicitis. Ann Surg. 2014 in press.
    1. Andersson M, Andersson RE. The appendicitis inflammatory response score: a tool for the diagnosis of acute appendicitis that outperforms the Alvarado score. World J Surg. 2008;32:1843–1849.
    1. Vanderbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med. 2007;4:1628–1654.
    1. Tugnoli G, Di Saverio S, Baldoni F, et al. Non Operative Treatment for Acute Appendicitis (NOTA) [Accessed February 22, 2013];March 29, 2010 Available at: .
    1. Tugnoli G, Giorgini E, Biscardi A, et al. The NOTA study: non-operative treatment for acute appendicitis: prospective study on the efficacy and safety of antibiotic treatment (amoxicillin and clavulanic acid) in patients with right sided lower abdominal pain. BMJ Open. 2011;1:e000006. doi:10.1136/bmjopen-2010-000006.
    1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–874.
    1. Alvarado A. A practical score for the early diagnosis of acute appendicitis. Ann Emerg Med. 1986;15:557–564.
    1. Svensson JF1, Patkova B, Almström M, Naji H, Hall NJ, Eaton S, Pierro A, Wester T. Nonoperative treatment with antibiotics versus surgery for acute nonperforated appendicitis in children: a pilot randomized controlled trial. Ann Surg. 2015 Jan;261(1):67–71. doi: 10.1097/SLA.0000000000000835.
    1. Natalie Hutchings, Wendy Wood, Isabel Reading, Erin Walker, Jane M. Blazeby, William van’t Hoff, Bridget Young, Esther M. Crawley, Simon Eaton, Maria Chorozoglou, Frances C Sherratt, Lucy Beasant, Harriet Corbett, Michael P. Stanton, Simon Grist, Elizabeth Dixon, Nigel J. Hall, et al. CONTRACT Study - CONservative TReatment of Appendicitis in Children (feasibility): study protocol for a randomised controlled Trial. Hutchings Trials. 2018;19:153. .
    1. Jane Xu, Yingrui Cyril Liu, Susan Adams, Jonathan Karpelowsky, Xu J, et al. Acute uncomplicated appendicitis study: rationale and protocol for a multicentre, prospective randomized controlled non-inferiority study to evaluate the safety and effectiveness of non-operative management in children with acute uncomplicated appendicitis. BMJ Open. 2016;6:e013299. doi: 10.1136/bmjopen-2016-013299.
    1. Nigel J Hall, Simon Eaton, Olivier Abbo, Alexis P Arnaud, Marianne Beaudin, Mary Brindle, Andreana Bütter, Dafydd Davies, Tim Jancelewicz, Kathy Johnson, Richard Keijzer, Eveline Lapidus-Krol, Martin Offringa, Nelson Piché, Risto Rintala, Erik Skarsgard, Jan F Svensson, Wendy J Ungar, Tomas Wester, Andrew R Willan, Augusto Zani, Shawn D St Peter, Agostino Pierro, Hall NJ, et al. Appendectomy versus non-operative treatment for acute uncomplicated appendicitis in children: study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial. BMJ Paediatrics Open. 2017;1:e000028. doi: 10.1136/bmjpo-2017-000028.
    1. Knaapen M1, van der Lee JH2, Bakx R1, The SL1, van Heurn EWE1, Heij HA1, Gorter RR1. APAC collaborative study group. Initial non-operative management of uncomplicated appendicitis in children: a protocol for a multicentre randomised controlled trial (APAC trial) BMJ Open. 2017 Nov 15;7(11):e018145. doi: 10.1136/bmjopen-2017-018145.
    1. Libin Huang, Yuan Yin, Lie Yang, Cun Wang, Yuan Li, Zongguang Zhou. Comparison of Antibiotic Therapy and Appendectomy for Acute Uncomplicated Appendicitis in Children A Meta-analysis. JAMA Pediatr. 2017 May;171(5):426–429. doi: 0.1001/jamapediatrics.2017.0057.
    1. Kessler U, Mosbahi S, Walker B, Hau EM, Cotton M, Peiry B, Berger S, Egger B. Conservative treatment versus surgery for uncomplicated appendicitis in children: a systematic review and meta-analysis. Arch Dis Child. 2017 Dec;102(12):1118–1124. doi: 10.1136/archdischild-2017-313127. Epub 2017 Aug.
    1. Georgiou R, Eaton S, Stanton MP, et al. Effi cacy and Safety of Nonoperative Treatment for Acute Appendicitis: A Meta-analysis. Pediatrics. 2017;139(3):e20163003.
    1. St Peter SD, Aguayo P, Fraser JD, Keckler SJ, Sharp SW, Leys CM, Murphy JP, Snyder CL, Sharp RJ, Andrews WS, Holcomb GW, 3rd, Ostlie DJ. Initial laparoscopic appendectomy versus initial nonoperative management and interval appendectomy for perforated appendicitis with abscess: a prospective, randomized trial. J Pediatr Surg. 2010 Jan;45(1):236–40. doi: 10.1016/j.jpedsurg.2009.10.039. PMID:20105610.
    1. Vaos G, et al. Immediate surgery or conservative treatment for complicated acute appendicitis in children? A meta-analysis, J Pediatr Surg. 2018 .
    1. Duggan EM, Marshall AP, Weaver KL, St Peter SD, Tice J, Wang L, Choi L, Blakely ML. A systematic review and individual patient data meta-analysis of published randomized clinical trials comparing early versus interval appendectomy for children with perforated appendicitis. Pediatr Surg Int. 2016 Jul;32(7):649–55. doi: 10.1007/s00383-016-3897-y. Epub 2016 May 9. Review. PMID: 27161128.

Source: PubMed

3
購読する